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-,EC,Date,Category,Paper ID,Title,Journal,Summary,
-,Yes,20190312,ewas,30760334,Epigenetic findings in periodontitis in UK twins: a cross-sectional study.,Clin Epigenetics,"Periodontitis in blood, buccal and adipose tissue (Twins UK).",
-,No,20190312,longitudinal,30764717,Longitudinal analysis of epigenome-wide DNA methylation reveals novel smoking-related loci in African Americans.,Epigenetics,Generalized estimating equestion (GEE) models used to investigate smoking and DNAm at two time points. Smokers tended to have greater DNAm change which was almost always linked to reduced DNAm levels.,
-,Yes,20190312,ewas,30765504,"Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course.",Eur Respir J,Childhood lung function and risks of asthma and COPD in cord blood (meta-analysis of 5 cohorts).  The approach used is prone to false positives.,
-,Yes,20190312,ewas,30765773,Association between DNA methylation in obesity-related genes and body mass index percentile in adolescents.,Sci Rep,"BMI and adolescent peripheral blood leukocytes. No tests survive adjustment for multiple tests, but functions of top genes 'make sense'.",
-,No,20190312,ewas,30771258,Genome-wide analysis of DNA methylation in relation to socioeconomic status during development and early adulthood.,Am J Phys Anthropol,Socio-economic position in young adult blood.?2546 associations! Study performed in a non-affluent Philippine population.?,
-,Yes,20190312,ewas,30773972,"Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood: an epigenome-wide association study.",Epigenetics,"Paternal pre-pregnancy obesity and offspring cord blood.?Observed sex-specific associations.  However, strongest association TAPBP was not replicated.?",
-,Yes,20190312,ewas,30777123,A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57.,Clin Epigenetics,Folic acid supplementation during pregnancy (RCT) linked to differentially methylated regulator of ZPF57 in cord blood.?,
-,Yes,20190312,ewas,30792424,Epigenome-wide association study in peripheral white blood cells involving insulin resistance.,Sci Rep,Insulin resistance and peripheral blood.798 CpG site associations observed!?,
-,No,20190312,methods,30793194,Using long-read sequencing to detect imprinted DNA methylation.,Nucleic Acids Res,Long-read nanopore sequencing identifies new imprinted regions in mouse.,
-,No,20190312,sex chromosomes,30793472,Age-dependent DNA methylation patterns on the Y chromosome in elderly males.,Aging Cell,"Y-chromosome derived DNAm age is different from autosomally-derived DNAm age.DNAm levels tend to increase with age, accelerate in the oldest individuals and associate negatively with mortality.",
-,Yes,20190312,ewas,30796027,A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Non-Alcoholic Fatty Liver Disease.,Diabetes,"Hepatic fat and peripheral blood.? Observe 22 CpG site associations in 3,400 European, 401 Hispanic and 724 African ancestry participants.?",
-,,20190312,ewas,30819252,Genome-wide DNA methylation and long-term ambient air pollution exposure in Korean adults.,Clin Epigenetics,Air pollution in adult peripheral blood.,
-,No,20190312,methods,30821575,Don't brush off buccal data heterogeneity.,Epigenetics,Recommendations for handling cellular heterogeneity in buccal DNAm. ,
-,Yes,20190312,ewas,30826615,Epigenetic marks of prenatal air pollution exposure found in multiple tissues relevant for child health.,Environ Int,Air pollution in cord and placenta. ,
-,Yes,20190312,ewas,30830696,Brain Imaging-Guided Analysis Reveals DNA Methylation Profiles Correlated with Insular Surface Area and Alcohol Use Disorder.,Alcohol Clin Exp Res,Alcohol use disorder associated with CpG sites associated with brain insular surface area.,
-,No,20190312,candidate,30831210,Differential BDNF methylation in combat exposed veterans and the association with exercise.,Gene,BDNF associated with combat and exercise in veterans.,
-,No,20190312,methods,30832291,Using Openly Accessible Resources to Strengthen Causal Inference in Epigenetic Epidemiology of Neurodevelopment and Mental Health.,Genes (Basel),How to use public resources for causal inference in Epigenetic Epidemiology of Neurodevelopment and Mental Health ,
-,Yes,20190312,ewas,30832715,A comparison of DNA methylation in newborn blood samples from infants with and without orofacial clefts.,Clin Epigenetics,Orofacial clefts and newborn blood. Fail to replicate findings based on ALSPAC and the Cleft Collective. ,
-,Yes,20190312,ewas,30833390,Genomic and molecular characterization of preterm birth.,Proc Natl Acad Sci USA,Preterm birth and maternal blood. Includes whole genome sequencing and RNA-seq,
-,No,20190312,dnam score,30842548,An epigenetic score for BMI based on DNA methylation correlates with poor physical health and major disease in the Lothian Birth Cohort.,Int J Obes (Lond),BMI score associated with health and disease in LBC.,
-,No,20190312,dnam age,30842553,Synchrony and asynchrony between an epigenetic clock and developmental timing.,Sci Rep,Developmental stage at least partially independent of DNAm age in mammalian neural retina.,
-,No,20190326,mechanism,30698680,Fumarates target the metabolic-epigenetic interplay of brain-homing T cells in multiple sclerosis.,Brain,Fumaric acid esters are highly effective immunomodulators in patients with multiple sclerosis. This effect appears to be due to DNA methylation changes in brain-homing CCR6+ CD4 and CD8 T cells.,
-,No,20190326,longitudinal,30867049,Impact of chemotherapy for breast cancer on leukocyte DNA methylation landscape and cognitive function: a prospective study.,Clin Epigenetics,Chemotherapy changes DNAm in blood.,
-,,20190326,ewas,30870065,Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk.,Epigenetics,Orofacial cleft associated with DNAm from blood spots collected at birth (includes VTRNA2-1 gene),
-,No,20190326,longitudinal,30871403,DNA methylation changes associated with Parkinson's disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood.,Epigenetics,Longitudinal DNAm changes and associations with treatment in Parkinsons disease,
-,,20190326,ewas,30872662,DNA methylation signature of smoking in lung cancer is enriched for exposure signatures in newborn and adult blood.,Sci Rep,Prenatal and own smoking DNAm associations in blood enriched in lung tumour DNAm differences.,
-,,20190326,ewas,30873861,DNA methylation abundantly associates with fetal alcohol spectrum disorder and its subphenotypes.,Epigenomics,Fetal alcohol syndrome associated with DNAm of blood collected in childhood (after age 5),
-,,20190326,ewas,30874594,Genomewide Study of Epigenetic Biomarkers of Opioid Dependence in European- American Women.,Sci Rep,Opiod dependence associated with DNAm in blood.,
-,No,20190326,methods,30875430,Bigmelon: tools for analysing large DNA methylation datasets.,Bioinformatics,Bigmelon is a tool for normalizing and analysing large DNAm datasets,
-,,20190326,ewas,30876376,Epigenome-wide association study reveals methylation pathways associated with childhood allergic sensitization.,Epigenetics,Allergic sensitisation associated with DNAm in blood in childhood.,
-,No,20190326,mechanism,30877840,Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline.,Neurobiol Aging,Vitamin intake and genetic variation within DNMT3L interact to influence cognitive decline.,
-,,20190326,ewas,30879037,"Shift work, DNA methylation and epigenetic age.",Int J Epidemiol,Shift work associated with DNAm and epigenetic age in blood.,
-,No,20190326,mechanism,30879057,"Prenatal smoke exposure, DNA methylation and a link between DRD1 and lung cancer.",Int J Epidemiol,Letter to the editor discusses our study of persistence of prenatal smoking DNAm effects in connection with a link between DRD1 and lung cancer .,
-,,20190326,ewas,30879397,Persistent epigenetic changes in adult daughters of older mothers.,Epigenetics,Maternal age with DNAm in blood collected in adulthood. ,
-,No,20190326,tissues,30885044,Locus-specific DNA methylation prediction in cord blood and placenta.,Epigenetics,CpG site correlations between placenta and cord blood DNAm. ,
-,,20190326,ewas,30893429,Epigenetic Associations with Estimated Glomerular Filtration Rate (eGFR) among Men with HIV Infection.,Clin Infect Dis,Kidney function in HIV associated with DNAm in blood.,
-,,20190326,ewas,30898171,Parallel profiling of DNA methylation and hydroxymethylation highlights neuropathology-associated epigenetic variation in Alzheimer's disease.,Clin Epigenetics,Degree of Alzheimer's disease pathology associated with DNAm and hydroxymethylation in entorhinal cortex.,
-,No,20190326,variation,30900359,Screening for rare epigenetic variations in autism and schizophrenia.,Hum Mutat,Epivariations' in blood DNAm linked to autism and schizophrenia (these are like rare variants),
-,No,20190326,comparison,30911103,Genome-wide Analysis Reveals DNA Methylation Alterations in Obesity Associated with High Risk of Colorectal Cancer.,Sci Rep,Associations of colorectal cancer and of obesity similar in the DNAm of blood,
-,No,20190326,dnam age,31738745,A meta-analysis of genome-wide association studies of epigenetic age acceleration,PLoS Genet,"An even larger GWAS of epigenetic age acceleration (n= 13,493) identifies a few novel genetic associations.",
-,Yes,20190401,ewas,30905381,"Sensitive Periods for the Effect of Childhood Adversity on DNA Methylation: Results From a Prospective, Longitudinal Study.",Biol Psychiatry,"DNA methylation at 7 years is associated with childhood adversity, mainly before age 3.",
-,No,20190401,ewas,30909978,Differential genome-wide DNA methylation patterns in childhood obesity.,BMC Res Notes,DNA methylation in blood at 13 years is associated with obesity but not prenatal maternal stress (n=31). ,
-,No,20190401,ewas,30913233,DNA methylation among firefighters.,PLoS ONE,DNA methylation in blood is different between new and incumbent firefighters (n=86). ,
-,No,20190401,ewas,30913238,Effects of early social deprivation on epigenetic statuses and adaptive behavior of young children: A study based on a cohort of institutionalized infants and toddlers.,PLoS ONE,DNA methylation in blood is different between children raised in families vs orphanages (n=58).,
-,No,20190401,epigenetics,30914725,Characteristics and homogeneity of N6-methylation in human genomes.,Sci Rep,"N-6 methylated deoxyadenosine (m6dA) was recently discovered in humans and other eukaryotes.  It is somewhat rare but consistent within cell types, and it is associated with higher gene expression.",
-,Yes,20190401,ewas,30915882,Novel DNA methylation sites associated with cigarette smoking among African Americans.,Epigenetics,"DNA methylation in saliva of African Americans associated with smoking, six novel sites identified and replicated.",
-,No,20190401,imprinting,30918249,Parent of origin genetic effects on methylation in humans are common and influence complex trait variation.,Nat Commun,"Parent of origin effects in DNA methylation observed at 171 novel loci. A PheWAS identified ""a previously unidentified imprinted locus associated with waist circumference"". ",
-,Yes,20190401,ewas,30925934,"Prenatal maternal antidepressants, anxiety, and depression and offspring DNA methylation: epigenome-wide associations at birth and persistence into early childhood.",Clin Epigenetics,DNA methylation in cord blood is associated with maternal antidepressant use in pregnancy.,
-,No,20190401,ewas,30926763,DNA methylation in genes of longevity-regulating pathways: association with obesity and metabolic complications.,Aging (Albany NY),"CpG sites associated with longevity included several associated with BMI and with age in patients with metabolic disorders, ""suggesting a role of DNAm in aging-related metabolic alterations"".",
-,No,20190408,methods,30922215,A (fire)cloud-based DNA methylation data preprocessing and quality control platform.,BMC Bioinformatics,A Bioconductor R package supports cloud-based preprocessing of a very large DNA methylation datasets.,
-,No,20190408,ewas,30924596,SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis.,Mol Oncol,Methylome-wide interaction between smoking cessation and lung cancer survival found that smoking cessation was beneficial only for those with low methylation levels at a specific CpG site.,
-,No,20190408,variation,30929737,Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.,Am J Hum Genet,"They train a model for detecting hereditary conditions using blood DNA methylation. ""This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases ..."" They further show how investigating ""epi-variation"" in individuals can be used to further narrow down a diagnosis.",
-,Yes,20190408,ewas,30935889,Identification of novel differentially methylated sites with potential as clinical predictors of impaired respiratory function and COPD.,EBioMedicine,Identification of novel differentially methylated sites with potential as clinical predictors of impaired respiratory function and COPD,
-,Yes,20190408,ewas,30938765,Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue.,Am J Epidemiol,Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue.,
-,Yes,20190408,ewas,30940212,Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.,Clin Epigenetics,Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study,
-,Yes,20190408,ewas,30941597,"Prosocial Emotion, Adolescence, and Warfare : DNA Methylation Associates with Culturally Salient Combat Variables.",Hum Nat,"Prosocial Emotion, Adolescence, and Warfare : DNA Methylation Associates with Culturally Salient Combat Variables.",
-,No,20190408,methods,30944378,A Network-guided Association Mapping Approach from DNA Methylation to Disease.,Sci Rep,"Describes a network-based method for using DNA methylation to distinguish between disease states (e.g. malignant vs benign tumours). Integrates associations between DNA methylation, gene expression and disease phenotype.",
-,No,20190415,mouse,30858345,Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses.,Genome Res,Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses.?,
-,No,20190415,mouse,30936186,Intra-individual methylomics detects the impact of early-life adversity.,Life Sci Alliance,Intra-individual methylomics detects the impact of early-life adversity.,
-,No,20190415,methods,30941158,A Multi-Cohort and Multi-Omics Meta-Analysis Framework to Identify Network-Based Gene Signatures.,Front Genet,A Multi-Cohort and Multi-Omics Meta-Analysis Framework to Identify Network-Based Gene Signatures.,
-,No,20190415,candidate,30947592,ERα Gene Promoter Methylation in Cognitive Function and Quality of Life of Patients With Alzheimer Disease.,J Geriatr Psychiatry Neurol,ER? Gene Promoter Methylation in Cognitive Function and Quality of Life of Patients With Alzheimer Disease.,
-,No,20190415,mouse,30948436,DNA (de)methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries.,Genome Res,DNA (de)methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries.,
-,No,20190415,candidate,30950195,DNA methylation-reprogrammed oxytocin receptor underlies insensitivity to oxytocin in pre-eclamptic placental vasculature.,J Cell Mol Med,DNA methylation-reprogrammed oxytocin receptor underlies insensitivity to oxytocin in pre-eclamptic placental vasculature.,
-,No,20190415,mouse,30955436,"Somatic expression of piRNA and associated machinery in the mouse identifies short, tissue-specific piRNA.",Epigenetics,"Somatic expression of piRNA and associated machinery in the mouse identifies short, tissue-specific piRNA",
-,,20190415,ewas,30956810,Pregnancy lipidomic profiles and DNA methylation in newborns from the CHAMACOS cohort.,Environ Epigenet,Pregnancy lipidomic profiles and DNA methylation in newborns from the CHAMACOS cohort.,
-,,20190415,ewas,30958317,Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease.,J Parkinsons Dis,Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease.,
-,,20190415,ewas,30966798,Environmental factors influence the epigenetic signature of newborns from mothers with gestational diabetes.,Epigenomics,Environmental factors influence the epigenetic signature of newborns from mothers with gestational diabetes.,
-,,20190415,ewas,30966880,Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight.,"Philos Trans R Soc Lond, B, Biol Sci",Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight.,
-,No,20190415,review,30982733,Epigenetics in Human Obesity and Type 2 Diabetes.,Cell Metab,Epigenetics in Human Obesity and Type 2 Diabetes,
-,No,20190429,ewas,30872577,Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements.,Nat Commun,Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements,
-,Yes,20190429,ewas,30906879,Residential exposure to radon and DNA methylation across the lifecourse: an exploratory study in the ALSPAC birth cohort.,Wellcome Open Res,Residential exposure to radon and DNA methylation across the lifecourse: an exploratory study in the ALSPAC birth cohort,
-,No,20190429,wgbs,30975860,The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight.,Science,The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight,
-,No,20190429,methods,30976086,Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders.,Mol Psychiatry,"After performing a typical EWAS, they “extended the regulatory networks related to sex-differential methylation and psychiatric disorders by integrating methylation quantitative trait loci (meQTLs), gene expression, and protein-protein interaction data.” ",
-,No,20190429,wgbs,30988170,Noninvasive Detection of Bladder Cancer by Shallow-Depth Genome-Wide Bisulfite Sequencing of Urinary Cell-Free DNA for Methylation and Copy Number Profiling.,Clin Chem,Noninvasive Detection of Bladder Cancer by Shallow-Depth Genome-Wide Bisulfite Sequencing of Urinary Cell-Free DNA for Methylation and Copy Number Profiling,
-,No,20190429,methods,30988719,An integrative module analysis of DNA methylation landscape in aging.,Exp Ther Med,"Identified modules in 3 different age groups, identified overlapping modules, and then found that was ‘dynamic’.  Somehow protein interactions and correlations between CpG sites were used to discover modules.",
-,Yes,20190429,ewas,30989176,Blood DNA methylation and breast cancer: A prospective case-cohort analysis in the Sister Study.,J Natl Cancer Inst,Blood DNA methylation and breast cancer: A prospective case-cohort analysis in the Sister Study.,
-,No,20190429,wgbs,30992551,Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy.,Genet Med,Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy,
-,No,20190429,methods,30999858,Walking pathways with positive feedback loops reveal DNA methylation biomarkers of colorectal cancer.,BMC Bioinformatics,Describe a method for linking changes in DNA methylation at putative transcription factor binding sites to changes in gene expression in tumor samples. Claim to use machine learning and artificial intelligence methods.,
-,No,20190429,ewas,31003786,Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults.,Biol Psychiatry,Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults.,
-,Yes,20190429,ewas,31004082,Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants.,Sci Rep,Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants. ,
-,,20190429,ewas,31008534,Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures-Gender matters.,Int J Cancer,Non-invasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures - Gender matters,
-,No,20190429,dnam age,31009935,"Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis.",Aging (Albany NY),"Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis. ",
-,No,20190429,wgbs,31009952,Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study.,Hum Mol Genet,Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study,
-,Yes,20190429,ewas,31010371,Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naĂŻve subjects.,Epigenetics,Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naďve subjects,
-,Yes,20190429,ewas,31015461,Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.,Nat Commun,Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight,
-,,20190429,ewas,31015518,Genome-wide DNA methylation analysis in obese women predicts an epigenetic signature for future endometrial cancer.,Sci Rep,Genome-wide DNA methylation analysis in obese women predicts an epigenetic signature for future endometrial cancer,
-,,20190520,ewas,31020763,"Neonatal amygdalae and hippocampi are influenced by genotype and prenatal environment, and reflected in the neonatal DNA methylome.",Genes Brain Behav,"Scans of neonatal amygdalae and hippocampi, genotype, cord blood DNA methylation, prenatal environment",
-,Yes,20190520,ewas,31024609,Genome-Wide DNA Methylation Profiles Reveal Common Epigenetic Patterns of Interferon-Related Genes in Multiple Autoimmune Diseases.,Front Genet,Multiple autoimmune diseases and CD4+ T cell methylation,
-,No,20190520,ewas,31026301,Maternal circadian disruption is associated with variation in placental DNA methylation.,PLoS ONE,Maternal circadian disruption (placenta),
-,No,20190520,epigenetics,31028648,Simultaneous Profiling of mRNA Transcriptome and DNA Methylome from a Single Cell.,Methods Mol Biol,Simultaneous Profiling of mRNA Transcriptome and DNA Methylome from a Single Cell,
-,,20190520,ewas,31031804,The Cord Blood Insulin and Mitochondrial DNA Content Related Methylome.,Front Genet,Cord Blood insulin and mitochondrial DNA content in cord blood. ,
-,Yes,20190520,ewas,31033411,"Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort.",Epigenetics,"Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort",
-,No,20190520,dnam age,31038702,Comparative validation of an epigenetic mortality risk score with three aging biomarkers for predicting mortality risks among older adult males.,Int J Epidemiol,Comparative validation of an epigenetic mortality risk score with three aging biomarkers for predicting mortality risks among older adult males,
-,,20190520,ewas,31039056,Associations between Maternal Tobacco Smoke Exposure and the Cord Blood [Formula: see text] DNA Methylome.,Environ Health Perspect,Maternal tobacco smoke exposure and cord blood. ,
-,Yes,20190520,ewas,31039828,Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk.,Clin Epigenetics,"Breast cancer, estrogen exposure and blood DNA methylation",
-,No,20190520,ewas,31053557,Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression.,EBioMedicine,Four immune cell types and multiple sclerosis progression,
-,No,20190520,ewas,31053723,Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis.,Nat Commun,Major psychosis in prefrontal cortex neurons.,
-,Yes,20190520,ewas,31062658,Epigenome-wide DNA methylation in placentas from preterm infants: association with maternal socioeconomic status.,Epigenetics,Socioeconomic Status in preterm infants (placenta),
-,No,20190520,methods,31063461,An integrative association method for omics data based on a modified Fisher's method with application to childhood asthma.,PLoS Genet,"Calculated a combined p-value of association between a trait and SNPs, DNAm and mRNA linked to a given gene",
-,No,20190520,ewas,31064978,DNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis.,Nat Commun,"Monozygotic twins clinically discordant for multiple sclerosis (n=45) have 7 CpG site associations, 2 validated",
-,No,20190520,reference,31068700,Next-generation characterization of the Cancer Cell Line Encyclopedia.,Nature,Next-generation characterization of the Cancer Cell Line Encyclopedia.,
-,No,20190520,epigenetics,31069058,Detection and analysis of RNA methylation.,F1000Res,Detection and analysis of RNA methylation.,
-,,20190520,ewas,31070508,Prenatal maternal depressive symptoms and infant DNA methylation: a longitudinal epigenome-wide study.,Nord J Psychiatry,Maternal depressive symptoms and infant saliva.  ,
-,Yes,20190520,ewas,31073081,Epigenome-wide association study of lung function level and its change.,Eur Respir J,Lung function change,
-,Yes,20190520,ewas,31076557,"Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle.",Proc Natl Acad Sci USA,"Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle.",
-,No,20190520,ewas,31086609,Maternal dietary glycaemic change during gestation influences insulin-related gene methylation in the placental tissue: a genome-wide methylation analysis.,Genes Nutr,Maternal dietary glycaemic change (placenta),
-,No,20190520,methods,31088362,Guidance for DNA methylation studies: statistical insights from the Illumina EPIC array.,BMC Genomics,Guidance for DNA methylation studies: statistical insights from the Illumina EPIC array,
-,No,20190520,ewas,31099405,Genome-wide gene expression in a pharmacological hormonal transition model and its relation to depressive symptoms.,Acta Psychiatr Scand,Pharmacological hormonal transition model and depressive symptoms.,
-,Yes,20190520,ewas,31100065,In-utero epigenetic factors are associated with early-onset myopia in young children.,PLoS ONE,Myopia at 3 predicted by 5 CpG sites in cord blood (n=519). ,
-,Yes,20190520,ewas,31101124,Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies.,Breast Cancer Res,"Breast cancer, estrogen exposure and blood DNA methylation",
-,No,20190603,global,30302724,"Methamphetamine (MA) Use Induces Specific Changes in LINE-1 Partial Methylation Patterns, Which Are Associated with MA-Induced Paranoia: a Multivariate and Neuronal Network Study.",Mol Neurobiol,"Methamphetamine (MA) Use Induces Specific Changes in LINE-1 Partial Methylation Patterns, Which Are Associated with MA-Induced Paranoia: a Multivariate and Neuronal Network Study",
-,Yes,20190603,ewas,30779925,Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation.,Gastroenterology,Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation,
-,No,20190603,ewas,31109152,Impact of Acute Aerobic Exercise on Genome-Wide DNA-Methylation in Natural Killer Cells-A Pilot Study.,Genes (Basel),Impact of Acute Aerobic Exercise on Genome-Wide DNA-Methylation in Natural Killer Cells-A Pilot Study,
-,No,20190603,dnam age,31113906,"Epigenetic clock analysis of human fibroblasts <i>in vitro</i>: effects of hypoxia, donor age, and expression of hTERT and SV40 largeT.",Aging (Albany NY),"Epigenetic clock analysis of human fibroblasts in vitro: effects of hypoxia, donor age, and expression of hTERT and SV40 largeT.",
-,No,20190603,ewas,31113950,Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms.,Nat Commun,Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms.,
-,No,20190603,ewas,31116258,Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents.,Braz J Psychiatry, Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents,
-,No,20190603,candidate,31122292,Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus.,Clin Epigenetics,Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus,
-,No,20190603,ewas,31132961,Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus.,Epigenetics,Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus,
-,No,20190603,dnam age,31138013,Human epigenetic ageing is logarithmic with time across the entire lifespan.,Epigenetics,Human Epigenetic Aging is Logarithmic with Time across the Entire LifeSpan,
-,Yes,20190603,ewas,31139831,Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations.,Sleep,Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations.,
-,No,20190610,ewas,31084332,Epigenome-Wide Association Study Indicates Hypomethylation of MTRNR2L8 in Large-Artery Atherosclerosis Stroke.,Stroke,Epigenome-Wide Association Study Indicates Hypomethylation of MTRNR2L8 in Large-Artery Atherosclerosis Stroke,
-,No,20190610,methods,31138268,OSCA: a tool for omic-data-based complex trait analysis.,Genome Biol,OSCA - Omics based tool for complex traits analysis ,
-,Yes,20190610,ewas,31142478,Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy.,Ann Rheum Dis,"Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy. ""80 blood samples from children (mean age=6.8 years) born to mothers with RA. As controls, blood samples from 354 children (mean age=6.0 years) from the population-based Generation R Study were used"" ""147 CpGs were differentially methylated""",
-,Yes,20190610,ewas,31143935,"Genetically predicted levels of DNA methylation biomarkers and breast cancer risk: data from 228,951 women of European descent.",J Natl Cancer Inst,"Genetically predicted levels of DNA methylation biomarkers and breast cancer risk: data from 228,951 women of European descent?",
-,No,20190610,genetics,31144443,CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease.,Aging Cell,"CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease. ""We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk.""",
-,Yes,20190610,ewas,31148503,Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis.,Environ Health Perspect,"Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis. "" exposure to PM10 (n=1,949) and PM2.5 (n=1,551) at maternal home addresses during pregnancy and newborn DNA methylation"" ""Six CpGs were significantly associated [false discovery rate (FDR) <0.05] with prenatal PM10 and 14 with PM2.5 exposure.""",
-,No,20190610,ewas,31152171,Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression.,Hum Mol Genet,Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression. Comb-p,
-,No,20190610,variation,31155008,A genomic atlas of systemic interindividual epigenetic variation in humans.,Genome Biol,A genomic atlas of systemic interindividual epigenetic variation in humans,
-,No,20190610,dnam age,31156022,Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts.,Epigenetics,"Human Aging DNA Methylation Signatures are Conserved but Accelerated in Cultured Fibroblasts. ""epigenetic aging is approximately 62x times faster in cultured cells than in the human body""",
-,Yes,20190610,ewas,31165884,Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals.,Am J Clin Nutr,"Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals. ""The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake"" ""Vitamin B-12 intake was not associated with DMPs""",
-,No,20190610,ewas,31166810,Evidence for type-specific DNA methylation patterns in epilepsy: a discordant monozygotic twin approach.,Epigenomics,"Evidence for type-specific DNA methylation patterns in epilepsy: a discordant monozygotic twin approach. ""15 monozygotic (MZ) twin pairs discordant for focal or generalized epilepsy"".  ""differentially methylated regions associated with OTX1 and ARID5B genes for generalized epilepsy and TTC39C and DLX5 genes for focal epilepsy""",
-,No,20190610,ewas,31167428,Network Analysis of the Potential Role of DNA Methylation in the Relationship between Plasma Carotenoids and Lipid Profile.,Nutrients,"Network Analysis of the Potential Role of DNA Methylation in the Relationship between Plasma Carotenoids and Lipid Profile. ""48 healthy subjects. Genome-wide DNA methylation levels of 20,687 out of 472,245 CpG sites in blood leukocytes were associated with total carotenoid concentrations""",
-,Yes,20190610,ewas,31169496,A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma.,Elife,A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma,
-,Yes,20190708,ewas,31197173,An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.,Nat Commun," 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication; identify DNAm associations with fasting glucose and insulin; ""Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D""",
-,No,20190708,methods,29481604,Detection and accurate false discovery rate control of differentially methylated regions from whole genome bisulfite sequencing.,Biostatistics,Detection and accurate false discovery rate control of differentially methylated regions from whole genome bisulfite sequencing,
-,No,20190708,mechanism,31230816,LINE-1 Evasion of Epigenetic Repression in Humans.,Mol Cell,"Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells but sometimes L1 escapes to cause somatic genome mosaicism in the brain.  Authors find ""a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation ... By analyzing 24 hippocampal neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion ... The source (donor) L1 for this insertion ... lacked the YY1 binding site, ... was highly mobile when tested in vitro ... [and was] hypomethylated ... in brain tissue.""",
-,No,20190708,methods,31173057,DepthFinder: A Tool to Determine the Optimal Read Depth for Reduced-Representation Sequencing.,Bioinformatics,,
-,No,20190708,dnam age,31173577,Investigation of bidirectional longitudinal associations between advanced epigenetic age and peripheral biomarkers of inflammation and metabolic syndrome.,Aging (Albany NY),n=179 Hannum epigenetic age associated with increased metabolic syndrome severity 2 years later,
-,No,20190708,global,31181146,Sleep duration and fragmentation in relation to leukocyte DNA methylation in adolescents.,Sleep,n=351 LINE1 methylation associated in a sex-specific way with sleep duration and fragmentation,
-,No,20190708,single gene,31182156,Smoking-associated AHRR demethylation in cord blood DNA: impact of CD235a+ nucleated red blood cells.,Clin Epigenetics,"""Prenatal smoke exposure was highly significantly associated with AHRR methylation in cord blood, CD14+ monocytes, and CD235a+?nRBCs. AHRR methylation levels in nRBCs and nRBC counts had minimal effect on cord blood methylation measurements. However, regression models using estimated nRBCs or actual nRBC counts outperformed those lacking these covariates.""",
-,Yes,20190708,variation,31186427,Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns.,Nat Commun,"VMR=variably methyalted regions n=2365 (4 cohorts)  ""Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G?+?E or GxE are functionally distinct.""",
-,Yes,20190708,ewas,31212707,Methylome-Wide Association Study in Peripheral White Blood Cells Focusing on Central Obesity and Inflammation.,Genes (Basel),"n=473, waist circumference, 669 associations",
-,Yes,20190708,ewas,31187518,DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics.,Clin Exp Allergy,"n=394, ""Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics.""",
-,Yes,20190708,ewas,10.1093/cdn/nzz037.FS11-06-19,Differences in DNA Methylation Patterns Between Vegans and Non-vegetarians in the AHS-2 Cohort (FS11-06-19).,Curr Dev Nutr,"n=137, nearly 3000 CpG site associations at FDR < 0.05",
-,No,20190708,dnam age,10.1093/cdn/nzz048.P11-036-19,Effects of Maternal Vitamin D3 Supplementation on Offspring Epigenetic Gestational Age Acceleration at Birth: A Randomized Controlled Trial (P11-036-19).,Curr Dev Nutr,"n=92, ""Vitamin D3 supplementation decreased ?DNAmGA by both Knight's clock (? = -0.89, P = 0.047) and Bohlin's clock (? = -0.71, P = 0.005) only in the black participants""",
-,No,20190708,ewas,10.1093/cdn/nzz048.P11-139-19,Differential DNA Methylation of Human Metastable Epialleles in Guatemalan Infants at Birth Due to Timing of a Maternal Lipid-Based Nutrition Supplement and Pre-Pregnancy BMI (P11-139-19).,Curr Dev Nutr,"n=45 LNS -3 months to delivery, n=45 LNS 12 weeks prior to delivery, n=45 no LNS; 269 ME regions bisulfite sequenced; a few associations with LNS and LNS timing",
-,Yes,20190708,ewas,10.1093/cdn/nzz037.OR31-06-19,Epigenome-wide Association Study of Diet Quality in the Women's Health Initiative (OR31-06-19).,Curr Dev Nutr,n=4529; 340 CpG sites associated with diet quality,
-,No,20190708,single cell,31178122,Single-Cell Multi-omic Integration Compares and Contrasts Features of Brain Cell Identity.,Cell,Single gene expression in mouse and human brain cells.  Single-cell DNA methylation in mouse brain cells.  Investigate cell type identity and mechanism.,
-,No,20190708,ewas,31179817,"DNA methylation, colon cancer and Mediterranean diet: results from the EPIC-Italy cohort.",Epigenetics,"""161 pairs from the Italian component of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, in which we looked for the methylation signals in DNA extracted from leucocytes associated with both CC and MD in 995 CpGs located in 48 inflammation genes. The DNA methylation signals detected in this analysis were validated in a subgroup of 47 case-control pairs and further replicated (where validated) in 95 new pairs by means of pyrosequencing. Among the CpG sites selected a-priori in inflammation-related genes, seven CpG sites were found to be associated with CC status and with MD, in line with its protective effect. Only two CpG sites (cg17968347-SERPINE1 and cg20674490-RUNX3) were validated using bisulphite pyrosequencing and, after replication, we found that DNA methylation of cg20674490-RUNX3 may be a potential molecular mediator explaining the protective effect of MD on CC onset.""",
-,Yes,20190708,sem,31200609,Exposure to polybrominated biphenyl and stochastic epigenetic mutations: application of a novel epigenetic approach to environmental exposure in the Michigan polybrominated biphenyl registry.,Epigenetics,"n=658. Weak associations and only in individuals exposed at higher ages.  Number of SEMs per individual was highly variable (119-18,309). ",
-,No,20190708,dnam age,31179827,Maternal dyslipidemia during early pregnancy and epigenetic ageing of the placenta.,Epigenetics,"n=262 ""maternal dyslipidemia due to low HDLc was associated with accelerated epigenetic ageing of the placenta among mothers with normal pre-pregnancy weight and a female fetus""",
-,Yes,20190708,ewas,31208937,Methylome-wide association study provides evidence of particulate matter air pollution-associated DNA methylation.,Environ Int,"n?=?8397, 12 cohorts, 1 CpG PM10, 2 CpGs PM2.5 and PM2.5-10",
-,No,20190708,methods,31216310,Machine learning approach yields epigenetic biomarkers of food allergy: A novel 13-gene signature to diagnose clinical reactivity.,PLoS ONE,An interesting introduction to machine learning using genomic data.  They reduce a 96-CpG signature down to 18 CpG sites.,
-,No,20190708,ewas,31217032,DNA methylation signature of human hippocampus in Alzheimer's disease is linked to neurogenesis.,Clin Epigenetics,n=26 cases vs n=12 controls. 188 differentially methylated CpG sites.,
-,Yes,20190708,ewas,31228611,Methylomic profiles reveal sex-specific differences in leukocyte composition associated with post-traumatic stress disorder.,Brain Behav Immun,n=483. Tested associations with lifetime PTSD in cell counts estimated from DNAm profiles. Higher monocytes observed in PTSD males.,
-,No,20190708,dnam age,31222117,Evaluation of six blood-based age prediction models using DNA methylation analysis by pyrosequencing.,Sci Rep,"n=100 blood donors (42 women and 58 men) aged from 19–65, <=5 CpG sites per model, MAD~5 (similar to Horvath but he is not referenced!)",
-,Yes,20190708,ewas,31233934,Genome-wide DNA methylation profiling of hip articular cartilage identifies differentially methylated loci associated with osteonecrosis of the femoral head.,Bone,"n=15 cases (osteonecrosis of the femoral head ONFH) and n=15 controls. DNAm measured in hip articular cartilage specimens, 2872 CpG sites differentially methylated.",
-,Yes,20190708,ewas,31230546,Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns.,Hypertension,maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]); cord blood methylation; HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites,
-,No,20190708,dnam age,31235674,Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels.,Aging (Albany NY),n=1012 placental samples; gestational predictor has r>0.95 with median error <1 week; cord GA clocks don't perform well in placenta,
-,No,20190708,ewas,31239533,Genome-wide methylation in alcohol use disorder subjects: implications for an epigenetic regulation of the cortico-limbic glucocorticoid receptors (NR3C1).,Mol Psychiatry, 25 pairs of control and individuals; prefrontal cortex; 5254  at p < 0.005 after testing 850K CpG sites! Apply adjustment for multiple tests for everything but the microarray analysis.,
-,Yes,20190708,ewas,31241004,Human exposure to trichloroethylene is associated with increased variability of blood DNA methylation that is enriched in genes and pathways related to autoimmune disease and cancer.,Epigenetics,n=67 exposed vs n=73 controls; 25 CpG sites had higher methlation variance in exposed individuals,
-,No,20190708,methods,31250700,Comparison of Illumina 450K and EPIC arrays in placental DNA methylation.,Epigenetics,"n=108 matched 450k/EPIC profiles of placenta methylation. ""We conclude that EPIC and 450K placental data can be combined, and we provide two lists of CpGs that should be excluded to avoid misleading results.""",
-,Yes,20190708,ewas,31253200,Comparative DNA methylomic analyses reveal potential origins of novel epigenetic biomarkers of insulin resistance in monocytes from virally suppressed HIV-infected adults.,Clin Epigenetics,"identified 123 differentially methylated CpG sites in ""monocytes in HIV-infected individuals (n = 37)"" between high and low insulin sensitivity. ""4 CpGs (cg27655935, cg02000426, cg10184328, and cg23085143) whose methylation levels independently predicted the insulin-resistant state at a higher confidence than that of clinical risk factors typically associated with insulin resistance (i.e., fasting glucose, 120-min oral glucose tolerance test, Framingham Risk Score, and Total to HDL cholesterol ratio)""",
-,No,20190708,single gene,31196964,Diagnostic value of RASSF1A methylation for breast cancer: a meta-analysis.,Biosci Rep,"19 papers, 1849 patients and 1542 controls, blood serum RASSF1A methylation best with sensitivity=0.55, diagnostic odds ratio=22.0 and AUC=0.86",
-,No,20190708,review,31103351,Epigenetic Regulation of the Social Brain.,Trends Neurosci,"""the role of the epigenetic network in regulating the enduring effects of social experiences during early-life, adolescence, and adulthood. We discuss research in animal models, primarily rodents, and associations between dysregulation of epigenetic mechanisms and human psychopathologies, specifically autism spectrum disorder (ASD) and schizophrenia.""",
-,No,20190708,methods,31022588,Analyzing DNA methylation patterns in subjects diagnosed with schizophrenia using machine learning methods.,J Psychiatr Res,"""post-mortem brain tissue from a cohort of 73 subjects diagnosed with schizophrenia and 52 control samples ... these methods did not uncover any significant signals ... suggesting that if there are methylation changes associated with schizophrenia, they are heterogeneous and complex with small effect.""
+EC,Date,Category,Paper ID,Title,Journal,Summary,
+Yes,20190312,ewas,30760334,Epigenetic findings in periodontitis in UK twins: a cross-sectional study.,Clin Epigenetics,"Periodontitis in blood, buccal and adipose tissue (Twins UK).",
+No,20190312,longitudinal,30764717,Longitudinal analysis of epigenome-wide DNA methylation reveals novel smoking-related loci in African Americans.,Epigenetics,Generalized estimating equestion (GEE) models used to investigate smoking and DNAm at two time points. Smokers tended to have greater DNAm change which was almost always linked to reduced DNAm levels.,
+Yes,20190312,ewas,30765504,"Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course.",Eur Respir J,Childhood lung function and risks of asthma and COPD in cord blood (meta-analysis of 5 cohorts).  The approach used is prone to false positives.,
+Yes,20190312,ewas,30765773,Association between DNA methylation in obesity-related genes and body mass index percentile in adolescents.,Sci Rep,"BMI and adolescent peripheral blood leukocytes. No tests survive adjustment for multiple tests, but functions of top genes 'make sense'.",
+No,20190312,ewas,30771258,Genome-wide analysis of DNA methylation in relation to socioeconomic status during development and early adulthood.,Am J Phys Anthropol,Socio-economic position in young adult blood.?2546 associations! Study performed in a non-affluent Philippine population.?,
+Yes,20190312,ewas,30773972,"Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood: an epigenome-wide association study.",Epigenetics,"Paternal pre-pregnancy obesity and offspring cord blood.?Observed sex-specific associations.  However, strongest association TAPBP was not replicated.?",
+Yes,20190312,ewas,30777123,A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57.,Clin Epigenetics,Folic acid supplementation during pregnancy (RCT) linked to differentially methylated regulator of ZPF57 in cord blood.?,
+Yes,20190312,ewas,30792424,Epigenome-wide association study in peripheral white blood cells involving insulin resistance.,Sci Rep,Insulin resistance and peripheral blood.798 CpG site associations observed!?,
+No,20190312,methods,30793194,Using long-read sequencing to detect imprinted DNA methylation.,Nucleic Acids Res,Long-read nanopore sequencing identifies new imprinted regions in mouse.,
+No,20190312,sex chromosomes,30793472,Age-dependent DNA methylation patterns on the Y chromosome in elderly males.,Aging Cell,"Y-chromosome derived DNAm age is different from autosomally-derived DNAm age.DNAm levels tend to increase with age, accelerate in the oldest individuals and associate negatively with mortality.",
+Yes,20190312,ewas,30796027,A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Non-Alcoholic Fatty Liver Disease.,Diabetes,"Hepatic fat and peripheral blood.? Observe 22 CpG site associations in 3,400 European, 401 Hispanic and 724 African ancestry participants.?",
+,20190312,ewas,30819252,Genome-wide DNA methylation and long-term ambient air pollution exposure in Korean adults.,Clin Epigenetics,Air pollution in adult peripheral blood.,
+No,20190312,methods,30821575,Don't brush off buccal data heterogeneity.,Epigenetics,Recommendations for handling cellular heterogeneity in buccal DNAm. ,
+Yes,20190312,ewas,30826615,Epigenetic marks of prenatal air pollution exposure found in multiple tissues relevant for child health.,Environ Int,Air pollution in cord and placenta. ,
+Yes,20190312,ewas,30830696,Brain Imaging-Guided Analysis Reveals DNA Methylation Profiles Correlated with Insular Surface Area and Alcohol Use Disorder.,Alcohol Clin Exp Res,Alcohol use disorder associated with CpG sites associated with brain insular surface area.,
+No,20190312,candidate,30831210,Differential BDNF methylation in combat exposed veterans and the association with exercise.,Gene,BDNF associated with combat and exercise in veterans.,
+No,20190312,methods,30832291,Using Openly Accessible Resources to Strengthen Causal Inference in Epigenetic Epidemiology of Neurodevelopment and Mental Health.,Genes (Basel),How to use public resources for causal inference in Epigenetic Epidemiology of Neurodevelopment and Mental Health ,
+Yes,20190312,ewas,30832715,A comparison of DNA methylation in newborn blood samples from infants with and without orofacial clefts.,Clin Epigenetics,Orofacial clefts and newborn blood. Fail to replicate findings based on ALSPAC and the Cleft Collective. ,
+Yes,20190312,ewas,30833390,Genomic and molecular characterization of preterm birth.,Proc Natl Acad Sci USA,Preterm birth and maternal blood. Includes whole genome sequencing and RNA-seq,
+No,20190312,dnam score,30842548,An epigenetic score for BMI based on DNA methylation correlates with poor physical health and major disease in the Lothian Birth Cohort.,Int J Obes (Lond),BMI score associated with health and disease in LBC.,
+No,20190312,dnam age,30842553,Synchrony and asynchrony between an epigenetic clock and developmental timing.,Sci Rep,Developmental stage at least partially independent of DNAm age in mammalian neural retina.,
+No,20190326,mechanism,30698680,Fumarates target the metabolic-epigenetic interplay of brain-homing T cells in multiple sclerosis.,Brain,Fumaric acid esters are highly effective immunomodulators in patients with multiple sclerosis. This effect appears to be due to DNA methylation changes in brain-homing CCR6+ CD4 and CD8 T cells.,
+No,20190326,longitudinal,30867049,Impact of chemotherapy for breast cancer on leukocyte DNA methylation landscape and cognitive function: a prospective study.,Clin Epigenetics,Chemotherapy changes DNAm in blood.,
+,20190326,ewas,30870065,Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk.,Epigenetics,Orofacial cleft associated with DNAm from blood spots collected at birth (includes VTRNA2-1 gene),
+No,20190326,longitudinal,30871403,DNA methylation changes associated with Parkinson's disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood.,Epigenetics,Longitudinal DNAm changes and associations with treatment in Parkinsons disease,
+,20190326,ewas,30872662,DNA methylation signature of smoking in lung cancer is enriched for exposure signatures in newborn and adult blood.,Sci Rep,Prenatal and own smoking DNAm associations in blood enriched in lung tumour DNAm differences.,
+,20190326,ewas,30873861,DNA methylation abundantly associates with fetal alcohol spectrum disorder and its subphenotypes.,Epigenomics,Fetal alcohol syndrome associated with DNAm of blood collected in childhood (after age 5),
+,20190326,ewas,30874594,Genomewide Study of Epigenetic Biomarkers of Opioid Dependence in European- American Women.,Sci Rep,Opiod dependence associated with DNAm in blood.,
+No,20190326,methods,30875430,Bigmelon: tools for analysing large DNA methylation datasets.,Bioinformatics,Bigmelon is a tool for normalizing and analysing large DNAm datasets,
+,20190326,ewas,30876376,Epigenome-wide association study reveals methylation pathways associated with childhood allergic sensitization.,Epigenetics,Allergic sensitisation associated with DNAm in blood in childhood.,
+No,20190326,mechanism,30877840,Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline.,Neurobiol Aging,Vitamin intake and genetic variation within DNMT3L interact to influence cognitive decline.,
+,20190326,ewas,30879037,"Shift work, DNA methylation and epigenetic age.",Int J Epidemiol,Shift work associated with DNAm and epigenetic age in blood.,
+No,20190326,mechanism,30879057,"Prenatal smoke exposure, DNA methylation and a link between DRD1 and lung cancer.",Int J Epidemiol,Letter to the editor discusses our study of persistence of prenatal smoking DNAm effects in connection with a link between DRD1 and lung cancer .,
+,20190326,ewas,30879397,Persistent epigenetic changes in adult daughters of older mothers.,Epigenetics,Maternal age with DNAm in blood collected in adulthood. ,
+No,20190326,tissues,30885044,Locus-specific DNA methylation prediction in cord blood and placenta.,Epigenetics,CpG site correlations between placenta and cord blood DNAm. ,
+,20190326,ewas,30893429,Epigenetic Associations with Estimated Glomerular Filtration Rate (eGFR) among Men with HIV Infection.,Clin Infect Dis,Kidney function in HIV associated with DNAm in blood.,
+,20190326,ewas,30898171,Parallel profiling of DNA methylation and hydroxymethylation highlights neuropathology-associated epigenetic variation in Alzheimer's disease.,Clin Epigenetics,Degree of Alzheimer's disease pathology associated with DNAm and hydroxymethylation in entorhinal cortex.,
+No,20190326,variation,30900359,Screening for rare epigenetic variations in autism and schizophrenia.,Hum Mutat,Epivariations' in blood DNAm linked to autism and schizophrenia (these are like rare variants),
+No,20190326,comparison,30911103,Genome-wide Analysis Reveals DNA Methylation Alterations in Obesity Associated with High Risk of Colorectal Cancer.,Sci Rep,Associations of colorectal cancer and of obesity similar in the DNAm of blood,
+No,20190326,dnam age,31738745,A meta-analysis of genome-wide association studies of epigenetic age acceleration,PLoS Genet,"An even larger GWAS of epigenetic age acceleration (n= 13,493) identifies a few novel genetic associations.",
+Yes,20190401,ewas,30905381,"Sensitive Periods for the Effect of Childhood Adversity on DNA Methylation: Results From a Prospective, Longitudinal Study.",Biol Psychiatry,"DNA methylation at 7 years is associated with childhood adversity, mainly before age 3.",
+No,20190401,ewas,30909978,Differential genome-wide DNA methylation patterns in childhood obesity.,BMC Res Notes,DNA methylation in blood at 13 years is associated with obesity but not prenatal maternal stress (n=31). ,
+No,20190401,ewas,30913233,DNA methylation among firefighters.,PLoS ONE,DNA methylation in blood is different between new and incumbent firefighters (n=86). ,
+No,20190401,ewas,30913238,Effects of early social deprivation on epigenetic statuses and adaptive behavior of young children: A study based on a cohort of institutionalized infants and toddlers.,PLoS ONE,DNA methylation in blood is different between children raised in families vs orphanages (n=58).,
+No,20190401,epigenetics,30914725,Characteristics and homogeneity of N6-methylation in human genomes.,Sci Rep,"N-6 methylated deoxyadenosine (m6dA) was recently discovered in humans and other eukaryotes.  It is somewhat rare but consistent within cell types, and it is associated with higher gene expression.",
+Yes,20190401,ewas,30915882,Novel DNA methylation sites associated with cigarette smoking among African Americans.,Epigenetics,"DNA methylation in saliva of African Americans associated with smoking, six novel sites identified and replicated.",
+No,20190401,imprinting,30918249,Parent of origin genetic effects on methylation in humans are common and influence complex trait variation.,Nat Commun,"Parent of origin effects in DNA methylation observed at 171 novel loci. A PheWAS identified ""a previously unidentified imprinted locus associated with waist circumference"". ",
+Yes,20190401,ewas,30925934,"Prenatal maternal antidepressants, anxiety, and depression and offspring DNA methylation: epigenome-wide associations at birth and persistence into early childhood.",Clin Epigenetics,DNA methylation in cord blood is associated with maternal antidepressant use in pregnancy.,
+No,20190401,ewas,30926763,DNA methylation in genes of longevity-regulating pathways: association with obesity and metabolic complications.,Aging (Albany NY),"CpG sites associated with longevity included several associated with BMI and with age in patients with metabolic disorders, ""suggesting a role of DNAm in aging-related metabolic alterations"".",
+No,20190408,methods,30922215,A (fire)cloud-based DNA methylation data preprocessing and quality control platform.,BMC Bioinformatics,A Bioconductor R package supports cloud-based preprocessing of a very large DNA methylation datasets.,
+No,20190408,ewas,30924596,SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis.,Mol Oncol,Methylome-wide interaction between smoking cessation and lung cancer survival found that smoking cessation was beneficial only for those with low methylation levels at a specific CpG site.,
+No,20190408,variation,30929737,Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.,Am J Hum Genet,"They train a model for detecting hereditary conditions using blood DNA methylation. ""This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases ..."" They further show how investigating ""epi-variation"" in individuals can be used to further narrow down a diagnosis.",
+Yes,20190408,ewas,30935889,Identification of novel differentially methylated sites with potential as clinical predictors of impaired respiratory function and COPD.,EBioMedicine,Identification of novel differentially methylated sites with potential as clinical predictors of impaired respiratory function and COPD,
+Yes,20190408,ewas,30938765,Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue.,Am J Epidemiol,Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue.,
+Yes,20190408,ewas,30940212,Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.,Clin Epigenetics,Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study,
+Yes,20190408,ewas,30941597,"Prosocial Emotion, Adolescence, and Warfare : DNA Methylation Associates with Culturally Salient Combat Variables.",Hum Nat,"Prosocial Emotion, Adolescence, and Warfare : DNA Methylation Associates with Culturally Salient Combat Variables.",
+No,20190408,methods,30944378,A Network-guided Association Mapping Approach from DNA Methylation to Disease.,Sci Rep,"Describes a network-based method for using DNA methylation to distinguish between disease states (e.g. malignant vs benign tumours). Integrates associations between DNA methylation, gene expression and disease phenotype.",
+No,20190415,mouse,30858345,Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses.,Genome Res,Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses.?,
+No,20190415,mouse,30936186,Intra-individual methylomics detects the impact of early-life adversity.,Life Sci Alliance,Intra-individual methylomics detects the impact of early-life adversity.,
+No,20190415,methods,30941158,A Multi-Cohort and Multi-Omics Meta-Analysis Framework to Identify Network-Based Gene Signatures.,Front Genet,A Multi-Cohort and Multi-Omics Meta-Analysis Framework to Identify Network-Based Gene Signatures.,
+No,20190415,candidate,30947592,ERα Gene Promoter Methylation in Cognitive Function and Quality of Life of Patients With Alzheimer Disease.,J Geriatr Psychiatry Neurol,ER? Gene Promoter Methylation in Cognitive Function and Quality of Life of Patients With Alzheimer Disease.,
+No,20190415,mouse,30948436,DNA (de)methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries.,Genome Res,DNA (de)methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries.,
+No,20190415,candidate,30950195,DNA methylation-reprogrammed oxytocin receptor underlies insensitivity to oxytocin in pre-eclamptic placental vasculature.,J Cell Mol Med,DNA methylation-reprogrammed oxytocin receptor underlies insensitivity to oxytocin in pre-eclamptic placental vasculature.,
+No,20190415,mouse,30955436,"Somatic expression of piRNA and associated machinery in the mouse identifies short, tissue-specific piRNA.",Epigenetics,"Somatic expression of piRNA and associated machinery in the mouse identifies short, tissue-specific piRNA",
+,20190415,ewas,30956810,Pregnancy lipidomic profiles and DNA methylation in newborns from the CHAMACOS cohort.,Environ Epigenet,Pregnancy lipidomic profiles and DNA methylation in newborns from the CHAMACOS cohort.,
+,20190415,ewas,30958317,Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease.,J Parkinsons Dis,Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease.,
+,20190415,ewas,30966798,Environmental factors influence the epigenetic signature of newborns from mothers with gestational diabetes.,Epigenomics,Environmental factors influence the epigenetic signature of newborns from mothers with gestational diabetes.,
+,20190415,ewas,30966880,Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight.,"Philos Trans R Soc Lond, B, Biol Sci",Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight.,
+No,20190415,review,30982733,Epigenetics in Human Obesity and Type 2 Diabetes.,Cell Metab,Epigenetics in Human Obesity and Type 2 Diabetes,
+No,20190429,ewas,30872577,Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements.,Nat Commun,Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements,
+Yes,20190429,ewas,30906879,Residential exposure to radon and DNA methylation across the lifecourse: an exploratory study in the ALSPAC birth cohort.,Wellcome Open Res,Residential exposure to radon and DNA methylation across the lifecourse: an exploratory study in the ALSPAC birth cohort,
+No,20190429,wgbs,30975860,The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight.,Science,The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight,
+No,20190429,methods,30976086,Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders.,Mol Psychiatry,"After performing a typical EWAS, they “extended the regulatory networks related to sex-differential methylation and psychiatric disorders by integrating methylation quantitative trait loci (meQTLs), gene expression, and protein-protein interaction data.” ",
+No,20190429,wgbs,30988170,Noninvasive Detection of Bladder Cancer by Shallow-Depth Genome-Wide Bisulfite Sequencing of Urinary Cell-Free DNA for Methylation and Copy Number Profiling.,Clin Chem,Noninvasive Detection of Bladder Cancer by Shallow-Depth Genome-Wide Bisulfite Sequencing of Urinary Cell-Free DNA for Methylation and Copy Number Profiling,
+No,20190429,methods,30988719,An integrative module analysis of DNA methylation landscape in aging.,Exp Ther Med,"Identified modules in 3 different age groups, identified overlapping modules, and then found that was ‘dynamic’.  Somehow protein interactions and correlations between CpG sites were used to discover modules.",
+Yes,20190429,ewas,30989176,Blood DNA methylation and breast cancer: A prospective case-cohort analysis in the Sister Study.,J Natl Cancer Inst,Blood DNA methylation and breast cancer: A prospective case-cohort analysis in the Sister Study.,
+No,20190429,wgbs,30992551,Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy.,Genet Med,Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy,
+No,20190429,methods,30999858,Walking pathways with positive feedback loops reveal DNA methylation biomarkers of colorectal cancer.,BMC Bioinformatics,Describe a method for linking changes in DNA methylation at putative transcription factor binding sites to changes in gene expression in tumor samples. Claim to use machine learning and artificial intelligence methods.,
+No,20190429,ewas,31003786,Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults.,Biol Psychiatry,Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults.,
+Yes,20190429,ewas,31004082,Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants.,Sci Rep,Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants. ,
+,20190429,ewas,31008534,Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures-Gender matters.,Int J Cancer,Non-invasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures - Gender matters,
+No,20190429,dnam age,31009935,"Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis.",Aging (Albany NY),"Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis. ",
+No,20190429,wgbs,31009952,Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study.,Hum Mol Genet,Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study,
+Yes,20190429,ewas,31010371,Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naĂŻve subjects.,Epigenetics,Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naďve subjects,
+Yes,20190429,ewas,31015461,Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.,Nat Commun,Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight,
+,20190429,ewas,31015518,Genome-wide DNA methylation analysis in obese women predicts an epigenetic signature for future endometrial cancer.,Sci Rep,Genome-wide DNA methylation analysis in obese women predicts an epigenetic signature for future endometrial cancer,
+,20190520,ewas,31020763,"Neonatal amygdalae and hippocampi are influenced by genotype and prenatal environment, and reflected in the neonatal DNA methylome.",Genes Brain Behav,"Scans of neonatal amygdalae and hippocampi, genotype, cord blood DNA methylation, prenatal environment",
+Yes,20190520,ewas,31024609,Genome-Wide DNA Methylation Profiles Reveal Common Epigenetic Patterns of Interferon-Related Genes in Multiple Autoimmune Diseases.,Front Genet,Multiple autoimmune diseases and CD4+ T cell methylation,
+No,20190520,ewas,31026301,Maternal circadian disruption is associated with variation in placental DNA methylation.,PLoS ONE,Maternal circadian disruption (placenta),
+No,20190520,epigenetics,31028648,Simultaneous Profiling of mRNA Transcriptome and DNA Methylome from a Single Cell.,Methods Mol Biol,Simultaneous Profiling of mRNA Transcriptome and DNA Methylome from a Single Cell,
+,20190520,ewas,31031804,The Cord Blood Insulin and Mitochondrial DNA Content Related Methylome.,Front Genet,Cord Blood insulin and mitochondrial DNA content in cord blood. ,
+Yes,20190520,ewas,31033411,"Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort.",Epigenetics,"Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort",
+No,20190520,dnam age,31038702,Comparative validation of an epigenetic mortality risk score with three aging biomarkers for predicting mortality risks among older adult males.,Int J Epidemiol,Comparative validation of an epigenetic mortality risk score with three aging biomarkers for predicting mortality risks among older adult males,
+,20190520,ewas,31039056,Associations between Maternal Tobacco Smoke Exposure and the Cord Blood [Formula: see text] DNA Methylome.,Environ Health Perspect,Maternal tobacco smoke exposure and cord blood. ,
+Yes,20190520,ewas,31039828,Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk.,Clin Epigenetics,"Breast cancer, estrogen exposure and blood DNA methylation",
+No,20190520,ewas,31053557,Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression.,EBioMedicine,Four immune cell types and multiple sclerosis progression,
+No,20190520,ewas,31053723,Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis.,Nat Commun,Major psychosis in prefrontal cortex neurons.,
+Yes,20190520,ewas,31062658,Epigenome-wide DNA methylation in placentas from preterm infants: association with maternal socioeconomic status.,Epigenetics,Socioeconomic Status in preterm infants (placenta),
+No,20190520,methods,31063461,An integrative association method for omics data based on a modified Fisher's method with application to childhood asthma.,PLoS Genet,"Calculated a combined p-value of association between a trait and SNPs, DNAm and mRNA linked to a given gene",
+No,20190520,ewas,31064978,DNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis.,Nat Commun,"Monozygotic twins clinically discordant for multiple sclerosis (n=45) have 7 CpG site associations, 2 validated",
+No,20190520,reference,31068700,Next-generation characterization of the Cancer Cell Line Encyclopedia.,Nature,Next-generation characterization of the Cancer Cell Line Encyclopedia.,
+No,20190520,epigenetics,31069058,Detection and analysis of RNA methylation.,F1000Res,Detection and analysis of RNA methylation.,
+,20190520,ewas,31070508,Prenatal maternal depressive symptoms and infant DNA methylation: a longitudinal epigenome-wide study.,Nord J Psychiatry,Maternal depressive symptoms and infant saliva.  ,
+Yes,20190520,ewas,31073081,Epigenome-wide association study of lung function level and its change.,Eur Respir J,Lung function change,
+Yes,20190520,ewas,31076557,"Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle.",Proc Natl Acad Sci USA,"Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle.",
+No,20190520,ewas,31086609,Maternal dietary glycaemic change during gestation influences insulin-related gene methylation in the placental tissue: a genome-wide methylation analysis.,Genes Nutr,Maternal dietary glycaemic change (placenta),
+No,20190520,methods,31088362,Guidance for DNA methylation studies: statistical insights from the Illumina EPIC array.,BMC Genomics,Guidance for DNA methylation studies: statistical insights from the Illumina EPIC array,
+No,20190520,ewas,31099405,Genome-wide gene expression in a pharmacological hormonal transition model and its relation to depressive symptoms.,Acta Psychiatr Scand,Pharmacological hormonal transition model and depressive symptoms.,
+Yes,20190520,ewas,31100065,In-utero epigenetic factors are associated with early-onset myopia in young children.,PLoS ONE,Myopia at 3 predicted by 5 CpG sites in cord blood (n=519). ,
+Yes,20190520,ewas,31101124,Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies.,Breast Cancer Res,"Breast cancer, estrogen exposure and blood DNA methylation",
+No,20190603,global,30302724,"Methamphetamine (MA) Use Induces Specific Changes in LINE-1 Partial Methylation Patterns, Which Are Associated with MA-Induced Paranoia: a Multivariate and Neuronal Network Study.",Mol Neurobiol,"Methamphetamine (MA) Use Induces Specific Changes in LINE-1 Partial Methylation Patterns, Which Are Associated with MA-Induced Paranoia: a Multivariate and Neuronal Network Study",
+Yes,20190603,ewas,30779925,Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation.,Gastroenterology,Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation,
+No,20190603,ewas,31109152,Impact of Acute Aerobic Exercise on Genome-Wide DNA-Methylation in Natural Killer Cells-A Pilot Study.,Genes (Basel),Impact of Acute Aerobic Exercise on Genome-Wide DNA-Methylation in Natural Killer Cells-A Pilot Study,
+No,20190603,dnam age,31113906,"Epigenetic clock analysis of human fibroblasts <i>in vitro</i>: effects of hypoxia, donor age, and expression of hTERT and SV40 largeT.",Aging (Albany NY),"Epigenetic clock analysis of human fibroblasts in vitro: effects of hypoxia, donor age, and expression of hTERT and SV40 largeT.",
+No,20190603,ewas,31113950,Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms.,Nat Commun,Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms.,
+No,20190603,ewas,31116258,Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents.,Braz J Psychiatry, Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents,
+No,20190603,candidate,31122292,Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus.,Clin Epigenetics,Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus,
+No,20190603,ewas,31132961,Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus.,Epigenetics,Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus,
+No,20190603,dnam age,31138013,Human epigenetic ageing is logarithmic with time across the entire lifespan.,Epigenetics,Human Epigenetic Aging is Logarithmic with Time across the Entire LifeSpan,
+Yes,20190603,ewas,31139831,Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations.,Sleep,Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations.,
+No,20190610,ewas,31084332,Epigenome-Wide Association Study Indicates Hypomethylation of MTRNR2L8 in Large-Artery Atherosclerosis Stroke.,Stroke,Epigenome-Wide Association Study Indicates Hypomethylation of MTRNR2L8 in Large-Artery Atherosclerosis Stroke,
+No,20190610,methods,31138268,OSCA: a tool for omic-data-based complex trait analysis.,Genome Biol,OSCA - Omics based tool for complex traits analysis ,
+Yes,20190610,ewas,31142478,Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy.,Ann Rheum Dis,"Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy. ""80 blood samples from children (mean age=6.8 years) born to mothers with RA. As controls, blood samples from 354 children (mean age=6.0 years) from the population-based Generation R Study were used"" ""147 CpGs were differentially methylated""",
+Yes,20190610,ewas,31143935,"Genetically predicted levels of DNA methylation biomarkers and breast cancer risk: data from 228,951 women of European descent.",J Natl Cancer Inst,"Genetically predicted levels of DNA methylation biomarkers and breast cancer risk: data from 228,951 women of European descent?",
+No,20190610,genetics,31144443,CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease.,Aging Cell,"CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease. ""We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk.""",
+Yes,20190610,ewas,31148503,Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis.,Environ Health Perspect,"Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis. "" exposure to PM10 (n=1,949) and PM2.5 (n=1,551) at maternal home addresses during pregnancy and newborn DNA methylation"" ""Six CpGs were significantly associated [false discovery rate (FDR) <0.05] with prenatal PM10 and 14 with PM2.5 exposure.""",
+No,20190610,ewas,31152171,Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression.,Hum Mol Genet,Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression. Comb-p,
+No,20190610,variation,31155008,A genomic atlas of systemic interindividual epigenetic variation in humans.,Genome Biol,A genomic atlas of systemic interindividual epigenetic variation in humans,
+No,20190610,dnam age,31156022,Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts.,Epigenetics,"Human Aging DNA Methylation Signatures are Conserved but Accelerated in Cultured Fibroblasts. ""epigenetic aging is approximately 62x times faster in cultured cells than in the human body""",
+Yes,20190610,ewas,31165884,Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals.,Am J Clin Nutr,"Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals. ""The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake"" ""Vitamin B-12 intake was not associated with DMPs""",
+No,20190610,ewas,31166810,Evidence for type-specific DNA methylation patterns in epilepsy: a discordant monozygotic twin approach.,Epigenomics,"Evidence for type-specific DNA methylation patterns in epilepsy: a discordant monozygotic twin approach. ""15 monozygotic (MZ) twin pairs discordant for focal or generalized epilepsy"".  ""differentially methylated regions associated with OTX1 and ARID5B genes for generalized epilepsy and TTC39C and DLX5 genes for focal epilepsy""",
+No,20190610,ewas,31167428,Network Analysis of the Potential Role of DNA Methylation in the Relationship between Plasma Carotenoids and Lipid Profile.,Nutrients,"Network Analysis of the Potential Role of DNA Methylation in the Relationship between Plasma Carotenoids and Lipid Profile. ""48 healthy subjects. Genome-wide DNA methylation levels of 20,687 out of 472,245 CpG sites in blood leukocytes were associated with total carotenoid concentrations""",
+Yes,20190610,ewas,31169496,A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma.,Elife,A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma,
+Yes,20190708,ewas,31197173,An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.,Nat Commun," 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication; identify DNAm associations with fasting glucose and insulin; ""Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D""",
+No,20190708,methods,29481604,Detection and accurate false discovery rate control of differentially methylated regions from whole genome bisulfite sequencing.,Biostatistics,Detection and accurate false discovery rate control of differentially methylated regions from whole genome bisulfite sequencing,
+No,20190708,mechanism,31230816,LINE-1 Evasion of Epigenetic Repression in Humans.,Mol Cell,"Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells but sometimes L1 escapes to cause somatic genome mosaicism in the brain.  Authors find ""a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation ... By analyzing 24 hippocampal neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion ... The source (donor) L1 for this insertion ... lacked the YY1 binding site, ... was highly mobile when tested in vitro ... [and was] hypomethylated ... in brain tissue.""",
+No,20190708,methods,31173057,DepthFinder: A Tool to Determine the Optimal Read Depth for Reduced-Representation Sequencing.,Bioinformatics,,
+No,20190708,dnam age,31173577,Investigation of bidirectional longitudinal associations between advanced epigenetic age and peripheral biomarkers of inflammation and metabolic syndrome.,Aging (Albany NY),n=179 Hannum epigenetic age associated with increased metabolic syndrome severity 2 years later,
+No,20190708,global,31181146,Sleep duration and fragmentation in relation to leukocyte DNA methylation in adolescents.,Sleep,n=351 LINE1 methylation associated in a sex-specific way with sleep duration and fragmentation,
+No,20190708,single gene,31182156,Smoking-associated AHRR demethylation in cord blood DNA: impact of CD235a+ nucleated red blood cells.,Clin Epigenetics,"""Prenatal smoke exposure was highly significantly associated with AHRR methylation in cord blood, CD14+ monocytes, and CD235a+?nRBCs. AHRR methylation levels in nRBCs and nRBC counts had minimal effect on cord blood methylation measurements. However, regression models using estimated nRBCs or actual nRBC counts outperformed those lacking these covariates.""",
+Yes,20190708,variation,31186427,Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns.,Nat Commun,"VMR=variably methyalted regions n=2365 (4 cohorts)  ""Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G?+?E or GxE are functionally distinct.""",
+Yes,20190708,ewas,31212707,Methylome-Wide Association Study in Peripheral White Blood Cells Focusing on Central Obesity and Inflammation.,Genes (Basel),"n=473, waist circumference, 669 associations",
+Yes,20190708,ewas,31187518,DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics.,Clin Exp Allergy,"n=394, ""Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics.""",
+Yes,20190708,ewas,10.1093/cdn/nzz037.FS11-06-19,Differences in DNA Methylation Patterns Between Vegans and Non-vegetarians in the AHS-2 Cohort (FS11-06-19).,Curr Dev Nutr,"n=137, nearly 3000 CpG site associations at FDR < 0.05",
+No,20190708,dnam age,10.1093/cdn/nzz048.P11-036-19,Effects of Maternal Vitamin D3 Supplementation on Offspring Epigenetic Gestational Age Acceleration at Birth: A Randomized Controlled Trial (P11-036-19).,Curr Dev Nutr,"n=92, ""Vitamin D3 supplementation decreased ?DNAmGA by both Knight's clock (? = -0.89, P = 0.047) and Bohlin's clock (? = -0.71, P = 0.005) only in the black participants""",
+No,20190708,ewas,10.1093/cdn/nzz048.P11-139-19,Differential DNA Methylation of Human Metastable Epialleles in Guatemalan Infants at Birth Due to Timing of a Maternal Lipid-Based Nutrition Supplement and Pre-Pregnancy BMI (P11-139-19).,Curr Dev Nutr,"n=45 LNS -3 months to delivery, n=45 LNS 12 weeks prior to delivery, n=45 no LNS; 269 ME regions bisulfite sequenced; a few associations with LNS and LNS timing",
+Yes,20190708,ewas,10.1093/cdn/nzz037.OR31-06-19,Epigenome-wide Association Study of Diet Quality in the Women's Health Initiative (OR31-06-19).,Curr Dev Nutr,n=4529; 340 CpG sites associated with diet quality,
+No,20190708,single cell,31178122,Single-Cell Multi-omic Integration Compares and Contrasts Features of Brain Cell Identity.,Cell,Single gene expression in mouse and human brain cells.  Single-cell DNA methylation in mouse brain cells.  Investigate cell type identity and mechanism.,
+No,20190708,ewas,31179817,"DNA methylation, colon cancer and Mediterranean diet: results from the EPIC-Italy cohort.",Epigenetics,"""161 pairs from the Italian component of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, in which we looked for the methylation signals in DNA extracted from leucocytes associated with both CC and MD in 995 CpGs located in 48 inflammation genes. The DNA methylation signals detected in this analysis were validated in a subgroup of 47 case-control pairs and further replicated (where validated) in 95 new pairs by means of pyrosequencing. Among the CpG sites selected a-priori in inflammation-related genes, seven CpG sites were found to be associated with CC status and with MD, in line with its protective effect. Only two CpG sites (cg17968347-SERPINE1 and cg20674490-RUNX3) were validated using bisulphite pyrosequencing and, after replication, we found that DNA methylation of cg20674490-RUNX3 may be a potential molecular mediator explaining the protective effect of MD on CC onset.""",
+Yes,20190708,sem,31200609,Exposure to polybrominated biphenyl and stochastic epigenetic mutations: application of a novel epigenetic approach to environmental exposure in the Michigan polybrominated biphenyl registry.,Epigenetics,"n=658. Weak associations and only in individuals exposed at higher ages.  Number of SEMs per individual was highly variable (119-18,309). ",
+No,20190708,dnam age,31179827,Maternal dyslipidemia during early pregnancy and epigenetic ageing of the placenta.,Epigenetics,"n=262 ""maternal dyslipidemia due to low HDLc was associated with accelerated epigenetic ageing of the placenta among mothers with normal pre-pregnancy weight and a female fetus""",
+Yes,20190708,ewas,31208937,Methylome-wide association study provides evidence of particulate matter air pollution-associated DNA methylation.,Environ Int,"n?=?8397, 12 cohorts, 1 CpG PM10, 2 CpGs PM2.5 and PM2.5-10",
+No,20190708,methods,31216310,Machine learning approach yields epigenetic biomarkers of food allergy: A novel 13-gene signature to diagnose clinical reactivity.,PLoS ONE,An interesting introduction to machine learning using genomic data.  They reduce a 96-CpG signature down to 18 CpG sites.,
+No,20190708,ewas,31217032,DNA methylation signature of human hippocampus in Alzheimer's disease is linked to neurogenesis.,Clin Epigenetics,n=26 cases vs n=12 controls. 188 differentially methylated CpG sites.,
+Yes,20190708,ewas,31228611,Methylomic profiles reveal sex-specific differences in leukocyte composition associated with post-traumatic stress disorder.,Brain Behav Immun,n=483. Tested associations with lifetime PTSD in cell counts estimated from DNAm profiles. Higher monocytes observed in PTSD males.,
+No,20190708,dnam age,31222117,Evaluation of six blood-based age prediction models using DNA methylation analysis by pyrosequencing.,Sci Rep,"n=100 blood donors (42 women and 58 men) aged from 19–65, <=5 CpG sites per model, MAD~5 (similar to Horvath but he is not referenced!)",
+Yes,20190708,ewas,31233934,Genome-wide DNA methylation profiling of hip articular cartilage identifies differentially methylated loci associated with osteonecrosis of the femoral head.,Bone,"n=15 cases (osteonecrosis of the femoral head ONFH) and n=15 controls. DNAm measured in hip articular cartilage specimens, 2872 CpG sites differentially methylated.",
+Yes,20190708,ewas,31230546,Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns.,Hypertension,maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]); cord blood methylation; HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites,
+No,20190708,dnam age,31235674,Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels.,Aging (Albany NY),n=1012 placental samples; gestational predictor has r>0.95 with median error <1 week; cord GA clocks don't perform well in placenta,
+No,20190708,ewas,31239533,Genome-wide methylation in alcohol use disorder subjects: implications for an epigenetic regulation of the cortico-limbic glucocorticoid receptors (NR3C1).,Mol Psychiatry, 25 pairs of control and individuals; prefrontal cortex; 5254  at p < 0.005 after testing 850K CpG sites! Apply adjustment for multiple tests for everything but the microarray analysis.,
+Yes,20190708,ewas,31241004,Human exposure to trichloroethylene is associated with increased variability of blood DNA methylation that is enriched in genes and pathways related to autoimmune disease and cancer.,Epigenetics,n=67 exposed vs n=73 controls; 25 CpG sites had higher methlation variance in exposed individuals,
+No,20190708,methods,31250700,Comparison of Illumina 450K and EPIC arrays in placental DNA methylation.,Epigenetics,"n=108 matched 450k/EPIC profiles of placenta methylation. ""We conclude that EPIC and 450K placental data can be combined, and we provide two lists of CpGs that should be excluded to avoid misleading results.""",
+Yes,20190708,ewas,31253200,Comparative DNA methylomic analyses reveal potential origins of novel epigenetic biomarkers of insulin resistance in monocytes from virally suppressed HIV-infected adults.,Clin Epigenetics,"identified 123 differentially methylated CpG sites in ""monocytes in HIV-infected individuals (n = 37)"" between high and low insulin sensitivity. ""4 CpGs (cg27655935, cg02000426, cg10184328, and cg23085143) whose methylation levels independently predicted the insulin-resistant state at a higher confidence than that of clinical risk factors typically associated with insulin resistance (i.e., fasting glucose, 120-min oral glucose tolerance test, Framingham Risk Score, and Total to HDL cholesterol ratio)""",
+No,20190708,single gene,31196964,Diagnostic value of RASSF1A methylation for breast cancer: a meta-analysis.,Biosci Rep,"19 papers, 1849 patients and 1542 controls, blood serum RASSF1A methylation best with sensitivity=0.55, diagnostic odds ratio=22.0 and AUC=0.86",
+No,20190708,review,31103351,Epigenetic Regulation of the Social Brain.,Trends Neurosci,"""the role of the epigenetic network in regulating the enduring effects of social experiences during early-life, adolescence, and adulthood. We discuss research in animal models, primarily rodents, and associations between dysregulation of epigenetic mechanisms and human psychopathologies, specifically autism spectrum disorder (ASD) and schizophrenia.""",
+No,20190708,methods,31022588,Analyzing DNA methylation patterns in subjects diagnosed with schizophrenia using machine learning methods.,J Psychiatr Res,"""post-mortem brain tissue from a cohort of 73 subjects diagnosed with schizophrenia and 52 control samples ... these methods did not uncover any significant signals ... suggesting that if there are methylation changes associated with schizophrenia, they are heterogeneous and complex with small effect.""
 
 ",
-,No,20190708,dnam age,30785999,"Epigenetic Age Acceleration in Adolescence Associates With BMI, Inflammation, and Risk Score for Middle Age Cardiovascular Disease.",J Clin Endocrinol Metab,"n=995; age =17.3 ± 0.6 years; EEAA (per 5 years) was associated with increased body mass index (BMI) of 2.4% at 17 and 22 years, increases of 23% in high-sensitivity C-reactive protein, 10% in interferon-?-inducible protein of 10 kDa, 4% in soluble TNF receptor 2, 3% increase in hard endpoints of CVD by 47 years of age after adjustment for conventional risk factors.",
-,Yes,20190708,ewas,31220268,Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue.,Hum Mol Genet,"prefrontal cortex, temporal cortex and cerebellum from 43 ASD patients and 38 controls. ""We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB""",
-,No,20190708,review,31046576,Epigenetic changes in healthy human skeletal muscle following exercise- a systematic review.,Epigenetics,"22 studies ""examined epigenetic modifications (DNA methylation, histone modifications and non-coding RNAs) in skeletal muscle, following either an acute bout of exercise, an exercise intervention in a pre/post design, or a case/control type of study."" Associations identified but role uncertain.",
-,No,20190708,methods,31114869,MEXPRESS update 2019.,Nucleic Acids Res,"""MEXPRESS (https://mexpress.be). It contains the latest TCGA data, additional types of omics and clinical data and extra functionality, allowing users to explore mechanisms of gene dysregulation beyond expression and DNA methylation.""",
-,No,20190715,methods,31221194,Essential guidelines for computational method benchmarking.,Genome Biol,Essential guidelines for computational method benchmarking.,
-,No,20190715,review,31284823,DNA hypermethylation in disease: mechanisms and clinical relevance.,Epigenetics,,
-,No,20190715,review,31284662,Telomerase Reverse Transcriptase (TERT) in Action: Cross-Talking with Epigenetics.,Int J Mol Sci,,
-,Yes,20190715,ewas,31282290,Epigenome-wide association study of DNA methylation and microRNA expression highlights novel pathways for human complex traits.,Epigenetics,"""We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (cis-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at r2<0.2. cis-miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 cis-miR-eQTM-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely.""",
-,No,20190715,ewas,31279243,Genome-wide DNA methylomic differences between dorsolateral prefrontal and temporal pole cortices of bipolar disorder.,J Psychiatr Res,"""20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850?K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups.""",
-,No,20190715,dnam age,31277270,Smoking-Related DNA Methylation is Associated with DNA Methylation Phenotypic Age Acceleration: The Veterans Affairs Normative Aging Study.,Int J Environ Res Public Health,n=692,
-,Yes,20190715,ewas,31266983,Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal key epigenetic differences at developmental genes.,Sci Rep,""" we characterised transcriptomes and methylomes of isolated adipocytes from matched SA and VA tissues of individuals with normal BMI to identify epigenetic differences and their contribution to cell type and depot-specific function.""",
-,Yes,20190715,ewas,31262328,DNA methylation links prenatal smoking exposure to later life health outcomes in offspring.,Clin Epigenetics,"""We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48?years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring ... 69 differentially methylated CpGs ... Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia.""",
-,No,20190715,ewas,31260916,Association between long-term air pollution exposure and DNA methylation: The REGICOR study.,Environ Res,"""A two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. ... NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured ...  Neither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated.""",
-,No,20190715,mr,31257439,An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility.,Int J Epidemiol,"""we identified 412 CpG sites where DNA methylation was associated with prenatal smoking. We then applied 2SMR to investigate potential downstream effects of these putative changes on 643 complex traits ... We identified 22 associations that survived multiple testing""",
-,Yes,20190715,ewas,31300640,The nasal methylome as a biomarker of asthma and airway inflammation in children.,Nat Commun,"""we collect nasal swabs from the anterior nares of 547 children (mean-age 12.9?y)  ... We perform nasal Epigenome-Wide Association analyses (EWAS) of current asthma, allergen sensitization, allergic rhinitis, fractional exhaled nitric oxide (FeNO) and lung function. We find ... asthma (285-CpGs), FeNO (8,372-CpGs; 191-DMRs), total IgE (3-CpGs; 3-DMRs), environment IgE (17-CpGs; 4-DMRs), allergic asthma (1,235-CpGs; 7-DMRs) and bronchodilator response (130-CpGs).""",
-,No,20190715,candidate,31300453,DNA Methylation Markers for Breast Cancer Detection in the Developing World.,Clin Cancer Res,"""Two case-control studies were conducted comparing cancer and benign breast tissue identified from clinical repositories in the U.S., China, and South Africa for marker selection/training (N=226) and testing (N=246). Twenty-five methylated markers were assayed ... In the independent test cohort, this panel yielded an AUC of 0.937 (95% CI = 0.900-0.970)""",
-,No,20190715,methods,31297508,MEpurity: estimating tumor purity using DNA methylation data.,Bioinformatics,"""a beta mixture model-based algorithm, to estimate the tumor purity based on tumor-only Illumina Infinium 450k methylation microarray data""",
-,No,20190715,global,31291495,Early life social and ecological determinants of global DNA methylation in wild spotted hyenas.,Mol Ecol,"""maternal rank [2.75%], anthropogenic disturbance, and prey availability early in life are associated with later life global DNA methylation""",
-,No,20190715,methods,31291459,coMethDMR: accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies with continuous phenotypes.,Nucleic Acids Res,"""a flexible, powerful, and accurate tool for identifying DMRs. Instead of testing all CpGs within a genomic region, coMethDMR carries out an additional step that selects co-methylated sub-regions first. Next, coMethDMR tests association between methylation levels within the sub-region and phenotype via a random coefficient mixed effects model that models both variations between CpG sites within the region and differential methylation simultaneously""",
-,Yes,20190715,ewas,31288836,Cell type-specific epigenetic links to schizophrenia risk in the brain.,Genome Biol,"""whole-genome methylomes (N?=?95) and transcriptomes (N?=?89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls"". Identified differences at FDR < 0.2: 60 in NeuN+ and 201 in OLIG2+.",
-,No,20190715,nlr,31288238,"The Prognostic Value of the Pretreatment Neutrophil/Lymphocyte Ratio in Patients with Glioblastoma Multiforme Brain Tumors: A Retrospective Cohort Study of Patients Treated with Combined Modality Surgery, Radiation Therapy, and Temozolomide Chemotherapy.",Oncology,"n=89; ""pretreatment NLR was not prognostic""",
-,No,20190722,dnam age,31211779,"Associations of genetics, behaviors, and life course circumstances with a novel aging and healthspan measure: Evidence from the Health and Retirement Study.",PLoS Med,"""Based on data from 2,339 adults (aged 51+ years, mean age 69.4 years, 56% female, and 93.9% non-Hispanic white) from the US Health and Retirement Study … genetic, behavioral, and socioenvironmental circumstances during childhood and adulthood account for about 30% of differences in"" PhenoAge variation. ""behaviors had the largest contribution to PhenoAge"".",
-,No,20190722,review,31249003,A periodic table of cell types.,Development,A framework for distinguishing between cell type and cell state in single-cell RNA-seq.,
-,No,20190722,review,31225507,Constitutional Mosaic Epimutations - a hidden cause of cancer?,Cell Stress,Mosaic methylation of genes linked genetically to cancer risk may cause cancer and be useful as biomarkers.,
-,No,20190722,methods,31308366,Detection of cell-type-specific risk-CpG sites in epigenome-wide association studies.,Nat Commun,A method for improving power of EWAS in complex tissues and actually to identify cell-type specific associations in complex tissues.,
-,No,20190722,review,31249591,Inferring Interaction Networks From Multi-Omics Data.,Front Genet,"""we review state-of-the-art techniques for inferring the topology of interaction networks from functional multi-omics data""",
-,No,20190722,epigenetics,31234833,RNA-Seq in 296 phased trios provides a high-resolution map of genomic imprinting.,BMC Biol,"""7 [new] transcripts showing parental bias in gene expression""",
-,No,20190722,somatic mutations,31300647,Brain somatic mutations observed in Alzheimer's disease associated with aging and dysregulation of tau phosphorylation.,Nat Commun,"""deep whole-exome sequencing (average read depth 584×) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD."" The amount of genetic variation increases with age in the brain but at 4.8-fold slower rate than in blood.  There is enrichment for variation accumulating near genes ""known to contribute to hyperphosphorylation of tau"".",
-,No,20190722,methods,31233496,Solving the missing heritability problem.,PLoS Genet,A letter describing challenges of expanding analyses to the whole genome and suggesting solutions.,
-,No,20190722,gene regulation,31249060,Dynamic genetic regulation of gene expression during cellular differentiation.,Science,Many e-QTLs have dynamic effects during differentiation.,
-,No,20190722,circulating,31234922,Comprehensive DNA methylation analysis of tissue of origin of plasma cell-free DNA by methylated CpG tandem amplification and sequencing (MCTA-Seq).,Clin Epigenetics,Use DNA methylation patterns of circulating DNA to identify tissue-of-origin. ,
-,No,20190722,methods,31318318,Methodological challenges in constructing DNA methylation risk scores.,Epigenetics,Mainly considers additional complications of methylation over genetic risk scores.,
-,Yes,20190722,ewas,31303497,"Tobacco smoking induces changes in true DNA methylation, hydroxymethylation and gene expression in bronchoalveolar lavage cells.",EBioMedicine,"""We identified 1667 total 5mC?+?5hmC, 1756 5mC and 67 5hmC differentially methylated positions (DMPs) between smokers and non-smokers (FDR-adjusted P <.05, absolute ?? >0.15)."" Most were novel for smoking differences.  Directions of 5mC and 5hmC differences indicated that smoking demethylated DNA via conversion to 5hmC.",
-,No,20190729,registration,31307412,A randomized controlled trial for overweight and obesity in preschoolers: the More and Less Europe study - an intervention within the STOP project.,BMC Public Health,"""A two-arm, parallel design randomized controlled trial in 300 2-to 6-year-old children with overweight and obesity ... children are randomized into the intervention or control group ... The intervention, the ML program, consists of 10-weekly group sessions which focus on evidence-based parenting practices, followed by the previously validated MINISTOP application for 6-months to support healthy eating and physical activity behaviors ..."" Outcomes considered after 9 months, including DNA methylation.",
-,No,20190729,cell types,31324783,Genetic mapping of cell type specificity for complex traits.,Nat Commun,"""...43 publicly available scRNA-seq datasets. We propose a 3-step workflow with conditional analyses within and between datasets, circumventing batch effects, to uncover associations of traits with cell types. Applying this method to 26 traits ...""",
-,No,20190729,methods,31300005,CONFINED: distinguishing biological from technical sources of variation by leveraging multiple methylation datasets.,Genome Biol,"""a reference-free method based on sparse canonical correlation analysis to separate the biological from technical sources of variability""",
-,Yes,20190729,ewas,31320639,Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936.,Nat Commun,"""genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n?=?750 healthy older adults). We identify 41 independent genetic loci for 33 proteins and 26 CpG sites for 9 proteins ... we also observe causal relationships between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels.""",
-,No,20190729,dnam age,31322503,"Optimism is not associated with two indicators of DNA methylation aging.
+No,20190708,dnam age,30785999,"Epigenetic Age Acceleration in Adolescence Associates With BMI, Inflammation, and Risk Score for Middle Age Cardiovascular Disease.",J Clin Endocrinol Metab,"n=995; age =17.3 ± 0.6 years; EEAA (per 5 years) was associated with increased body mass index (BMI) of 2.4% at 17 and 22 years, increases of 23% in high-sensitivity C-reactive protein, 10% in interferon-?-inducible protein of 10 kDa, 4% in soluble TNF receptor 2, 3% increase in hard endpoints of CVD by 47 years of age after adjustment for conventional risk factors.",
+Yes,20190708,ewas,31220268,Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue.,Hum Mol Genet,"prefrontal cortex, temporal cortex and cerebellum from 43 ASD patients and 38 controls. ""We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB""",
+No,20190708,review,31046576,Epigenetic changes in healthy human skeletal muscle following exercise- a systematic review.,Epigenetics,"22 studies ""examined epigenetic modifications (DNA methylation, histone modifications and non-coding RNAs) in skeletal muscle, following either an acute bout of exercise, an exercise intervention in a pre/post design, or a case/control type of study."" Associations identified but role uncertain.",
+No,20190708,methods,31114869,MEXPRESS update 2019.,Nucleic Acids Res,"""MEXPRESS (https://mexpress.be). It contains the latest TCGA data, additional types of omics and clinical data and extra functionality, allowing users to explore mechanisms of gene dysregulation beyond expression and DNA methylation.""",
+No,20190715,methods,31221194,Essential guidelines for computational method benchmarking.,Genome Biol,Essential guidelines for computational method benchmarking.,
+No,20190715,review,31284823,DNA hypermethylation in disease: mechanisms and clinical relevance.,Epigenetics,,
+No,20190715,review,31284662,Telomerase Reverse Transcriptase (TERT) in Action: Cross-Talking with Epigenetics.,Int J Mol Sci,,
+Yes,20190715,ewas,31282290,Epigenome-wide association study of DNA methylation and microRNA expression highlights novel pathways for human complex traits.,Epigenetics,"""We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (cis-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at r2<0.2. cis-miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 cis-miR-eQTM-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely.""",
+No,20190715,ewas,31279243,Genome-wide DNA methylomic differences between dorsolateral prefrontal and temporal pole cortices of bipolar disorder.,J Psychiatr Res,"""20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850?K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups.""",
+No,20190715,dnam age,31277270,Smoking-Related DNA Methylation is Associated with DNA Methylation Phenotypic Age Acceleration: The Veterans Affairs Normative Aging Study.,Int J Environ Res Public Health,n=692,
+Yes,20190715,ewas,31266983,Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal key epigenetic differences at developmental genes.,Sci Rep,""" we characterised transcriptomes and methylomes of isolated adipocytes from matched SA and VA tissues of individuals with normal BMI to identify epigenetic differences and their contribution to cell type and depot-specific function.""",
+Yes,20190715,ewas,31262328,DNA methylation links prenatal smoking exposure to later life health outcomes in offspring.,Clin Epigenetics,"""We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48?years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring ... 69 differentially methylated CpGs ... Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia.""",
+No,20190715,ewas,31260916,Association between long-term air pollution exposure and DNA methylation: The REGICOR study.,Environ Res,"""A two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. ... NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured ...  Neither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated.""",
+No,20190715,mr,31257439,An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility.,Int J Epidemiol,"""we identified 412 CpG sites where DNA methylation was associated with prenatal smoking. We then applied 2SMR to investigate potential downstream effects of these putative changes on 643 complex traits ... We identified 22 associations that survived multiple testing""",
+Yes,20190715,ewas,31300640,The nasal methylome as a biomarker of asthma and airway inflammation in children.,Nat Commun,"""we collect nasal swabs from the anterior nares of 547 children (mean-age 12.9?y)  ... We perform nasal Epigenome-Wide Association analyses (EWAS) of current asthma, allergen sensitization, allergic rhinitis, fractional exhaled nitric oxide (FeNO) and lung function. We find ... asthma (285-CpGs), FeNO (8,372-CpGs; 191-DMRs), total IgE (3-CpGs; 3-DMRs), environment IgE (17-CpGs; 4-DMRs), allergic asthma (1,235-CpGs; 7-DMRs) and bronchodilator response (130-CpGs).""",
+No,20190715,candidate,31300453,DNA Methylation Markers for Breast Cancer Detection in the Developing World.,Clin Cancer Res,"""Two case-control studies were conducted comparing cancer and benign breast tissue identified from clinical repositories in the U.S., China, and South Africa for marker selection/training (N=226) and testing (N=246). Twenty-five methylated markers were assayed ... In the independent test cohort, this panel yielded an AUC of 0.937 (95% CI = 0.900-0.970)""",
+No,20190715,methods,31297508,MEpurity: estimating tumor purity using DNA methylation data.,Bioinformatics,"""a beta mixture model-based algorithm, to estimate the tumor purity based on tumor-only Illumina Infinium 450k methylation microarray data""",
+No,20190715,global,31291495,Early life social and ecological determinants of global DNA methylation in wild spotted hyenas.,Mol Ecol,"""maternal rank [2.75%], anthropogenic disturbance, and prey availability early in life are associated with later life global DNA methylation""",
+No,20190715,methods,31291459,coMethDMR: accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies with continuous phenotypes.,Nucleic Acids Res,"""a flexible, powerful, and accurate tool for identifying DMRs. Instead of testing all CpGs within a genomic region, coMethDMR carries out an additional step that selects co-methylated sub-regions first. Next, coMethDMR tests association between methylation levels within the sub-region and phenotype via a random coefficient mixed effects model that models both variations between CpG sites within the region and differential methylation simultaneously""",
+Yes,20190715,ewas,31288836,Cell type-specific epigenetic links to schizophrenia risk in the brain.,Genome Biol,"""whole-genome methylomes (N?=?95) and transcriptomes (N?=?89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls"". Identified differences at FDR < 0.2: 60 in NeuN+ and 201 in OLIG2+.",
+No,20190715,nlr,31288238,"The Prognostic Value of the Pretreatment Neutrophil/Lymphocyte Ratio in Patients with Glioblastoma Multiforme Brain Tumors: A Retrospective Cohort Study of Patients Treated with Combined Modality Surgery, Radiation Therapy, and Temozolomide Chemotherapy.",Oncology,"n=89; ""pretreatment NLR was not prognostic""",
+No,20190722,dnam age,31211779,"Associations of genetics, behaviors, and life course circumstances with a novel aging and healthspan measure: Evidence from the Health and Retirement Study.",PLoS Med,"""Based on data from 2,339 adults (aged 51+ years, mean age 69.4 years, 56% female, and 93.9% non-Hispanic white) from the US Health and Retirement Study … genetic, behavioral, and socioenvironmental circumstances during childhood and adulthood account for about 30% of differences in"" PhenoAge variation. ""behaviors had the largest contribution to PhenoAge"".",
+No,20190722,review,31249003,A periodic table of cell types.,Development,A framework for distinguishing between cell type and cell state in single-cell RNA-seq.,
+No,20190722,review,31225507,Constitutional Mosaic Epimutations - a hidden cause of cancer?,Cell Stress,Mosaic methylation of genes linked genetically to cancer risk may cause cancer and be useful as biomarkers.,
+No,20190722,methods,31308366,Detection of cell-type-specific risk-CpG sites in epigenome-wide association studies.,Nat Commun,A method for improving power of EWAS in complex tissues and actually to identify cell-type specific associations in complex tissues.,
+No,20190722,review,31249591,Inferring Interaction Networks From Multi-Omics Data.,Front Genet,"""we review state-of-the-art techniques for inferring the topology of interaction networks from functional multi-omics data""",
+No,20190722,epigenetics,31234833,RNA-Seq in 296 phased trios provides a high-resolution map of genomic imprinting.,BMC Biol,"""7 [new] transcripts showing parental bias in gene expression""",
+No,20190722,somatic mutations,31300647,Brain somatic mutations observed in Alzheimer's disease associated with aging and dysregulation of tau phosphorylation.,Nat Commun,"""deep whole-exome sequencing (average read depth 584×) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD."" The amount of genetic variation increases with age in the brain but at 4.8-fold slower rate than in blood.  There is enrichment for variation accumulating near genes ""known to contribute to hyperphosphorylation of tau"".",
+No,20190722,methods,31233496,Solving the missing heritability problem.,PLoS Genet,A letter describing challenges of expanding analyses to the whole genome and suggesting solutions.,
+No,20190722,gene regulation,31249060,Dynamic genetic regulation of gene expression during cellular differentiation.,Science,Many e-QTLs have dynamic effects during differentiation.,
+No,20190722,circulating,31234922,Comprehensive DNA methylation analysis of tissue of origin of plasma cell-free DNA by methylated CpG tandem amplification and sequencing (MCTA-Seq).,Clin Epigenetics,Use DNA methylation patterns of circulating DNA to identify tissue-of-origin. ,
+No,20190722,methods,31318318,Methodological challenges in constructing DNA methylation risk scores.,Epigenetics,Mainly considers additional complications of methylation over genetic risk scores.,
+Yes,20190722,ewas,31303497,"Tobacco smoking induces changes in true DNA methylation, hydroxymethylation and gene expression in bronchoalveolar lavage cells.",EBioMedicine,"""We identified 1667 total 5mC?+?5hmC, 1756 5mC and 67 5hmC differentially methylated positions (DMPs) between smokers and non-smokers (FDR-adjusted P <.05, absolute ?? >0.15)."" Most were novel for smoking differences.  Directions of 5mC and 5hmC differences indicated that smoking demethylated DNA via conversion to 5hmC.",
+No,20190729,registration,31307412,A randomized controlled trial for overweight and obesity in preschoolers: the More and Less Europe study - an intervention within the STOP project.,BMC Public Health,"""A two-arm, parallel design randomized controlled trial in 300 2-to 6-year-old children with overweight and obesity ... children are randomized into the intervention or control group ... The intervention, the ML program, consists of 10-weekly group sessions which focus on evidence-based parenting practices, followed by the previously validated MINISTOP application for 6-months to support healthy eating and physical activity behaviors ..."" Outcomes considered after 9 months, including DNA methylation.",
+No,20190729,cell types,31324783,Genetic mapping of cell type specificity for complex traits.,Nat Commun,"""...43 publicly available scRNA-seq datasets. We propose a 3-step workflow with conditional analyses within and between datasets, circumventing batch effects, to uncover associations of traits with cell types. Applying this method to 26 traits ...""",
+No,20190729,methods,31300005,CONFINED: distinguishing biological from technical sources of variation by leveraging multiple methylation datasets.,Genome Biol,"""a reference-free method based on sparse canonical correlation analysis to separate the biological from technical sources of variability""",
+Yes,20190729,ewas,31320639,Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936.,Nat Commun,"""genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n?=?750 healthy older adults). We identify 41 independent genetic loci for 33 proteins and 26 CpG sites for 9 proteins ... we also observe causal relationships between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels.""",
+No,20190729,dnam age,31322503,"Optimism is not associated with two indicators of DNA methylation aging.
 ",Aging (Albany NY),"""Data were from the Women's Health Initiative (WHI) (N=3,298) and the Veterans Affairs Normative Aging Study (NAS) (N=514), and included dispositional and explanatory style optimism measures. We evaluated ... two DNA methylation algorithms, intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA)""",
-,Yes,20190729,ewas,31324826,"Distinct epigenetic profiles in children with perinatally-acquired HIV on antiretroviral therapy.
+Yes,20190729,ewas,31324826,"Distinct epigenetic profiles in children with perinatally-acquired HIV on antiretroviral therapy.
 ",Sci Rep,"""DNA methylation profiles in whole blood from 120 HIV-infected children on antiretroviral therapy (ART) and 60 frequency age-matched HIV-uninfected children aged 4-9 years in Johannesburg, South Africa ... 1,309 differentially-methylated (DM) CpG sites""",
-,No,20190729,plasma,31332191,Methylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases.,Nat Commun,The fractional concentration and size of EBV DNA from blood plasma can be used to identify individuals with nasopharyngeal carcinoma. This paper shows that the performance of this approach can be significantly improved by additionally considering DNA methylation patterns in EBV DNA (positive predictive value increased by 35.1%).,
-,No,20190729,cohort,31342890,TwinLIFE: The Twin Longitudinal Investigation of FEtal Discordance,Twin Res Hum Genet,"""we will chart intrapair differences in DNA methylation focusing on mesenchymal stromal cells isolated from cord ... Next, we will follow up the MC twins for growth, cardiovascular and neurodevelopmental outcomes during childhood ... The current target is to include 100 MC twin pairs""",
-,Yes,20190729,ewas,29934819,Gene expression and DNA methylation are extensively coordinated with MRI-based brain microstructural characteristics.,Brain Imaging Behav,"""We utilize postmortem neuroimaging in tandem with gene expression and DNA methylation, from 222 deeply-phenotyped persons in a longitudinal aging cohort. Expression of hundreds of genes and methylation at thousands of loci are related to the microstructure of extensive regions of this same set of brains, as assessed by MRI. """,
-,No,20190805,ewas,31195163,DNA methylation from germline cells in veterans with PTSD.,J Psychiatr Res,"In 299 ""trauma-exposed Vietnam veterans ... 3 CpG sites associated with PTSD [19 vs 19] in sperm"".  They also tested associations in peripheral blood [48 vs 48] but none were genome-wide significant and the overlap with sperm was small (using nominal p < 0.05). ",
-,No,20190805,methods,31368477,PyMethylProcess - convenient high-throughput preprocessing workflow for DNA methylation data.,Bioinformatics,Python program that combines multiple R packages together to allow analysis of Illumina methylation bead chips (includes for example minfi and meffil).  Purpose is to make DNA methylation datasets available for Python visualization and machine learning tools.,
-,No,20190805,methods,31366909,Cell-type-specific resolution epigenetics without the need for cell sorting or single-cell biology.,Nat Commun,"Similarly to 31308366, a method to identify cell-type specific associations in complex tissues. ""Tensor Composition Analysis (TCA) ... emulates the scenario in which each individual in the bulk data has been profiled with a single-cell resolution and then signals were aggregated in each cell population of the individual separately.""",
-,No,20190805,ewas,31350827,Differentially methylated regions in bipolar disorder and suicide.,Am J Med Genet B Neuropsychiatr Genet,"""Using the SureSelectXT system, Methyl-Seq, we investigated the DNA methylation status of CpG sites throughout the genome [of prefrontal cortex] in 50 BD individuals (23 subjects who died by suicide and 27 subjects who died from other causes) and 31 nonpsychiatric controls ... One DMR from the BDS-NC analysis, located in ARHGEF38, was significantly hypomethylated (23.4%) in BDS subjects.""",
-,Yes,20190805,ewas,31349361,Can social support during pregnancy affect maternal DNA methylation? Findings from a cohort of African-Americans.,Pediatr Res,"n=250, blood collected after delivery, a few associations with lack of support from the baby's father and from family and friends",
-,No,20190805,ewas,31331382,A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers.,Clin Epigenetics,"18 current smokers and 21 never smokers; EPIC and RNA-seq. Nine CpGs associated with smoking status including CYP1B1, AHRR. 61 CpG sites associated with quantity of smoking including CYP1B1. Increased expression of CYP1B1  and 13 other transcripts in smokers. Six transcripts were downregulated. No differential expression was observed for AHRR. ",
-,Yes,20190805,ewas,31346403,Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits.,Mol Autism,"In 708 children, no associations observed with autism or autism traits or concordance between the two in cord blood DNA methylation.  However, a concordance was observed with autism EWAS in brain.",
-,No,20190805,mechanism,31269015,Cross-species functional modules link proteostasis to human normal aging.,PLoS Comput Biol,"""we integrate evolutionary and functional information of normal aging across human and model organisms at three levels: gene-level, process-level, and network-level. We identify evolutionarily conserved modules of normal aging across diverse taxa, and notably show proteostasis to be conserved in normal aging. Additionally, we find that mechanisms related to protein quality control network are enriched for genes harboring genetic variants associated with 22 age-related human traits and associated to caloric restriction.""",
-,Yes,20190812,ewas,31333715,Gut Microbiota Composition Is Associated With the Global DNA Methylation Pattern in Obesity.,Front Genet,"""Twenty patients were selected based on their Bacteroidetes-to-Firmicutes ratio (BFR): HighBFR group (BFR > 2.5, n = 10) and LowBFR group (BFR < 1.2, n = 10). Genome-wide analysis of DNA methylation pattern in both whole blood and visceral adipose tissue of these selected patients was performed ... ",
-,No,20190812,gene regulation,31375681,Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding.,Nat Commun,Use CRISPR-Cas9 to omit a binding site and show resulting reduced TF binding and changes gene expression and chromatin.,
-,Yes,20190812,ewas,31367216,Epigenome-wide association study of asthma and wheeze characterizes loci within HK1.,Allergy Asthma Clin Immunol,"""10 CpG sites associated with adolescent asthma"" in n=370 and of which 5 replicated in ALSPAC (age 17).  Gene expression of one linked gene was predictive of wheezing in infancy in cord blood.",
-,No,20190812,ewas,31393794,Customized MethylC-Capture Sequencing to Evaluate Variation in the Human Sperm DNA Methylome Representative of Altered Folate Metabolism.,Environ Health Perspect,Performed WGBS on sperm and found 1 million CpG sites with intermediate levels of methylation ('dynamic sperm CpGs) and investigated a panel of CpG sites (3 million) in sperm of 30 men and observed effects of MTHFR genotype and folate supplementation.,
-,No,20190812,review,31393092,Evaluation of the usefulness of saliva for DNA methylation analysis in cohort studies.,Neuropsychopharmacol Rep,Found that number of CpG sites with population variation in saliva similar to blood and therefore potentially as useful as blood for EWAS.,
-,No,20190812,dnam age,31387022,"Air pollution, particulate matter composition and methylation-based biologic age.",Environ Int,"n?=?2747 women;  estimated residential exposure to PM2.5, PM10 and NO2; Hannum, Horvath and Levine epigenetic clocks; NO2 associated with Hannum; age acceleration varied by PM2.5 component cluster.",
-,Yes,20190812,ewas,31386212,Epigenome-wide DNA Methylation Association Analysis Identified Novel Loci in Peripheral Cells for Alcohol Consumption among European American Male Veterans.,Alcohol Clin Exp Res,n=1135; AUDIT-Consumption; 70 CpG site associations in the EPIC array; 6 previously reported,
-,No,20190812,methods,31384045,Joint profiling of DNA methylation and chromatin architecture in single cells.,Nat Methods,"Methyl-HiC, that can simultaneously capture the chromosome conformation and DNA methylome in a cell. ",
-,No,20190812,dnam age,31379754,"Interaction Among Sex, Aging, and Epigenetic Processes Concerning Visceral Fat, Insulin Resistance, and Dyslipidaemia.",Front Endocrinol (Lausanne),"""Two different study samples of 366 and 269 adult participants were analyzed. Anthropometric, biochemical (including the triglycerides-glucose (TyG) index), and blood pressure measurements were assessed following standardized methods. Body composition measurements by Dual-energy X-ray absorptiometry (DXA) were also performed for the second sample. Methylation data were assessed by Infinium Human Methylation BeadChip (Illumina) in peripheral white blood cells."" Methylation profiles were used to generate various estimates of DNAm age ... ""these findings showed that there are different mechanisms affecting epigenetic age acceleration depending on sex.""",
-,No,20190812,dnam age,31375641,Environmental exposure to polybrominated biphenyl (PBB) associates with an increased rate of biological aging.,Aging (Albany NY),"population highly exposed to PBB (N=658) ""Higher PBB levels associated with increased age acceleration (intrinsic: ?=0.24, 95%CI=0.01-0.46, p = 0.03; extrinsic: ?=0.39, 95%CI=0.12-0.65, p = 0.004; and phenotypic: ?=0.30, 95%CI=0.05-0.54, p = 0.01).""",
-,No,20190812,review,31369552,"Human placental methylome in the interplay of adverse placental health, environmental exposure, and pregnancy outcome.",PLoS Genet,"""In this review, we cover recent advances in DNA methylation in the context of placental function and development, as well as the interaction between the pregnancy and the environment.""",
-,No,20190812,methods,31356589,The impact of DNA methylation on the cancer proteome.,PLoS Comput Biol,"""refines nominations for epigenetic driver genes by leveraging quantitative high-throughput proteomic data to select only genes where DNA methylation is predictive of protein abundance.""  Would be interesting to know how protein-methylation associations in cancer differ from those in blood.",
-,No,20190812,dnam age,31395791,Sex differences in the associations of placental epigenetic aging with fetal growth.,Aging (Albany NY),"""PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks."" n=152 males, n=149 females.",
-,No,20190910,ewas,30694562,Genome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures,Int J Cancer,"""436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study"" NULL",
-,Yes,20190909,ewas,31481539, Differences in genome-wide DNA methylation profiles in breast milk by race and lactation duration,Cancer Prev Res (Phila),"""Breast milk samples ... from ... U.S. black (n=57) and white (n=82) women, ages 19 to 44"".  284 race differences, 227 CpG sites associated with lactation duration, negatively associated with lactation time.",
-,Yes,20190909,ewas,31477727, Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood,Nat Commun,"149 neonatal and 158 adult  ART-conceived and 58 neonatal and 75 adult controls (neonatal Guthrie cards, adults 22-35). 2340 DMPs, 136 with >5% DNAm difference, 6 of these had >5% DNAm difference in adulthood.",
-,No,20190909,ewas,31477685, Genome-wide profiling of DNA methylome and transcriptome in peripheral blood monocytes for major depression: A Monozygotic Discordant Twin Study,Transl Psychiatry,"RNA-seq and EPIC methylation in peripheral blood monocytes for 79 adult monozygotic twin pairs discordant for major depressive disorder, 39 DMRs (DMRcate with ad hoc criteria) and 30 DEGs",
-,Yes,20190909,ewas,31477683, Epigenome-wide association study of depression symptomatology in elderly monozygotic twins,Transl Psychiatry,"blood for 724 monozygotic Danish twins, 2 CpG sites associated with depression symptomology score",
-,No,20190909,ewas,31195163, DNA methylation from germline cells in veterans with PTSD,J Psychiatr Res,"38 semen samples (16 with PTSD, 22 controls), 3 DMPs, some evidence that nominally associated sites enriched for PTSD and mental health associations in blood",
-,No,20190909,candidate,31452782, Tumor-induced DNA methylation in the white blood cells of patients with colorectal cancer,Oncol Lett,"Throught a complex procedure, PLOD1 and MMP9 chosen to differentiate between cancer (32) and controls (59). MMP9 methylation in white blood cells differentiated with high sensitivity (90.63%) and high specificity (96.49%) and a positive predictive value of 93.33% and a negative predictive value of 93.22%.",
-,No,20190909,candidate,31464656, Duration of breastfeeding is associated with leptin (LEP) DNA methylation profiles and BMI in 10-year-old children,Clin Epigenetics,"""In the Isle of Wight Birth Cohort, peripheral blood DNAm at 23 cytosine-phosphate-guanine sites (CpGs) in the LEP locus in 10-year-old (n = 297) samples and 16 CpGs in 18-year-old (n = 305) samples, were generated using the Illumina Infinium MethylationEPIC and HumanMethylation450 Beadchips respectively ... Both total and exclusive breastfeeding duration were associated with DNAm at four LEP CpG sites at 10 years (P value < 0.05), and not at 18 years.""",
-,No,20190909,dnam age,31466081, Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2,Neuropsychopharmacology,"331 AUD and 201 HC; Hannum, Horvath and Phenoage DNAm clocks; GWAS of Phenoage in 154 European and 156 African individuals with AUD; Phenoage was accelerated 2.22 years higher in AUD than controls (p?=?1.85E-5); APOL2 the only GWAS finding",
-,No,20190909,methods,31455416, Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data,Clin Epigenetics,Found improved cell count estimates by: (1) filtering out 'unpure' references samples and combining what remained for the four available references to obtain a single reference and (2) selecting CpG sites for estimating cell counts using the IDOL iterative algorithm (rather than the procedure implemented in minfi). Replicated result in Generation R.,
-,Yes,20190909,ewas,31461406, Epigenome-wide association study of leukocyte telomere length,Aging (Albany NY),"""EWAS of leukocyte telomere length using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins."" 823 CpG site associations.",
-,Yes,20190909,ewas,31451752, An epigenome-wide analysis of cord blood DNA methylation reveals sex-specific effect of exposure to bisphenol A,Sci Rep,"bisphenol A concentrations and methylation in cord blood (n=277); 27 and 16 CpG sites with FDR < 0.05 in males and females, respectively. Evidence for sex-specificity evaluated by show the two sets of sites had distinct functional properties/enrichments.",
-,Yes,20190909,ewas,31450665, Epigenome-Wide Association Analysis of Differentially Methylated Signals in Blood Samples of Patients with Non-Small-Cell Lung Cancer,J Clin Med,"peripheral blood for 150 cases vs 150 controls, no differences except in sub-analysis of smokers -- 2 DMPs.",
-,No,20190909,methods,31443682, Statistical predictions with glmnet,Clin Epigenetics,"""We provide guidelines on how to obtain parsimonious models with low mean squared error and include easy to follow walk-through examples for each step in R.""  Mainly how to pick the best 'alpha' parameter - how much to weight the l1 and l2 norm penalties.",
-,Yes,20190909,ewas,31424985, Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease,Circulation,"11,461 free of CHD, 1895 developed CHD over next 11 years, 52 DMPs at baseline",
-,No,20190909,database,31428785, CFEA: a cell-free epigenome atlas in human diseases,Nucleic Acids Res,"epigenetic profiles: 5mC, 5hmC and NP (nucleosome positioning); 27 human diseases",
-,Yes,20190909,ewas,31426852, Novel age-associated DNA methylation changes and epigenetic age acceleration in middle-aged African Americans and whites,Clin Epigenetics,"n=487; 4930 age-associated sites in Africans, 469 in 'whites'; Africans had lower extrinsic DNAm acceleration; African women the lowest.",
-,No,20190909,ewas,31453433, DNA Methylation Trajectories During Pregnancy,Epigenet Insights,"blood collected before (~1.6 years), during (any time) and after pregnancy (4 days) (n=21); 196 CpG sites with intra-individual change, mostly decreasing methylation",
-,Yes,20190909,ewas,31404209,Acetaminophen use during pregnancy and DNA methylation in the placenta of the extremely low gestational age newborn (ELGAN) cohort.,Environ Epigenet,acetominophen use during pregnancy prior to weak 28 in n=286 placentas; 42 DMPs; some weak evidence of sex-specific associations,
-,No,20190909,dnam age,31443728,Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing.,Genome Med,"Build age predictors in DNAm from 13,661 blood samples and 259 saliva samples; show that prediction will be perfect with large enough training sample; association of DNAm age acceleration decreases as age prediction accuracy increases",
-,No,20190909,methods,31399127,Accurate ethnicity prediction from placental DNA methylation data.,Epigenetics Chromatin,"""Data from 509 placental samples were used to develop PlaNET and show that it accurately predicts (accuracy = 0.938, kappa = 0.823) major classes of self-reported ethnicity/race (African: n = 58, Asian: n = 53, Caucasian: n = 389)""",
-,No,20190909,database,31462275,A unified encyclopedia of human functional DNA elements through fully automated annotation of 164 human cell types.,Genome Biol,"""we present annotations of 164 human cell types using 1615 data sets."" From these, ""we developed a measure of the importance of each genomic position ... and combined all annotations into a single, cell type-agnostic encyclopedia that catalogs all human regulatory elements.""",
-,Yes,20190916,ewas,31510868,Body Mass Index Drives Changes in DNA Methylation: A Longitudinal Study.,Circ Res,n=995 White and n=490 Black from the Bogalusa Heart Study; DNAm and BMI measured 6.2 years apart in 439 white and 201 Black; replication in 252 White and 228 Black from the Georgia Stress and Heart Study; 349 CpG sites (266 novel) in Whites and 36 (21 novel) in Blacks with replicated associated with BMI; 8 sites in common; cross-lagged panel analyses identified paths from BMI to DNAm but not the opposite.,
-,Yes,20190916,ewas,31509016,Socioeconomic status and DNA methylation from birth through mid-childhood: a prospective study in Project Viva.,Epigenomics,"DNAm for 609 children at birth (cord), age 3 and age 7 (peripheral blood) in Project VIVA. Differences were tested between the top and bottom 10% of SES. 4 differences observed in cord and 1 persisted beyond birth.  (Details should be confirmed as I was not able to obtain a copy of the paper).",
-,Yes,20190916,ewas,31506343,Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.,Diabetes,"Case-control study of T2DM, DNAm measured in blood collected 'before onset'.  18 differentially methylated CpG sites, 3 observed previously. 16 had meQTLs, one indicated a causal role for DNAm.",
-,Yes,20190916,ewas,31506065,The effect of age on DNA methylation in whole blood among Bangladeshi men and women,BMC Genomics,blood for 400 adult participants (189 males and 211 females) from Bangladesh; age range 25-70; 986 CpG sites associated with age among men and 3479 among women; over 60% replicated; resulting age predictor had R=0.8 correlation with chronological age,
-,No,20190916,methods,31504104,Methods for Dealing With Missing Covariate Data in Epigenome-Wide Association Studies.,Am J Epidemiol,,
-,No,20190916,review,31501771,The NIH Common Fund/Roadmap Epigenomics Program: Successes of a comprehensive consortium.,Sci Adv,"""Here we comment on the outcomes from this program: the scientific contributions made possible by a consortium approach and the challenges, benefits, and lessons learned from this group science effort."" ",
-,Yes,20190916,ewas,31501512,A methylation study of long-term depression risk.,Mol Psychiatry,"""blood DNA methylation profiles (MBD-seq) from 581 MDD patients at baseline with MDD status 6 years later""; ""A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P?=?2.0?×?10-16).""  DNA methylation risk score had AUC=0.724, better than genetic or clinical predictors.",
-,Yes,20190916,ewas,31497855,Placental DNA Methylation Mediates the Association of Prenatal Maternal Smoking on Birth Weight.,Am J Epidemiol,n=441 placentas; 71 CpG sites associated with prenatal smoking; 7 found to mediate effect (50-87% of 175g effect),
-,No,20190916,dnam score,31494793,Validated inference of smoking habits from blood with a finite DNA methylation marker set.,Eur J Epidemiol,"""Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N?=?3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901.""  AUC=0.7 for former, 0.78 for never, 0.8 for >10 pack-years.  Children age 6 found to be non-smokers even with prenatal smoking exposure. ",
-,No,20190916,mechanism,31485078,The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.,Nature,"""NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions.""",
-,No,20190916,ewas,31477183,Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer's disease,Clin Epigenetics,23 disease discordant twin pairs; blood methylation profiles obtained from blood; 11 genomic regions with >15% methylation difference; follow-up analysis in 120 twin pairs indicates that one region selected for replication was caused by the disease state.,
-,No,20190916,methods,31484546,TOAST: improving reference-free cell composition estimation by cross-cell type differential analysis.,Genome Biol,Reference-free methods highly dependent on the set of CpG sites selected to estimate cell counts. Most methods essentially end up selecting the most variable sites. The authors show that by iteratively applying the reference-free method and then using the output to identify cell-type discordant CpG sites which are then fed into the next application of the reference-free method improves the final result.,
-,Yes,20190923,ewas,31536415,Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking.,Epigenomics,"""We separately meta-analyzed newborn blood DNA methylation, in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers) ... we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways""",
-,No,20190923,ewas,31536135,In utero bisphenol A exposure is linked with sex specific changes in the transcriptome and methylome of human amniocytes.,J Clin Endocrinol Metab,"19 controls, 16 exposed;  RNA-seq, RRBS for DNAm profiling, Hi-C; exposure and DNAm measured in amnyotic fluid; 36 DMRs in males, 14 in females, 101 DE genes in males, 1 in females, Hi-C identified interactions between 24 DE genes and DMRs in males and 12 DE genes and DMRs in females.",
-,Yes,20190923,ewas,31530476,Age-related changes in DNA methylation affect renal histology and post-transplant fibrosis.,Kidney Int,"""we profiled genome-wide changes in DNA methylation (over 800 000 CpG sites) in 95 renal biopsies obtained prior to kidney transplantation from donors aged 16 to 73 years. Donor age significantly associated with the methylation of 92 778 CpGs ... age-associated changes in DNA methylation at the time of transplantation predict future injury of transplanted kidneys""",
-,No,20190923,ewas,31513634,Genome-wide analysis of DNA methylation profile identifies differentially methylated loci associated with human intervertebral disc degeneration.,Genome Biol,"DNA methylation profiles of human intervertebral disc tissues, specifically nucleus pulpous (NP) tissues, with early (n=8) and advanced stages of disc degeneration (n=8). 220 DMPs enriched in cell-cell adhesion.",
-,No,20190923,ewas,31506096,Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation.,Clin Epigenetics,"""The study compared three 12-week interventions to (1) simultaneously increase exercise and fruit/vegetable intake, while decreasing sedentary leisure screen time; (2) sequentially increase fruit/vegetable intake and decrease leisure screen time first, then increase exercise; (3) increase sleep and decrease stress (control). We collected blood samples at baseline, 3 and 9 months, and measured DNA methylation using the Illumina EPIC (850?k) BeadChip."" In 68 individuals, DNAm was not different between controls (n=12) and pooled intervention groups (simultaneous n=25; sequential n=21) but did observe 154 DMRs at 3 months and 298 at 9 months (using DMRcate). Only 1 DMR appeared at both times.",
-,No,20190923,methods,31501549,Simultaneous profiling of 3D genome structure and DNA methylation in single human cells.,Nat Methods,Describe 'methyl-3C' sequencing in order to generate 3D structure and DNAm simultaneously.  Use to show differences between 14 different cortical cell types.,
-,No,20190923,ewas,31439477,Fasting unmasks differential fat and muscle transcriptional regulation of metabolic gene sets in low versus normal birth weight men.,EBioMedicine,Gene expression and DNAm measured in subcutaneous fat and skeletal muscle men before and after 36h of fasting.  Genes in oxidative phosphorylation were lower in low birth weight men before fasting and higher after fasting.  DNAm changes were not observed (n=8 low birth weight; n=8 normal birth weight).,
-,No,20190923,cohort,31467051,The Uppsala-Stockholm Assisted Reproductive Techniques (UppStART) study.,BMJ Open,"In case someone is interested ART: ""The cohort includes 971 participants (n= 514 women; n= 457 men), and 129 pregnancies were achieved from the first IVF cycle included in the study."" Biological samples will be collected.",
-,No,20190923,gene regulation,31514731,The first enhancer in an enhancer chain safeguards subsequent enhancer-promoter contacts from a distance.,Genome Biol ,"""Using Hi-C data in multiple cell lines, we report a comprehensive map of promoters and active enhancers connected by chromatin contacts, spanning 9000 enhancer chains in 4 human cell lines associated with 2600 human genes.  We find that ... the primary, critical enhancer is distal, commonly located further away than other enhancers. This first, distal enhancer establishes contacts with multiple regulatory elements and safeguards a complex regulatory program of its target gene.""",
-,No,20190923,methods,31510704,Weighted elastic net for unsupervised domain adaptation with application to age prediction from DNA methylation data.,Bioinformatics,"DNAm models derived in one dataset, often fail to perform well in other datasets due to technical or even biological differences, e.g. a model of age may be applied in a new tissue or to samples from individuals from a different age range. Robustness can be improved by weighting the contribution of CpG sites to an elastic net model by how well its dependencies on other CpG sites agrees between training and testing datasets. As evidence of this, weighted elastic net generates improved models of age in cerebellum when cerebellum is not included in the training dataset.",
-,No,20190923,ase,31455884,Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage.,Nat Neurosci ,"""When ASE is observed in ASD, the allele with lower population frequency (minor allele) is preferentially more highly expressed than the major allele, opposite to the canonical pattern. Importantly, genes showing ASE in ASD are enriched in those downregulated in ASD postmortem brains and in genes harboring de novo mutations in ASD.""",
-,No,20190930,ewas,31542994,Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes.,Epigenetics,"This study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling. Genome wide EPIC methylation and expression levels of candidate miRNAs measured in 60 HD, 33 controls. Independent cohort of 107 alcohol depednent subjects. Two CpG-sites for HD - cg18222192 (MIR708) and cg01299774 (MIR4456). Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. ",
-,No,20190930,ewas,31538540,Battle of epigenetic proportions: comparing Illumina's EPIC methylation microarrays and TruSeq targeted bisulfite sequencing.,Epigenetics,"Bisulphite sequencing becoming a cheaper alternative to microarrays. Conducted a comparison study - cord blood samples - four newborns in duplicates using both the Illumina HumanMethylationEPIC BeadChip and the Illumina TruSeq Methyl Capture EPIC Kit. Evaluated both platforms in regard to coverage, reproducibility, and identification of differential methylation. We conclude that with current analytic goals microarrays still outperform bisulphite sequencing for precise quantification of DNA methylation.",
-,No,20190930,mr,31549173,Appraising the causal relevance of DNA methylation for risk of lung cancer.,Int J Epidemiol,"DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. A large meta analysis and 2 sample MR finds that previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.",
-,No,20190930,ml,31521637,Artificial intelligence analysis of newborn leucocyte epigenomic markers for the prediction of autism.,Brain Res,EWAS of newborn leucocyte (blood spot) DNA in autism as defined at the time of sample collection. 14 autism cases and 10 controls. The accuracy of cytosine methylation for autism detection using six different Machine Learning/Artificial Intelligence (AI) approaches including Deep-Learning (DL) was determined. Our findings suggest significant epigenetic role in autism development and epigenetic markers appeared highly accurate for newborn prediction.,
-,No,20190930,review,31530287,"Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?",Clin Epigenetics,"To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks.",
-,No,20190930,epigenetics,31533842,Identification of key DNA methylation-driven genes in prostate adenocarcinoma: an integrative analysis of TCGA methylation data.,J Transl Med,"Methylated hub genes, including MAOB and RTP4, can be regarded as novel biomarkers for accurate PCa diagnosis and treatment. Further studies are needed to draw more attention to the roles of these hub genes in the occurrence and development of PCa.",
-,No,20190930,ewas,31556946,Epigenome-wide association study of narcolepsy-affected lateral hypothalamic brain and overlapping DNA methylation profiles between narcolepsy and multiple sclerosis,Sleep,"Lateral hypothalamic (LH) and temporal cortex (TC) post mortem brain samples – 11 narcolepsy 15 non-narcolepsy. DMRs found located in the mylein base protein region - overlap between profiles of narcolepsy and MS, potential therapeutic targets. ?",
-,No,20191013,dnam age,31480455,Association of Obesity with DNA Methylation Age Acceleration in African American Mothers from the InterGEN Study.,Int J Mol Sci,n=232 saliva samples from African American women (average age 30); 1 kg/m^2 increase in BMI associated with 0.14 years increase in DNAm age acceleration,
-,No,20191013,methods,31484776,GeneFishing to reconstruct context specific portraits of biological processes.,PNAS,"GeneFishing uses simultation and omic data in a semisupervised approach to prioritize sets of genes.  Given a set of genes, GeneFishing identifies a more complete list of all genes with related expression patterns.  As a proof of principle, from 21 genes involved in cholesterol metabolism as bait, they identify a new gene GLO1 previously unlinked to cholesterol metabolism. However, when knocked down in a cell line, cellular cholesterol ester levels increased. ",
-,No,20191013,database,31501517,A compendium of promoter-centered long-range chromatin interactions in the human genome.,Nat Genet,Hi-C of 27 human cell/tissue types used to identify interactions between promoters and infer target genes of regulatory elements and regulatory function of 27K noncoding sequence variants.,
-,No,20191013,methods,31530853,Horizontal and vertical integrative analysis methods for mental disorders omics data.,Sci Rep,Showcase 'vertical' and 'horizontal' integretion; horizontal analysis of bipolar and schizophrenia simultaneously; vertical analysis of gene expression and copy number; sparse principal component analysis,
-,No,20191013,meqtl,31537805,Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease.,Nat Commun,n=4170 blood samples; identify 4.7M cis and 630K trans meQTLs targetting 120K CpG sites; replicated in 1347 individuals from two studies; MR performed using cis-meQTLs and GWAS of cardiovascular traits; 92 causal CpG sites; identify 22 trans-meQTL 'hotspots' targeting > 30 CpG sites; these hotspots act in cis on expression of nearby genes,
-,No,20191013,database,31551426,CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder.,Sci Data,RNA-seq and SNPs (n=980); ATAC-seq (n=269); dorsolateral prefrontal cortex; schizophrenic (n=353); bipolar disorder (n=120),
-,No,20191013,methods,31552104,"In Epigenomic Studies, Including Cell-Type Adjustments in Regression Models Can Introduce Multicollinearity, Resulting in Apparent Reversal of Direction of Association.",Front Genet,n=812 at age 17 (Western Australian Pregnancy Cohort Study); EWAS of BMI adjusted for age and sex; cell counts estimated using the Houseman algorithm; associations in the CDKN2A promoter reversed direction when adjusted for cell counts; reason: correlation high between cell counts and promoter methylation,
-,Yes,20191013,ewas,31552803,Smoking and blood DNA methylation: an epigenome-wide association study and assessment of reversibility.,Epigenetics,"n=5044; Melbourne Collaborative Cohort Study; smoking; n=1032 have blood collected 11 years later; 4496 sites associated with ever smoking; 1326 of these new; 2.75 half-life for the smoking score (i.e. in 2.75 years, half of the smoking effect has disappeared); 368 CpG sites change upon smoking cessation ",
-,No,20191013,epigenetics,31554518,Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation.,Genome Biol,Characterise neocortical DNAm across the first 20 years; most dramatic changes in the first 5 years; neighboring CpG and CpH levels are correlated; CpG and CpH levels define 6 developmental trajectories; identify gene expression effects linked only to CpH and not CpG levels.,
-,No,20191013,dnam age,31554804,Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells.,Nat Commun,"Use single-cell transcriptomes and methylomes in mouse muscle stem cells. Find evidence that 'epigenetic drift ... in promoters is associated with the degradation of coherent transcriptional networks during stem cell aging"".",
-,No,20191013,ewas,31566019,Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men.,Endocr Res,"muscle progenitor cells from 23 LBW and 15 NBW controls; 56 CpG sites differentially methylated; 14 genes differentially expressed; follow-up experimental work determined that ""Silencing of FYN and HDAC7 was
+No,20190729,plasma,31332191,Methylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases.,Nat Commun,The fractional concentration and size of EBV DNA from blood plasma can be used to identify individuals with nasopharyngeal carcinoma. This paper shows that the performance of this approach can be significantly improved by additionally considering DNA methylation patterns in EBV DNA (positive predictive value increased by 35.1%).,
+No,20190729,cohort,31342890,TwinLIFE: The Twin Longitudinal Investigation of FEtal Discordance,Twin Res Hum Genet,"""we will chart intrapair differences in DNA methylation focusing on mesenchymal stromal cells isolated from cord ... Next, we will follow up the MC twins for growth, cardiovascular and neurodevelopmental outcomes during childhood ... The current target is to include 100 MC twin pairs""",
+Yes,20190729,ewas,29934819,Gene expression and DNA methylation are extensively coordinated with MRI-based brain microstructural characteristics.,Brain Imaging Behav,"""We utilize postmortem neuroimaging in tandem with gene expression and DNA methylation, from 222 deeply-phenotyped persons in a longitudinal aging cohort. Expression of hundreds of genes and methylation at thousands of loci are related to the microstructure of extensive regions of this same set of brains, as assessed by MRI. """,
+No,20190805,ewas,31195163,DNA methylation from germline cells in veterans with PTSD.,J Psychiatr Res,"In 299 ""trauma-exposed Vietnam veterans ... 3 CpG sites associated with PTSD [19 vs 19] in sperm"".  They also tested associations in peripheral blood [48 vs 48] but none were genome-wide significant and the overlap with sperm was small (using nominal p < 0.05). ",
+No,20190805,methods,31368477,PyMethylProcess - convenient high-throughput preprocessing workflow for DNA methylation data.,Bioinformatics,Python program that combines multiple R packages together to allow analysis of Illumina methylation bead chips (includes for example minfi and meffil).  Purpose is to make DNA methylation datasets available for Python visualization and machine learning tools.,
+No,20190805,methods,31366909,Cell-type-specific resolution epigenetics without the need for cell sorting or single-cell biology.,Nat Commun,"Similarly to 31308366, a method to identify cell-type specific associations in complex tissues. ""Tensor Composition Analysis (TCA) ... emulates the scenario in which each individual in the bulk data has been profiled with a single-cell resolution and then signals were aggregated in each cell population of the individual separately.""",
+No,20190805,ewas,31350827,Differentially methylated regions in bipolar disorder and suicide.,Am J Med Genet B Neuropsychiatr Genet,"""Using the SureSelectXT system, Methyl-Seq, we investigated the DNA methylation status of CpG sites throughout the genome [of prefrontal cortex] in 50 BD individuals (23 subjects who died by suicide and 27 subjects who died from other causes) and 31 nonpsychiatric controls ... One DMR from the BDS-NC analysis, located in ARHGEF38, was significantly hypomethylated (23.4%) in BDS subjects.""",
+Yes,20190805,ewas,31349361,Can social support during pregnancy affect maternal DNA methylation? Findings from a cohort of African-Americans.,Pediatr Res,"n=250, blood collected after delivery, a few associations with lack of support from the baby's father and from family and friends",
+No,20190805,ewas,31331382,A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers.,Clin Epigenetics,"18 current smokers and 21 never smokers; EPIC and RNA-seq. Nine CpGs associated with smoking status including CYP1B1, AHRR. 61 CpG sites associated with quantity of smoking including CYP1B1. Increased expression of CYP1B1  and 13 other transcripts in smokers. Six transcripts were downregulated. No differential expression was observed for AHRR. ",
+Yes,20190805,ewas,31346403,Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits.,Mol Autism,"In 708 children, no associations observed with autism or autism traits or concordance between the two in cord blood DNA methylation.  However, a concordance was observed with autism EWAS in brain.",
+No,20190805,mechanism,31269015,Cross-species functional modules link proteostasis to human normal aging.,PLoS Comput Biol,"""we integrate evolutionary and functional information of normal aging across human and model organisms at three levels: gene-level, process-level, and network-level. We identify evolutionarily conserved modules of normal aging across diverse taxa, and notably show proteostasis to be conserved in normal aging. Additionally, we find that mechanisms related to protein quality control network are enriched for genes harboring genetic variants associated with 22 age-related human traits and associated to caloric restriction.""",
+Yes,20190812,ewas,31333715,Gut Microbiota Composition Is Associated With the Global DNA Methylation Pattern in Obesity.,Front Genet,"""Twenty patients were selected based on their Bacteroidetes-to-Firmicutes ratio (BFR): HighBFR group (BFR > 2.5, n = 10) and LowBFR group (BFR < 1.2, n = 10). Genome-wide analysis of DNA methylation pattern in both whole blood and visceral adipose tissue of these selected patients was performed ... ",
+No,20190812,gene regulation,31375681,Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding.,Nat Commun,Use CRISPR-Cas9 to omit a binding site and show resulting reduced TF binding and changes gene expression and chromatin.,
+Yes,20190812,ewas,31367216,Epigenome-wide association study of asthma and wheeze characterizes loci within HK1.,Allergy Asthma Clin Immunol,"""10 CpG sites associated with adolescent asthma"" in n=370 and of which 5 replicated in ALSPAC (age 17).  Gene expression of one linked gene was predictive of wheezing in infancy in cord blood.",
+No,20190812,ewas,31393794,Customized MethylC-Capture Sequencing to Evaluate Variation in the Human Sperm DNA Methylome Representative of Altered Folate Metabolism.,Environ Health Perspect,Performed WGBS on sperm and found 1 million CpG sites with intermediate levels of methylation ('dynamic sperm CpGs) and investigated a panel of CpG sites (3 million) in sperm of 30 men and observed effects of MTHFR genotype and folate supplementation.,
+No,20190812,review,31393092,Evaluation of the usefulness of saliva for DNA methylation analysis in cohort studies.,Neuropsychopharmacol Rep,Found that number of CpG sites with population variation in saliva similar to blood and therefore potentially as useful as blood for EWAS.,
+No,20190812,dnam age,31387022,"Air pollution, particulate matter composition and methylation-based biologic age.",Environ Int,"n?=?2747 women;  estimated residential exposure to PM2.5, PM10 and NO2; Hannum, Horvath and Levine epigenetic clocks; NO2 associated with Hannum; age acceleration varied by PM2.5 component cluster.",
+Yes,20190812,ewas,31386212,Epigenome-wide DNA Methylation Association Analysis Identified Novel Loci in Peripheral Cells for Alcohol Consumption among European American Male Veterans.,Alcohol Clin Exp Res,n=1135; AUDIT-Consumption; 70 CpG site associations in the EPIC array; 6 previously reported,
+No,20190812,methods,31384045,Joint profiling of DNA methylation and chromatin architecture in single cells.,Nat Methods,"Methyl-HiC, that can simultaneously capture the chromosome conformation and DNA methylome in a cell. ",
+No,20190812,dnam age,31379754,"Interaction Among Sex, Aging, and Epigenetic Processes Concerning Visceral Fat, Insulin Resistance, and Dyslipidaemia.",Front Endocrinol (Lausanne),"""Two different study samples of 366 and 269 adult participants were analyzed. Anthropometric, biochemical (including the triglycerides-glucose (TyG) index), and blood pressure measurements were assessed following standardized methods. Body composition measurements by Dual-energy X-ray absorptiometry (DXA) were also performed for the second sample. Methylation data were assessed by Infinium Human Methylation BeadChip (Illumina) in peripheral white blood cells."" Methylation profiles were used to generate various estimates of DNAm age ... ""these findings showed that there are different mechanisms affecting epigenetic age acceleration depending on sex.""",
+No,20190812,dnam age,31375641,Environmental exposure to polybrominated biphenyl (PBB) associates with an increased rate of biological aging.,Aging (Albany NY),"population highly exposed to PBB (N=658) ""Higher PBB levels associated with increased age acceleration (intrinsic: ?=0.24, 95%CI=0.01-0.46, p = 0.03; extrinsic: ?=0.39, 95%CI=0.12-0.65, p = 0.004; and phenotypic: ?=0.30, 95%CI=0.05-0.54, p = 0.01).""",
+No,20190812,review,31369552,"Human placental methylome in the interplay of adverse placental health, environmental exposure, and pregnancy outcome.",PLoS Genet,"""In this review, we cover recent advances in DNA methylation in the context of placental function and development, as well as the interaction between the pregnancy and the environment.""",
+No,20190812,methods,31356589,The impact of DNA methylation on the cancer proteome.,PLoS Comput Biol,"""refines nominations for epigenetic driver genes by leveraging quantitative high-throughput proteomic data to select only genes where DNA methylation is predictive of protein abundance.""  Would be interesting to know how protein-methylation associations in cancer differ from those in blood.",
+No,20190812,dnam age,31395791,Sex differences in the associations of placental epigenetic aging with fetal growth.,Aging (Albany NY),"""PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks."" n=152 males, n=149 females.",
+No,20190910,ewas,30694562,Genome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures,Int J Cancer,"""436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study"" NULL",
+Yes,20190909,ewas,31481539, Differences in genome-wide DNA methylation profiles in breast milk by race and lactation duration,Cancer Prev Res (Phila),"""Breast milk samples ... from ... U.S. black (n=57) and white (n=82) women, ages 19 to 44"".  284 race differences, 227 CpG sites associated with lactation duration, negatively associated with lactation time.",
+Yes,20190909,ewas,31477727, Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood,Nat Commun,"149 neonatal and 158 adult  ART-conceived and 58 neonatal and 75 adult controls (neonatal Guthrie cards, adults 22-35). 2340 DMPs, 136 with >5% DNAm difference, 6 of these had >5% DNAm difference in adulthood.",
+No,20190909,ewas,31477685, Genome-wide profiling of DNA methylome and transcriptome in peripheral blood monocytes for major depression: A Monozygotic Discordant Twin Study,Transl Psychiatry,"RNA-seq and EPIC methylation in peripheral blood monocytes for 79 adult monozygotic twin pairs discordant for major depressive disorder, 39 DMRs (DMRcate with ad hoc criteria) and 30 DEGs",
+Yes,20190909,ewas,31477683, Epigenome-wide association study of depression symptomatology in elderly monozygotic twins,Transl Psychiatry,"blood for 724 monozygotic Danish twins, 2 CpG sites associated with depression symptomology score",
+No,20190909,ewas,31195163, DNA methylation from germline cells in veterans with PTSD,J Psychiatr Res,"38 semen samples (16 with PTSD, 22 controls), 3 DMPs, some evidence that nominally associated sites enriched for PTSD and mental health associations in blood",
+No,20190909,candidate,31452782, Tumor-induced DNA methylation in the white blood cells of patients with colorectal cancer,Oncol Lett,"Throught a complex procedure, PLOD1 and MMP9 chosen to differentiate between cancer (32) and controls (59). MMP9 methylation in white blood cells differentiated with high sensitivity (90.63%) and high specificity (96.49%) and a positive predictive value of 93.33% and a negative predictive value of 93.22%.",
+No,20190909,candidate,31464656, Duration of breastfeeding is associated with leptin (LEP) DNA methylation profiles and BMI in 10-year-old children,Clin Epigenetics,"""In the Isle of Wight Birth Cohort, peripheral blood DNAm at 23 cytosine-phosphate-guanine sites (CpGs) in the LEP locus in 10-year-old (n = 297) samples and 16 CpGs in 18-year-old (n = 305) samples, were generated using the Illumina Infinium MethylationEPIC and HumanMethylation450 Beadchips respectively ... Both total and exclusive breastfeeding duration were associated with DNAm at four LEP CpG sites at 10 years (P value < 0.05), and not at 18 years.""",
+No,20190909,dnam age,31466081, Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2,Neuropsychopharmacology,"331 AUD and 201 HC; Hannum, Horvath and Phenoage DNAm clocks; GWAS of Phenoage in 154 European and 156 African individuals with AUD; Phenoage was accelerated 2.22 years higher in AUD than controls (p?=?1.85E-5); APOL2 the only GWAS finding",
+No,20190909,methods,31455416, Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data,Clin Epigenetics,Found improved cell count estimates by: (1) filtering out 'unpure' references samples and combining what remained for the four available references to obtain a single reference and (2) selecting CpG sites for estimating cell counts using the IDOL iterative algorithm (rather than the procedure implemented in minfi). Replicated result in Generation R.,
+Yes,20190909,ewas,31461406, Epigenome-wide association study of leukocyte telomere length,Aging (Albany NY),"""EWAS of leukocyte telomere length using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins."" 823 CpG site associations.",
+Yes,20190909,ewas,31451752, An epigenome-wide analysis of cord blood DNA methylation reveals sex-specific effect of exposure to bisphenol A,Sci Rep,"bisphenol A concentrations and methylation in cord blood (n=277); 27 and 16 CpG sites with FDR < 0.05 in males and females, respectively. Evidence for sex-specificity evaluated by show the two sets of sites had distinct functional properties/enrichments.",
+Yes,20190909,ewas,31450665, Epigenome-Wide Association Analysis of Differentially Methylated Signals in Blood Samples of Patients with Non-Small-Cell Lung Cancer,J Clin Med,"peripheral blood for 150 cases vs 150 controls, no differences except in sub-analysis of smokers -- 2 DMPs.",
+No,20190909,methods,31443682, Statistical predictions with glmnet,Clin Epigenetics,"""We provide guidelines on how to obtain parsimonious models with low mean squared error and include easy to follow walk-through examples for each step in R.""  Mainly how to pick the best 'alpha' parameter - how much to weight the l1 and l2 norm penalties.",
+Yes,20190909,ewas,31424985, Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease,Circulation,"11,461 free of CHD, 1895 developed CHD over next 11 years, 52 DMPs at baseline",
+No,20190909,database,31428785, CFEA: a cell-free epigenome atlas in human diseases,Nucleic Acids Res,"epigenetic profiles: 5mC, 5hmC and NP (nucleosome positioning); 27 human diseases",
+Yes,20190909,ewas,31426852, Novel age-associated DNA methylation changes and epigenetic age acceleration in middle-aged African Americans and whites,Clin Epigenetics,"n=487; 4930 age-associated sites in Africans, 469 in 'whites'; Africans had lower extrinsic DNAm acceleration; African women the lowest.",
+No,20190909,ewas,31453433, DNA Methylation Trajectories During Pregnancy,Epigenet Insights,"blood collected before (~1.6 years), during (any time) and after pregnancy (4 days) (n=21); 196 CpG sites with intra-individual change, mostly decreasing methylation",
+Yes,20190909,ewas,31404209,Acetaminophen use during pregnancy and DNA methylation in the placenta of the extremely low gestational age newborn (ELGAN) cohort.,Environ Epigenet,acetominophen use during pregnancy prior to weak 28 in n=286 placentas; 42 DMPs; some weak evidence of sex-specific associations,
+No,20190909,dnam age,31443728,Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing.,Genome Med,"Build age predictors in DNAm from 13,661 blood samples and 259 saliva samples; show that prediction will be perfect with large enough training sample; association of DNAm age acceleration decreases as age prediction accuracy increases",
+No,20190909,methods,31399127,Accurate ethnicity prediction from placental DNA methylation data.,Epigenetics Chromatin,"""Data from 509 placental samples were used to develop PlaNET and show that it accurately predicts (accuracy = 0.938, kappa = 0.823) major classes of self-reported ethnicity/race (African: n = 58, Asian: n = 53, Caucasian: n = 389)""",
+No,20190909,database,31462275,A unified encyclopedia of human functional DNA elements through fully automated annotation of 164 human cell types.,Genome Biol,"""we present annotations of 164 human cell types using 1615 data sets."" From these, ""we developed a measure of the importance of each genomic position ... and combined all annotations into a single, cell type-agnostic encyclopedia that catalogs all human regulatory elements.""",
+Yes,20190916,ewas,31510868,Body Mass Index Drives Changes in DNA Methylation: A Longitudinal Study.,Circ Res,n=995 White and n=490 Black from the Bogalusa Heart Study; DNAm and BMI measured 6.2 years apart in 439 white and 201 Black; replication in 252 White and 228 Black from the Georgia Stress and Heart Study; 349 CpG sites (266 novel) in Whites and 36 (21 novel) in Blacks with replicated associated with BMI; 8 sites in common; cross-lagged panel analyses identified paths from BMI to DNAm but not the opposite.,
+Yes,20190916,ewas,31509016,Socioeconomic status and DNA methylation from birth through mid-childhood: a prospective study in Project Viva.,Epigenomics,"DNAm for 609 children at birth (cord), age 3 and age 7 (peripheral blood) in Project VIVA. Differences were tested between the top and bottom 10% of SES. 4 differences observed in cord and 1 persisted beyond birth.  (Details should be confirmed as I was not able to obtain a copy of the paper).",
+Yes,20190916,ewas,31506343,Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.,Diabetes,"Case-control study of T2DM, DNAm measured in blood collected 'before onset'.  18 differentially methylated CpG sites, 3 observed previously. 16 had meQTLs, one indicated a causal role for DNAm.",
+Yes,20190916,ewas,31506065,The effect of age on DNA methylation in whole blood among Bangladeshi men and women,BMC Genomics,blood for 400 adult participants (189 males and 211 females) from Bangladesh; age range 25-70; 986 CpG sites associated with age among men and 3479 among women; over 60% replicated; resulting age predictor had R=0.8 correlation with chronological age,
+No,20190916,methods,31504104,Methods for Dealing With Missing Covariate Data in Epigenome-Wide Association Studies.,Am J Epidemiol,,
+No,20190916,review,31501771,The NIH Common Fund/Roadmap Epigenomics Program: Successes of a comprehensive consortium.,Sci Adv,"""Here we comment on the outcomes from this program: the scientific contributions made possible by a consortium approach and the challenges, benefits, and lessons learned from this group science effort."" ",
+Yes,20190916,ewas,31501512,A methylation study of long-term depression risk.,Mol Psychiatry,"""blood DNA methylation profiles (MBD-seq) from 581 MDD patients at baseline with MDD status 6 years later""; ""A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P?=?2.0?×?10-16).""  DNA methylation risk score had AUC=0.724, better than genetic or clinical predictors.",
+Yes,20190916,ewas,31497855,Placental DNA Methylation Mediates the Association of Prenatal Maternal Smoking on Birth Weight.,Am J Epidemiol,n=441 placentas; 71 CpG sites associated with prenatal smoking; 7 found to mediate effect (50-87% of 175g effect),
+No,20190916,dnam score,31494793,Validated inference of smoking habits from blood with a finite DNA methylation marker set.,Eur J Epidemiol,"""Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N?=?3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901.""  AUC=0.7 for former, 0.78 for never, 0.8 for >10 pack-years.  Children age 6 found to be non-smokers even with prenatal smoking exposure. ",
+No,20190916,mechanism,31485078,The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.,Nature,"""NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions.""",
+No,20190916,ewas,31477183,Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer's disease,Clin Epigenetics,23 disease discordant twin pairs; blood methylation profiles obtained from blood; 11 genomic regions with >15% methylation difference; follow-up analysis in 120 twin pairs indicates that one region selected for replication was caused by the disease state.,
+No,20190916,methods,31484546,TOAST: improving reference-free cell composition estimation by cross-cell type differential analysis.,Genome Biol,Reference-free methods highly dependent on the set of CpG sites selected to estimate cell counts. Most methods essentially end up selecting the most variable sites. The authors show that by iteratively applying the reference-free method and then using the output to identify cell-type discordant CpG sites which are then fed into the next application of the reference-free method improves the final result.,
+Yes,20190923,ewas,31536415,Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking.,Epigenomics,"""We separately meta-analyzed newborn blood DNA methylation, in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers) ... we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways""",
+No,20190923,ewas,31536135,In utero bisphenol A exposure is linked with sex specific changes in the transcriptome and methylome of human amniocytes.,J Clin Endocrinol Metab,"19 controls, 16 exposed;  RNA-seq, RRBS for DNAm profiling, Hi-C; exposure and DNAm measured in amnyotic fluid; 36 DMRs in males, 14 in females, 101 DE genes in males, 1 in females, Hi-C identified interactions between 24 DE genes and DMRs in males and 12 DE genes and DMRs in females.",
+Yes,20190923,ewas,31530476,Age-related changes in DNA methylation affect renal histology and post-transplant fibrosis.,Kidney Int,"""we profiled genome-wide changes in DNA methylation (over 800 000 CpG sites) in 95 renal biopsies obtained prior to kidney transplantation from donors aged 16 to 73 years. Donor age significantly associated with the methylation of 92 778 CpGs ... age-associated changes in DNA methylation at the time of transplantation predict future injury of transplanted kidneys""",
+No,20190923,ewas,31513634,Genome-wide analysis of DNA methylation profile identifies differentially methylated loci associated with human intervertebral disc degeneration.,Genome Biol,"DNA methylation profiles of human intervertebral disc tissues, specifically nucleus pulpous (NP) tissues, with early (n=8) and advanced stages of disc degeneration (n=8). 220 DMPs enriched in cell-cell adhesion.",
+No,20190923,ewas,31506096,Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation.,Clin Epigenetics,"""The study compared three 12-week interventions to (1) simultaneously increase exercise and fruit/vegetable intake, while decreasing sedentary leisure screen time; (2) sequentially increase fruit/vegetable intake and decrease leisure screen time first, then increase exercise; (3) increase sleep and decrease stress (control). We collected blood samples at baseline, 3 and 9 months, and measured DNA methylation using the Illumina EPIC (850?k) BeadChip."" In 68 individuals, DNAm was not different between controls (n=12) and pooled intervention groups (simultaneous n=25; sequential n=21) but did observe 154 DMRs at 3 months and 298 at 9 months (using DMRcate). Only 1 DMR appeared at both times.",
+No,20190923,methods,31501549,Simultaneous profiling of 3D genome structure and DNA methylation in single human cells.,Nat Methods,Describe 'methyl-3C' sequencing in order to generate 3D structure and DNAm simultaneously.  Use to show differences between 14 different cortical cell types.,
+No,20190923,ewas,31439477,Fasting unmasks differential fat and muscle transcriptional regulation of metabolic gene sets in low versus normal birth weight men.,EBioMedicine,Gene expression and DNAm measured in subcutaneous fat and skeletal muscle men before and after 36h of fasting.  Genes in oxidative phosphorylation were lower in low birth weight men before fasting and higher after fasting.  DNAm changes were not observed (n=8 low birth weight; n=8 normal birth weight).,
+No,20190923,cohort,31467051,The Uppsala-Stockholm Assisted Reproductive Techniques (UppStART) study.,BMJ Open,"In case someone is interested ART: ""The cohort includes 971 participants (n= 514 women; n= 457 men), and 129 pregnancies were achieved from the first IVF cycle included in the study."" Biological samples will be collected.",
+No,20190923,gene regulation,31514731,The first enhancer in an enhancer chain safeguards subsequent enhancer-promoter contacts from a distance.,Genome Biol ,"""Using Hi-C data in multiple cell lines, we report a comprehensive map of promoters and active enhancers connected by chromatin contacts, spanning 9000 enhancer chains in 4 human cell lines associated with 2600 human genes.  We find that ... the primary, critical enhancer is distal, commonly located further away than other enhancers. This first, distal enhancer establishes contacts with multiple regulatory elements and safeguards a complex regulatory program of its target gene.""",
+No,20190923,methods,31510704,Weighted elastic net for unsupervised domain adaptation with application to age prediction from DNA methylation data.,Bioinformatics,"DNAm models derived in one dataset, often fail to perform well in other datasets due to technical or even biological differences, e.g. a model of age may be applied in a new tissue or to samples from individuals from a different age range. Robustness can be improved by weighting the contribution of CpG sites to an elastic net model by how well its dependencies on other CpG sites agrees between training and testing datasets. As evidence of this, weighted elastic net generates improved models of age in cerebellum when cerebellum is not included in the training dataset.",
+No,20190923,ase,31455884,Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage.,Nat Neurosci ,"""When ASE is observed in ASD, the allele with lower population frequency (minor allele) is preferentially more highly expressed than the major allele, opposite to the canonical pattern. Importantly, genes showing ASE in ASD are enriched in those downregulated in ASD postmortem brains and in genes harboring de novo mutations in ASD.""",
+No,20190930,ewas,31542994,Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes.,Epigenetics,"This study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling. Genome wide EPIC methylation and expression levels of candidate miRNAs measured in 60 HD, 33 controls. Independent cohort of 107 alcohol depednent subjects. Two CpG-sites for HD - cg18222192 (MIR708) and cg01299774 (MIR4456). Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. ",
+No,20190930,ewas,31538540,Battle of epigenetic proportions: comparing Illumina's EPIC methylation microarrays and TruSeq targeted bisulfite sequencing.,Epigenetics,"Bisulphite sequencing becoming a cheaper alternative to microarrays. Conducted a comparison study - cord blood samples - four newborns in duplicates using both the Illumina HumanMethylationEPIC BeadChip and the Illumina TruSeq Methyl Capture EPIC Kit. Evaluated both platforms in regard to coverage, reproducibility, and identification of differential methylation. We conclude that with current analytic goals microarrays still outperform bisulphite sequencing for precise quantification of DNA methylation.",
+No,20190930,mr,31549173,Appraising the causal relevance of DNA methylation for risk of lung cancer.,Int J Epidemiol,"DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. A large meta analysis and 2 sample MR finds that previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.",
+No,20190930,ml,31521637,Artificial intelligence analysis of newborn leucocyte epigenomic markers for the prediction of autism.,Brain Res,EWAS of newborn leucocyte (blood spot) DNA in autism as defined at the time of sample collection. 14 autism cases and 10 controls. The accuracy of cytosine methylation for autism detection using six different Machine Learning/Artificial Intelligence (AI) approaches including Deep-Learning (DL) was determined. Our findings suggest significant epigenetic role in autism development and epigenetic markers appeared highly accurate for newborn prediction.,
+No,20190930,review,31530287,"Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?",Clin Epigenetics,"To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks.",
+No,20190930,epigenetics,31533842,Identification of key DNA methylation-driven genes in prostate adenocarcinoma: an integrative analysis of TCGA methylation data.,J Transl Med,"Methylated hub genes, including MAOB and RTP4, can be regarded as novel biomarkers for accurate PCa diagnosis and treatment. Further studies are needed to draw more attention to the roles of these hub genes in the occurrence and development of PCa.",
+No,20190930,ewas,31556946,Epigenome-wide association study of narcolepsy-affected lateral hypothalamic brain and overlapping DNA methylation profiles between narcolepsy and multiple sclerosis,Sleep,"Lateral hypothalamic (LH) and temporal cortex (TC) post mortem brain samples – 11 narcolepsy 15 non-narcolepsy. DMRs found located in the mylein base protein region - overlap between profiles of narcolepsy and MS, potential therapeutic targets. ?",
+No,20191013,dnam age,31480455,Association of Obesity with DNA Methylation Age Acceleration in African American Mothers from the InterGEN Study.,Int J Mol Sci,n=232 saliva samples from African American women (average age 30); 1 kg/m^2 increase in BMI associated with 0.14 years increase in DNAm age acceleration,
+No,20191013,methods,31484776,GeneFishing to reconstruct context specific portraits of biological processes.,PNAS,"GeneFishing uses simultation and omic data in a semisupervised approach to prioritize sets of genes.  Given a set of genes, GeneFishing identifies a more complete list of all genes with related expression patterns.  As a proof of principle, from 21 genes involved in cholesterol metabolism as bait, they identify a new gene GLO1 previously unlinked to cholesterol metabolism. However, when knocked down in a cell line, cellular cholesterol ester levels increased. ",
+No,20191013,database,31501517,A compendium of promoter-centered long-range chromatin interactions in the human genome.,Nat Genet,Hi-C of 27 human cell/tissue types used to identify interactions between promoters and infer target genes of regulatory elements and regulatory function of 27K noncoding sequence variants.,
+No,20191013,methods,31530853,Horizontal and vertical integrative analysis methods for mental disorders omics data.,Sci Rep,Showcase 'vertical' and 'horizontal' integretion; horizontal analysis of bipolar and schizophrenia simultaneously; vertical analysis of gene expression and copy number; sparse principal component analysis,
+No,20191013,meqtl,31537805,Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease.,Nat Commun,n=4170 blood samples; identify 4.7M cis and 630K trans meQTLs targetting 120K CpG sites; replicated in 1347 individuals from two studies; MR performed using cis-meQTLs and GWAS of cardiovascular traits; 92 causal CpG sites; identify 22 trans-meQTL 'hotspots' targeting > 30 CpG sites; these hotspots act in cis on expression of nearby genes,
+No,20191013,database,31551426,CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder.,Sci Data,RNA-seq and SNPs (n=980); ATAC-seq (n=269); dorsolateral prefrontal cortex; schizophrenic (n=353); bipolar disorder (n=120),
+No,20191013,methods,31552104,"In Epigenomic Studies, Including Cell-Type Adjustments in Regression Models Can Introduce Multicollinearity, Resulting in Apparent Reversal of Direction of Association.",Front Genet,n=812 at age 17 (Western Australian Pregnancy Cohort Study); EWAS of BMI adjusted for age and sex; cell counts estimated using the Houseman algorithm; associations in the CDKN2A promoter reversed direction when adjusted for cell counts; reason: correlation high between cell counts and promoter methylation,
+Yes,20191013,ewas,31552803,Smoking and blood DNA methylation: an epigenome-wide association study and assessment of reversibility.,Epigenetics,"n=5044; Melbourne Collaborative Cohort Study; smoking; n=1032 have blood collected 11 years later; 4496 sites associated with ever smoking; 1326 of these new; 2.75 half-life for the smoking score (i.e. in 2.75 years, half of the smoking effect has disappeared); 368 CpG sites change upon smoking cessation ",
+No,20191013,epigenetics,31554518,Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation.,Genome Biol,Characterise neocortical DNAm across the first 20 years; most dramatic changes in the first 5 years; neighboring CpG and CpH levels are correlated; CpG and CpH levels define 6 developmental trajectories; identify gene expression effects linked only to CpH and not CpG levels.,
+No,20191013,dnam age,31554804,Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells.,Nat Commun,"Use single-cell transcriptomes and methylomes in mouse muscle stem cells. Find evidence that 'epigenetic drift ... in promoters is associated with the degradation of coherent transcriptional networks during stem cell aging"".",
+No,20191013,ewas,31566019,Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men.,Endocr Res,"muscle progenitor cells from 23 LBW and 15 NBW controls; 56 CpG sites differentially methylated; 14 genes differentially expressed; follow-up experimental work determined that ""Silencing of FYN and HDAC7 was
 associated with impaired myotube formation, which for HDAC7 reduced muscle glucose uptake.""",
-,No,20191013,genetics,31575865,Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth.,Nat Commun,"GWAS of BMI at 12 points from 0-8 (9286 children) in MOBA; transient effects in the leptin receptor -- no effect at birth, increasing to peak at 6-12 months, little effect after age 5; transient effects in the leptin gene peaking at 1.5 years; replicated in 5235 children",
-,No,20191013,database,31584095,EWAS Data Hub: a resource of DNA methylation array data and metadata.,Nucleic Acids Res,"75,344 publicly available DNA methylation profiles; normalized to remove batch effects; 81 tissues/cell types; https://bigd.big.ac.cn/ewas/datahub",
-,No,20191013,ewas,31587037,5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns.,Mutagenesis,5mC and 5hmC measured in cord blood; n=41 (CHAMACOS); low levels of 5hmC; concordance 0.25 between 5mC and 5hmC+5mC; 5hmC at 21 CpG sites associated with sex; ,
-,No,20191013,dnam score,31591380,"Epigenetic signatures of smoking associate with cognitive function, brain structure, and mental and physical health outcomes in the Lothian Birth Cohort 1936.",Transl Psychiatry,"n=895 age 70 years (LBC1936); blood DNAm; 230-CpG site smoking score associated with smoking, pack years, cognitive function, structural brain integrity, physical health and psychosocial health. Score associations with cognitive function, dietary patterns, stroke, mortality, MRI volumetric measures were stronger than self-report.",
-,No,20191013,meqtl,31591588,Genome-wide germline correlates of the epigenetic landscape of prostate cancer.,Nat Med,"With 241 discovery and 348 validation patients with germline WGS and prostate tumor methylation, identified and validated 1178 loci with altered DNA methylation in tumor but not nonmalignant tissue.  Provide evidence that these tumor meQTLs influence chromatin structure and RNA and protein abundance.  ",
-,Yes,20191013,ewas,31594917,Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants.,Transl Psychiatry,n=211 MDD and n=112 controls age 18-60; 8-week escitalopram (SRI anti-depressant); n=82 responders and n=95 non-responders among MDD; 303 CpG sites differentially methylated; 2009 differentially expressed genes; 3 promoter CpG sites associated with gene expression; one site  replicated externally in n=71 responders and n=76 non-responders; AUC = 0.59 for this site to differentiate between responders and non-responders; healthy controls were compared to MDD to ensure that methylation responder differences weren't due to MDD status.,
-,Yes,20191013,ewas,31596135,Genome-wide DNA methylation changes in placenta tissues associated with small for gestational age newborns; cohort study in the Chinese population.,Epigenomics,n=1292; placenta; 39 small for gestational age; 2012 CpG sites associated with SG; 5 CpG sites associated with folic acid supplementation (FAM198A),
-,Yes,20191013,ewas,31600381,"Reproduction, DNA methylation and biological age.",Hum Reprod,"n=2356 women age 35-74 (Sister Study); whole blood; Hannum, Horvath and Phenoage epigenetic clocks; weak associations between parity and epigenetic age acceleration; further weakened by adjustment for BMI; weak associations with abnormal glucose tolerance; parity associated with 17 CpG sites",
-,Yes,20191021,ewas,31601636,Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium.,Diabetes care,"7 pregnancy cohorts (3,677 mother-newborn pairs (317 with GDM)) . Two DMRs hypomethylated in newborns exposed to GDM ",
-,No,20191021,ewas,31594949,International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. ,Nat Comms,"Multi-ethnic cohort including - 30,000 PTSD cases / 170,000 controls 
+No,20191013,genetics,31575865,Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth.,Nat Commun,"GWAS of BMI at 12 points from 0-8 (9286 children) in MOBA; transient effects in the leptin receptor -- no effect at birth, increasing to peak at 6-12 months, little effect after age 5; transient effects in the leptin gene peaking at 1.5 years; replicated in 5235 children",
+No,20191013,database,31584095,EWAS Data Hub: a resource of DNA methylation array data and metadata.,Nucleic Acids Res,"75,344 publicly available DNA methylation profiles; normalized to remove batch effects; 81 tissues/cell types; https://bigd.big.ac.cn/ewas/datahub",
+No,20191013,ewas,31587037,5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns.,Mutagenesis,5mC and 5hmC measured in cord blood; n=41 (CHAMACOS); low levels of 5hmC; concordance 0.25 between 5mC and 5hmC+5mC; 5hmC at 21 CpG sites associated with sex; ,
+No,20191013,dnam score,31591380,"Epigenetic signatures of smoking associate with cognitive function, brain structure, and mental and physical health outcomes in the Lothian Birth Cohort 1936.",Transl Psychiatry,"n=895 age 70 years (LBC1936); blood DNAm; 230-CpG site smoking score associated with smoking, pack years, cognitive function, structural brain integrity, physical health and psychosocial health. Score associations with cognitive function, dietary patterns, stroke, mortality, MRI volumetric measures were stronger than self-report.",
+No,20191013,meqtl,31591588,Genome-wide germline correlates of the epigenetic landscape of prostate cancer.,Nat Med,"With 241 discovery and 348 validation patients with germline WGS and prostate tumor methylation, identified and validated 1178 loci with altered DNA methylation in tumor but not nonmalignant tissue.  Provide evidence that these tumor meQTLs influence chromatin structure and RNA and protein abundance.  ",
+Yes,20191013,ewas,31594917,Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants.,Transl Psychiatry,n=211 MDD and n=112 controls age 18-60; 8-week escitalopram (SRI anti-depressant); n=82 responders and n=95 non-responders among MDD; 303 CpG sites differentially methylated; 2009 differentially expressed genes; 3 promoter CpG sites associated with gene expression; one site  replicated externally in n=71 responders and n=76 non-responders; AUC = 0.59 for this site to differentiate between responders and non-responders; healthy controls were compared to MDD to ensure that methylation responder differences weren't due to MDD status.,
+Yes,20191013,ewas,31596135,Genome-wide DNA methylation changes in placenta tissues associated with small for gestational age newborns; cohort study in the Chinese population.,Epigenomics,n=1292; placenta; 39 small for gestational age; 2012 CpG sites associated with SG; 5 CpG sites associated with folic acid supplementation (FAM198A),
+Yes,20191013,ewas,31600381,"Reproduction, DNA methylation and biological age.",Hum Reprod,"n=2356 women age 35-74 (Sister Study); whole blood; Hannum, Horvath and Phenoage epigenetic clocks; weak associations between parity and epigenetic age acceleration; further weakened by adjustment for BMI; weak associations with abnormal glucose tolerance; parity associated with 17 CpG sites",
+Yes,20191021,ewas,31601636,Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium.,Diabetes care,"7 pregnancy cohorts (3,677 mother-newborn pairs (317 with GDM)) . Two DMRs hypomethylated in newborns exposed to GDM ",
+No,20191021,ewas,31594949,International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. ,Nat Comms,"Multi-ethnic cohort including - 30,000 PTSD cases / 170,000 controls 
 Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. 
 Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. 
 ",
-,Yes,20191021,ewas,31582393,DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes,Blood Adv,"141 patients with MDS – bone marrow samples
+Yes,20191021,ewas,31582393,DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes,Blood Adv,"141 patients with MDS – bone marrow samples
 NMF was performed on the 3% most variably methylated CpG tiles (n = 7,382) 
 “…we demonstrate that using novel computational methods to agnostically classify primary MDS patients by their DNAm patterns can identify subtypes of MDS characterized by distinct patterns of genetic lesions, regulatory region methylation, and prognostic risk. Our results highlight the importance of DNAm in MDS disease biology as a convergent oncogenic phenotype and support future studies investigating DNAm profiles as clinically relevant biomarkers.”
 ",
-,No,20191021,mechanism,31582723,Genetic risk for Alzheimer's dementia predicts motor deficits through multi-omic systems in older adults,Transl Psychiatry,"Integrative analysis to untangle the molecular paths from genetic risk to motor impairment [n=1,885] 
+No,20191021,mechanism,31582723,Genetic risk for Alzheimer's dementia predicts motor deficits through multi-omic systems in older adults,Transl Psychiatry,"Integrative analysis to untangle the molecular paths from genetic risk to motor impairment [n=1,885] 
 “To identify specific molecular features that potentially medicate the genetic risk into motor dysfunction, we examined brain multi-omics, including transcriptome, DNA methylation, histone acetylation (H3K9AC), and targeted proteomics, as well as diverse neuropathologies.”
 AD-PRS compared to several motor phenotypes 
 Genetic risk for Alzheimer’s dementia influenced motor functions in older adults, suggesting that cognitive and motor impairment share, at least in part, an underlying genetic architecture. 
 ",
-,No,20191021,dnam age,31611402,The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells,Proc Natl Acad Sci U S A,"1,721 genome-wide epithelial buccal cell DNAm profiles - 0 – 20 years 
+No,20191021,dnam age,31611402,The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells,Proc Natl Acad Sci U S A,"1,721 genome-wide epithelial buccal cell DNAm profiles - 0 – 20 years 
 Elastic net penalized regression was used to select 94 CpG sites
 “DNAm at these 94 CpG sites was highly predictive of age in the test cohort…the Pediatric-Buccal-Epigenetic clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes.”
 
 ",
-,No,20191021,dnam score,31609642,A Four Marker Digital PCR Toolkit for Detecting Heavy Alcohol Consumption and the Effectiveness of Its Treatment,J Insur Med,"143 participants with current HAC and 200 abstinent controls. We show that a set of 4 digital PCR assays that have a AUC 0.96 for detecting those with HAC. “After a mean of 21 days of inpatient enforced abstinence, methylation status at one of these markers, cg04987734, began to revert to baseline values.” ",
-,No,20191021,ewas,31645664,Successful treatment of post-traumatic stress disorder reverses DNA methylation marks,Mol Psychiatry,"Investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for ?
+No,20191021,dnam score,31609642,A Four Marker Digital PCR Toolkit for Detecting Heavy Alcohol Consumption and the Effectiveness of Its Treatment,J Insur Med,"143 participants with current HAC and 200 abstinent controls. We show that a set of 4 digital PCR assays that have a AUC 0.96 for detecting those with HAC. “After a mean of 21 days of inpatient enforced abstinence, methylation status at one of these markers, cg04987734, began to revert to baseline values.” ",
+No,20191021,ewas,31645664,Successful treatment of post-traumatic stress disorder reverses DNA methylation marks,Mol Psychiatry,"Investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for ?
 
 PTSD in soldiers in remission (N?=?21)?
 
@@ -339,7 +339,7 @@ Successful treatment of PTSD was accompanied by significant changes in DNA methy
 Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms ?
 
 “Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD.”?",
-,No,20191021,dnam score,31646666,A seven?DNA methylation signature as a novel prognostic biomarker in breast cancer ,J Cell Biochem,"The DNA methylation data of BC was downloaded from:?
+No,20191021,dnam score,31646666,A seven?DNA methylation signature as a novel prognostic biomarker in breast cancer ,J Cell Biochem,"The DNA methylation data of BC was downloaded from:?
 
 The Cancer Genome Atlas ?
 
@@ -352,7 +352,7 @@ The RNA?Seq data and clinical information of patients were downloaded from TCGA
 7 DMSs were identified - their expression levels were negatively correlated with the DNA methylation level and not affected by age, subtypes, or tumour stages.?
 
 “We proposed that these seven differentially DNA methylation sites can be used as a novel prognostic biomarker for BC - AUC?=?0.74”?",
-,Yes,20191021,ewas,31642367,Epigenome?Wide Association Study for All?Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ123),J Am Heart Assoc,"EWAS for all?cause mortality with whole?transcriptome data in a cardiovascular cohort ?
+Yes,20191021,ewas,31642367,Epigenome?Wide Association Study for All?Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ123),J Am Heart Assoc,"EWAS for all?cause mortality with whole?transcriptome data in a cardiovascular cohort ?
 
 Cases - participants with mortality ?7 days post-catheterization / controls - alive with ?2 years of follow?up. ?
 
@@ -363,20 +363,20 @@ In the discovery set (450k, 55 cases, 49 controls), 25,629 (6.5%) probes were di
 Differential methylation in CASZ1 may serve as a genomic regulatory element associated with increased risk of death in cardiovascular patients.?
 
 “Our findings are unique when compared with 2 previous EWAS of all?cause mortality”?",
-,No,20191021,dnam score,31640781,Random forest-based modelling to detect biomarkers for prostate cancer progression,Clin Epigenetics,"The clinical course of prostate cancer (PCa) is highly variable, demanding an individualized approach to therapy. Overtreatment of indolent PCa cases, which likely do not progress to aggressive stages, may be associated with severe side effects and considerable costs. These could be avoided by utilizing robust prognostic markers to guide treatment decisions.?
+No,20191021,dnam score,31640781,Random forest-based modelling to detect biomarkers for prostate cancer progression,Clin Epigenetics,"The clinical course of prostate cancer (PCa) is highly variable, demanding an individualized approach to therapy. Overtreatment of indolent PCa cases, which likely do not progress to aggressive stages, may be associated with severe side effects and considerable costs. These could be avoided by utilizing robust prognostic markers to guide treatment decisions.?
 ?
 Random forest-based classification model to predict aggressive behaviour of prostate cancer. ?
 DNA methylation changes between PCa cases with good or poor prognosis (discovery cohort with n?=?70) - randomly split into a training (80%) and a test set (20%) - AUC 95%. ?
 ?
 Using the ICGC cohort of early- and late-onset prostate cancer (n?=?222) and the TCGA PRAD cohort (n?=?477) for external validation, AUCs for sensitivity analyses were 77.1% and 68.7%, respectively. ?",
-,No,20191021,dnam score,31618096,AHRR Methylation is a Significant Predictor of Mortality Risk in Framingham Heart Study.,J Insur Med,"We analysed the relationship of methylation at cg05575921 and cg04987734 (quantitative marker of heavy alcohol consumption (HAC)) to mortality ?
+No,20191021,dnam score,31618096,AHRR Methylation is a Significant Predictor of Mortality Risk in Framingham Heart Study.,J Insur Med,"We analysed the relationship of methylation at cg05575921 and cg04987734 (quantitative marker of heavy alcohol consumption (HAC)) to mortality ?
 
 n = 2,278  average age ~66 years?
 
 “we found that the inclusion of both cg05575921 and cg04987734 methylation to a base model consisting of age and sex only, or to a model containing 11 commonly used mortality risk factors, improved risk prediction…prediction accuracy for the base model plus methylation data was increased compared to the base model plus known predictors of mortality (CHD, COPD, or stroke).” ?
 
 Cg05575921, and to a smaller extent cg04987734, are strong predictors of mortality risk in older Americans?",
-,No,20191104,ewas,31667917,Epigenetics Predicts Serum 25-hydroxyvitamin D<sub>3</sub> Response to Vitamin D<sub>3</sub> Supplementation in African Americans.,Mol Nutr Food Res,"16-week trial?
+No,20191104,ewas,31667917,Epigenetics Predicts Serum 25-hydroxyvitamin D<sub>3</sub> Response to Vitamin D<sub>3</sub> Supplementation in African Americans.,Mol Nutr Food Res,"16-week trial?
 
 N=64 African Americans?
 
@@ -389,7 +389,7 @@ Responder = serum 25(OH)D concentration at or above expected levels given supple
 cg07873128 [OSBPL5] ?
 
 OSBPL5 regulates cholesterol balance and calcium homeostasis",
-,Yes,20191104,ewas,31652233,Physical Activity and Genome-wide DNA Methylation: The REGICOR Study.,Med Sci Sports Exerc,"N=619 from REGICOR?
+Yes,20191104,ewas,31652233,Physical Activity and Genome-wide DNA Methylation: The REGICOR Study.,Med Sci Sports Exerc,"N=619 from REGICOR?
 
 N=1735?
 
@@ -402,7 +402,7 @@ Two 'non-linear' associations with moderate vigorous:?
 cg24155427 (p-value=1.19E-10) linked to smoking, lupus, aging?
 
 cg09565397 (p-value=1.59E-10) linked to BMI",
-,No,20191104,ewas,31651337,Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis.,BMC Med Genomics,"Systemic sclerosis is 'a rare autoimmune connective tissue disease'?
+No,20191104,ewas,31651337,Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis.,BMC Med Genomics,"Systemic sclerosis is 'a rare autoimmune connective tissue disease'?
 
 N=9 patients vs N=9 controls?
 
@@ -413,14 +413,14 @@ CD4+ T lymphocytes?
 599 DMRs?
 
 Linked to genes involved in Wnt/beta-catenin signaling pathway, skin lesion formation and progression, and angiogenesis",
-,No,20191104,ewas,31640099,"Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer's Disease-Precursor Phenotypes, and Metabolic Morbidities.",J Alzheimers Dis,"Mild cognitive impairment a common precursor of Alzheimer’s disease?
+No,20191104,ewas,31640099,"Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer's Disease-Precursor Phenotypes, and Metabolic Morbidities.",J Alzheimers Dis,"Mild cognitive impairment a common precursor of Alzheimer’s disease?
 
 N=45 mild cognitive impaired vs N=45 controls?
 
 10 CpG sites differentially methylated in blood?
 
 ""gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes""",
-,No,20191104,ewas,31639064,Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths.,Clin Epigenetics,"Longitudinal EWAS that 'subtracts' age effects?
+No,20191104,ewas,31639064,Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths.,Clin Epigenetics,"Longitudinal EWAS that 'subtracts' age effects?
 
 N=24 youths with increase dimensional psychopathology over 3 years?
 
@@ -431,7 +431,7 @@ Blood collected at both assessments?
 15 linked to differentially expressed genes?
 
 ""We implemented a methodological framework to reduce the effect of chronological age on DNA methylation using an independent population of 140 youths and the effect of puberty using data from the literature""",
-,No,20191104,dnam age,31636290,"DNA methylation-based biological age, genome-wide average DNA methylation, and conventional breast cancer risk factors.",Sci Rep,"Surprise! Associations with genome-wide average methylation?
+No,20191104,dnam age,31636290,"DNA methylation-based biological age, genome-wide average DNA methylation, and conventional breast cancer risk factors.",Sci Rep,"Surprise! Associations with genome-wide average methylation?
 
 N=479 from the Australian Mammographic Density Twins and Sisters?
 
@@ -446,7 +446,7 @@ Genome-wide average methylation?
 DNAm age associated with BMI, smoking (!), alcohol, age at menarche?
 
 Average DNAm associated with smoking, parity, age at first birth",
-,No,20191104,ewas,31628932,Artificial Intelligence and the detection of pediatric concussion using epigenomic analysis.,Brain Res,"How much do we believe this??
+No,20191104,ewas,31628932,Artificial Intelligence and the detection of pediatric concussion using epigenomic analysis.,Brain Res,"How much do we believe this??
 
 N=17 concussion cases vs 18 controls?
 
@@ -465,7 +465,7 @@ Train on 80% (n=28), test on 20% (n=7)?
 Lasso identified 3 site model with AUC=0.98.?
 
 Deep learning performed similarly.",
-,No,20191104,dnam age,31640709,Intrinsic and extrinsic epigenetic age acceleration are associated with hypertensive target organ damage in older African Americans.,BMC Med Genomics,"Investigates DNAm age acceleration relationship with cardiovascular mortality?
+No,20191104,dnam age,31640709,Intrinsic and extrinsic epigenetic age acceleration are associated with hypertensive target organ damage in older African Americans.,BMC Med Genomics,"Investigates DNAm age acceleration relationship with cardiovascular mortality?
 
 N=1390 African Americans from GENOA study?
 
@@ -476,28 +476,28 @@ Organ damage assessed in follow-up (2000-2004)?
 IEAA (Horvath intrinsic) associated with 4 markers of damage?
 
 EEAA (Horvath extrinsic) with 1 marker of damage",
-,No,20191104,methods,31601707,Genetic regulatory variation in populations informs transcriptome analysis in rare disease.,Science,,
-,No,20191104,methods,31651351,IMAGE: high-powered detection of genetic effects on DNA methylation using integrated methylation QTL mapping and allele-specific analysis.,Genome Biol,"mQTL analysis in sequenced DNAm profiles is a bit different?
+No,20191104,methods,31601707,Genetic regulatory variation in populations informs transcriptome analysis in rare disease.,Science,,
+No,20191104,methods,31651351,IMAGE: high-powered detection of genetic effects on DNA methylation using integrated methylation QTL mapping and allele-specific analysis.,Genome Biol,"mQTL analysis in sequenced DNAm profiles is a bit different?
 
 Method for mQTL analysis for whole-genome bisulfite sequenced DNAm profiles?
 
 e.g. accounts for 'count nature' of sequencing data?
 
 e.g. analyses allele-specific methylation patterns in heterozygous individuals",
-,No,20191111,circulating,31695765,Genome-wide discovery and validation of diagnostic DNA methylation-based biomarkers for hepatocellular cancer detection in circulating cell free DNA.,Theranostics,"Blood biomarker for identifying HCC in individuals with liver cirrhosis.
+No,20191111,circulating,31695765,Genome-wide discovery and validation of diagnostic DNA methylation-based biomarkers for hepatocellular cancer detection in circulating cell free DNA.,Theranostics,"Blood biomarker for identifying HCC in individuals with liver cirrhosis.
 “As liver cirrhosis is the principal risk state for HCC development, markers to detect early HCC within this patient population are urgently needed.”
 N=22 per group, Illumina 450k for circulating cell free DNA (cfDNA)
 AUC > 0.95 in validation (N=15 per group) and publicly available liver tissue data
 Liver tissue predictors did not work well in cfDNA
 
 ",
-,Yes,20191111,ewas,31691802,Methylation changes in the peripheral blood of filipinos with type 2 diabetes suggest spurious transcription initiation at TXNIP.,Hum Mol Genet,"Functional investigation of loss of TXNIP methylation in T2D
+Yes,20191111,ewas,31691802,Methylation changes in the peripheral blood of filipinos with type 2 diabetes suggest spurious transcription initiation at TXNIP.,Hum Mol Genet,"Functional investigation of loss of TXNIP methylation in T2D
 N=218 controls and N=147 cases
 177 differentially methylated CpG sites
 3 sites near TXNIP replicate previous study
 “The TXNIP downmethylation coincided with increased transcription at the 3’-UTR, H3K36me3 histone markings, and Sp1 binding, suggesting spurious transcription initiation at the TXNIP 3’-UTR as a functional consequence of T2D methylation changes”
 ",
-,No,20191111,dnam score,31675985,Analysis of the clinical significance of DNA methylation in gastric cancer based on a genome-wide high-resolution array.,Clin Epigenetics,"3-CpG site predictor of GC recurrence and survival in blood and tissue
+No,20191111,dnam score,31675985,Analysis of the clinical significance of DNA methylation in gastric cancer based on a genome-wide high-resolution array.,Clin Epigenetics,"3-CpG site predictor of GC recurrence and survival in blood and tissue
 Patients had received surgery for GC
 EWAS of tumor and adjacent normal in N=16
 Top 3 associations evaluated with respect to metastases, GC stage, survival rate
@@ -505,24 +505,24 @@ N=141 tumor and adjacent normal
 N=106 plasma
 Associations observed but …
 ",
-,No,20191111,initiative,30053424,The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders.,Cell,"Huge effort to understand neuropsychiatric disorders using ‘systems biology’
+No,20191111,initiative,30053424,The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders.,Cell,"Huge effort to understand neuropsychiatric disorders using ‘systems biology’
 ",
-,No,20191111,initiative,31681422,Identification of Biomarkers in Neuropsychiatric Disorders Based on Systems Biology and Epigenetics.,Front Genet,"A systems biology biomarker is a subnetwork of features rather than a single or simply a collection of features.  Predicts that they will perform better.
+No,20191111,initiative,31681422,Identification of Biomarkers in Neuropsychiatric Disorders Based on Systems Biology and Epigenetics.,Front Genet,"A systems biology biomarker is a subnetwork of features rather than a single or simply a collection of features.  Predicts that they will perform better.
 ",
-,No,20191111,mitochondria,31665742,Human mitochondrial DNA is extensively methylated in a non-CpG context.,Nucleic Acids Res,"First DNA methylation profiles of mitochrondrial DNAm
+No,20191111,mitochondria,31665742,Human mitochondrial DNA is extensively methylated in a non-CpG context.,Nucleic Acids Res,"First DNA methylation profiles of mitochrondrial DNAm
 Bisulfite sequencing used to measure mitochondrial DNAm
 “mitochondrial genomes are extensively methylated predominantly at non-CpG sites”
 “DNMT3B knockdown cells displayed a comparatively pronounced global reduction in mtDNA methylation with concomitant increases in gene expression”
 ",
-,No,20191111,methods,31596850,Bayesian multivariate reanalysis of large genetic studies identifies many new associations.,PLoS Genet,"Improve power of EWAS, particularly in cohort studies?
+No,20191111,methods,31596850,Bayesian multivariate reanalysis of large genetic studies identifies many new associations.,PLoS Genet,"Improve power of EWAS, particularly in cohort studies?
 “in simulation experiments, multivariate analyses have been shown to be more powerful at detecting associations [than univariate analysis]”
 13 large studies of related traits
 anthropometric traits (GIANT), plasma lipid traits (GlobalLipids), and red blood cell traits (HaemgenRBC)
 many new associations (433 in total across the 13 studies) 
 many replicate
 ",
-,No,20191111,ewas,31659193,Grandmothers' smoking in pregnancy is associated with a reduced prevalence of early-onset myopia.,Sci Rep,,
-,No,20191111,epigenetics,31665072,"Smoking index, lifestyle factors, and genomic instability assessed by single-cell gel electrophoresis: a cross-sectional study in subjects from Yucatan, Mexico.",Clin Epigenetics,"Associations of genomic instability with lifestyle (it is an epigenetic trait)
+No,20191111,ewas,31659193,Grandmothers' smoking in pregnancy is associated with a reduced prevalence of early-onset myopia.,Sci Rep,,
+No,20191111,epigenetics,31665072,"Smoking index, lifestyle factors, and genomic instability assessed by single-cell gel electrophoresis: a cross-sectional study in subjects from Yucatan, Mexico.",Clin Epigenetics,"Associations of genomic instability with lifestyle (it is an epigenetic trait)
 “Genomic instability was evaluated through a single-cell gel electrophoresis using peripheral blood mononuclear cells in three different conditions of oxidative stress”
 N=82
 Associated with:
@@ -532,7 +532,7 @@ Diet
 Long sitting hours
 Radiation
 ",
-,No,20191118,methods,31703168,An Integrated Multi-Omics Approach to Identify Genetic Underpinnings of Heart Failure and its Echocardiographic Precursors: The Framingham Heart Study.,Circ Genom Precis Med,"Obtain biological insight and improve robustness by identifying genes implicated in multiple omics?
+No,20191118,methods,31703168,An Integrated Multi-Omics Approach to Identify Genetic Underpinnings of Heart Failure and its Echocardiographic Precursors: The Framingham Heart Study.,Circ Genom Precis Med,"Obtain biological insight and improve robustness by identifying genes implicated in multiple omics?
 
 Heart failure has heterogeneous causes, making GWAS likely to miss relevant loci?
 8372 Framingham Heart Study participants?
@@ -543,7 +543,7 @@ Perform a GWAS, EWAS and TWAS?
 Produce gene orderings from each (by statistical significance)?
 Merge orderings into a single ordering (robust rank aggregation)?
 Results: several new genes identified that had been previously implicated, for example, in animal models.?",
-,No,20191118,methods,31699133,CRUP: a comprehensive framework to predict condition-specific regulatory units.,Genome Biol,"Identify enhancers and target genes most relevant to a condition?
+No,20191118,methods,31699133,CRUP: a comprehensive framework to predict condition-specific regulatory units.,Genome Biol,"Identify enhancers and target genes most relevant to a condition?
 
 Input: H3K4me1, H3K4me3, H3K27ac and gene expression profiles across conditions.?
 
@@ -560,7 +560,7 @@ Step 3. CRUP-ET: enhancer targets?
   Target = gene expression is associated with enhancer activity across conditions?
 
 * condition = phenotype, exposure, state, etc.?",
-,No,20191125,dnam age,31746071,Accelerated hippocampal biological aging in bipolar disorder.,Bipolar Disord,"Biological aging in hippocampus?
+No,20191125,dnam age,31746071,Accelerated hippocampal biological aging in bipolar disorder.,Bipolar Disord,"Biological aging in hippocampus?
 
 N=32 BD vs 32 controls?
 
@@ -573,7 +573,7 @@ Results?
 All aging estimates correlated (|R|~0.3)?
 
 Mitochondrial copy number higher in BD (p = 0.047)?",
-,No,20191125,ewas,31745236,Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence.,Mol Psychiatry,"Evidence that DNA methylation mediates genotype effect on alcohol dependence?
+No,20191125,ewas,31745236,Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence.,Mol Psychiatry,"Evidence that DNA methylation mediates genotype effect on alcohol dependence?
 
 Dorsolateral prefrontal cortex and nucleus accumbens ?
 
@@ -596,7 +596,7 @@ DLGAP2-defficient mice had reduced alcohol consumption?
 ?
 
 ?",
-,No,20191125,mechanism,31745090,Transposable element expression in tumors is associated with immune infiltration and increased antigenicity.,Nat Commun,"Analysis of TCGA to discovers therapeutic approach to cancer?
+No,20191125,mechanism,31745090,Transposable element expression in tumors is associated with immune infiltration and increased antigenicity.,Nat Commun,"Analysis of TCGA to discovers therapeutic approach to cancer?
 
 Quantify transposable element (TE) expression in RNA-seq data?
 
@@ -607,7 +607,7 @@ Quantify transposable element (TE) expression in RNA-seq data?
 Subfamilies most consistently overexpressed were associated with 'antiviral or DNA damage responses'?
 
 Suggests a therapy: reactivation certain TEs + immunotherapy?",
-,Yes,20191125,ewas,31744183,DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood.,Nutrients,"Large EWAS of breastfeeding?
+Yes,20191125,ewas,31744183,DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood.,Nutrients,"Large EWAS of breastfeeding?
 
 Buccal cells from N=1006 twins age ~9.5 (Netherlands Twin Register)?
 
@@ -618,7 +618,7 @@ In sub-group <= 10 years: 4 CpG sites?
 Not replicated in NTR (n=98) or ALSPAC (n=938, age ~ 7, blood)?
 
 Three previously identified CpG sites replicated here?",
-,Yes,20191125,ewas,31739726,Race-specific alterations in DNA methylation among middle-aged African Americans and Whites with Metabolic Syndrome.,Epigenetics,"Example of a poorly written EWAS paper?
+Yes,20191125,ewas,31739726,Race-specific alterations in DNA methylation among middle-aged African Americans and Whites with Metabolic Syndrome.,Epigenetics,"Example of a poorly written EWAS paper?
 
 AAs (n=225, 11% MS) and White (n=233, 20% MS) middle aged adults?
 
@@ -627,7 +627,7 @@ Report findings without adjustment for multiple tests?
 Manhattan plots show Bonferroni and FDR thresholds but labelling poor?
 
 On the upside, supplementary tables provide summary statistics for all nominally significant CpG sites (p < 0.01) for multiple EWAS models?",
-,No,20191125,dnam age,31738745,A meta-analysis of genome-wide association studies of epigenetic age acceleration.,PLoS Genet,"GWAS of DNAm age acceleration?
+No,20191125,dnam age,31738745,A meta-analysis of genome-wide association studies of epigenetic age acceleration.,PLoS Genet,"GWAS of DNAm age acceleration?
 
 N=13493?
 
@@ -638,7 +638,7 @@ N=13493?
 Nominal inverse associations with father's age at death?
 
 Hannum-EAA nominally associated with smoking behavior and education?",
-,No,20191125,methods,31727104,Evaluation of commonly used analysis strategies for epigenome- and transcriptome-wide association studies through replication of large-scale population studies.,Genome Biol,"Evaluation of EWAS and TWAS methods?
+No,20191125,methods,31727104,Evaluation of commonly used analysis strategies for epigenome- and transcriptome-wide association studies through replication of large-scale population studies.,Genome Biol,"Evaluation of EWAS and TWAS methods?
 
 N=2900 (4 cohorts) ?
 
@@ -653,7 +653,7 @@ DNAm and RNA-seq: normalization or statistical test has little effect on results
 DNAm and RNA-seq: adjusting for cell counts or hidden confounders improves replication?
 
 ?",
-,No,20191125,biomarker,31682707,Association of Adverse Experiences and Exposure to Violence in Childhood and Adolescence With Inflammatory Burden in Young People.,JAMA Pediatr,"There's a new and independent measure of inflammation linked to adversity?
+No,20191125,biomarker,31682707,Association of Adverse Experiences and Exposure to Violence in Childhood and Adolescence With Inflammatory Burden in Young People.,JAMA Pediatr,"There's a new and independent measure of inflammation linked to adversity?
 
 N=1391 from the Environmental Risk Longitudinal Twin Study?
 
@@ -668,8 +668,8 @@ CRP, IL6 and suPAR (soluable urokinase plasminogen activator receptor, a new bio
 +0.26 ng/mL suPAR in those with multiple experience compared to none?
 
 Adjusting for CRP and IL6 increased the strength of these effects?",
-,Yes,20191125,ewas,29198723,DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.,Am J Hum Genet,,
-,Yes,20191216,ewas,31789449,Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data.,Addict Biol,"Thousands of CpG sites associated with alcohol intake.?
+Yes,20191125,ewas,29198723,DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.,Am J Hum Genet,,
+Yes,20191216,ewas,31789449,Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data.,Addict Biol,"Thousands of CpG sites associated with alcohol intake.?
 
 N=5606 Melbourne Collaborative Cohort Study (MCCS)?
 
@@ -684,7 +684,7 @@ N=5606 Melbourne Collaborative Cohort Study (MCCS)?
 Interactions: associations stronger in men, non-smokers, lower intake?
 
 Question: could these associations produce a better alcohol biomarker??",
-,No,20191216,dnam score,31775873,Validation and characterisation of a DNA methylation alcohol biomarker across the life course.,Clin Epigenetics,"Published alcohol intake biomarker not as good as advertised?
+No,20191216,dnam score,31775873,Validation and characterisation of a DNA methylation alcohol biomarker across the life course.,Clin Epigenetics,"Published alcohol intake biomarker not as good as advertised?
 
 N=1049 ALSPAC mothers?
 
@@ -697,7 +697,7 @@ Explains 14.3% in HN5000 a clinical cohort with higher intake?
 Explains even less in ALSPAC adolescents?
 
 No pre-intake or parent-to-offspring prediction ?",
-,No,20191216,dnam age,31767039,DNA methylation aging clocks: challenges and recommendations.,Genome Biol,"Critical review of DNAm aging clocks with recommendations for future research?
+No,20191216,dnam age,31767039,DNA methylation aging clocks: challenges and recommendations.,Genome Biol,"Critical review of DNAm aging clocks with recommendations for future research?
 
 Differentiate between 'biological' and 'chronological' aging – biological aging is too complex and tissue-specific for a single DNAm clock?
 
@@ -712,7 +712,7 @@ Single-cell analysis of aging changes and disease?
 Generation of robust non-human data of aging?
 
 Inclusion of epigenetics within current genetic ethical and legal frameworks?",
-,No,20191216,sex chromosomes,31748747,Genetic predisposition to mosaic Y chromosome loss in blood.,Nature,"Mosaic loss of Y  associated with genotype and is a marker of genomic instability?
+No,20191216,sex chromosomes,31748747,Genetic predisposition to mosaic Y chromosome loss in blood.,Nature,"Mosaic loss of Y  associated with genotype and is a marker of genomic instability?
 
 UK Biobank (N=205K) and replicated in n=757K?
 
@@ -727,7 +727,7 @@ Therefore, LOY in blood indicates general genomic instability ?
 ?
 
 Question: How much does clonal mosaicism affect DNAm analyses? e.g. DNAm age??",
-,Yes,20191216,ewas,31791392,Changes in DNA methylation from pre- to post-adolescence are associated with pubertal exposures.,Clin Epigenetics,"Many CpG sites change in DNA methylation across puberty?
+Yes,20191216,ewas,31791392,Changes in DNA methylation from pre- to post-adolescence are associated with pubertal exposures.,Clin Epigenetics,"Many CpG sites change in DNA methylation across puberty?
 
 Whole blood DNAm from Isle of Wight birth cohort (n=325)?
 
@@ -738,7 +738,7 @@ DNAm changes between 10 and 18 years of age?
 1179 CpG sites with gender-specific changes (none replicated in ALSPAC)?
 
 Question: which of these changes are specific to puberty and not generally to increasing age?",
-,Yes,20191216,ewas,31772264,DNA methylation changes in infants between 6 and 52 weeks.,Sci Rep,"DNA methylation changes with age in infants?
+Yes,20191216,ewas,31772264,DNA methylation changes in infants between 6 and 52 weeks.,Sci Rep,"DNA methylation changes with age in infants?
 
 N=214 infant saliva samples (6 weeks old n?=?62, 52 weeks old n?=?30, or both n?=?61)?
 
@@ -747,7 +747,7 @@ DMPs at 42 genes, 36 with increased methylation.?
 ?
 
 Question: how do these changes compare to DNAm changes with increasing age at older ages??",
-,Yes,20191216,ewas,31791327,DNA methylation is associated with lung function in never smokers.,Respir Res,"Lung function associated with DNAm in never smokers??
+Yes,20191216,ewas,31791327,DNA methylation is associated with lung function in never smokers.,Respir Res,"Lung function associated with DNAm in never smokers??
 
 Whole blood of never smokers?
 
@@ -760,97 +760,97 @@ No genome-wide associations ?
 36 at p < 0.0001 of which 35 novel?
 
 Can we conclude this? ""DNA methylation is also associated with FEV1/FVC in subjects that never smoked""?",
-,No,20200113,sex chromosomes,31767861,Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age.,Nat Commun,"Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. Skewed XCI toward one parental X has been observed in several complex human traits, but the extent to which genetics and environment influence skewed XCI is largely unexplored. To address this, we quantify XCI-skew in multiple tissues and immune cell types in a twin cohort. Within an individual, XCI-skew differs between blood, fat and skin tissue, but is shared across immune cell types. XCI skew increases with age in blood, but not other tissues, and is associated with smoking. XCI-skew is increased in twins with Rheumatoid Arthritis compared to unaffected identical co-twins. XCI-skew is heritable in blood of females &gt;55 years old (h<sup>2</sup> = 0.34), but not in younger individuals or other tissues. This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner.",
-,No,20200113,prediction,31762318,Genome-wide analysis of DNA methylation identifies two CpG sites for the early screening of colorectal cancer.,Epigenomics,"<b>Aim:</b> To identify a panel of DNA methylation markers for the early diagnosis of colorectal cancer (CRC). <b>Materials &amp; methods:</b> Using public omics data and our pyrosequencing data, we developed and validated a global methylation model and a CpG-methylation-based model for CRC screening. <b>Results:</b> Both of the models yielded high sensitivity and specificity for distinguishing CRC and its precursors (colorectal adenoma and colorectal laterally spreading tumor) from normal controls in eight independent datasets and our newly collected samples. More importantly, the two-CpG-based model showed high specificity in excluding inflammatory bowel diseases and other 13 cancer types. <b>Conclusion:</b> A diagnostic model based on two CpGs (cg09239744 and cg12587766) may be a powerful tool for CRC screening.",
-,Yes,20200113,ewas,31811260,Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.,Mol Psychiatry,"DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.",
-,Yes,20200113,ewas,31892367,Newborn and childhood differential DNA methylation and liver fat in school-age children.,Clin Epigenetics,"Non-alcoholic fatty liver disease is the most common chronic liver disease in children in western countries. Adverse early-life exposures are associated with higher liver fat percentages in children. Differential DNA methylation may underlie these associations. We aimed to identify differential DNA methylation in newborns and children associated with liver fat accumulation in childhood. We also examined whether DNA methylation at 22 cytosine-phosphate-guanine sites (CpGs) associated with adult non-alcoholic fatty liver disease is associated with liver fat in children. Within a population-based prospective cohort study, we analyzed epigenome-wide DNA methylation data of 785 newborns and 344 10-year-old children in relation to liver fat fraction at 10 years. DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Illumina). We measured liver fat fraction by Magnetic Resonance Imaging. Associations of single CpG DNA methylation at the two-time points with liver fat accumulation were analyzed using robust linear regression models. We also analyzed differentially methylation regions using the dmrff package. We looked-up associations of 22 known adult CpGs at both ages with liver fat at 10 years. The median liver fat fraction was 2.0% (95% range 1.3, 5.1). No single CpGs and no differentially methylated regions were associated with liver fat accumulation. None of the 22 known adult CpGs were associated with liver fat in children. DNA methylation at birth and in childhood was not associated with liver fat accumulation in 10-year-old children in this study. This may be due to modest sample sizes or DNA methylation changes being a consequence rather than a determinant of liver fat.",
-,Yes,20200113,ewas,31892350,An epigenome-wide association study of sex-specific chronological ageing.,Genome Med,"Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 individuals between the ages of 18 and 87 years, with replication in a further 4450 individuals between the ages of 18 and 93 years. Linear regression models were applied, with stringent genome-wide significance thresholds (p &lt; 3.6 × 10<sup>-8</sup>) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds. Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10, an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = - 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction. The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.",
-,Yes,20200113,ewas,31880793,Association of Periconception Paternal Body Mass Index With Persistent Changes in DNA Methylation of Offspring in Childhood.,JAMA Netw Open,"While prenatal nutrition and maternal obesity are recognized as important contributors to epigenetic changes and childhood obesity, the role of paternal obesity in the epigenome of offspring has not been well studied. To test whether periconception paternal body mass index (BMI) is associated with DNA methylation patterns in newborns, to examine associations between maternal and paternal BMI and the epigenome of offspring, and to examine persistence of epigenetic marks at ages 3 and 7 years. Project Viva is a prebirth cohort study of mothers and children including 2128 live births that enrolled mothers from April 1999 to July 2002 and followed offspring to adolescence. This study analyzed the subset of participants with available data on paternal BMI and DNA methylation in offspring blood in the newborn period, at age 3 years, and at age 7 years. Data were analyzed from July 2017 to October 2019. The primary exposure was paternal periconception BMI; associations were adjusted for maternal prepregnancy BMI and stratified according to maternal BMI above or below 25. The primary outcome was genome-wide DNA methylation patterns in offspring blood collected at birth, age 3 years, and age 7 years. A total of 429 father-mother-infant triads were included. The mean (SD) periconception paternal BMI was 26.4 (4.0) and mean maternal prepregnancy BMI was 24.5 (5.2); 268 fathers had BMI greater than or equal to 25 (mean [SD], 28.5 [3.3]) and 161 had BMI less than 25 (mean [SD], 22.8 [1.8]). Paternal BMI greater than or equal to 25 was associated with increased offspring birth weight compared with paternal BMI less than 25 (mean [SD] z score, 0.38 [0.91] vs 0.11 [0.96]; P = .004). Cord blood DNA methylation at 9 CpG sites was associated with paternal BMI independent of maternal BMI (q &lt; .05). Methylation at cg04763273, between TFAP2C and BMP7, decreased by 5% in cord blood with every 1-unit increase in paternal BMI (P = 3.13 × 10-8); hypomethylation at this site persisted at ages 3 years and 7 years. Paternal BMI was associated with methylation at cg01029450 in the promoter region of the ARFGAP3 gene; methylation at this site was also associated with lower infant birth weight (β = -0.0003; SD = 0.0001; P = .03) and with higher BMI z score at age 3 years. In this study, paternal BMI was associated with DNA methylation, birth weight, and childhood BMI z score in offspring.",
-,Yes,20200113,ewas,31851703,Association of cord blood methylation with neonatal leptin: An epigenome wide association study.,PLoS ONE,"Neonatal adiposity is a risk factor for childhood obesity. Investigating contributors to neonatal adiposity is important for understanding early life obesity risk. Epigenetic changes of metabolic genes in cord blood may contribute to excessive neonatal adiposity and subsequent childhood obesity. This study aims to evaluate the association of cord blood DNA methylation patterns with anthropometric measures and cord blood leptin, a biomarker of neonatal adiposity. A cross-sectional study was performed on a multiethnic cohort of 114 full term neonates born to mothers without gestational diabetes at a university hospital. Cord blood was assayed for leptin and for epigenome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariable linear regression was used to analyze associations between individual CpG sites as well as differentially methylated regions in cord blood DNA with measures of newborn adiposity including anthropometrics (birth weight, fat mass and percent body fat) and cord blood leptin. False discovery rate was estimated to account for multiple comparisons. 247 CpG sites as well as 18 differentially methylated gene regions were associated with cord blood leptin but no epigenetic changes were associated with birth weight, fat mass or percent body fat. Genes of interest identified in this study are DNAJA4, TFR2, SMAD3, PLAG1, FGF1, and HNF4A. Epigenetic changes in cord blood DNA are associated with cord blood leptin levels, a measure of neonatal adiposity.",
-,No,20200113,pwas,31792462,Plasma protein patterns as comprehensive indicators of health.,Nat Med,"Proteins are effector molecules that mediate the functions of genes<sup>1,2</sup> and modulate comorbidities<sup>3-10</sup>, behaviors and drug treatments<sup>11</sup>. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning<sup>12-16</sup> coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.",
-,No,20200113,meqtl,31861999,MethylToSNP: identifying SNPs in Illumina DNA methylation array data.,Epigenetics Chromatin,"Current array-based methods for the measurement of DNA methylation rely on the process of sodium bisulfite conversion to differentiate between methylated and unmethylated cytosine bases in DNA. In the absence of genotype data this process can lead to ambiguity in data interpretation when a sample has polymorphisms at a methylation probe site. A common way to minimize this problem is to exclude such potentially problematic sites, with some methods removing as much as 60% of array probes from consideration before data analysis. Here, we present an algorithm implemented in an R Bioconductor package, MethylToSNP, which detects a characteristic data pattern to infer sites likely to be confounded by polymorphisms. Additionally, the tool provides a stringent reliability score to allow thresholding on SNP predictions. We calibrated parameters and thresholds used by the algorithm on simulated and real methylation data sets. We illustrate findings using methylation data from YRI (Yoruba in Ibadan, Nigeria), CEPH (European descent) and KhoeSan (southern African) populations. Our polymorphism predictions made using MethylToSNP have been validated through SNP databases and bisulfite and genomic sequencing. The benefits of this method are threefold. First, it prevents extensive data loss by considering only SNPs specific to the individuals in the study. Second, it offers the possibility to identify new polymorphisms in samples for which there is little known about the genetic landscape. Third, it identifies variants as they exist in functional regions of a genome, such as in CTCF (transcriptional repressor) sites and enhancers, that may be common alleles or personal mutations with potential to deleteriously affect genomic regulatory activities. We demonstrate that MethylToSNP is applicable to the Illumina 450K and Illumina 850K EPIC array data and is also backwards compatible to the 27K methylation arrays. Going forward, this kind of nuanced approach can increase the amount of information derived from precious data sets by considering samples of the project individually to enable more informed decisions about data cleaning.",
-,Yes,20200113,ewas,31889537,Cell Type-Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder.,Biol Psychiatry,"We sought to characterize methylation changes in brain and blood associated with major depressive disorder (MDD). As analyses of bulk tissue may obscure association signals and hamper the biological interpretation of findings, these changes were studied on a cell type-specific level. In 3 collections of human postmortem brain (n = 206) and 1 collection of blood samples (N = 1132) of MDD cases and controls, we used epigenomic deconvolution to perform cell type-specific methylome-wide association studies within subpopulations of neurons/glia for the brain data and granulocytes/T cells/B cells/monocytes for the blood data. Sorted neurons/glia from a fourth postmortem brain collection (n = 58) were used for validation purposes. Cell type-specific methylome-wide association studies identified multiple findings in neurons/glia that were detected across brain collections and were reproducible in physically sorted nuclei. Cell type-specific analyses in blood samples identified methylome-wide significant associations in T cells, monocytes, and whole blood that replicated findings from a past methylation study of MDD. Pathway analyses implicated p75 neurotrophin receptor/nerve growth factor signaling and innate immune toll-like receptor signaling in MDD. Top results in neurons, glia, bulk brain, T cells, monocytes, and whole blood were enriched for genes supported by genome-wide association studies for MDD and other psychiatric disorders. We both replicated and identified novel MDD-methylation associations in human brain and blood samples at a cell type-specific level. Our results provide mechanistic insights into how the immune system may interact with the brain to affect MDD susceptibility. Importantly, our findings involved associations with MDD in human samples that implicated many closely related biological pathways. These disease-linked sites and pathways represent promising new therapeutic targets for MDD.",
-,No,20200113,somatic mutations,31874648,The somatic mutation landscape of the human body.,Genome Biol,"Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet they remain largely uncharacterized. To gain a better understanding of the genome-wide distribution and functional impact of somatic mutations, we leverage the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, reveals a wide diversity of tissue-specific mutation profiles associated with gene expression levels and chromatin states. For example, lung samples with low expression of the mismatch-repair gene MLH1 show a mutation signature of deficient mismatch repair. In addition, we find pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which are under positive selection and are highly enriched in many healthy tissues. These findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis.",
-,Yes,20200113,ewas,31882564,Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy,Diabetes,"The placenta participates in maternal insulin sensitivity changes during pregnancy, however mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75g oral glucose tolerance tests at ?26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using IlluminaEPIC arrays. Using linear regression models to quantify associations at 720,077 CpGs, adjusted for maternal age, gravidity, smoking, body mass index, child sex and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P<6.94x10-8). Among genes annotated to these 188 CpGs, we found enrichment in targets for microRNAs, histone modifications, and in parent-of-origin DNA methylation including H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1 Mendelian Randomization analyses revealed 5 loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy.",
-,Yes,20200113,ewas,31915053,Epigenome-wide association study of seizures in childhood and adolescence.,Clin Epigenetics,,
-,,20200113,ewas,31877125,Human sperm displays rapid responses to diet.,PLoS Biol,"The global rise in obesity and steady decline in sperm quality are two alarming trends that have emerged during recent decades. In parallel, evidence from model organisms shows that paternal diet can affect offspring metabolic health in a process involving sperm tRNA-derived small RNA (tsRNA). Here, we report that human sperm are acutely sensitive to nutrient flux, both in terms of sperm motility and changes in sperm tsRNA. Over the course of a 2-week diet intervention, in which we first introduced a healthy diet followed by a diet rich in sugar, sperm motility increased and stabilized at high levels. Small RNA-seq on repeatedly sampled sperm from the same individuals revealed that tsRNAs were up-regulated by eating a high-sugar diet for just 1 week. Unsupervised clustering identified two independent pathways for the biogenesis of these tsRNAs: one involving a novel class of fragments with specific cleavage in the T-loop of mature nuclear tRNAs and the other exclusively involving mitochondrial tsRNAs. Mitochondrial involvement was further supported by a similar up-regulation of mitochondrial rRNA-derived small RNA (rsRNA). Notably, the changes in sugar-sensitive tsRNA were positively associated with simultaneous changes in sperm motility and negatively associated with obesity in an independent clinical cohort. This rapid response to a dietary intervention on tsRNA in human sperm is attuned with the paternal intergenerational metabolic responses found in model organisms. More importantly, our findings suggest shared diet-sensitive mechanisms between sperm motility and the biogenesis of tsRNA, which provide novel insights about the interplay between nutrition and male reproductive health.",
-,Yes,20200113,ewas,31900413,Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits.,Nat Commun,"DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.",
-,Yes,20200113,ewas,31910897,Replication and expansion of epigenome-wide association literature in a black South African population.,Clin Epigenetics,"DNA methylation is associated with non-communicable diseases (NCDs) and related traits. Methylation data on continental African ancestries are currently scarce, even though there are known genetic and epigenetic differences between ancestral groups and a high burden of NCDs in Africans. Furthermore, the degree to which current literature can be extrapolated to the understudied African populations, who have limited resources to conduct independent large-scale analysis, is not yet known. To this end, this study examines the reproducibility of previously published epigenome-wide association studies of DNA methylation conducted in different ethinicities, on factors related to NCDs, by replicating findings in 120 South African Batswana men aged 45 to 88 years. In addition, novel associations between methylation and NCD-related factors are investigated using the Illumina EPIC BeadChip. Up to 86% of previously identified epigenome-wide associations with NCD-related traits (alcohol consumption, smoking, body mass index, waist circumference, C-reactive protein, blood lipids and age) overlapped with those observed here and a further 13% were directionally consistent. Only 1% of the replicated associations presented with effects opposite to findings in other ancestral groups. The majority of these inconcistencies were associated with population-specific genomic variance. In addition, we identified eight new 450K array CpG associations not previously reported in other ancestries, and 11 novel EPIC CpG associations with alcohol consumption. The successful replication of existing EWAS findings in this African population demonstrates that blood-based 450K EWAS findings from commonly investigated ancestries can largely be extrapolated to ethnicities for which epigenetic data are not yet available. Possible population-specific differences in 14% of the tested associations do, however, motivate the need to include a diversity of ethnic groups in future epigenetic research. The novel associations found with the enhanced coverage of the Illumina EPIC array support its usefulness to expand epigenetic literature.",
-,No,20200113,dnam age,31831772,A genomic predictor of lifespan in vertebrates.,Sci Rep,"Biological ageing and its mechanistic underpinnings are of immense biomedical and ecological significance. Ageing involves the decline of diverse biological functions and places a limit on a species' maximum lifespan. Ageing is associated with epigenetic changes involving DNA methylation. Furthermore, an analysis of mammals showed that the density of CpG sites in gene promoters, which are targets for DNA methylation, is correlated with lifespan. Using 252 whole genomes and databases of animal age and promotor sequences, we show a pattern across vertebrates. We also derive a predictive lifespan clock based on CpG density in a selected set of promoters. The lifespan clock accurately predicts maximum lifespan in vertebrates (R<sup>2</sup> = 0.76) from the density of CpG sites within only 42 selected promoters. Our lifespan clock provides a wholly new method for accurately estimating lifespan using genome sequences alone and enables estimation of this challenging parameter for both poorly understood and extinct species.",
-,No,20200127,methods,31717838,Discrimination of DNA Methylation Signal from Background Variation for Clinical Diagnostics.,Int J Mol Sci,"Advances in the study of human DNA methylation variation offer a new avenue for the translation of epigenetic research results to clinical applications. Although current approaches to methylome analysis have been helpful in revealing an epigenetic influence in major human diseases, this type of analysis has proven inadequate for the translation of these advances to clinical diagnostics. As in any clinical test, the use of a methylation signal for diagnostic purposes requires the estimation of an optimal cutoff value for the signal, which is necessary to discriminate a signal induced by a disease state from natural background variation. To address this issue, we propose the application of a fundamental signal detection theory and machine learning approaches. Simulation studies and tests of two available methylome datasets from autism and leukemia patients demonstrate the feasibility of this approach in clinical diagnostics, providing high discriminatory power for the methylation signal induced by disease, as well as high classification performance. Specifically, the analysis of whole biomarker genomic regions could suffice for a diagnostic, markedly decreasing its cost.",
-,Yes,20200127,ewas,31857576,Edematous severe acute malnutrition is characterized by hypomethylation of DNA.,Nat Commun,"Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.",
-,No,20200127,dnam age,31847916,Systematic underestimation of the epigenetic clock and age acceleration in older subjects.,Genome Biol,"The Horvath epigenetic clock is widely used. It predicts age quite well from 353 CpG sites in the DNA methylation profile in unknown samples and has been used to calculate &quot;age acceleration&quot; in various tissues and environments. The model systematically underestimates age in tissues from older people. This is seen in all examined tissues but most strongly in the cerebellum and is consistently observed in multiple datasets. Age acceleration is thus age-dependent, and this can lead to spurious associations. The current literature includes examples of association tests with age acceleration calculated in a wide variety of ways. The concept of an epigenetic clock is compelling, but caution should be taken in interpreting associations with age acceleration. Association tests of age acceleration should include age as a covariate.",
-,No,20200127,prediction,32296024,DNA methylation markers in the diagnosis and prognosis of common leukemias.,Signal Transduct Target Ther,"The ability to identify a specific type of leukemia using minimally invasive biopsies holds great promise to improve the diagnosis, treatment selection, and prognosis prediction of patients. Using genome-wide methylation profiling and machine learning methods, we investigated the utility of CpG methylation status to differentiate blood from patients with acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML) from normal blood. We established a CpG methylation panel that can distinguish ALL and AML blood from normal blood as well as ALL blood from AML blood with high sensitivity and specificity. We then developed a methylation-based survival classifier with 23 CpGs for ALL and 20 CpGs for AML that could successfully divide patients into high-risk and low-risk groups, with significant differences in clinical outcome in each leukemia type. Together, these findings demonstrate that methylation profiles can be highly sensitive and specific in the accurate diagnosis of ALL and AML, with implications for the prediction of prognosis and treatment selection.",
-,No,20200127,ewas,31959221,"The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients.",Clin Epigenetics,"Severe obesity is a growing, worldwide burden and conventional therapies including radical change of diet and/or increased physical activity have limited results. Bariatric surgery has been proposed as an alternative therapy showing promising results. It leads to substantial weight loss and improvement of comorbidities such as type 2 diabetes. Increased adiposity is associated with changes in epigenetic profile, including DNA methylation. We investigated the effect of bariatric surgery on clinical profile, DNA methylation, and biological age estimated using Horvath's epigenetic clock. To determine the impact of bariatric surgery and subsequent weight loss on clinical traits, a cohort of 40 severely obese individuals (BMI = 30-73 kg/m<sup>2</sup>) was examined at the time of surgery and at three follow-up visits, i.e., 3, 6, and 12 months after surgery. The majority of the individuals were women (65%) and the mean age at surgery was 45.1 ± 8.1 years. We observed a significant decrease over time in BMI, fasting glucose, HbA1c, HOMA-IR, insulin, total cholesterol, triglycerides, LDL and free fatty acids levels, and a significant small increase in HDL levels (all p values &lt; 0.05). Epigenome-wide association analysis revealed 4857 differentially methylated CpG sites 12 months after surgery (at Bonferroni-corrected p value &lt; 1.09 × 10<sup>-7</sup>). Including BMI change in the model decreased the number of significantly differentially methylated CpG sites by 51%. Gene set enrichment analysis identified overrepresentation of multiple processes including regulation of transcription, RNA metabolic, and biosynthetic processes in the cell. Bariatric surgery in severely obese patients resulted in a decrease in both biological age and epigenetic age acceleration (EAA) (mean = - 0.92, p value = 0.039). Our study shows that bariatric surgery leads to substantial BMI decrease and improvement of clinical outcomes observed 12 months after surgery. These changes explained part of the association between bariatric surgery and DNA methylation. We also observed a small, but significant improvement of biological age. These epigenetic changes may be modifiable by environmental lifestyle factors and could be used as potential biomarkers for obesity and in the future for obesity related comorbidities.",
-,Yes,20200127,ewas,31943067,Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer.,Hum Mol Genet,"Prior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts. DNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. Through an Epigenome Wide Association Study we explored CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer using linear mixed effects models adjusted for history of breast biopsy, age, RefFreeCellMix cell estimates, time of delivery, array chip, and subject as random effect. We identified 58 differentially methylated CpG sites associated with a subsequent breast cancer diagnosis (q-value &lt; 0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls. Breast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors and improving primary and secondary prevention of breast cancer.",
-,Yes,20200127,ewas,31932625,Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma.,Sci Rep,"DNA methylation (DNAm) profiles in central airway epithelial cells (AECs) may play a key role in pathological processes in asthma. The goal of the current study is to compare the diagnostic performance of DNAm markers across three tissues: AECs, nasal epithelial cells (NECs), and peripheral blood mononuclear cells (PBMCs). Additionally, we focused on the results using the machine learning algorithm in the context of multi-locus effects to evaluate the diagnostic performance of the optimal subset of CpG sites. We obtained 74 subjects with asthma and 41 controls from AECs, 15 subjects with asthma and 14 controls from NECs, 697 subjects with asthma and 97 controls from PBMCs. Epigenome-wide DNA methylation levels in AECs, NECs and PBMCs were measured using the Infinium Human Methylation 450 K BeadChip. Overlap analysis across the three different sample sources at the locus and pathway levels were studied to investigate shared or unique pathophysiological processes of asthma across tissues. Using the top 100 asthma-associated methylation markers as classifiers from each dataset, we found that both AEC- and NEC-based DNAm signatures exerted a lower classification error than the PBMC-based DNAm markers (p-value = 0.0002). The area-under-the-curve (AUC) analysis based on out-of-bag errors using the random forest classification algorithm revealed that PBMC-, NEC-, and AEC-based methylation data yielded 31 loci (AUC: 0.87), 8 loci (AUC: 0.99), and 4 loci (AUC: 0.97) from each optimal subset of tissue-specific markers, respectively. We also discovered the locus-locus interaction of DNAm levels of the CDH6 gene and RAPGEF3 gene might interact with each other to jointly predict the risk of asthma - which suggests the pivotal role of cell-cell junction in the pathological changes of asthma. Both AECs and NECs might provide better diagnostic accuracy and efficacy levels than PBMCs. Further research is warranted to evaluate how these tissue-specific DNAm markers classify and predict asthma risk.",
-,No,20200127,epigenetics,31949157,Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer.,Nat Commun,"Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.",
-,No,20200210,epigenetics,31999955,ATAC-Me Captures Prolonged DNA Methylation of Dynamic Chromatin Accessibility Loci during Cell Fate Transitions.,Mol Cell,"DNA methylation of enhancers is dynamic, cell-type specific, and vital for cell fate progression. However, current models inadequately define its role within the hierarchy of gene regulation. Analysis of independent datasets shows an unanticipated overlap between DNA methylation and chromatin accessibility at enhancers of steady-state stem cells, suggesting that these two opposing features might exist concurrently. To define their temporal relationship, we developed ATAC-Me, which probes accessibility and methylation from single DNA library preparations. We identified waves of accessibility occurring rapidly across thousands of myeloid enhancers in a monocyte-to-macrophage cell fate model. Prolonged methylation states were observed at a majority of these sites, while transcription of nearby genes tracked closely with accessibility. ATAC-Me uncovers a significant disconnect between chromatin accessibility, DNA methylation status, and gene activity. This unexpected observation highlights the value of ATAC-Me in constructing precise molecular timelines for understanding the role of DNA methylation in gene regulation.",
-,Yes,20200210,ewas,32007686,Selenium-associated DNA methylation modifications in placenta and neurobehavioral development of newborns: An epigenome-wide study of two U.S. birth cohorts.,Environ Int,"Selenium (Se) levels in pregnancy have been linked to neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impacts of environmental exposures on fetal development; however, very few studies have been done elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns' neurobehavior. We measured placental Se concentrations in 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 newborns in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 BeadChip, and newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores. We identified five Se-related differentially methylated CpG sites. Among them was cg09674502 (GFI1), where selenium concentration was positively associated with methylation (β-coefficient = 1.11, FDR-adjusted p-value = 0.045), and where we observed that a one percent methylation level increase was associated with a 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). We also observed for each interquartile range (IQR) increase in selenium concentration in the placenta, there was 1.76 times greater odds of higher hypotonicity (OR [95% CI] = 1.76 [1.12, 2.82]). Placental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.",
-,No,20200210,methods,32003784,decorate: Differential Epigenetic Correlation Test.,Bioinformatics,"Identifying correlated epigenetic features and finding differences in correlation between individuals with disease compared to controls can give novel insight into disease biology. This framework has been successful in analysis of gene expression data, but application to epigenetic data has been limited by the computational cost, lack of scalable software and lack of robust statistical tests. Decorate, differential epigenetic correlation test, identifies correlated epigenetic features and finds clusters of features that are differentially correlated between two or more subsets of the data. The software scales to genome-wide datasets of epigenetic assays on hundreds of individuals. We apply decorate to four large-scale datasets of DNA methylation, ATAC-seq and histone modification ChIP-seq. decorate R package is available from https://github.com/GabrielHoffman/decorate. Supplementary data are available at Bioinformatics online.",
-,No,20200210,methods,32000657,Detection of suspicious interactions of spiking covariates in methylation data.,BMC Bioinformatics,"In methylation analyses like epigenome-wide association studies, a high amount of biomarkers is tested for an association between the measured continuous outcome and different covariates. In the case of a continuous covariate like smoking pack years (SPY), a measure of lifetime exposure to tobacco toxins, a spike at zero can occur. Hence, all non-smokers are generating a peak at zero, while the smoking patients are distributed over the other SPY values. Additionally, the spike might also occur on the right side of the covariate distribution, if a category &quot;heavy smoker&quot; is designed. Here, we will focus on methylation data with a spike at the left or the right of the distribution of a continuous covariate. After the methylation data is generated, analysis is usually performed by preprocessing, quality control, and determination of differentially methylated sites, often performed in pipeline fashion. Hence, the data is processed in a string of methods, which are available in one software package. The pipelines can distinguish between categorical covariates, i.e. for group comparisons or continuous covariates, i.e. for linear regression. The differential methylation analysis is often done internally by a linear regression without checking its inherent assumptions. A spike in the continuous covariate is ignored and can cause biased results. We have reanalysed five data sets, four freely available from ArrayExpress, including methylation data and smoking habits reported by smoking pack years. Therefore, we generated an algorithm to check for the occurrences of suspicious interactions between the values associated with the spike position and the non-spike positions of the covariate. Our algorithm helps to decide if a suspicious interaction can be found and further investigations should be carried out. This is mostly important, because the information on the differentially methylated sites will be used for post-hoc analyses like pathway analyses. We help to check for the validation of the linear regression assumptions in a methylation analysis pipeline. These assumptions should also be considered for machine learning approaches. In addition, we are able to detect outliers in the continuous covariate. Therefore, more statistical robust results should be produced in methylation analysis using our algorithm as a preprocessing step.",
-,Yes,20200210,ewas,31999706,Associations between high blood pressure and DNA methylation.,PLoS ONE,"High blood pressure is a major risk factor for cardiovascular disease and is influenced by both environmental and genetic factors. Epigenetic processes including DNA methylation potentially mediate the relationship between genetic factors, the environment and cardiovascular disease. Despite an increased risk of hypertension and cardiovascular disease in individuals of South Asians compared to Europeans, it is not clear whether associations between blood pressure and DNA methylation differ between these groups. We performed an epigenome-wide association study and differentially methylated region (DMR) analysis to identify DNA methylation sites and regions that were associated with systolic blood pressure, diastolic blood pressure and hypertension. We analyzed samples from 364 European and 348 South Asian men (first generation migrants to the UK) from the Southall And Brent REvisited cohort, measuring DNA methylation from blood using the Illumina Infinium® HumanMethylation450 BeadChip. One CpG site was found to be associated with DBP in trans-ancestry analyses (i.e. both ethnic groups combined), while in Europeans alone seven CpG sites were associated with DBP. No associations were identified between DNA methylation and either SBP or hypertension. Comparison of effect sizes between South Asian and European EWAS for DBP, SBP and hypertension revealed little concordance between analyses. DMR analysis identified several regions with known relationships with CVD and its risk factors. This study identified differentially methylated sites and regions associated with blood pressure and revealed ethnic differences in these associations. These findings may point to molecular pathways which may explain the elevated cardiovascular disease risk experienced by those of South Asian ancestry when compared to Europeans.",
-,Yes,20200210,ewas,31995399,DNA Methylation is Predictive of Mortality in Current and Former Smokers.,Am J Respir Crit Care Med,"Smoking results in at least a decade lower life expectancy. Mortality among current smokers is two to three times as high as never smokers. DNA methylation is an epigenetic modification of the human genome that has been associated with both cigarette smoking and mortality. We sought to identify DNA methylation marks in blood predictive of mortality in a subset of the COPDGene study, representing 101 deaths among 667 current and former smokers. We assayed genome-wide DNA methylation in non-Hispanic white smokers with and without COPD using blood samples from the COPDGene enrollment visit. We tested whether DNA methylation was associated with mortality in models adjusted for COPD status, age, sex, current-smoking status, and pack-years of cigarette smoking. Replication was performed in a subset of 231 individuals from the ECLIPSE study. We identified seven CpG sites associated with mortality (FDR &lt; 20%) that replicated in the ECLIPSE cohort (p &lt; 0.05). None of these marks were associated with longitudinal lung function decline in survivors, smoking history or current smoking status. However, differential methylation of two replicated PIK3CD sites were associated with lung function at enrollment (p &lt; 0.05). We also observed associations between DNA methylation and gene expression for the PIK3CD sites. This study is the first to identify variable DNA methylation associated with all-cause mortality in smokers with and without COPD. Evaluating predictive epigenomic marks of smokers in peripheral blood may allow for targeted risk stratification and aid in delivery of future tailored therapeutic interventions.",
-,Yes,20200210,ewas,31992121,Epigenomics of being bullied: changes in DNA methylation following bullying exposure.,Epigenetics,"Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined <i>n</i> = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to <i>5-HTT</i> and <i>NR3C1</i>. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (<i>b</i> = -2.67e-03, SE = 4.97e-04, <i>p</i> = 7.17e-08). This site is annotated to <i>RAB14</i>, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for <i>5-HTT</i> and <i>NR3C1</i>. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation.",
-,Yes,20200210,ewas,31985870,Coagulation factor VIII: Relationship to Cardiovascular Disease Risk and Whole Genome Sequence and Epigenome-Wide Analysis in African Americans.,J Thromb Haemost,"Prospective studies have suggested higher factor VIII (FVIII) levels is an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans. We measured FVIII levels in ~3,400 AAs from the community-based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations. We assessed cross-sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome-wide methylation array. Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B-type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome-wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant. Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.",
-,No,20200210,methods,31985744,CoMeBack: DNA Methylation Array Data Analysis for Co-Methylated Regions.,Bioinformatics,"High-dimensional DNA methylation (DNAm) array coverage, while sparse in the context of the entire DNA methylome, still constitutes a very large number of CpG probes. The ensuing multiple test corrections affect the statistical power to detect associations, likely contributing to prevalent limited reproducibility. Array probes measuring proximal CpG sites often have correlated levels of DNAm that may not only be biologically meaningful but also imply statistical dependence and redundancy. New methods that account for such correlations between adjacent probes may enable improved specificity, discovery, and interpretation of statistical associations in DNAm array data. We developed a method named Co-Methylation with genomic CpG Background (CoMeBack), that estimates DNA co-methylation, defined as proximal CpG probes with correlated DNAm across individuals. CoMeBack outputs Co-methylated Regions (CMRs), spanning sets of array probes constructed based on all genomic CpG sites, including those not measured on the array, and without any phenotypic variable inputs. This approach can reduce the multiple test correction burden, while enhancing the discovery and specificity of statistical associations. We constructed and validated CMRs in whole blood, using publicly available Illumina Infinium 450K array (450K) data from over 5,000 individuals. These CMRs were enriched for enhancer chromatin states, and binding site motifs for several transcription factors involved in blood physiology. We illustrated how CMR-based Epigenome Wide Association Studies (EWAS) can improve discovery and reduce false positives for associations with chronological age. https://bitbucket.org/flopflip/comeback. Supplementary data are available at Bioinformatics online.",
-,No,20200210,dnam age,31981007,One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project.,Geroscience,"Mediterranean diet has been proposed to promote healthy aging, but its effects on aging biomarkers have been poorly investigated. We evaluated the impact of a 1-year Mediterranean-like diet in a pilot study including 120 elderly healthy subjects from the NU-AGE study (60 Italians, 60 Poles) by measuring the changes in their epigenetic age, assessed by Horvath's clock. We observed a trend towards epigenetic rejuvenation of participants after nutritional intervention. The effect was statistically significant in the group of Polish females and in subjects who were epigenetically older at baseline. A genome-wide association study of epigenetic age changes after the intervention did not return significant (adjusted p value &lt; 0.05) loci. However, we identified small-effect alleles (nominal p value &lt; 10-4), mapping in genes enriched in pathways related to energy metabolism, regulation of cell cycle, and of immune functions. Together, these findings suggest that Mediterranean diet can promote epigenetic rejuvenation but with country-, sex-, and individual-specific effects, thus highlighting the need for a personalized approach to nutritional interventions.",
-,No,20200210,methods,31969180,A curated benchmark of enhancer-gene interactions for evaluating enhancer-target gene prediction methods.,Genome Biol,"Many genome-wide collections of candidate cis-regulatory elements (cCREs) have been defined using genomic and epigenomic data, but it remains a major challenge to connect these elements to their target genes. To facilitate the development of computational methods for predicting target genes, we develop a Benchmark of candidate Enhancer-Gene Interactions (BENGI) by integrating the recently developed Registry of cCREs with experimentally derived genomic interactions. We use BENGI to test several published computational methods for linking enhancers with genes, including signal correlation and the TargetFinder and PEP supervised learning methods. We find that while TargetFinder is the best-performing method, it is only modestly better than a baseline distance method for most benchmark datasets when trained and tested with the same cell type and that TargetFinder often does not outperform the distance method when applied across cell types. Our results suggest that current computational methods need to be improved and that BENGI presents a useful framework for method development and testing.",
-,No,20200210,mitochondria,31941967,Breastfeeding predicts blood mitochondrial DNA content in adolescents.,Sci Rep,"Nutrition during early childhood is linked to metabolic programming. We hypothesized that breastfeeding has long-term consequences on the energy metabolism exemplified by mitochondrial DNA (mtDNA). As part of the third cycle of the Flemish Environment and Health Study (FLEHSIII) cohort, 303 adolescents aged 14-15 years were included. We associated breastfeeding and blood mtDNA content 14-15 years later while adjusting for confounding variables. Compared with non-breastfed adolescents, mtDNA content was 23.1% (95%CI: 4.4-45.2; p = 0.013) higher in breastfed adolescents. Being breastfed for 1-10 weeks, 11-20 weeks, and &gt;20 weeks, was associated with a higher mtDNA content of respectively 16.0% (95%CI: -7.1-44.9; p = 0.191), 23.5% (95%CI: 0.8-51.3; p = 0.042), and 31.5% (95%CI: 4.3-65.7; p = 0.021). Our study showed a positive association between breastfeeding and mtDNA content in adolescents which gradually increased with longer periods of breastfeeding. Higher mtDNA content may be an underlying mechanism of the beneficial effects of breastfeeding on children's metabolism.",
-,Yes,20200316,ewas,32071425,Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain.,Int J Obes (Lond),"Maternal obesity prior to or during pregnancy influences fetal growth, predisposing the offspring to increased risk for obesity across the life course. Placental epigenetic mechanisms may underlie these associations. We conducted an epigenome-wide association study to identify placental DNA methylation changes associated with maternal prepregnancy body mass index (BMI) and rate of gestational weight gain at first (GWG1), second (GWG2), and third trimester (GWG3). Participants of the NICHD Fetal Growth Studies with genome-wide placental DNA methylation (n = 301) and gene expression (n = 75) data were included. Multivariable-adjusted regression models were used to test the associations of 1 kg/m<sup>2</sup> increase in prepregnancy BMI or 1 kg/week increase in GWG with DNA methylation levels. Genes harboring top differentially methylated CpGs (FDR P &lt; 0.05) were evaluated for placental gene expression. We assessed whether DNA methylation sites known to be associated with BMI in child or adult tissues, were also associated with maternal prepregnancy BMI in placenta. Prepregnancy BMI was associated with DNA methylation at cg14568196[EGFL7], cg15339142[VETZ], and cg02301019[AC092377.1] (FDR P &lt; 0.05, P ranging from 1.4 × 10<sup>-10</sup> to 1.7 × 10<sup>-9</sup>). GWG1 or GWG2 was associated with DNA methylation at cg17918270[MYT1L], cg20735365[DLX5], and cg17451688[SLC35F3] (FDR P &lt; 0.05, P ranging from 6.4 × 10<sup>-10</sup> to 1.2 × 10<sup>-8</sup>). Both prepregnancy BMI and DNA methylation at cg1456819 [EGFL7] were negatively correlated with EGFL7 expression in placenta (P &lt; 0.05). Several CpGs previously implicated in obesity traits in children and adults were associated with prepregnancy BMI in placenta. Functional annotations revealed that EGFL7 is highly expressed in placenta and the differentially methylated CpG sites near EGFL7 and VEZT were cis-meQTL targets in blood. We identified placental DNA methylation changes at novel loci associated with prepregnancy BMI and GWG. The overlap between CpGs associated with obesity traits in placenta and other tissues in children and adults suggests that epigenetic mechanisms in placenta may give insights to early origins of obesity.",
-,Yes,20200316,dnam age,32067420,An epigenetic clock for human skeletal muscle.,J Cachexia Sarcopenia Muscle,"Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation (HM) arrays (HM27, HM450, or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome-wide association study of age-associated DNA methylation patterns in skeletal muscle. The newly developed clock uses 200 cytosine-phosphate-guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine-phosphate-guanine dinucleotides of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan-tissue clock, P &lt; 0.0001) and an average correlation of � = 0.62 between actual and predicted age across datasets (vs. � = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate &lt; 0.005. However, gene set enrichment analysis did not reveal any enrichment for gene ontologies. We have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an r package called Muscle Epigenetic Age Test available on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.",
-,Yes,20200316,ewas,32066674,Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden.,Transl Psychiatry,"Epigenetic variation in peripheral tissues is being widely studied as a molecular biomarker of complex disease and disease-related exposures. To date, few studies have examined differences in DNA methylation associated with attention-deficit hyperactivity disorder (ADHD). In this study, we profiled genetic and methylomic variation across the genome in saliva samples from children (age 7-12 years) with clinically established ADHD (N = 391) and nonpsychiatric controls (N = 213). We tested for differentially methylated positions (DMPs) associated with both ADHD diagnosis and ADHD polygenic risk score, by using linear regression models including smoking, medication effects, and other potential confounders in our statistical models. Our results support previously reported associations between ADHD and DNA methylation levels at sites annotated to VIPR2, and identify several novel disease-associated DMPs (p &lt; 1e-5), although none of them were genome-wide significant. The two top-ranked, ADHD-associated DMPs (cg17478313 annotated to SLC7A8 and cg21609804 annotated to MARK2) are also significantly associated with nearby SNPs (p = 1.2e-46 and p = 2.07e-59), providing evidence that disease-associated DMPs are under genetic control. We also report a genome-wide significant association between ADHD polygenic risk and variable DNA methylation at a site annotated to the promoter of GART and SON (p = 6.71E-8). Finally, we show that ADHD-associated SNPs colocalize with SNPs associated with methylation levels in saliva. This is the first large-scale study of DNA methylation in children with ADHD. Our results represent novel epigenetic biomarkers for ADHD that may be useful for patient stratification, reinforce the importance of genetic effects on DNA methylation, and provide plausible molecular mechanisms for ADHD risk variants.",
-,No,20200316,omics,32051591,MAFG-driven astrocytes promote CNS inflammation.,Nature,"Multiple sclerosis is a chronic inflammatory disease of the CNS<sup>1</sup>. Astrocytes contribute to the pathogenesis of multiple sclerosis<sup>2</sup>, but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.",
-,Yes,20200316,dnam scores,32049268,Association of a Reproducible Epigenetic Risk Profile for Schizophrenia With Brain Methylation and Function.,JAMA Psychiatry,"Schizophrenia is a severe mental disorder in which epigenetic mechanisms may contribute to illness risk. Epigenetic profiles can be derived from blood cells, but to our knowledge, it is unknown whether these predict established brain alterations associated with schizophrenia. To identify an epigenetic signature (quantified as polymethylation score [PMS]) of schizophrenia using machine learning applied to genome-wide blood DNA-methylation data; evaluate whether differences in blood-derived PMS are mirrored in data from postmortem brain samples; test whether the PMS is associated with alterations of dorsolateral prefrontal cortex hippocampal (DLPFC-HC) connectivity during working memory in healthy controls (HC); explore the association between interactions between polygenic and epigenetic risk with DLPFC-HC connectivity; and test the specificity of the signature compared with other serious psychiatric disorders. In this case-control study conducted from 2008 to 2018 in sites in Germany, the United Kingdom, the United States, and Australia, blood DNA-methylation data from 2230 whole-blood samples from 6 independent cohorts comprising HC (1238 [55.5%]) and participants with schizophrenia (803 [36.0%]), bipolar disorder (39 [1.7%]), major depressive disorder 35 [1.6%]), and autism (27 [1.2%]), and first-degree relatives of all patient groups (88 [3.9%]) were analyzed. DNA-methylation data were further explored from 244 postmortem DLPFC samples from 136 HC and 108 patients with schizophrenia. Neuroimaging and genome-wide association data were available for 393 HC. The latter data was used to calculate a polygenic risk score (PRS) for schizophrenia. The data were analyzed in 2019. The accuracy of schizophrenia control classification based on machine learning using epigenetic data; association of schizophrenia PMS scores with DLPFC-HC connectivity; and association of the interaction between PRS and PMS with DLPFC-HC connectivity. This study included 7488 participants (4395 men [58.7%]), of whom 3158 (2230 men [70.6%]) received a diagnosis of schizophrenia. The PMS signature was associated with schizophrenia across 3 independent data sets (area under the curve [AUC] from 0.69 to 0.78; P value from 0.049 to 1.24 × 10-7) and data from postmortem DLPFC samples (AUC = 0.63; P = 1.42 × 10-4), but not with major depressive disorder (AUC = 0.51; P = .16), autism (AUC = 0.53; P = .66), or bipolar disorder (AUC = 0.58; P = .21). Pathways contributing most to the classification included synaptic processes. Healthy controls with schizophrenia-like PMS showed significantly altered DLPFC-HC connectivity (validation methylation/magnetic resonance imaging, t &lt; -3.81; P for familywise error, &lt;.04; validation magnetic resonance imaging, t &lt; -3.54; P for familywise error, &lt;.02), mirroring the lack of functional decoupling in schizophrenia. There was no significant association of the interaction between PMS and PRS with DLPFC-HC connectivity (P &gt; .19). We identified a reproducible blood DNA-methylation signature specific for schizophrenia that was correlated with altered functional DLPFC-HC coupling during working memory and mapped to methylation differences found in DLPFC postmortem samples. This indicates a possible epigenetic contribution to a schizophrenia intermediate phenotype and suggests that PMS could be of interest to be studied in the context of multimodal biomarkers for disease stratification and treatment personalization.",
-,No,20200316,omics,32047265,Variations and expression features of CYP2D6 contribute to schizophrenia risk.,Mol Psychiatry,"Genome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown. Here, we analyze 1497 RNA-seq data in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Then, we colocalize eGene and eJunction with SCZ GWAS using SMR and fine mapping. Multiple ChIP-seq data and DNA methylation data generated from brain were used for identifying the causal variants. Finally, we used a hypothesis-free (no SCZ risk loci considered) enrichment analysis to determine implicated pathways. We identified 171 genes and eight splicing junctions located within four genes (SNX19, ARL6IP4, APOPT1, and CYP2D6) that potentially contribute to SCZ susceptibility. Among the genes, CYP2D6 is significantly associated with SCZ SNPs in eGene and eJunction. In-depth examination of the CYP2D6 region revealed that a nonsynonymous single nucleotide variant rs16947 is strongly associated with a higher abundance of CYP2D6 exon 3 skipping junctions. While we found rs133377 and other functional SNPs in high linkage disequilibrium with rs16947 (r<sup>2</sup> = 0.9539), histone acetylation analysis showed they are located within active transcription start sites. Furthermore, our data-driven enrichment analysis showed that CYP2D6 is significantly involved in drug metabolism of codeine, tamoxifen, and citalopram. Our study facilitates an understanding of the genetic architecture of SCZ and provides new drug targets.",
-,Yes,20200316,ewas,32034291,"DNA methylation signature on phosphatidylethanol, not on self-reported alcohol consumption, predicts hazardous alcohol consumption in two distinct populations.",Mol Psychiatry,"The process of diagnosing hazardous alcohol drinking (HAD) is based on self-reported data and is thereby vulnerable to bias. There has been an interest in developing epigenetic biomarkers for HAD that might complement clinical assessment. Because alcohol consumption has been previously linked to DNA methylation (DNAm), we aimed to select DNAm signatures in blood to predict HAD from two demographically and clinically distinct populations (N<sub>total</sub> = 1,549). We first separately conducted an epigenome-wide association study (EWAS) for phosphatidylethanol (PEth), an objective measure of alcohol consumption, and for self-reported alcohol consumption in Cohort 1. We identified 83 PEth-associated CpGs, including 23 CpGs previously associated with alcohol consumption or alcohol use disorder. In contrast, no CpG reached epigenome-wide significance on self-reported alcohol consumption. Using a machine learning approach, two CpG subsets from EWAS on PEth and on self-reported alcohol consumption from Cohort 1 were separately tested for the prediction of HAD in Cohort 2. We found that a subset of 143 CpGs selected from the EWAS on PEth showed an excellent prediction of HAD with the area under the receiver operating characteristic curve (AUC) of 89.4% in training set and 73.9% in validation set of Cohort 2. However, CpGs preselected from the EWAS on self-reported alcohol consumption showed a poor prediction of HAD with AUC 75.2% in training set and 57.6% in validation set. Our results demonstrate that an objective measure for alcohol consumption is a more informative phenotype than self-reported data for revealing epigenetic mechanisms. The PEth-associated DNAm signature in blood could serve as a robust biomarker for alcohol consumption.",
-,Yes,20200316,ewas,32033992,Epigenetic Link Between Statin Therapy and Type 2 Diabetes.,Diabetes Care,"To investigate the role of epigenetics in statins' diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. Five cohort studies' participants (<i>n</i> = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. Discovery (<i>n</i> = 6,820) and replication (<i>n</i> = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 Ă— 10<sup>-25</sup> [<i>DHCR24</i>]), cg10177197 (3.94 Ă— 10<sup>-08</sup> [<i>DHCR24</i>]), cg06500161 (2.67 Ă— 10<sup>-23</sup> [<i>ABCG1</i>]), cg27243685 (6.01 Ă— 10<sup>-09</sup> [<i>ABCG1</i>]), and cg05119988 (7.26 Ă— 10<sup>-12</sup> [<i>SC4MOL</i>]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that <i>ABCG1</i> methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and <i>ABCG1</i> methylation were associated with <i>ABCG1</i> downregulation, suggesting epigenetic regulations of <i>ABCG1</i> expression. Further, outcomes insulin and HOMA-IR were significantly associated with <i>ABCG1</i> expression. This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins' effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to <i>ABCG1</i> epigenetic regulation.",
-,No,20200316,epigenetics,32033622,Essential concepts are missing: Foreign DNA in food invades the organisms' cells and can lead to stochastic epigenetic alterations with a wide range of possible pathogenetic consequences.,Clin Epigenetics,"In this article, a new concept for general pathogenesis has been proposed. Advances in molecular genetics have led to the realization that essential concepts in the framework of molecular biology are still missing. Clinical medicine is plagued by similar shortcomings: The questioning of current paradigms could open new vistas and invite challenging approaches. This article presents an unconventional idea. Foreign DNA which is regularly ingested with the essential food supply is not completely degraded. Small quantities of fragmented DNA rather persist transiently in the gastro-intestinal tract of mice and can be traced to various organ systems, except for cells in the germ line. Foreign DNA entering and persisting in mammalian cells can stochastically lead to genome-wide alterations of transcriptional and CpG DNA methylation profiles. In the course of food-ingested DNA invading somatic cells, completely new cell types can be generated which might be involved in the causation of common ailments. Projects emanating from this perception merit critical analysis and rigorous pursuit.",
-,No,20200316,dnam age,32041686,"Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up. 32041685",Elife,"Biological age measurements (BAs) assess aging-related physiological change and predict health risks among individuals of the same chronological age (CA). Multiple BAs have been proposed and are well studied individually but not jointly. We included 845 individuals and 3973 repeated measurements from a Swedish population-based cohort and examined longitudinal trajectories, correlations, and mortality associations of nine BAs across 20 years follow-up. We found the longitudinal growth of functional BAs accelerated around age 70; average levels of BA curves differed by sex across the age span (50-90 years). All BAs were correlated to varying degrees; correlations were mostly explained by CA. Individually, all BAs except for telomere length were associated with mortality risk independently of CA. The largest effects were seen for methylation age estimators (GrimAge) and the frailty index (FI). In joint models, two methylation age estimators (Horvath and GrimAge) and FI remained predictive, suggesting they are complementary in predicting mortality. ",
-,No,20200316,dnam age,32029736,Sexual-dimorphism in human immune system aging.,Nat Commun,"Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naĂŻve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune phenotypes can be visualized at https://immune-aging.jax.org to provide insights into future studies.",
-,No,20200316,single cell,32033589,Eleven grand challenges in single-cell data science.,Genome Biol,"The recent boom in microfluidics and combinatorial indexing strategies, combined with low sequencing costs, has empowered single-cell sequencing technology. Thousands-or even millions-of cells analyzed in a single experiment amount to a data revolution in single-cell biology and pose unique data science problems. Here, we outline eleven challenges that will be central to bringing this emerging field of single-cell data science forward. For each challenge, we highlight motivating research questions, review prior work, and formulate open problems. This compendium is for established researchers, newcomers, and students alike, highlighting interesting and rewarding problems for the coming years.",
-,Yes,20200316,ewas,32161338,Lifetime Ultraviolet Radiation Exposure and DNA Methylation in Blood Leukocytes: The Norwegian Women and Cancer Study.,Sci Rep,"Ultraviolet radiation (UVR) exposure is a leading cause of skin cancers and an ubiquitous environmental exposure. However, the molecular mechanisms relating UVR exposure to melanoma is not fully understood. We aimed to investigate if lifetime UVR exposure could be robustly associated to DNA methylation (DNAm). We assessed DNAm in whole blood in three data sets (n = 183, 191, and 125) from the Norwegian Woman and Cancer cohort, using Illumina platforms. We studied genome-wide DNAm, targeted analyses of CpG sites indicated in the literature, global methylation, and accelerated aging. Lifetime history of UVR exposure (residential ambient UVR, sunburns, sunbathing vacations and indoor tanning) was collected by questionnaires. We used one data set for discovery and the other two for replication. One CpG site showed a genome-wide significant association to cumulative UVR exposure (cg01884057) (p<sub>nominal</sub> = 3.96e-08), but was not replicated in any of the two replication sets (p<sub>nominal</sub> ≥ 0.42). Two CpG sites (cg05860019, cg00033666) showed suggestive associations with the other UVR exposures. We performed extensive analyses of the association between long-term UVR exposure and DNAm. There was no indication of a robust effect of past UVR exposure on DNAm.",
-,No,20200316,dnam scores,32160902,Epigenetic predictors of all-cause mortality are associated with objective measures of neighborhood disadvantage in an urban population.,Clin Epigenetics,"Neighborhood characteristics are robust predictors of overall health and mortality risk for residents. Though there has been some investigation of the role that molecular indicators may play in mediating neighborhood exposures, there has been little effort to incorporate newly developed epigenetic biomarkers into our understanding of neighborhood characteristics and health outcomes. Using 157 participants of the Detroit Neighborhood Health Study with detailed assessments of neighborhood characteristics and genome-wide DNA methylation profiling via the Illumina 450K methylation array, we assessed the relationship between objective neighborhood characteristics and a validated DNA methylation-based epigenetic mortality risk score (eMRS). Associations were adjusted for age, race, sex, ever smoking, ever alcohol usage, education, years spent in neighborhood, and employment. A secondary model additionally adjusted for personal neighborhood perception. We summarized 19 neighborhood quality indicators assessed for participants into 9 principal components which explained over 90% of the variance in the data and served as metrics of objective neighborhood quality exposures. Of the nine principal components utilized for this study, one was strongly associated with the eMRS (β = 0.15; 95% confidence interval = 0.06-0.24; P = 0.002). This principal component (PC7) was most strongly driven by the presence of abandoned cars, poor streets, and non-art graffiti. Models including both PC7 and individual indicators of neighborhood perception indicated that only PC7 and not neighborhood perception impacted the eMRS. When stratified on neighborhood indicators of greenspace, we observed a potentially protective effect of large mature trees as this feature substantially attenuated the observed association. Objective measures of neighborhood disadvantage are significantly associated with an epigenetic predictor of mortality risk, presenting a potential novel avenue by which neighborhood-level exposures may impact health. Associations were independent of an individual's perception of their neighborhood and attenuated by neighborhood greenspace features. More work should be done to determine molecular risk factors associated with neighborhoods, and potentially protective neighborhood features against adverse molecular effects.",
-,Yes,20200316,ewas,32144264,Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease.,Nat Commun,"An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.",
-,es,20200316,ewas,32114984,Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.,Genome Med,"Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P &lt; 1.06 × 10<sup>- 7</sup>, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.",
-,Yes,20200316,ewas,32085844,Effect of early parenteral nutrition during paediatric critical illness on DNA methylation as a potential mediator of impaired neurocognitive development: a pre-planned secondary analysis of the PEPaNIC international randomised controlled trial.,Lancet Respir Med,"Early use of parenteral nutrition in the paediatric intensive care unit (PICU) negatively affects development of executive functions, externalising behaviour, and visual-motor integration 2 years later, compared with omitting parenteral nutrition until PICU day 8 (late parenteral nutrition). The molecular basis of this finding is uncertain. We aimed to test the hypothesis that DNA methylation changes occur during critical illness and that early parenteral nutrition (or a specific macronutrient component hereof) contributes to these changes, which could explain its negative effects on neurocognitive development. This pre-planned secondary analysis of the multicentre PEPaNIC trial (2012-18) included all patients with a last PICU day blood sample (n=825, aged 0-17 years at PICU admission) who were randomly allocated (1:1) to early parenteral nutrition or late parenteral nutrition, as compared with 352 demographically matched healthy children. Investigators were masked to treatment allocation. We used the Infinium Human MethylationEPIC BeadChip to determine the genome-wide peripheral blood leukocyte DNA methylation of 865�859 CpG sites, yielding high-quality results for 403 patients allocated to early parenteral nutrition and for 411 patients allocated to late parenteral nutrition. Applying a false discovery rate of less than 0·05, DNA methylation of patients on the last PICU day was compared with that of healthy children, after excluding all CpG sites differentially methylated upon PICU admission, because these reflected pre-admission conditions and altered leukocyte composition. We used bootstrapped multivariable linear and non-linear regression analyses to assess the effect of early parenteral nutrition versus late parenteral nutrition on illness-induced alterations in DNA methylation and to what extent differentially methylated CpG sites explained impaired neurocognitive development 2 years later. During PICU stay, 159 CpG sites were methylated differently in patients admitted to the PICU than in healthy children, with mean effect sizes of 2·6% (SD 2·5) up to 21·6% (p&lt;0·02). These differentially methylated CpG sites occurred in genes involved in brain development, plasticity, and signalling; neuronal differentiation, migration, and growth; metabolism; transcriptional regulation; physical development and locomotion; and several neurodegenerative and neuropsychiatric diseases. Early parenteral nutrition and, in particular, the dose of amino acids, independently contributed to the differential methylation of 37 (23%) of these 159 CpG sites (p=0·0001 to 0·050), which could explain the adverse effect of early parenteral nutrition on neurocognitive development at 2-year follow-up (R<sup>2</sup> 0·61 [SD 0·01]). Early parenteral nutrition during paediatric critical illness altered DNA methylation, which suggests a plausible molecular basis for its negative effect on long-term neurocognitive development. Early administration of amino acids, rather than of glucose or lipids, mostly explained the aberrant DNA methylation-a finding that requires further investigation. European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and European Society for Clinical Nutrition and Metabolism.",
-,Yes,20200316,ewas,32080920,Acute alcohol withdrawal and recovery in men lead to profound changes in DNA methylation profiles: a longitudinal clinical study.,Addiction,"Withdrawal is a serious and sometimes life-threatening event in alcohol-dependent individuals. It has been suggested that epigenetic processes may play a role in this context. This study aimed to identify genes and pathways involved in such processes which hint to relevant mechanisms underlying withdrawal. Cross-sectional case-control study and longitudinal within-cases study during alcohol withdrawal and after 2 weeks of recovery SETTING: Addiction medicine departments in two university hospitals in southern Germany. Ninety-nine alcohol-dependent male patients receiving in-patient treatment and suffering from severe withdrawal symptoms during detoxification and 95 age-matched male controls. Epigenome-wide methylation patterns were analyzed in patients during acute alcohol withdrawal and after 2 weeks of recovery, as well as in age-matched controls using Illumina EPIC bead chips. Methylation levels of patients and controls were tested for association with withdrawal status. Tests were adjusted for technical and batch effects, age, smoking and cell type distribution. Single-site analysis, as well as an analysis of differentially methylated regions and gene ontology analysis, were performed. We found pronounced epigenome-wide significant [false discovery rate (FDR) &lt; 0.05] differences between patients during withdrawal and after 2 weeks [2876 cytosine-phosphate-guanine (CpG) sites], as well as between patients and controls (9845 and 6094 CpG sites comparing patients at time-point 1 and patients at time-point 2 versus controls, respectively). Analysis of differentially methylated regions and involved pathways revealed an over-representation of gene ontology terms related to the immune system response. Differences between patients and controls diminished after recovery (&gt; 800 CpG sites less), suggesting a partial reversibility of alcohol- and withdrawal-related methylation. Acute alcohol withdrawal in severely dependent male patients appears to be associated with extensive changes in epigenome-wide methylation patterns. In particular, genes involved in immune system response seem to be affected by this condition.",
-,Yes,20200316,ewas,32078381,Differential DNA Methylation in Placenta Associated With Maternal Blood Pressure During Pregnancy.,Hypertension,"Abnormal blood pressure during pregnancy is associated with impaired fetal growth, predisposing the offspring to cardiometabolic abnormalities over the life-course. Placental DNA methylation may be the regulatory pathway through which maternal blood pressure influences fetal and adult health outcomes. Epigenome-wide association study of 301 participants with placenta sample examined associations between DNA methylation and millimetre of mercury increases in systolic and diastolic blood pressure in each trimester. Findings were further examined using gene expression, gene pathway, and functional annotation analyses. Cytosine-(phosphate)-guanine (CpGs) known to be associated with cardiometabolic traits were evaluated. Increased maternal systolic and diastolic blood pressure were associated with methylation of 3 CpGs in the first, 6 CpGs in the second, and 15 CpGs in the third trimester at 5% false discovery rate (<i>P</i> values ranging from 6.6Ă—10<sup>-15</sup> to 2.3Ă—10<sup>-7</sup>). Several CpGs were enriched in pathways including cardiovascular-metabolic development (<i>P</i>=1.0Ă—10<sup>-45</sup>). Increased systolic and diastolic blood pressure were associated with increased CpG methylation and gene expression at <i>COL12A1</i>, a collagen family gene known for regulatory functions in the heart. Out of 304 previously reported CpGs known to be associated with cardiometabolic traits, 36 placental CpGs were associated with systolic and diastolic blood pressure in our data. The present study provides the first evidence for associations between placental DNA methylation and increased maternal blood pressure during pregnancy at genes implicated in cardiometabolic diseases. Identification of blood pressure-associated methylated sites in the placenta may provide clues to early origins of cardiometabolic dysfunction and inform guidelines for early prevention. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00912132.",
-,No,20200316,mitochondria,32066501,Platelet mitochondrial DNA methylation predicts future cardiovascular outcome in adults with overweight and obesity.,Clin Epigenetics,"The association between obesity and cardiovascular disease (CVD) is proven, but why some adults with obesity develop CVD while others remain disease-free is poorly understood. Here, we investigated whether mitochondrial DNA (mtDNA) methylation in platelets is altered prior to CVD development in a population of adults with overweight and obesity. We devised a nested case-control study of 200 adults with overweight or obesity who were CVD-free at baseline, of whom 84 developed CVD within 5 years, while 116 remained CVD-free. Platelet mtDNA was isolated from plasma samples at baseline, and mtDNA methylation was quantified in mitochondrially encoded cytochrome-C-oxidase I (MT-CO1; nt6797 and nt6807), II (MT-CO2; nt8113 and nt8117), and III (MT-CO3; nt9444 and nt9449); tRNA leucine 1 (MT-TL1; nt3247 and nt3254); D-loop (nt16383); tRNA phenylalanine (MT-TF; nt624); and light-strand-origin-of-replication (MT-OLR; nt5737, nt5740, and nt5743) by bisulfite-pyrosequencing. Logistic regression was used to estimate the contribution of mtDNA methylation to future CVD risk. ROC curve analysis was used to identify the optimal mtDNA methylation threshold for future CVD risk prediction. A model was generated incorporating methylation at three loci (score 0, 1, or 2 according to 0, 1, or 2-3 hypermethylated loci, respectively), adjusted for potential confounders, such as diastolic and systolic blood pressure, fasting blood glucose, and cholesterol ratio. mtDNA methylation at MT-CO1 nt6807 (OR = 1.08, 95% CI 1.02-1.16; P = 0.014), MT-CO3 nt9444 (OR = 1.22, 95% CI 1.02-1.46, P = 0.042), and MT-TL1 nt3254 (OR = 1.30, 95% CI 1.05-1.61, P = 0.008) was higher at baseline in those who developed CVD by follow-up, compared with those who remained CVD-free. Combined use of the three loci significantly enhanced risk prediction, with hazard ratios of 1.38 (95% CI 0.68-2.78) and 2.68 (95% CI 1.41-5.08) for individuals with score 1 or 2, respectively (P = 0.003). Methylation at these sites was independent of conventional CVD risk factors, including inflammation markers, fasting blood glucose concentration, and blood pressure. Methylations of MT-CO1, MT-CO3, and MT-TL1 are, together, strong predictors of future CVD incidence. Since methylation of these mtDNA domains was independent of conventional CVD risk factors, these markers may represent a novel intrinsic predictor of CVD risk in adults with overweight and obesity.",
-,No,20200323,prediction,32194204,Derivation of poly-methylomic profile scores for schizophrenia.,Prog Neuropsychopharmacol Biol Psychiatry,"Schizophrenia and bipolar disorder share biological features and environmental risk factors that may be associated with altered DNA methylation. In this study we sought to: 1) construct a novel 'Poly-Methylomic Profile Score (PMPS)' by transforming schizophrenia-associated epigenome-wide methylation from a previously published epigenome-wide association study (EWAS) into a single quantitative metric; and 2) examine associations between the PMPS and clinical status in an independent sample of 57 schizophrenia (SZ) cases, 59 bipolar disorder (BD) cases and 55 healthy controls (HC) for whom blood-derived DNA methylation was quantified using the Illumina 450 K methylation beadchip. We constructed five PMPSs at different p-value thresholds by summing methylation beta-values weighted by individual-CpG effect sizes from the meta-analysis of a previously published schizophrenia EWAS (comprising three separate cohorts with 675 [353 SZ and 322 HC] discovery cohort participants, 847 [414 SZ and 433 HC] replication cohort participants, and 96 monozygotic twin-pairs discordant for SZ). All SZ PMPSs were elevated in SZ participants relative to HCs, with the score calculated at a p-value threshold of 1 × 10<sup>-5</sup> accounting for the greatest amount of variance. All PMPSs were elevated in SZ relative to BD and none of the PMPSs were increased in BD, or in a combined cohort of BD and SZ cases, relative to HCs. PMPSs were also not associated with positive or negative symptom severity. That this SZ-derived PMPSs was elevated in SZ, but not BD, suggests that epigenome-wide methylation patterns may represent distinct pathophysiology that is yet to be elucidated.",
-,Yes,20200323,ewas,32188935,Epigenome-wide association study for perceived discrimination among sub-Saharan African migrants in Europe - the RODAM study.,Sci Rep,"Sub-Saharan African (SSA) migrants in Europe experience psychosocial stressors, such as perceived discrimination (PD). The effect of such a stressor on health could potentially be mediated via epigenetics. In this study we performed an epigenome-wide association study (EWAS) to assess the association between levels of PD with genome-wide DNA methylation profiles in SSA migrants. The Illumina 450 K DNA-methylation array was used on whole blood samples of 340 Ghanaian adults residing in three European cities from the cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) study. PD was assessed using sum scores of the Everyday Discrimination Scale (EDS). Differentially methylated positions and regions (DMPs and DMRs) were identified through linear regression analysis. Two hypo-methylated DMPs, namely cg13986138 (CYFIP1) and cg10316525(ANKRD63), were found to be associated with PD. DMR analysis identified 47 regions associated with the PD. To the best of our knowledge, this survey is the first EWAS for PD in first generation SSA migrants. We identified two DMPs associated with PD. Whether these associations underlie a consequence or causal effect within the scope of biological functionality needs additional research.",
-,Yes,20200323,ewas,32180791,Mendelian Randomization Identifies CpG Methylation Sites With Mediation Effects for Genetic Influences on BMD in Peripheral Blood Monocytes.,Front Genet,"Osteoporosis is mainly characterized by low bone mineral density (BMD) and is an increasingly serious public health concern. DNA methylation is a major epigenetic mechanism that may contribute to the variation in BMD and may mediate the effects of genetic and environmental factors of osteoporosis. In this study, we performed an epigenome-wide DNA methylation analysis in peripheral blood monocytes of 118 Caucasian women with extreme BMD values. Further, we developed and implemented a novel analytical framework that integrates Mendelian randomization with genetic fine mapping and colocalization to evaluate the causal relationships between DNA methylation and BMD phenotype. We identified 2,188 differentially methylated CpGs (DMCs) between the low and high BMD groups and distinguished 30 DMCs that may mediate the genetic effects on BMD. The causal relationship was further confirmed by eliminating the possibility of horizontal pleiotropy, linkage effect and reverse causality. The fine-mapping analysis determined 25 causal variants that are most likely to affect the methylation levels at these mediator DMCs. The majority of the causal methylation quantitative loci and DMCs reside within cell type-specific histone mark peaks, enhancers, promoters, promoter flanking regions and CTCF binding sites, supporting the regulatory potentials of these loci. The established causal pathways from genetic variant to BMD phenotype mediated by DNA methylation provide a gene list to aid in designing future functional studies and lead to a better understanding of the genetic and epigenetic mechanisms underlying the variation of BMD.",
-,Yes,20200323,ewas,32171335,An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.,Clin Epigenetics,"Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10<sup>-7</sup>, p<sub>adj</sub> = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10<sup>-6</sup>), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10<sup>-5</sup>, p<sub>adj</sub> = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including &quot;Response to lipopolysaccharide&quot; (p = 6.97 × 10<sup>-6</sup>, p<sub>adj</sub> = 0.042). The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.",
-,Yes,20200323,dnam age,32164769,Estimating breast tissue-specific DNA methylation age using next-generation sequencing data.,Clin Epigenetics,"DNA methylation (DNAm) age has been widely accepted as an epigenetic biomarker for biological aging. Emerging evidence suggests that DNAm age can be tissue-specific and female breast tissue ages faster than other parts of the body. The Horvath clock, which estimates DNAm age across multiple tissues, has been shown to be poorly calibrated in breast issue. We aim to develop a model to estimate breast tissue-specific DNAm age. Genome-wide DNA methylation sequencing data were generated for 459 normal, 107 tumor, and 45 paired adjacent-normal breast tissue samples. We determined a novel set of 286 breast tissue-specific clock CpGs using penalized linear regression and developed a model to estimate breast tissue-specific DNAm age. The model was applied to estimate breast tissue-specific DNAm age in different breast tissue types and in tumors with distinct clinical characteristics to investigate cancer-related aging effects. Our estimated breast tissue-specific DNAm age was highly correlated with chronological age (r = 0.88; p = 2.9 × 10<sup>-31</sup>) in normal breast tissue. Breast tumor tissue samples exhibited a positive epigenetic age acceleration, where DNAm age was on average 7 years older than respective chronological age (p = 1.8 × 10<sup>-8</sup>). In age-matched analyses, tumor breast tissue appeared 12 and 13 years older in DNAm age than adjacent-normal and normal breast tissue (p = 4.0 × 10<sup>-6</sup> and 1.0 × 10<sup>-6</sup>, respectively). Both HER2+ and hormone-receptor positive subtypes demonstrated significant acceleration in DNAm ages (p = 0.04 and 3.8 × 10<sup>-6</sup>, respectively), while no apparent DNAm age acceleration was observed for triple-negative breast tumors. We observed a non-linear pattern of epigenetic age acceleration with breast tumor grade. In addition, early-staged tumors showed a positive epigenetic age acceleration (p = 0.003) while late-staged tumors exhibited a non-significant negative epigenetic age acceleration (p = 0.10). The intended applications for this model are wide-spread and have been shown to provide biologically meaningful results for cancer-related aging effects in breast tumor tissue. Future studies are warranted to explore whether breast tissue-specific epigenetic age acceleration is predictive of breast cancer development, treatment response, and survival as well as the clinical utility of whether this model can be extended to blood samples.",
-,No,20200323,eqtl,32149610,The single-cell eQTLGen consortium.,Elife,"In recent years, functional genomics approaches combining genetic information with bulk RNA-sequencing data have identified the downstream expression effects of disease-associated genetic risk factors through so-called expression quantitative trait locus (eQTL) analysis. Single-cell RNA-sequencing creates enormous opportunities for mapping eQTLs across different cell types and in dynamic processes, many of which are obscured when using bulk methods. Rapid increase in throughput and reduction in cost per cell now allow this technology to be applied to large-scale population genetics studies. To fully leverage these emerging data resources, we have founded the single-cell eQTLGen consortium (sc-eQTLGen), aimed at pinpointing the cellular contexts in which disease-causing genetic variants affect gene expression. Here, we outline the goals, approach and potential utility of the sc-eQTLGen consortium. We also provide a set of study design considerations for future single-cell eQTL studies.",
-,Yes,20200330,ewas,32190749,Age at onset of different pubertal signs in boys and girls and differential DNA methylation at age 10 and 18 years: an epigenome-wide follow-up study.,Hum Reprod Open,"Is the age of onset of pubertal markers related to subsequent changes in DNA methylation (DNAm)? We identified 273 cytosine-phosphate-guanine (CpG) dinucleotides in girls and 67 CpGs in boys that were related to puberty and that were replicable in two other investigations. Previously, 457 CpGs (not gender-specific) and 347 (in girls) and 50 (in boys), respectively, were found to be associated with puberty, according to investigations of studies from Denmark (20 girls and 31 boys) and North America (30 girls and 25 boys). The study was based on a birth cohort of 1456 participants born in 1989/90, with follow-up at age 10 and 18 years. The follow-up included 470 participants with information on DNAm and age of pubertal onset (244 girls and 226 boys). Age of pubertal onset was ascertained retrospectively at age 18 years. Using the Pubertal Development Scale, both genders were asked about ages of onset of growth spurt, body hair growth and skin changes. Ages at voice deepening and growth of facial hair were inquired from boys; ages at breast development and menarche from girls. Blood samples were collected at 10 and 18 years of age. DNA was extracted using a standard salting out procedure. The methylation level for each CpG site was assessed using one of two different platforms. DNAm was measured by a ratio of intensities denoted as <i>β</i> values for each CpG site. After quality control, 349 455 CpG sites were available for analysis. <i>M</i> values were calculated (log2(<i>β</i>/(1-<i>β</i>)) to approximate a normal distribution, and their levels were adjusted for blood cell proportions. Linear mixed models were applied to test the association between age of pubertal markers and repeated measurement of DNAm at 10 and 18 years. In girls, a total of 63 019 CpGs statistically significantly changed after occurrence of any of the five pubertal events and 13 487 were changed subsequent to all five events: the respective number is boys were 3072 and 301. To further exclude false-positive findings, we investigated which CpGs were replicable in prior studies from Denmark or North America, resulting in 273 replicable CpG in girls and 67 CpGs in boys (236 and 68 genes, respectively). Most identified genes are known to be related to biological processes of puberty; however, genetic polymorphisms of only four of these genes were previously linked to pubertal markers in humans. The relative age of pubertal onset to the age of DNAm measurements does not allow causal inference, since DNAm at an earlier age may have affected the pubertal age or pubertal age may have altered later DNAm. This investigation concentrates on autosomes. CpGs on X and Y chromosomes are not included in the current study. Assessment of biological processes involved in pubertal transitions should include epigenetic information. Differential DNAm related to puberty needs to be investigated to determine whether it can act as an early marker for adult diseases known to be associated with puberty. This work was supported by NIH grants R03HD092776 (Epigenetic characterization of pubertal transitions) and R01AI121226. The 10-year follow-up of this study was funded by National Asthma Campaign, UK (Grant No 364), and the 18-year follow-up by a grant from the National Heart and Blood Institute (R01 HL082925). The authors have no conflicts to report.",
-,No,20200406,ewas,32238836,Major surgery induces acute changes in measured DNA methylation associated with immune response pathways.,Sci Rep,"Surgery is an invasive procedure evoking acute inflammatory and immune responses that can influence risk for postoperative complications including cognitive dysfunction and delirium. Although the specific mechanisms driving these responses have not been well-characterized, they are hypothesized to involve the epigenetic regulation of gene expression. We quantified genome-wide levels of DNA methylation in peripheral blood mononuclear cells (PBMCs) longitudinally collected from a cohort of elderly patients undergoing major surgery, comparing samples collected at baseline to those collected immediately post-operatively and at discharge from hospital. We identified acute changes in measured DNA methylation at sites annotated to immune system genes, paralleling changes in serum-levels of markers including C-reactive protein (CRP) and Interleukin 6 (IL-6) measured in the same individuals. Many of the observed changes in measured DNA methylation were consistent across different types of major surgery, although there was notable heterogeneity between surgery types at certain loci. The acute changes in measured DNA methylation induced by surgery are relatively stable in the post-operative period, generally persisting until discharge from hospital. Our results highlight the dramatic alterations in gene regulation induced by invasive surgery, primarily reflecting upregulation of the immune system in response to trauma, wound healing and anaesthesia.",
-,Yes,20200406,ewas,32237968,DNA methylation profiling identifies a high effect genetic variant for lipoprotein(a) levels.,Epigenetics,"Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF &lt;0.02) at the CpG site that largely explained the observed methylation effect. Rs76735376 is an expression quantitative trait loci for the LPA gene and could affect expression by altering enhancer activity. This EWAS for plasma Lp(a) identified a single CpG site within LPA. This association is due to an uncommon, but highly effective genetic variant, which was not in significant linkage disequilibrium with other variants known to influence Lp(a) levels or apo(a) isoform size. This study highlights the utility of CpG site methylation to identify potentially important genetic associations that would not be readily apparent in a comparable size genetic association study.",
-,No,20200406,dnam score,32228717,The association of DNA methylation with body mass index: distinguishing between predictors and biomarkers.,Clin Epigenetics,"DNA methylation is associated with body mass index (BMI), but it is not clear if methylation scores are biomarkers for extant BMI or predictive of future BMI. Here, we explore the causal nature and predictive utility of DNA methylation measured in peripheral blood with BMI and cardiometabolic traits. Analyses were conducted across the life course using the ARIES cohort of mothers (n = 792) and children (n = 906), for whom DNA methylation and genetic profiles and BMI at multiple time points (3 in children at birth, in childhood and in adolescence; 2 in mothers during pregnancy and in middle age) were available. Genetic and DNA methylation scores for BMI were derived using published associations between BMI and DNA methylation and genotype. Causal relationships between methylation and BMI were assessed using Mendelian randomisation and cross-lagged models. The DNA methylation scores in adult women explained 10% of extant BMI variance. However, less extant variance was explained by scores generated in the same women during pregnancy (2% BMI variance) and in older children (15-17 years; 3% BMI variance). Similarly, little extant variance was explained in younger children (at birth and at 7 years; 1% and 2%, respectively). These associations remained following adjustment for smoking exposure and education levels. The DNA methylation score was found to be a poor predictor of future BMI using linear and cross-lagged models, suggesting that DNA methylation variation does not cause later variation in BMI. However, there was some evidence to suggest that BMI is predictive of later DNA methylation. Mendelian randomisation analyses also support this direction of effect, although evidence is weak. Finally, we find that DNA methylation scores for BMI are associated with extant cardiometabolic traits independently of BMI and genetic score. The age-specific nature of DNA methylation associations with BMI, lack of causal relationship and limited predictive ability of future BMI indicate that DNA methylation is likely influenced by BMI and might more accurately be considered a biomarker of BMI and related outcomes rather than a predictor. Future epigenome-wide association studies may benefit from further examining associations between early DNA methylation and later health outcomes.",
-,No,20200406,epigenetics,32228436,The genome-wide landscape of C:G &gt; T:A polymorphism at the CpG contexts in the human population.,BMC Genomics,"The C:G &gt; T:A substitution at the CpG dinucleotide contexts is the most frequent substitution type in genome evolution. The mutational process is obviously ongoing in the human germline; however, its impact on common and rare genomic polymorphisms has not been comprehensively investigated yet. Here we observed the landscape and dynamics of C:G &gt; T:A substitutions from population-scale human genome sequencing datasets including ~ 4300 whole-genomes from the 1000 Genomes and the pan-cancer analysis of whole genomes (PCAWG) Project and ~ 60,000 whole-exomes from the Exome Aggregation Consortium (ExAC) database. Of the 28,084,558 CpG sites in the human reference genome, 26.0% show C:G &gt; T:A substitution in the dataset. Remarkably, CpGs in CpG islands (CGIs) have a much lower frequency of such mutations (5.6%). Interestingly, the mutation frequency of CGIs is not uniform with a significantly higher C:G &gt; T:A substitution rate for intragenic CGIs compared to other types. For non-CGI CpGs, the mutation rate was positively correlated with the distance from the nearest CGI up to 2 kb. Finally, we found the impact of negative selection for coding CpG mutations resulting in amino acid change. This study provides the first unbiased rate of C:G &gt; T:A substitution at the CpG dinucleotide contexts, using population-scale human genome sequencing data. Our findings provide insights into the dynamics of the mutation acquisition in the human genome.",
-,No,20200406,epigenetics,32203468,DNA methylation disruption reshapes the hematopoietic differentiation landscape.,Nat Genet,"Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies<sup>1-3</sup> and clonal hematopoiesis<sup>4,5</sup>. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.",
-,Yes,20200406,ewas,32202197,Identification of 20 novel loci associated to ischemic stroke. Epigenome-Wide Association Study.,Epigenetics,"<b>Rationale</b>. DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1-2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism.<b>Objective</b>. To detect epigenetic variants associated to stroke occurrence and stroke subtypes.<b>Methods and Results</b>. A two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N=226 and N=166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus <i>ZFHX3</i>, which includes known genetic variants associated with stroke. The pathways associated to these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways.<b>Conclusions</b>. We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.",
-,No,20200406,sem,32216821,"DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936.",Clin Epigenetics,"DNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the inter-quartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples. Here, we showed an association between age and log<sub>10</sub>-transformed DNA methylation outlier burden in a large cross-sectional cohort, the Generation Scotland Family Health Study (N = 7010, β = 0.0091, p &lt; 2 × 10<sup>-16</sup>), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, β = 0.033, p = 7.9 × 10<sup>-4</sup>) and 1936 (N = 898, β = 0.0079, p = 0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, body mass index (BMI), smoking, and batch effects. In Generation Scotland, the increase in epigenetic outlier burden with age was not purely an artefact of an increase in DNA methylation level variability with age (epigenetic drift). Log<sub>10</sub>-transformed DNA methylation outlier burden in Generation Scotland was not related to self-reported, or family history of, age-related diseases, and it was not heritable (SNP-based heritability of 4.4%, p = 0.18). Finally, DNA methylation outlier burden was not significantly related to survival in either of the Lothian Birth Cohorts individually or in the meta-analysis after correction for multiple testing (HR<sub>meta</sub> = 1.12; 95% CI<sub>meta</sub> = [1.02; 1.21]; p<sub>meta</sub> = 0.021). These findings suggest that, while it does not associate with ageing-related health outcomes, DNA methylation outlier burden does track chronological ageing and may also relate to survival. DNA methylation outlier burden may thus be useful as a marker of biological ageing.",
-,No,20200406,circulating,32221288,Mapping the breast cancer metastatic cascade onto ctDNA using genetic and epigenetic clonal tracking.,Nat Commun,"Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient's cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment.",
-,No,20200406,epigenetics,32211199,Cannabis use and the sperm epigenome: a budding concern?,Environ Epigenet,"The United States is swiftly moving toward increased legalization of medical and recreational cannabis. Currently considered the most commonly used illicit psychoactive drug, recreational cannabis is legal in 11 states and Washington, DC, and male use is an important and understudied concern. Questions remain, however, about the potential long-term consequences of this exposure and how cannabis might impact the epigenetic integrity of sperm in such a way that could influence the health and development of offspring. This review summarizes cannabis use and potency in the USA, provides a brief overview of DNA methylation as an epigenetic mechanism that is vulnerable in sperm to environmental exposures including cannabis, and summarizes studies that have examined the effects of parental exposure to cannabis or delta-9 tetrahydrocannabinol (THC, the main psychoactive component of cannabis) on the epigenetic profile of the gametes and behavior of offspring. These studies have demonstrated significant changes to the sperm DNA methylome following cannabis use in humans, and THC exposure in rats. Furthermore, the use of rodent models has shown methylation and behavioral changes in rats born to fathers exposed to THC or synthetic cannabinoids, or to parents who were both exposed to THC. These data substantiate an urgent need for additional studies assessing the effects of cannabis exposure on childhood health and development. This is especially true given the current growing state of cannabis use in the USA.",
-,No,20200504,ewas,32345361,Exploratory analysis of age and sex dependent DNA methylation patterns on the X-chromosome in whole blood samples.,Genome Med,"Large numbers of autosomal sites are found differentially methylated in the aging genome. Due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation (XCI) in females, this has not been explored for the X chromosome. Using data from middle age to elderly individuals (age 55+ years) from two Danish cohorts of monozygotic twins and the Scottish Lothian Birth Cohort 1921, we conducted an X-chromosome-wide analysis of age-associated DNA methylation patterns with consideration of stably inferred XCI status. Through analysing and comparing sex-specific X-linked DNA methylation changes over age late in life, we identified 123, 293 and 55 CpG sites significant (FDR &lt; 0.05) only in males, only in females and in both sexes of Danish twins. All findings were significantly replicated in the two Danish twin cohorts. CpG sites escaping XCI are predominantly de-methylated with increasing age across cohorts. In contrast, CpGs highly methylated in both sexes are methylated even further with increasing age. Among the replicated sites in Danish samples, 16 (13%), 24 (8.2%) and 3 (5.5%) CpGs were further validated in LBC1921 (FDR &lt; 0.05). The X-chromosome of whole blood leukocytes displays age- and sex-dependent DNA methylation patterns in relation to XCI across cohorts.",
-,Yes,20200504,ewas,32343731,A genome-wide analysis of DNA methylation identifies a novel association signal for Lp(a) concentrations in the LPA promoter.,PLoS ONE,"Lipoprotein(a) [Lp(a)] is a major cardiovascular risk factor, which is largely genetically determined by one major gene locus, the LPA gene. Many aspects of the transcriptional regulation of LPA are poorly understood and the role of epigenetics has not been addressed yet. Therefore, we conducted an epigenome-wide analysis of DNA methylation on Lp(a) levels in two population-based studies (total n = 2208). We identified a CpG site in the LPA promoter which was significantly associated with Lp(a) concentrations. Surprisingly, the identified CpG site was found to overlap the SNP rs76735376. We genotyped this SNP de-novo in three studies (total n = 7512). The minor allele of rs76735376 (1.1% minor allele frequency) was associated with increased Lp(a) values (p = 1.01e-59) and explained 3.5% of the variation of Lp(a). Statistical mediation analysis showed that the effect on Lp(a) is rather originating from the base change itself and is not mediated by DNA methylation levels. This finding is supported by eQTL data from 208 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. To evaluate, whether the association signal at rs76735376 may actually be derived from a stronger eQTL signal in LD with this SNP, eQTL association results of all correlated SNPs (r2≥0.1) were integrated with genetic association results. This analysis pinpointed to rs10455872 as the potential trigger of the effect of rs76735376. Furthermore, both SNPs coincide with short apo(a) isoforms. Adjusting for both, rs10455872 and the apo(a) isoforms diminished the effect size of rs76735376 to 5.38 mg/dL (p = 0.0463). This indicates that the effect of rs76735376 can be explained by both an independent effect of the SNP and a strong correlation with rs10455872 and apo(a) isoforms.",
-,Yes,20200504,ewas,32327964,A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins.,Front Neurosci,"Monozygotic twins are genetically identical but rarely phenotypically identical. Epigenetic and transcriptional variation could influence this phenotypic discordance. Investigation of intra-pair differences in molecular markers and a given phenotype in monozygotic twins controls most of the genetic contribution, enabling studies of the molecular features of the phenotype. This study aimed to identify genes associated with cognition in later life using integrated enrichment analyses of the results of blood-derived intra-pair epigenome-wide and transcriptome-wide association analyses of cognition in 452 middle-aged and old-aged monozygotic twins (56-80 years). Integrated analyses were performed with an unsupervised approach using KeyPathwayMiner, and a supervised approach using the KEGG and Reactome databases. The supervised approach identified several enriched gene sets, including &quot;neuroactive ligand receptor interaction&quot; (<i>p</i>-value = 1.62<sup>�</sup>10-2), &quot;Neurotrophin signaling&quot; (<i>p</i>-value = 2.52<sup>�</sup>10-3), &quot;Alzheimer's disease&quot; (<i>p</i>-value = 1.20<sup>�</sup>10-2), and &quot;long-term depression&quot; (<i>p</i>-value = 1.62<sup>�</sup>10-2). The unsupervised approach resulted in a 238 gene network, including the Alzheimer's disease gene <i>APP</i> (Amyloid Beta Precursor Protein) as an exception node, and several novel candidate genes. The strength of the unsupervised method is that it can reveal previously uncharacterized sub-pathways and detect interplay between biological processes, which remain undetected by the current supervised methods. In conclusion, this study identified several previously reported cognition genes and pathways and, additionally, puts forward novel candidates for further verification and validation.",
-,No,20200504,dnam score,32308120,Epigenomic Assessment of Cardiovascular Disease Risk and Interactions With Traditional Risk Metrics.,J Am Heart Assoc,"Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics.",
-,No,20200504,epigenetics,32275652,Stochastic modeling reveals kinetic heterogeneity in post-replication DNA methylation.,PLoS Comput Biol,"DNA methylation is a heritable epigenetic modification that plays an essential role in mammalian development. Genomic methylation patterns are dynamically maintained, with DNA methyltransferases mediating inheritance of methyl marks onto nascent DNA over cycles of replication. A recently developed experimental technique employing immunoprecipitation of bromodeoxyuridine labeled nascent DNA followed by bisulfite sequencing (Repli-BS) measures post-replication temporal evolution of cytosine methylation, thus enabling genome-wide monitoring of methylation maintenance. In this work, we combine statistical analysis and stochastic mathematical modeling to analyze Repli-BS data from human embryonic stem cells. We estimate site-specific kinetic rate constants for the restoration of methyl marks on &gt;10 million uniquely mapped cytosines within the CpG (cytosine-phosphate-guanine) dinucleotide context across the genome using Maximum Likelihood Estimation. We find that post-replication remethylation rate constants span approximately two orders of magnitude, with half-lives of per-site recovery of steady-state methylation levels ranging from shorter than ten minutes to five hours and longer. Furthermore, we find that kinetic constants of maintenance methylation are correlated among neighboring CpG sites. Stochastic mathematical modeling provides insight to the biological mechanisms underlying the inference results, suggesting that enzyme processivity and/or collaboration can produce the observed kinetic correlations. Our combined statistical/mathematical modeling approach expands the utility of genomic datasets and disentangles heterogeneity in methylation patterns arising from replication-associated temporal dynamics versus stable cell-to-cell differences.",
-,No,20200504,dnam age,32264940,"Adverse childhood experiences, DNA methylation age acceleration, and cortisol in UK children: a prospective population-based cohort study.",Clin Epigenetics,"Epigenetic mechanisms may partly explain the persistent effects of adverse childhood experiences (ACEs) on health outcomes in later life. DNA methylation can predict chronological age, and advanced methylation-predicted age beyond chronological age (DNA methylation age acceleration) is associated with ACEs, adverse mental and physical health, and elevated diurnal and baseline salivary cortisol. Childhood adversity is also associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which produces the neuroendocrine hormone cortisol. It remains unknown whether these associations are specific to certain types of adversity. Herein, we investigate the associations of ACEs with DNA methylation age acceleration and plasma cortisol in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. In this study of the children in ALSPAC, we used multiple linear regression to examine associations of cumulative exposure to ACE, as well as exposure to ten individual types of ACEs, with Horvath-estimated DNA methylation age acceleration and with baseline plasma cortisol. The ten ACEs were those included in the World Health Organization's ACE International Questionnaire. Data on ACEs were prospectively collected from age 0-14 years. DNA methylation age acceleration and plasma cortisol were measured at mean 17.1 years and 15.5 years, respectively. We included 974 UK children in the present study. Exposure to four or more ACEs compared to zero was associated with DNA methylation age acceleration in girls (β, 95% CI = 1.65, 0.25 to 3.04 years) but not in boys (β, 95% CI = - 0.11, - 1.48 to 1.26 years). Also, in girls, emotional abuse and physical abuse were each associated with DNA methylation age acceleration (β, 95% CI = 1.20, 0.15 to 2.26 years and β, 95% CI = 1.22, 0.06 to 2.38 years, respectively). No other ACEs were associated with accelerated DNA methylation age in either sex. Associations were also null between ACE and cortisol, and cortisol and DNA methylation age acceleration. In this prospective population-based study of UK children, cumulative ACE exposure, emotional abuse, and physical abuse between age 0 and 14 years were each associated with Horvath-estimated DNA methylation age acceleration at age 17 years in girls but not in boys.",
-,Yes,20200504,ewas,32264874,Changes of DNA methylation are associated with changes in lung function during adolescence.,Respir Res,"Adolescence is a significant period for the gender-dependent development of lung function. Prior studies have shown that DNA methylation (DNA-M) is associated with lung function and DNA-M at some cytosine-phosphate-guanine dinucleotide sites (CpGs) changes over time. This study examined whether changes of DNA-M at lung-function-related CpGs are associated with changes in lung function during adolescence for each gender, and if so, the biological significance of the detected CpGs. Genome-scale DNA-M was measured in peripheral blood samples at ages 10 (n = 330) and 18 years (n = 476) from the Isle of Wight (IOW) birth cohort in United Kingdom, using Illumina Infinium arrays (450 K and EPIC). Spirometry was conducted at both ages. A training and testing method was used to screen 402,714 CpGs for their potential associations with lung function. Linear regressions were applied to assess the association of changes in lung function with changes of DNA-M at those CpGs potentially related to lung function. Adolescence-related and personal and family-related confounders were included in the model. The analyses were stratified by gender. Multiple testing was adjusted by controlling false discovery rate of 0.05. Findings were further examined in two independent birth cohorts, the Avon Longitudinal Study of Children and Parents (ALSPAC) and the Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohort. Pathway analyses were performed on genes to which the identified CpGs were mapped. For females, 42 CpGs showed statistically significant associations with change in FEV<sub>1</sub>/FVC, but none for change in FEV<sub>1</sub> or FVC. No CpGs were identified for males. In replication analyses, 16 and 21 of the 42 CpGs showed the same direction of associations among the females in the ALSPAC and BAMSE cohorts, respectively, with 11 CpGs overlapping across all the three cohorts. Through pathway analyses, significant biological processes were identified that have previously been related to lung function development. The detected 11 CpGs in all three cohorts have the potential to serve as the candidate epigenetic markers for changes in lung function during adolescence in females.",
-,No,20200504,prediction,32245523,Machine learning and clinical epigenetics: a review of challenges for diagnosis and classification.,Clin Epigenetics,"Machine learning is a sub-field of artificial intelligence, which utilises large data sets to make predictions for future events. Although most algorithms used in machine learning were developed as far back as the 1950s, the advent of big data in combination with dramatically increased computing power has spurred renewed interest in this technology over the last two decades. Within the medical field, machine learning is promising in the development of assistive clinical tools for detection of e.g. cancers and prediction of disease. Recent advances in deep learning technologies, a sub-discipline of machine learning that requires less user input but more data and processing power, has provided even greater promise in assisting physicians to achieve accurate diagnoses. Within the fields of genetics and its sub-field epigenetics, both prime examples of complex data, machine learning methods are on the rise, as the field of personalised medicine is aiming for treatment of the individual based on their genetic and epigenetic profiles. We now have an ever-growing number of reported epigenetic alterations in disease, and this offers a chance to increase sensitivity and specificity of future diagnostics and therapies. Currently, there are limited studies using machine learning applied to epigenetics. They pertain to a wide variety of disease states and have used mostly supervised machine learning methods.",
-,No,20200504,epigenetics,32234052,Successful generation of epigenetic disease model mice by targeted demethylation of the epigenome.,Genome Biol,"Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders. We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain. We generate model mice for Silver-Russell syndrome (SRS), an imprinting disorder, by target-specific DNA demethylation in the H19 differentially methylated region. Like SRS patients, these mice show H19 upregulation and Igf2 downregulation, leading to severe intrauterine and postnatal growth retardation. This is the first report of an imprinting disease model animal generated by targeted demethylation of specific loci of the epigenome in fertilized eggs. Epigenome-edited animals are also useful for exploring the causative epimutations in epigenetic diseases.",
-,No,20200504,epigenetics,32223889,Reversible promoter methylation determines fluctuating expression of acute phase proteins.,Elife,"Acute phase reactants (APRs) are secretory proteins exhibiting large expression changes in response to proinflammatory cytokines. Here we show that the expression pattern of a major human APR, that is <i>C-reactive protein</i> (<i>CRP</i>), is casually determined by DNMT3A and TET2-tuned promoter methylation status. <i>CRP</i> features a CpG-poor promoter with its CpG motifs located in binding sites of STAT3, C/EBP-β and NF-κB. These motifs are highly methylated at the resting state, but undergo STAT3- and NF-κB-dependent demethylation upon cytokine stimulation, leading to markedly enhanced recruitment of C/EBP-β that boosts <i>CRP</i> expression. Withdrawal of cytokines, by contrast, results in a rapid recovery of promoter methylation and termination of <i>CRP</i> induction. Further analysis suggests that reversible methylation also regulates the expression of highly inducible genes carrying CpG-poor promoters with APRs as representatives. Therefore, these CpG-poor promoters may evolve CpG-containing TF binding sites to harness dynamic methylation for prompt and reversible responses.",
-,Yes,20200518,ewas,32398718,Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation.,Mol Psychiatry,"Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p &lt; 10<sup>-24</sup>). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.",
-,Yes,20200518,ewas,32388307,Genome-wide DNA methylation analysis reveals significant impact of long-term ambient air pollution exposure on biological functions related to mitochondria and immune response.,Environ Pollut,"Exposure to long-term ambient air pollution is believed to have adverse effects on human health. However, the mechanisms underlying these impacts are poorly understood. DNA methylation, a crucial epigenetic modification, is susceptible to environmental factors and likely involved in these processes. We conducted a whole-genome bisulfite sequencing study on 120 participants from a highly polluted region (HPR) and a less polluted region (LPR) in China, where the HPR had much higher concentrations of five air pollutants (PM<sub>2.5</sub>, PM<sub>10</sub>, SO<sub>2</sub>, NO<sub>2</sub>, and CO) (fold difference 1.6 to 6.6 times; P value 1.80E-07 to 3.19E-23). Genome-wide methylation analysis revealed 371 DMRs in subjects from the two areas and these DMRs were located primarily in gene regulatory elements such as promoters and enhancers. Gene enrichment analysis showed that DMR-related genes were significantly enriched in diseases related to pulmonary disorders and cancers and in biological processes related to mitochondrial assembly and cytokine production. Further, HPR participants showed a higher mtDNA copy number. Of those identified DMRs, 15 were significantly correlated with mtDNA copy number. Finally, cytokine assay indicated that an increased plasma interleukin-5 level was associated with greater air pollution. Taken together, our findings suggest that exposure to long-term ambient air pollution can lead to alterations in DNA methylation whose functions relate to mitochondria and immune responses.",
-,Yes,20200518,ewas,32381493,Epigenome-Wide Association Study of DNA Methylation and Adult Asthma in the Agricultural Lung Health Study.,Eur Respir J,"Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma. Studies in adults are rare, and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a U.S. agricultural cohort. Atopy was defined by serum specific immunoglobulin E. Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous CpGs were differentially methylated in non-atopic asthma (8 at family-wise error rate [FWER] p&lt;9Ă—10<sup>-8</sup>; 524 at False Discovery Rate [FDR]&lt;0.05) and implicated 382 novel genes. More CpGs were identified in atopic asthma (181 at FWER; 1086 at FDR) and implicated 569 novel genes. 104 FDR CpGs overlapped. 35% of CpGs in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpGs in non-atopic and atopic asthma. Many CpGs from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease and implicate novel genes associated with non-atopic and atopic asthma.",
-,Yes,20200518,ewas,32361995,Genome-wide DNA methylation patterns associated with sleep and mental health in children: a population-based study.,J Child Psychol Psychiatry,"DNA methylation (DNAm) has been implicated in the biology of sleep. Yet, how DNAm patterns across the genome relate to different sleep outcomes, and whether these associations overlap with mental health is currently unknown. Here, we investigated associations of DNAm with sleep and mental health in a pediatric population. This cross-sectional study included 465 10-year-old children (51.3% female) from the Generation R Study. Genome-wide DNAm levels were measured using the Illumina 450K array (peripheral blood). Sleep problems were assessed from self-report and mental health outcomes from maternal questionnaires. Wrist actigraphy was used in 188 11-year-old children to calculate sleep duration and midpoint sleep. Weighted gene co-expression network analysis was used to identify highly comethylated DNAm 'modules', which were tested for associations with sleep and mental health outcomes. We identified 64 DNAm modules, one of which associated with sleep duration after covariate and multiple testing adjustment. This module included CpG sites spanning 9 genes on chromosome 17, including MAPT - a key regulator of Tau proteins in the brain involved in neuronal function - as well as genes previously implicated in sleep duration. Follow-up analyses suggested that DNAm variation in this region is under considerable genetic control and shows strong blood-brain concordance. DNAm modules associated with sleep did not overlap with those associated with mental health. We identified one DNAm region associated with sleep duration, including genes previously reported by recent GWAS studies. Further research is warranted to examine the functional role of this region and its longitudinal association with sleep.",
-,Yes,20200518,ewas,32354366,Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis.,Clin Epigenetics,"Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p &gt; 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (&lt; 18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p &lt; 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways. Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363.",
-,No,20200518,candidate,32346601,DNA methylation in APOE: The relationship with Alzheimer's and with cardiovascular health.,Alzheimers Dement (N Y),"Genetic variation in the apolipoprotein E (<i>APOE</i>) gene is associated with Alzheimer's disease (AD) and risk factors for cardiovascular disease (CVD). DNA methylationat <i>APOE</i> has been associated with altered cognition and AD. It is unclear if epigenetic marks could be used for predicting future disease. We assessed blood-based DNA methylation at 13 CpGs in the <i>APOE</i> gene in 5828 participants from the Generation Scotland (GS) cohort. Using linear mixed models regression, we examined the relationships among <i>APOE</i> methylation, cognition, cholesterol, the family history of AD and the risk for CVD. DNA methylation at two CpGs was associated with the ratio of total cholesterol and HDL cholesterol, but not with cognition, family history of AD, or the risk of CVD. <i>APOE</i> methylation is associated with the levels of blood cholesterol, but there is no evidence for the utility of <i>APOE</i> methylation as a biomarker for predicting AD or CVD.",
-,No,20200518,chromatin interactions,32345984,Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data.,Nat Commun,"Promoter-anchored chromatin interactions (PAIs) play a pivotal role in transcriptional regulation. Current high-throughput technologies for detecting PAIs, such as promoter capture Hi-C, are not scalable to large cohorts. Here, we present an analytical approach that uses summary-level data from cohort-based DNA methylation (DNAm) quantitative trait locus (mQTL) studies to predict PAIs. Using mQTL data from human peripheral blood ([Formula: see text]), we predict 34,797 PAIs which show strong overlap with the chromatin contacts identified by previous experimental assays. The promoter-interacting DNAm sites are enriched in enhancers or near expression QTLs. Genes whose promoters are involved in PAIs are more actively expressed, and gene pairs with promoter-promoter interactions are enriched for co-expression. Integration of the predicted PAIs with GWAS data highlight interactions among 601 DNAm sites associated with 15 complex traits. This study demonstrates the use of mQTL data to predict PAIs and provides insights into the role of PAIs in complex trait variation.",
-,No,20200518,ewas,31554518,Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation,Genome Biol,"BACKGROUND:
+No,20200113,sex chromosomes,31767861,Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age.,Nat Commun,"Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. Skewed XCI toward one parental X has been observed in several complex human traits, but the extent to which genetics and environment influence skewed XCI is largely unexplored. To address this, we quantify XCI-skew in multiple tissues and immune cell types in a twin cohort. Within an individual, XCI-skew differs between blood, fat and skin tissue, but is shared across immune cell types. XCI skew increases with age in blood, but not other tissues, and is associated with smoking. XCI-skew is increased in twins with Rheumatoid Arthritis compared to unaffected identical co-twins. XCI-skew is heritable in blood of females &gt;55 years old (h<sup>2</sup> = 0.34), but not in younger individuals or other tissues. This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner.",
+No,20200113,prediction,31762318,Genome-wide analysis of DNA methylation identifies two CpG sites for the early screening of colorectal cancer.,Epigenomics,"<b>Aim:</b> To identify a panel of DNA methylation markers for the early diagnosis of colorectal cancer (CRC). <b>Materials &amp; methods:</b> Using public omics data and our pyrosequencing data, we developed and validated a global methylation model and a CpG-methylation-based model for CRC screening. <b>Results:</b> Both of the models yielded high sensitivity and specificity for distinguishing CRC and its precursors (colorectal adenoma and colorectal laterally spreading tumor) from normal controls in eight independent datasets and our newly collected samples. More importantly, the two-CpG-based model showed high specificity in excluding inflammatory bowel diseases and other 13 cancer types. <b>Conclusion:</b> A diagnostic model based on two CpGs (cg09239744 and cg12587766) may be a powerful tool for CRC screening.",
+Yes,20200113,ewas,31811260,Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.,Mol Psychiatry,"DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.",
+Yes,20200113,ewas,31892367,Newborn and childhood differential DNA methylation and liver fat in school-age children.,Clin Epigenetics,"Non-alcoholic fatty liver disease is the most common chronic liver disease in children in western countries. Adverse early-life exposures are associated with higher liver fat percentages in children. Differential DNA methylation may underlie these associations. We aimed to identify differential DNA methylation in newborns and children associated with liver fat accumulation in childhood. We also examined whether DNA methylation at 22 cytosine-phosphate-guanine sites (CpGs) associated with adult non-alcoholic fatty liver disease is associated with liver fat in children. Within a population-based prospective cohort study, we analyzed epigenome-wide DNA methylation data of 785 newborns and 344 10-year-old children in relation to liver fat fraction at 10 years. DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Illumina). We measured liver fat fraction by Magnetic Resonance Imaging. Associations of single CpG DNA methylation at the two-time points with liver fat accumulation were analyzed using robust linear regression models. We also analyzed differentially methylation regions using the dmrff package. We looked-up associations of 22 known adult CpGs at both ages with liver fat at 10 years. The median liver fat fraction was 2.0% (95% range 1.3, 5.1). No single CpGs and no differentially methylated regions were associated with liver fat accumulation. None of the 22 known adult CpGs were associated with liver fat in children. DNA methylation at birth and in childhood was not associated with liver fat accumulation in 10-year-old children in this study. This may be due to modest sample sizes or DNA methylation changes being a consequence rather than a determinant of liver fat.",
+Yes,20200113,ewas,31892350,An epigenome-wide association study of sex-specific chronological ageing.,Genome Med,"Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 individuals between the ages of 18 and 87 years, with replication in a further 4450 individuals between the ages of 18 and 93 years. Linear regression models were applied, with stringent genome-wide significance thresholds (p &lt; 3.6 × 10<sup>-8</sup>) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds. Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10, an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = - 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction. The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.",
+Yes,20200113,ewas,31880793,Association of Periconception Paternal Body Mass Index With Persistent Changes in DNA Methylation of Offspring in Childhood.,JAMA Netw Open,"While prenatal nutrition and maternal obesity are recognized as important contributors to epigenetic changes and childhood obesity, the role of paternal obesity in the epigenome of offspring has not been well studied. To test whether periconception paternal body mass index (BMI) is associated with DNA methylation patterns in newborns, to examine associations between maternal and paternal BMI and the epigenome of offspring, and to examine persistence of epigenetic marks at ages 3 and 7 years. Project Viva is a prebirth cohort study of mothers and children including 2128 live births that enrolled mothers from April 1999 to July 2002 and followed offspring to adolescence. This study analyzed the subset of participants with available data on paternal BMI and DNA methylation in offspring blood in the newborn period, at age 3 years, and at age 7 years. Data were analyzed from July 2017 to October 2019. The primary exposure was paternal periconception BMI; associations were adjusted for maternal prepregnancy BMI and stratified according to maternal BMI above or below 25. The primary outcome was genome-wide DNA methylation patterns in offspring blood collected at birth, age 3 years, and age 7 years. A total of 429 father-mother-infant triads were included. The mean (SD) periconception paternal BMI was 26.4 (4.0) and mean maternal prepregnancy BMI was 24.5 (5.2); 268 fathers had BMI greater than or equal to 25 (mean [SD], 28.5 [3.3]) and 161 had BMI less than 25 (mean [SD], 22.8 [1.8]). Paternal BMI greater than or equal to 25 was associated with increased offspring birth weight compared with paternal BMI less than 25 (mean [SD] z score, 0.38 [0.91] vs 0.11 [0.96]; P = .004). Cord blood DNA methylation at 9 CpG sites was associated with paternal BMI independent of maternal BMI (q &lt; .05). Methylation at cg04763273, between TFAP2C and BMP7, decreased by 5% in cord blood with every 1-unit increase in paternal BMI (P = 3.13 × 10-8); hypomethylation at this site persisted at ages 3 years and 7 years. Paternal BMI was associated with methylation at cg01029450 in the promoter region of the ARFGAP3 gene; methylation at this site was also associated with lower infant birth weight (β = -0.0003; SD = 0.0001; P = .03) and with higher BMI z score at age 3 years. In this study, paternal BMI was associated with DNA methylation, birth weight, and childhood BMI z score in offspring.",
+Yes,20200113,ewas,31851703,Association of cord blood methylation with neonatal leptin: An epigenome wide association study.,PLoS ONE,"Neonatal adiposity is a risk factor for childhood obesity. Investigating contributors to neonatal adiposity is important for understanding early life obesity risk. Epigenetic changes of metabolic genes in cord blood may contribute to excessive neonatal adiposity and subsequent childhood obesity. This study aims to evaluate the association of cord blood DNA methylation patterns with anthropometric measures and cord blood leptin, a biomarker of neonatal adiposity. A cross-sectional study was performed on a multiethnic cohort of 114 full term neonates born to mothers without gestational diabetes at a university hospital. Cord blood was assayed for leptin and for epigenome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariable linear regression was used to analyze associations between individual CpG sites as well as differentially methylated regions in cord blood DNA with measures of newborn adiposity including anthropometrics (birth weight, fat mass and percent body fat) and cord blood leptin. False discovery rate was estimated to account for multiple comparisons. 247 CpG sites as well as 18 differentially methylated gene regions were associated with cord blood leptin but no epigenetic changes were associated with birth weight, fat mass or percent body fat. Genes of interest identified in this study are DNAJA4, TFR2, SMAD3, PLAG1, FGF1, and HNF4A. Epigenetic changes in cord blood DNA are associated with cord blood leptin levels, a measure of neonatal adiposity.",
+No,20200113,pwas,31792462,Plasma protein patterns as comprehensive indicators of health.,Nat Med,"Proteins are effector molecules that mediate the functions of genes<sup>1,2</sup> and modulate comorbidities<sup>3-10</sup>, behaviors and drug treatments<sup>11</sup>. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning<sup>12-16</sup> coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.",
+No,20200113,meqtl,31861999,MethylToSNP: identifying SNPs in Illumina DNA methylation array data.,Epigenetics Chromatin,"Current array-based methods for the measurement of DNA methylation rely on the process of sodium bisulfite conversion to differentiate between methylated and unmethylated cytosine bases in DNA. In the absence of genotype data this process can lead to ambiguity in data interpretation when a sample has polymorphisms at a methylation probe site. A common way to minimize this problem is to exclude such potentially problematic sites, with some methods removing as much as 60% of array probes from consideration before data analysis. Here, we present an algorithm implemented in an R Bioconductor package, MethylToSNP, which detects a characteristic data pattern to infer sites likely to be confounded by polymorphisms. Additionally, the tool provides a stringent reliability score to allow thresholding on SNP predictions. We calibrated parameters and thresholds used by the algorithm on simulated and real methylation data sets. We illustrate findings using methylation data from YRI (Yoruba in Ibadan, Nigeria), CEPH (European descent) and KhoeSan (southern African) populations. Our polymorphism predictions made using MethylToSNP have been validated through SNP databases and bisulfite and genomic sequencing. The benefits of this method are threefold. First, it prevents extensive data loss by considering only SNPs specific to the individuals in the study. Second, it offers the possibility to identify new polymorphisms in samples for which there is little known about the genetic landscape. Third, it identifies variants as they exist in functional regions of a genome, such as in CTCF (transcriptional repressor) sites and enhancers, that may be common alleles or personal mutations with potential to deleteriously affect genomic regulatory activities. We demonstrate that MethylToSNP is applicable to the Illumina 450K and Illumina 850K EPIC array data and is also backwards compatible to the 27K methylation arrays. Going forward, this kind of nuanced approach can increase the amount of information derived from precious data sets by considering samples of the project individually to enable more informed decisions about data cleaning.",
+Yes,20200113,ewas,31889537,Cell Type-Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder.,Biol Psychiatry,"We sought to characterize methylation changes in brain and blood associated with major depressive disorder (MDD). As analyses of bulk tissue may obscure association signals and hamper the biological interpretation of findings, these changes were studied on a cell type-specific level. In 3 collections of human postmortem brain (n = 206) and 1 collection of blood samples (N = 1132) of MDD cases and controls, we used epigenomic deconvolution to perform cell type-specific methylome-wide association studies within subpopulations of neurons/glia for the brain data and granulocytes/T cells/B cells/monocytes for the blood data. Sorted neurons/glia from a fourth postmortem brain collection (n = 58) were used for validation purposes. Cell type-specific methylome-wide association studies identified multiple findings in neurons/glia that were detected across brain collections and were reproducible in physically sorted nuclei. Cell type-specific analyses in blood samples identified methylome-wide significant associations in T cells, monocytes, and whole blood that replicated findings from a past methylation study of MDD. Pathway analyses implicated p75 neurotrophin receptor/nerve growth factor signaling and innate immune toll-like receptor signaling in MDD. Top results in neurons, glia, bulk brain, T cells, monocytes, and whole blood were enriched for genes supported by genome-wide association studies for MDD and other psychiatric disorders. We both replicated and identified novel MDD-methylation associations in human brain and blood samples at a cell type-specific level. Our results provide mechanistic insights into how the immune system may interact with the brain to affect MDD susceptibility. Importantly, our findings involved associations with MDD in human samples that implicated many closely related biological pathways. These disease-linked sites and pathways represent promising new therapeutic targets for MDD.",
+No,20200113,somatic mutations,31874648,The somatic mutation landscape of the human body.,Genome Biol,"Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet they remain largely uncharacterized. To gain a better understanding of the genome-wide distribution and functional impact of somatic mutations, we leverage the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, reveals a wide diversity of tissue-specific mutation profiles associated with gene expression levels and chromatin states. For example, lung samples with low expression of the mismatch-repair gene MLH1 show a mutation signature of deficient mismatch repair. In addition, we find pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which are under positive selection and are highly enriched in many healthy tissues. These findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis.",
+Yes,20200113,ewas,31882564,Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy,Diabetes,"The placenta participates in maternal insulin sensitivity changes during pregnancy, however mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75g oral glucose tolerance tests at ?26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using IlluminaEPIC arrays. Using linear regression models to quantify associations at 720,077 CpGs, adjusted for maternal age, gravidity, smoking, body mass index, child sex and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P<6.94x10-8). Among genes annotated to these 188 CpGs, we found enrichment in targets for microRNAs, histone modifications, and in parent-of-origin DNA methylation including H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1 Mendelian Randomization analyses revealed 5 loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy.",
+Yes,20200113,ewas,31915053,Epigenome-wide association study of seizures in childhood and adolescence.,Clin Epigenetics,,
+,20200113,ewas,31877125,Human sperm displays rapid responses to diet.,PLoS Biol,"The global rise in obesity and steady decline in sperm quality are two alarming trends that have emerged during recent decades. In parallel, evidence from model organisms shows that paternal diet can affect offspring metabolic health in a process involving sperm tRNA-derived small RNA (tsRNA). Here, we report that human sperm are acutely sensitive to nutrient flux, both in terms of sperm motility and changes in sperm tsRNA. Over the course of a 2-week diet intervention, in which we first introduced a healthy diet followed by a diet rich in sugar, sperm motility increased and stabilized at high levels. Small RNA-seq on repeatedly sampled sperm from the same individuals revealed that tsRNAs were up-regulated by eating a high-sugar diet for just 1 week. Unsupervised clustering identified two independent pathways for the biogenesis of these tsRNAs: one involving a novel class of fragments with specific cleavage in the T-loop of mature nuclear tRNAs and the other exclusively involving mitochondrial tsRNAs. Mitochondrial involvement was further supported by a similar up-regulation of mitochondrial rRNA-derived small RNA (rsRNA). Notably, the changes in sugar-sensitive tsRNA were positively associated with simultaneous changes in sperm motility and negatively associated with obesity in an independent clinical cohort. This rapid response to a dietary intervention on tsRNA in human sperm is attuned with the paternal intergenerational metabolic responses found in model organisms. More importantly, our findings suggest shared diet-sensitive mechanisms between sperm motility and the biogenesis of tsRNA, which provide novel insights about the interplay between nutrition and male reproductive health.",
+Yes,20200113,ewas,31900413,Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits.,Nat Commun,"DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.",
+Yes,20200113,ewas,31910897,Replication and expansion of epigenome-wide association literature in a black South African population.,Clin Epigenetics,"DNA methylation is associated with non-communicable diseases (NCDs) and related traits. Methylation data on continental African ancestries are currently scarce, even though there are known genetic and epigenetic differences between ancestral groups and a high burden of NCDs in Africans. Furthermore, the degree to which current literature can be extrapolated to the understudied African populations, who have limited resources to conduct independent large-scale analysis, is not yet known. To this end, this study examines the reproducibility of previously published epigenome-wide association studies of DNA methylation conducted in different ethinicities, on factors related to NCDs, by replicating findings in 120 South African Batswana men aged 45 to 88 years. In addition, novel associations between methylation and NCD-related factors are investigated using the Illumina EPIC BeadChip. Up to 86% of previously identified epigenome-wide associations with NCD-related traits (alcohol consumption, smoking, body mass index, waist circumference, C-reactive protein, blood lipids and age) overlapped with those observed here and a further 13% were directionally consistent. Only 1% of the replicated associations presented with effects opposite to findings in other ancestral groups. The majority of these inconcistencies were associated with population-specific genomic variance. In addition, we identified eight new 450K array CpG associations not previously reported in other ancestries, and 11 novel EPIC CpG associations with alcohol consumption. The successful replication of existing EWAS findings in this African population demonstrates that blood-based 450K EWAS findings from commonly investigated ancestries can largely be extrapolated to ethnicities for which epigenetic data are not yet available. Possible population-specific differences in 14% of the tested associations do, however, motivate the need to include a diversity of ethnic groups in future epigenetic research. The novel associations found with the enhanced coverage of the Illumina EPIC array support its usefulness to expand epigenetic literature.",
+No,20200113,dnam age,31831772,A genomic predictor of lifespan in vertebrates.,Sci Rep,"Biological ageing and its mechanistic underpinnings are of immense biomedical and ecological significance. Ageing involves the decline of diverse biological functions and places a limit on a species' maximum lifespan. Ageing is associated with epigenetic changes involving DNA methylation. Furthermore, an analysis of mammals showed that the density of CpG sites in gene promoters, which are targets for DNA methylation, is correlated with lifespan. Using 252 whole genomes and databases of animal age and promotor sequences, we show a pattern across vertebrates. We also derive a predictive lifespan clock based on CpG density in a selected set of promoters. The lifespan clock accurately predicts maximum lifespan in vertebrates (R<sup>2</sup> = 0.76) from the density of CpG sites within only 42 selected promoters. Our lifespan clock provides a wholly new method for accurately estimating lifespan using genome sequences alone and enables estimation of this challenging parameter for both poorly understood and extinct species.",
+No,20200127,methods,31717838,Discrimination of DNA Methylation Signal from Background Variation for Clinical Diagnostics.,Int J Mol Sci,"Advances in the study of human DNA methylation variation offer a new avenue for the translation of epigenetic research results to clinical applications. Although current approaches to methylome analysis have been helpful in revealing an epigenetic influence in major human diseases, this type of analysis has proven inadequate for the translation of these advances to clinical diagnostics. As in any clinical test, the use of a methylation signal for diagnostic purposes requires the estimation of an optimal cutoff value for the signal, which is necessary to discriminate a signal induced by a disease state from natural background variation. To address this issue, we propose the application of a fundamental signal detection theory and machine learning approaches. Simulation studies and tests of two available methylome datasets from autism and leukemia patients demonstrate the feasibility of this approach in clinical diagnostics, providing high discriminatory power for the methylation signal induced by disease, as well as high classification performance. Specifically, the analysis of whole biomarker genomic regions could suffice for a diagnostic, markedly decreasing its cost.",
+Yes,20200127,ewas,31857576,Edematous severe acute malnutrition is characterized by hypomethylation of DNA.,Nat Commun,"Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.",
+No,20200127,dnam age,31847916,Systematic underestimation of the epigenetic clock and age acceleration in older subjects.,Genome Biol,"The Horvath epigenetic clock is widely used. It predicts age quite well from 353 CpG sites in the DNA methylation profile in unknown samples and has been used to calculate &quot;age acceleration&quot; in various tissues and environments. The model systematically underestimates age in tissues from older people. This is seen in all examined tissues but most strongly in the cerebellum and is consistently observed in multiple datasets. Age acceleration is thus age-dependent, and this can lead to spurious associations. The current literature includes examples of association tests with age acceleration calculated in a wide variety of ways. The concept of an epigenetic clock is compelling, but caution should be taken in interpreting associations with age acceleration. Association tests of age acceleration should include age as a covariate.",
+No,20200127,prediction,32296024,DNA methylation markers in the diagnosis and prognosis of common leukemias.,Signal Transduct Target Ther,"The ability to identify a specific type of leukemia using minimally invasive biopsies holds great promise to improve the diagnosis, treatment selection, and prognosis prediction of patients. Using genome-wide methylation profiling and machine learning methods, we investigated the utility of CpG methylation status to differentiate blood from patients with acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML) from normal blood. We established a CpG methylation panel that can distinguish ALL and AML blood from normal blood as well as ALL blood from AML blood with high sensitivity and specificity. We then developed a methylation-based survival classifier with 23 CpGs for ALL and 20 CpGs for AML that could successfully divide patients into high-risk and low-risk groups, with significant differences in clinical outcome in each leukemia type. Together, these findings demonstrate that methylation profiles can be highly sensitive and specific in the accurate diagnosis of ALL and AML, with implications for the prediction of prognosis and treatment selection.",
+No,20200127,ewas,31959221,"The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients.",Clin Epigenetics,"Severe obesity is a growing, worldwide burden and conventional therapies including radical change of diet and/or increased physical activity have limited results. Bariatric surgery has been proposed as an alternative therapy showing promising results. It leads to substantial weight loss and improvement of comorbidities such as type 2 diabetes. Increased adiposity is associated with changes in epigenetic profile, including DNA methylation. We investigated the effect of bariatric surgery on clinical profile, DNA methylation, and biological age estimated using Horvath's epigenetic clock. To determine the impact of bariatric surgery and subsequent weight loss on clinical traits, a cohort of 40 severely obese individuals (BMI = 30-73 kg/m<sup>2</sup>) was examined at the time of surgery and at three follow-up visits, i.e., 3, 6, and 12 months after surgery. The majority of the individuals were women (65%) and the mean age at surgery was 45.1 ± 8.1 years. We observed a significant decrease over time in BMI, fasting glucose, HbA1c, HOMA-IR, insulin, total cholesterol, triglycerides, LDL and free fatty acids levels, and a significant small increase in HDL levels (all p values &lt; 0.05). Epigenome-wide association analysis revealed 4857 differentially methylated CpG sites 12 months after surgery (at Bonferroni-corrected p value &lt; 1.09 × 10<sup>-7</sup>). Including BMI change in the model decreased the number of significantly differentially methylated CpG sites by 51%. Gene set enrichment analysis identified overrepresentation of multiple processes including regulation of transcription, RNA metabolic, and biosynthetic processes in the cell. Bariatric surgery in severely obese patients resulted in a decrease in both biological age and epigenetic age acceleration (EAA) (mean = - 0.92, p value = 0.039). Our study shows that bariatric surgery leads to substantial BMI decrease and improvement of clinical outcomes observed 12 months after surgery. These changes explained part of the association between bariatric surgery and DNA methylation. We also observed a small, but significant improvement of biological age. These epigenetic changes may be modifiable by environmental lifestyle factors and could be used as potential biomarkers for obesity and in the future for obesity related comorbidities.",
+Yes,20200127,ewas,31943067,Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer.,Hum Mol Genet,"Prior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts. DNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. Through an Epigenome Wide Association Study we explored CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer using linear mixed effects models adjusted for history of breast biopsy, age, RefFreeCellMix cell estimates, time of delivery, array chip, and subject as random effect. We identified 58 differentially methylated CpG sites associated with a subsequent breast cancer diagnosis (q-value &lt; 0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls. Breast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors and improving primary and secondary prevention of breast cancer.",
+Yes,20200127,ewas,31932625,Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma.,Sci Rep,"DNA methylation (DNAm) profiles in central airway epithelial cells (AECs) may play a key role in pathological processes in asthma. The goal of the current study is to compare the diagnostic performance of DNAm markers across three tissues: AECs, nasal epithelial cells (NECs), and peripheral blood mononuclear cells (PBMCs). Additionally, we focused on the results using the machine learning algorithm in the context of multi-locus effects to evaluate the diagnostic performance of the optimal subset of CpG sites. We obtained 74 subjects with asthma and 41 controls from AECs, 15 subjects with asthma and 14 controls from NECs, 697 subjects with asthma and 97 controls from PBMCs. Epigenome-wide DNA methylation levels in AECs, NECs and PBMCs were measured using the Infinium Human Methylation 450 K BeadChip. Overlap analysis across the three different sample sources at the locus and pathway levels were studied to investigate shared or unique pathophysiological processes of asthma across tissues. Using the top 100 asthma-associated methylation markers as classifiers from each dataset, we found that both AEC- and NEC-based DNAm signatures exerted a lower classification error than the PBMC-based DNAm markers (p-value = 0.0002). The area-under-the-curve (AUC) analysis based on out-of-bag errors using the random forest classification algorithm revealed that PBMC-, NEC-, and AEC-based methylation data yielded 31 loci (AUC: 0.87), 8 loci (AUC: 0.99), and 4 loci (AUC: 0.97) from each optimal subset of tissue-specific markers, respectively. We also discovered the locus-locus interaction of DNAm levels of the CDH6 gene and RAPGEF3 gene might interact with each other to jointly predict the risk of asthma - which suggests the pivotal role of cell-cell junction in the pathological changes of asthma. Both AECs and NECs might provide better diagnostic accuracy and efficacy levels than PBMCs. Further research is warranted to evaluate how these tissue-specific DNAm markers classify and predict asthma risk.",
+No,20200127,epigenetics,31949157,Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer.,Nat Commun,"Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.",
+No,20200210,epigenetics,31999955,ATAC-Me Captures Prolonged DNA Methylation of Dynamic Chromatin Accessibility Loci during Cell Fate Transitions.,Mol Cell,"DNA methylation of enhancers is dynamic, cell-type specific, and vital for cell fate progression. However, current models inadequately define its role within the hierarchy of gene regulation. Analysis of independent datasets shows an unanticipated overlap between DNA methylation and chromatin accessibility at enhancers of steady-state stem cells, suggesting that these two opposing features might exist concurrently. To define their temporal relationship, we developed ATAC-Me, which probes accessibility and methylation from single DNA library preparations. We identified waves of accessibility occurring rapidly across thousands of myeloid enhancers in a monocyte-to-macrophage cell fate model. Prolonged methylation states were observed at a majority of these sites, while transcription of nearby genes tracked closely with accessibility. ATAC-Me uncovers a significant disconnect between chromatin accessibility, DNA methylation status, and gene activity. This unexpected observation highlights the value of ATAC-Me in constructing precise molecular timelines for understanding the role of DNA methylation in gene regulation.",
+Yes,20200210,ewas,32007686,Selenium-associated DNA methylation modifications in placenta and neurobehavioral development of newborns: An epigenome-wide study of two U.S. birth cohorts.,Environ Int,"Selenium (Se) levels in pregnancy have been linked to neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impacts of environmental exposures on fetal development; however, very few studies have been done elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns' neurobehavior. We measured placental Se concentrations in 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 newborns in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 BeadChip, and newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores. We identified five Se-related differentially methylated CpG sites. Among them was cg09674502 (GFI1), where selenium concentration was positively associated with methylation (β-coefficient = 1.11, FDR-adjusted p-value = 0.045), and where we observed that a one percent methylation level increase was associated with a 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). We also observed for each interquartile range (IQR) increase in selenium concentration in the placenta, there was 1.76 times greater odds of higher hypotonicity (OR [95% CI] = 1.76 [1.12, 2.82]). Placental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.",
+No,20200210,methods,32003784,decorate: Differential Epigenetic Correlation Test.,Bioinformatics,"Identifying correlated epigenetic features and finding differences in correlation between individuals with disease compared to controls can give novel insight into disease biology. This framework has been successful in analysis of gene expression data, but application to epigenetic data has been limited by the computational cost, lack of scalable software and lack of robust statistical tests. Decorate, differential epigenetic correlation test, identifies correlated epigenetic features and finds clusters of features that are differentially correlated between two or more subsets of the data. The software scales to genome-wide datasets of epigenetic assays on hundreds of individuals. We apply decorate to four large-scale datasets of DNA methylation, ATAC-seq and histone modification ChIP-seq. decorate R package is available from https://github.com/GabrielHoffman/decorate. Supplementary data are available at Bioinformatics online.",
+No,20200210,methods,32000657,Detection of suspicious interactions of spiking covariates in methylation data.,BMC Bioinformatics,"In methylation analyses like epigenome-wide association studies, a high amount of biomarkers is tested for an association between the measured continuous outcome and different covariates. In the case of a continuous covariate like smoking pack years (SPY), a measure of lifetime exposure to tobacco toxins, a spike at zero can occur. Hence, all non-smokers are generating a peak at zero, while the smoking patients are distributed over the other SPY values. Additionally, the spike might also occur on the right side of the covariate distribution, if a category &quot;heavy smoker&quot; is designed. Here, we will focus on methylation data with a spike at the left or the right of the distribution of a continuous covariate. After the methylation data is generated, analysis is usually performed by preprocessing, quality control, and determination of differentially methylated sites, often performed in pipeline fashion. Hence, the data is processed in a string of methods, which are available in one software package. The pipelines can distinguish between categorical covariates, i.e. for group comparisons or continuous covariates, i.e. for linear regression. The differential methylation analysis is often done internally by a linear regression without checking its inherent assumptions. A spike in the continuous covariate is ignored and can cause biased results. We have reanalysed five data sets, four freely available from ArrayExpress, including methylation data and smoking habits reported by smoking pack years. Therefore, we generated an algorithm to check for the occurrences of suspicious interactions between the values associated with the spike position and the non-spike positions of the covariate. Our algorithm helps to decide if a suspicious interaction can be found and further investigations should be carried out. This is mostly important, because the information on the differentially methylated sites will be used for post-hoc analyses like pathway analyses. We help to check for the validation of the linear regression assumptions in a methylation analysis pipeline. These assumptions should also be considered for machine learning approaches. In addition, we are able to detect outliers in the continuous covariate. Therefore, more statistical robust results should be produced in methylation analysis using our algorithm as a preprocessing step.",
+Yes,20200210,ewas,31999706,Associations between high blood pressure and DNA methylation.,PLoS ONE,"High blood pressure is a major risk factor for cardiovascular disease and is influenced by both environmental and genetic factors. Epigenetic processes including DNA methylation potentially mediate the relationship between genetic factors, the environment and cardiovascular disease. Despite an increased risk of hypertension and cardiovascular disease in individuals of South Asians compared to Europeans, it is not clear whether associations between blood pressure and DNA methylation differ between these groups. We performed an epigenome-wide association study and differentially methylated region (DMR) analysis to identify DNA methylation sites and regions that were associated with systolic blood pressure, diastolic blood pressure and hypertension. We analyzed samples from 364 European and 348 South Asian men (first generation migrants to the UK) from the Southall And Brent REvisited cohort, measuring DNA methylation from blood using the Illumina Infinium® HumanMethylation450 BeadChip. One CpG site was found to be associated with DBP in trans-ancestry analyses (i.e. both ethnic groups combined), while in Europeans alone seven CpG sites were associated with DBP. No associations were identified between DNA methylation and either SBP or hypertension. Comparison of effect sizes between South Asian and European EWAS for DBP, SBP and hypertension revealed little concordance between analyses. DMR analysis identified several regions with known relationships with CVD and its risk factors. This study identified differentially methylated sites and regions associated with blood pressure and revealed ethnic differences in these associations. These findings may point to molecular pathways which may explain the elevated cardiovascular disease risk experienced by those of South Asian ancestry when compared to Europeans.",
+Yes,20200210,ewas,31995399,DNA Methylation is Predictive of Mortality in Current and Former Smokers.,Am J Respir Crit Care Med,"Smoking results in at least a decade lower life expectancy. Mortality among current smokers is two to three times as high as never smokers. DNA methylation is an epigenetic modification of the human genome that has been associated with both cigarette smoking and mortality. We sought to identify DNA methylation marks in blood predictive of mortality in a subset of the COPDGene study, representing 101 deaths among 667 current and former smokers. We assayed genome-wide DNA methylation in non-Hispanic white smokers with and without COPD using blood samples from the COPDGene enrollment visit. We tested whether DNA methylation was associated with mortality in models adjusted for COPD status, age, sex, current-smoking status, and pack-years of cigarette smoking. Replication was performed in a subset of 231 individuals from the ECLIPSE study. We identified seven CpG sites associated with mortality (FDR &lt; 20%) that replicated in the ECLIPSE cohort (p &lt; 0.05). None of these marks were associated with longitudinal lung function decline in survivors, smoking history or current smoking status. However, differential methylation of two replicated PIK3CD sites were associated with lung function at enrollment (p &lt; 0.05). We also observed associations between DNA methylation and gene expression for the PIK3CD sites. This study is the first to identify variable DNA methylation associated with all-cause mortality in smokers with and without COPD. Evaluating predictive epigenomic marks of smokers in peripheral blood may allow for targeted risk stratification and aid in delivery of future tailored therapeutic interventions.",
+Yes,20200210,ewas,31992121,Epigenomics of being bullied: changes in DNA methylation following bullying exposure.,Epigenetics,"Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined <i>n</i> = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to <i>5-HTT</i> and <i>NR3C1</i>. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (<i>b</i> = -2.67e-03, SE = 4.97e-04, <i>p</i> = 7.17e-08). This site is annotated to <i>RAB14</i>, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for <i>5-HTT</i> and <i>NR3C1</i>. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation.",
+Yes,20200210,ewas,31985870,Coagulation factor VIII: Relationship to Cardiovascular Disease Risk and Whole Genome Sequence and Epigenome-Wide Analysis in African Americans.,J Thromb Haemost,"Prospective studies have suggested higher factor VIII (FVIII) levels is an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans. We measured FVIII levels in ~3,400 AAs from the community-based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations. We assessed cross-sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome-wide methylation array. Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B-type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome-wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant. Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.",
+No,20200210,methods,31985744,CoMeBack: DNA Methylation Array Data Analysis for Co-Methylated Regions.,Bioinformatics,"High-dimensional DNA methylation (DNAm) array coverage, while sparse in the context of the entire DNA methylome, still constitutes a very large number of CpG probes. The ensuing multiple test corrections affect the statistical power to detect associations, likely contributing to prevalent limited reproducibility. Array probes measuring proximal CpG sites often have correlated levels of DNAm that may not only be biologically meaningful but also imply statistical dependence and redundancy. New methods that account for such correlations between adjacent probes may enable improved specificity, discovery, and interpretation of statistical associations in DNAm array data. We developed a method named Co-Methylation with genomic CpG Background (CoMeBack), that estimates DNA co-methylation, defined as proximal CpG probes with correlated DNAm across individuals. CoMeBack outputs Co-methylated Regions (CMRs), spanning sets of array probes constructed based on all genomic CpG sites, including those not measured on the array, and without any phenotypic variable inputs. This approach can reduce the multiple test correction burden, while enhancing the discovery and specificity of statistical associations. We constructed and validated CMRs in whole blood, using publicly available Illumina Infinium 450K array (450K) data from over 5,000 individuals. These CMRs were enriched for enhancer chromatin states, and binding site motifs for several transcription factors involved in blood physiology. We illustrated how CMR-based Epigenome Wide Association Studies (EWAS) can improve discovery and reduce false positives for associations with chronological age. https://bitbucket.org/flopflip/comeback. Supplementary data are available at Bioinformatics online.",
+No,20200210,dnam age,31981007,One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project.,Geroscience,"Mediterranean diet has been proposed to promote healthy aging, but its effects on aging biomarkers have been poorly investigated. We evaluated the impact of a 1-year Mediterranean-like diet in a pilot study including 120 elderly healthy subjects from the NU-AGE study (60 Italians, 60 Poles) by measuring the changes in their epigenetic age, assessed by Horvath's clock. We observed a trend towards epigenetic rejuvenation of participants after nutritional intervention. The effect was statistically significant in the group of Polish females and in subjects who were epigenetically older at baseline. A genome-wide association study of epigenetic age changes after the intervention did not return significant (adjusted p value &lt; 0.05) loci. However, we identified small-effect alleles (nominal p value &lt; 10-4), mapping in genes enriched in pathways related to energy metabolism, regulation of cell cycle, and of immune functions. Together, these findings suggest that Mediterranean diet can promote epigenetic rejuvenation but with country-, sex-, and individual-specific effects, thus highlighting the need for a personalized approach to nutritional interventions.",
+No,20200210,methods,31969180,A curated benchmark of enhancer-gene interactions for evaluating enhancer-target gene prediction methods.,Genome Biol,"Many genome-wide collections of candidate cis-regulatory elements (cCREs) have been defined using genomic and epigenomic data, but it remains a major challenge to connect these elements to their target genes. To facilitate the development of computational methods for predicting target genes, we develop a Benchmark of candidate Enhancer-Gene Interactions (BENGI) by integrating the recently developed Registry of cCREs with experimentally derived genomic interactions. We use BENGI to test several published computational methods for linking enhancers with genes, including signal correlation and the TargetFinder and PEP supervised learning methods. We find that while TargetFinder is the best-performing method, it is only modestly better than a baseline distance method for most benchmark datasets when trained and tested with the same cell type and that TargetFinder often does not outperform the distance method when applied across cell types. Our results suggest that current computational methods need to be improved and that BENGI presents a useful framework for method development and testing.",
+No,20200210,mitochondria,31941967,Breastfeeding predicts blood mitochondrial DNA content in adolescents.,Sci Rep,"Nutrition during early childhood is linked to metabolic programming. We hypothesized that breastfeeding has long-term consequences on the energy metabolism exemplified by mitochondrial DNA (mtDNA). As part of the third cycle of the Flemish Environment and Health Study (FLEHSIII) cohort, 303 adolescents aged 14-15 years were included. We associated breastfeeding and blood mtDNA content 14-15 years later while adjusting for confounding variables. Compared with non-breastfed adolescents, mtDNA content was 23.1% (95%CI: 4.4-45.2; p = 0.013) higher in breastfed adolescents. Being breastfed for 1-10 weeks, 11-20 weeks, and &gt;20 weeks, was associated with a higher mtDNA content of respectively 16.0% (95%CI: -7.1-44.9; p = 0.191), 23.5% (95%CI: 0.8-51.3; p = 0.042), and 31.5% (95%CI: 4.3-65.7; p = 0.021). Our study showed a positive association between breastfeeding and mtDNA content in adolescents which gradually increased with longer periods of breastfeeding. Higher mtDNA content may be an underlying mechanism of the beneficial effects of breastfeeding on children's metabolism.",
+Yes,20200316,ewas,32071425,Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain.,Int J Obes (Lond),"Maternal obesity prior to or during pregnancy influences fetal growth, predisposing the offspring to increased risk for obesity across the life course. Placental epigenetic mechanisms may underlie these associations. We conducted an epigenome-wide association study to identify placental DNA methylation changes associated with maternal prepregnancy body mass index (BMI) and rate of gestational weight gain at first (GWG1), second (GWG2), and third trimester (GWG3). Participants of the NICHD Fetal Growth Studies with genome-wide placental DNA methylation (n = 301) and gene expression (n = 75) data were included. Multivariable-adjusted regression models were used to test the associations of 1 kg/m<sup>2</sup> increase in prepregnancy BMI or 1 kg/week increase in GWG with DNA methylation levels. Genes harboring top differentially methylated CpGs (FDR P &lt; 0.05) were evaluated for placental gene expression. We assessed whether DNA methylation sites known to be associated with BMI in child or adult tissues, were also associated with maternal prepregnancy BMI in placenta. Prepregnancy BMI was associated with DNA methylation at cg14568196[EGFL7], cg15339142[VETZ], and cg02301019[AC092377.1] (FDR P &lt; 0.05, P ranging from 1.4 × 10<sup>-10</sup> to 1.7 × 10<sup>-9</sup>). GWG1 or GWG2 was associated with DNA methylation at cg17918270[MYT1L], cg20735365[DLX5], and cg17451688[SLC35F3] (FDR P &lt; 0.05, P ranging from 6.4 × 10<sup>-10</sup> to 1.2 × 10<sup>-8</sup>). Both prepregnancy BMI and DNA methylation at cg1456819 [EGFL7] were negatively correlated with EGFL7 expression in placenta (P &lt; 0.05). Several CpGs previously implicated in obesity traits in children and adults were associated with prepregnancy BMI in placenta. Functional annotations revealed that EGFL7 is highly expressed in placenta and the differentially methylated CpG sites near EGFL7 and VEZT were cis-meQTL targets in blood. We identified placental DNA methylation changes at novel loci associated with prepregnancy BMI and GWG. The overlap between CpGs associated with obesity traits in placenta and other tissues in children and adults suggests that epigenetic mechanisms in placenta may give insights to early origins of obesity.",
+Yes,20200316,dnam age,32067420,An epigenetic clock for human skeletal muscle.,J Cachexia Sarcopenia Muscle,"Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation (HM) arrays (HM27, HM450, or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome-wide association study of age-associated DNA methylation patterns in skeletal muscle. The newly developed clock uses 200 cytosine-phosphate-guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine-phosphate-guanine dinucleotides of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan-tissue clock, P &lt; 0.0001) and an average correlation of � = 0.62 between actual and predicted age across datasets (vs. � = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate &lt; 0.005. However, gene set enrichment analysis did not reveal any enrichment for gene ontologies. We have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an r package called Muscle Epigenetic Age Test available on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.",
+Yes,20200316,ewas,32066674,Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden.,Transl Psychiatry,"Epigenetic variation in peripheral tissues is being widely studied as a molecular biomarker of complex disease and disease-related exposures. To date, few studies have examined differences in DNA methylation associated with attention-deficit hyperactivity disorder (ADHD). In this study, we profiled genetic and methylomic variation across the genome in saliva samples from children (age 7-12 years) with clinically established ADHD (N = 391) and nonpsychiatric controls (N = 213). We tested for differentially methylated positions (DMPs) associated with both ADHD diagnosis and ADHD polygenic risk score, by using linear regression models including smoking, medication effects, and other potential confounders in our statistical models. Our results support previously reported associations between ADHD and DNA methylation levels at sites annotated to VIPR2, and identify several novel disease-associated DMPs (p &lt; 1e-5), although none of them were genome-wide significant. The two top-ranked, ADHD-associated DMPs (cg17478313 annotated to SLC7A8 and cg21609804 annotated to MARK2) are also significantly associated with nearby SNPs (p = 1.2e-46 and p = 2.07e-59), providing evidence that disease-associated DMPs are under genetic control. We also report a genome-wide significant association between ADHD polygenic risk and variable DNA methylation at a site annotated to the promoter of GART and SON (p = 6.71E-8). Finally, we show that ADHD-associated SNPs colocalize with SNPs associated with methylation levels in saliva. This is the first large-scale study of DNA methylation in children with ADHD. Our results represent novel epigenetic biomarkers for ADHD that may be useful for patient stratification, reinforce the importance of genetic effects on DNA methylation, and provide plausible molecular mechanisms for ADHD risk variants.",
+No,20200316,omics,32051591,MAFG-driven astrocytes promote CNS inflammation.,Nature,"Multiple sclerosis is a chronic inflammatory disease of the CNS<sup>1</sup>. Astrocytes contribute to the pathogenesis of multiple sclerosis<sup>2</sup>, but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.",
+Yes,20200316,dnam scores,32049268,Association of a Reproducible Epigenetic Risk Profile for Schizophrenia With Brain Methylation and Function.,JAMA Psychiatry,"Schizophrenia is a severe mental disorder in which epigenetic mechanisms may contribute to illness risk. Epigenetic profiles can be derived from blood cells, but to our knowledge, it is unknown whether these predict established brain alterations associated with schizophrenia. To identify an epigenetic signature (quantified as polymethylation score [PMS]) of schizophrenia using machine learning applied to genome-wide blood DNA-methylation data; evaluate whether differences in blood-derived PMS are mirrored in data from postmortem brain samples; test whether the PMS is associated with alterations of dorsolateral prefrontal cortex hippocampal (DLPFC-HC) connectivity during working memory in healthy controls (HC); explore the association between interactions between polygenic and epigenetic risk with DLPFC-HC connectivity; and test the specificity of the signature compared with other serious psychiatric disorders. In this case-control study conducted from 2008 to 2018 in sites in Germany, the United Kingdom, the United States, and Australia, blood DNA-methylation data from 2230 whole-blood samples from 6 independent cohorts comprising HC (1238 [55.5%]) and participants with schizophrenia (803 [36.0%]), bipolar disorder (39 [1.7%]), major depressive disorder 35 [1.6%]), and autism (27 [1.2%]), and first-degree relatives of all patient groups (88 [3.9%]) were analyzed. DNA-methylation data were further explored from 244 postmortem DLPFC samples from 136 HC and 108 patients with schizophrenia. Neuroimaging and genome-wide association data were available for 393 HC. The latter data was used to calculate a polygenic risk score (PRS) for schizophrenia. The data were analyzed in 2019. The accuracy of schizophrenia control classification based on machine learning using epigenetic data; association of schizophrenia PMS scores with DLPFC-HC connectivity; and association of the interaction between PRS and PMS with DLPFC-HC connectivity. This study included 7488 participants (4395 men [58.7%]), of whom 3158 (2230 men [70.6%]) received a diagnosis of schizophrenia. The PMS signature was associated with schizophrenia across 3 independent data sets (area under the curve [AUC] from 0.69 to 0.78; P value from 0.049 to 1.24 × 10-7) and data from postmortem DLPFC samples (AUC = 0.63; P = 1.42 × 10-4), but not with major depressive disorder (AUC = 0.51; P = .16), autism (AUC = 0.53; P = .66), or bipolar disorder (AUC = 0.58; P = .21). Pathways contributing most to the classification included synaptic processes. Healthy controls with schizophrenia-like PMS showed significantly altered DLPFC-HC connectivity (validation methylation/magnetic resonance imaging, t &lt; -3.81; P for familywise error, &lt;.04; validation magnetic resonance imaging, t &lt; -3.54; P for familywise error, &lt;.02), mirroring the lack of functional decoupling in schizophrenia. There was no significant association of the interaction between PMS and PRS with DLPFC-HC connectivity (P &gt; .19). We identified a reproducible blood DNA-methylation signature specific for schizophrenia that was correlated with altered functional DLPFC-HC coupling during working memory and mapped to methylation differences found in DLPFC postmortem samples. This indicates a possible epigenetic contribution to a schizophrenia intermediate phenotype and suggests that PMS could be of interest to be studied in the context of multimodal biomarkers for disease stratification and treatment personalization.",
+No,20200316,omics,32047265,Variations and expression features of CYP2D6 contribute to schizophrenia risk.,Mol Psychiatry,"Genome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown. Here, we analyze 1497 RNA-seq data in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Then, we colocalize eGene and eJunction with SCZ GWAS using SMR and fine mapping. Multiple ChIP-seq data and DNA methylation data generated from brain were used for identifying the causal variants. Finally, we used a hypothesis-free (no SCZ risk loci considered) enrichment analysis to determine implicated pathways. We identified 171 genes and eight splicing junctions located within four genes (SNX19, ARL6IP4, APOPT1, and CYP2D6) that potentially contribute to SCZ susceptibility. Among the genes, CYP2D6 is significantly associated with SCZ SNPs in eGene and eJunction. In-depth examination of the CYP2D6 region revealed that a nonsynonymous single nucleotide variant rs16947 is strongly associated with a higher abundance of CYP2D6 exon 3 skipping junctions. While we found rs133377 and other functional SNPs in high linkage disequilibrium with rs16947 (r<sup>2</sup> = 0.9539), histone acetylation analysis showed they are located within active transcription start sites. Furthermore, our data-driven enrichment analysis showed that CYP2D6 is significantly involved in drug metabolism of codeine, tamoxifen, and citalopram. Our study facilitates an understanding of the genetic architecture of SCZ and provides new drug targets.",
+Yes,20200316,ewas,32034291,"DNA methylation signature on phosphatidylethanol, not on self-reported alcohol consumption, predicts hazardous alcohol consumption in two distinct populations.",Mol Psychiatry,"The process of diagnosing hazardous alcohol drinking (HAD) is based on self-reported data and is thereby vulnerable to bias. There has been an interest in developing epigenetic biomarkers for HAD that might complement clinical assessment. Because alcohol consumption has been previously linked to DNA methylation (DNAm), we aimed to select DNAm signatures in blood to predict HAD from two demographically and clinically distinct populations (N<sub>total</sub> = 1,549). We first separately conducted an epigenome-wide association study (EWAS) for phosphatidylethanol (PEth), an objective measure of alcohol consumption, and for self-reported alcohol consumption in Cohort 1. We identified 83 PEth-associated CpGs, including 23 CpGs previously associated with alcohol consumption or alcohol use disorder. In contrast, no CpG reached epigenome-wide significance on self-reported alcohol consumption. Using a machine learning approach, two CpG subsets from EWAS on PEth and on self-reported alcohol consumption from Cohort 1 were separately tested for the prediction of HAD in Cohort 2. We found that a subset of 143 CpGs selected from the EWAS on PEth showed an excellent prediction of HAD with the area under the receiver operating characteristic curve (AUC) of 89.4% in training set and 73.9% in validation set of Cohort 2. However, CpGs preselected from the EWAS on self-reported alcohol consumption showed a poor prediction of HAD with AUC 75.2% in training set and 57.6% in validation set. Our results demonstrate that an objective measure for alcohol consumption is a more informative phenotype than self-reported data for revealing epigenetic mechanisms. The PEth-associated DNAm signature in blood could serve as a robust biomarker for alcohol consumption.",
+Yes,20200316,ewas,32033992,Epigenetic Link Between Statin Therapy and Type 2 Diabetes.,Diabetes Care,"To investigate the role of epigenetics in statins' diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. Five cohort studies' participants (<i>n</i> = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. Discovery (<i>n</i> = 6,820) and replication (<i>n</i> = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 Ă— 10<sup>-25</sup> [<i>DHCR24</i>]), cg10177197 (3.94 Ă— 10<sup>-08</sup> [<i>DHCR24</i>]), cg06500161 (2.67 Ă— 10<sup>-23</sup> [<i>ABCG1</i>]), cg27243685 (6.01 Ă— 10<sup>-09</sup> [<i>ABCG1</i>]), and cg05119988 (7.26 Ă— 10<sup>-12</sup> [<i>SC4MOL</i>]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that <i>ABCG1</i> methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and <i>ABCG1</i> methylation were associated with <i>ABCG1</i> downregulation, suggesting epigenetic regulations of <i>ABCG1</i> expression. Further, outcomes insulin and HOMA-IR were significantly associated with <i>ABCG1</i> expression. This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins' effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to <i>ABCG1</i> epigenetic regulation.",
+No,20200316,epigenetics,32033622,Essential concepts are missing: Foreign DNA in food invades the organisms' cells and can lead to stochastic epigenetic alterations with a wide range of possible pathogenetic consequences.,Clin Epigenetics,"In this article, a new concept for general pathogenesis has been proposed. Advances in molecular genetics have led to the realization that essential concepts in the framework of molecular biology are still missing. Clinical medicine is plagued by similar shortcomings: The questioning of current paradigms could open new vistas and invite challenging approaches. This article presents an unconventional idea. Foreign DNA which is regularly ingested with the essential food supply is not completely degraded. Small quantities of fragmented DNA rather persist transiently in the gastro-intestinal tract of mice and can be traced to various organ systems, except for cells in the germ line. Foreign DNA entering and persisting in mammalian cells can stochastically lead to genome-wide alterations of transcriptional and CpG DNA methylation profiles. In the course of food-ingested DNA invading somatic cells, completely new cell types can be generated which might be involved in the causation of common ailments. Projects emanating from this perception merit critical analysis and rigorous pursuit.",
+No,20200316,dnam age,32041686,"Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up. 32041685",Elife,"Biological age measurements (BAs) assess aging-related physiological change and predict health risks among individuals of the same chronological age (CA). Multiple BAs have been proposed and are well studied individually but not jointly. We included 845 individuals and 3973 repeated measurements from a Swedish population-based cohort and examined longitudinal trajectories, correlations, and mortality associations of nine BAs across 20 years follow-up. We found the longitudinal growth of functional BAs accelerated around age 70; average levels of BA curves differed by sex across the age span (50-90 years). All BAs were correlated to varying degrees; correlations were mostly explained by CA. Individually, all BAs except for telomere length were associated with mortality risk independently of CA. The largest effects were seen for methylation age estimators (GrimAge) and the frailty index (FI). In joint models, two methylation age estimators (Horvath and GrimAge) and FI remained predictive, suggesting they are complementary in predicting mortality. ",
+No,20200316,dnam age,32029736,Sexual-dimorphism in human immune system aging.,Nat Commun,"Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naĂŻve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune phenotypes can be visualized at https://immune-aging.jax.org to provide insights into future studies.",
+No,20200316,single cell,32033589,Eleven grand challenges in single-cell data science.,Genome Biol,"The recent boom in microfluidics and combinatorial indexing strategies, combined with low sequencing costs, has empowered single-cell sequencing technology. Thousands-or even millions-of cells analyzed in a single experiment amount to a data revolution in single-cell biology and pose unique data science problems. Here, we outline eleven challenges that will be central to bringing this emerging field of single-cell data science forward. For each challenge, we highlight motivating research questions, review prior work, and formulate open problems. This compendium is for established researchers, newcomers, and students alike, highlighting interesting and rewarding problems for the coming years.",
+Yes,20200316,ewas,32161338,Lifetime Ultraviolet Radiation Exposure and DNA Methylation in Blood Leukocytes: The Norwegian Women and Cancer Study.,Sci Rep,"Ultraviolet radiation (UVR) exposure is a leading cause of skin cancers and an ubiquitous environmental exposure. However, the molecular mechanisms relating UVR exposure to melanoma is not fully understood. We aimed to investigate if lifetime UVR exposure could be robustly associated to DNA methylation (DNAm). We assessed DNAm in whole blood in three data sets (n = 183, 191, and 125) from the Norwegian Woman and Cancer cohort, using Illumina platforms. We studied genome-wide DNAm, targeted analyses of CpG sites indicated in the literature, global methylation, and accelerated aging. Lifetime history of UVR exposure (residential ambient UVR, sunburns, sunbathing vacations and indoor tanning) was collected by questionnaires. We used one data set for discovery and the other two for replication. One CpG site showed a genome-wide significant association to cumulative UVR exposure (cg01884057) (p<sub>nominal</sub> = 3.96e-08), but was not replicated in any of the two replication sets (p<sub>nominal</sub> ≥ 0.42). Two CpG sites (cg05860019, cg00033666) showed suggestive associations with the other UVR exposures. We performed extensive analyses of the association between long-term UVR exposure and DNAm. There was no indication of a robust effect of past UVR exposure on DNAm.",
+No,20200316,dnam scores,32160902,Epigenetic predictors of all-cause mortality are associated with objective measures of neighborhood disadvantage in an urban population.,Clin Epigenetics,"Neighborhood characteristics are robust predictors of overall health and mortality risk for residents. Though there has been some investigation of the role that molecular indicators may play in mediating neighborhood exposures, there has been little effort to incorporate newly developed epigenetic biomarkers into our understanding of neighborhood characteristics and health outcomes. Using 157 participants of the Detroit Neighborhood Health Study with detailed assessments of neighborhood characteristics and genome-wide DNA methylation profiling via the Illumina 450K methylation array, we assessed the relationship between objective neighborhood characteristics and a validated DNA methylation-based epigenetic mortality risk score (eMRS). Associations were adjusted for age, race, sex, ever smoking, ever alcohol usage, education, years spent in neighborhood, and employment. A secondary model additionally adjusted for personal neighborhood perception. We summarized 19 neighborhood quality indicators assessed for participants into 9 principal components which explained over 90% of the variance in the data and served as metrics of objective neighborhood quality exposures. Of the nine principal components utilized for this study, one was strongly associated with the eMRS (β = 0.15; 95% confidence interval = 0.06-0.24; P = 0.002). This principal component (PC7) was most strongly driven by the presence of abandoned cars, poor streets, and non-art graffiti. Models including both PC7 and individual indicators of neighborhood perception indicated that only PC7 and not neighborhood perception impacted the eMRS. When stratified on neighborhood indicators of greenspace, we observed a potentially protective effect of large mature trees as this feature substantially attenuated the observed association. Objective measures of neighborhood disadvantage are significantly associated with an epigenetic predictor of mortality risk, presenting a potential novel avenue by which neighborhood-level exposures may impact health. Associations were independent of an individual's perception of their neighborhood and attenuated by neighborhood greenspace features. More work should be done to determine molecular risk factors associated with neighborhoods, and potentially protective neighborhood features against adverse molecular effects.",
+Yes,20200316,ewas,32144264,Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease.,Nat Commun,"An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.",
+es,20200316,ewas,32114984,Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.,Genome Med,"Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P &lt; 1.06 × 10<sup>- 7</sup>, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.",
+Yes,20200316,ewas,32085844,Effect of early parenteral nutrition during paediatric critical illness on DNA methylation as a potential mediator of impaired neurocognitive development: a pre-planned secondary analysis of the PEPaNIC international randomised controlled trial.,Lancet Respir Med,"Early use of parenteral nutrition in the paediatric intensive care unit (PICU) negatively affects development of executive functions, externalising behaviour, and visual-motor integration 2 years later, compared with omitting parenteral nutrition until PICU day 8 (late parenteral nutrition). The molecular basis of this finding is uncertain. We aimed to test the hypothesis that DNA methylation changes occur during critical illness and that early parenteral nutrition (or a specific macronutrient component hereof) contributes to these changes, which could explain its negative effects on neurocognitive development. This pre-planned secondary analysis of the multicentre PEPaNIC trial (2012-18) included all patients with a last PICU day blood sample (n=825, aged 0-17 years at PICU admission) who were randomly allocated (1:1) to early parenteral nutrition or late parenteral nutrition, as compared with 352 demographically matched healthy children. Investigators were masked to treatment allocation. We used the Infinium Human MethylationEPIC BeadChip to determine the genome-wide peripheral blood leukocyte DNA methylation of 865�859 CpG sites, yielding high-quality results for 403 patients allocated to early parenteral nutrition and for 411 patients allocated to late parenteral nutrition. Applying a false discovery rate of less than 0·05, DNA methylation of patients on the last PICU day was compared with that of healthy children, after excluding all CpG sites differentially methylated upon PICU admission, because these reflected pre-admission conditions and altered leukocyte composition. We used bootstrapped multivariable linear and non-linear regression analyses to assess the effect of early parenteral nutrition versus late parenteral nutrition on illness-induced alterations in DNA methylation and to what extent differentially methylated CpG sites explained impaired neurocognitive development 2 years later. During PICU stay, 159 CpG sites were methylated differently in patients admitted to the PICU than in healthy children, with mean effect sizes of 2·6% (SD 2·5) up to 21·6% (p&lt;0·02). These differentially methylated CpG sites occurred in genes involved in brain development, plasticity, and signalling; neuronal differentiation, migration, and growth; metabolism; transcriptional regulation; physical development and locomotion; and several neurodegenerative and neuropsychiatric diseases. Early parenteral nutrition and, in particular, the dose of amino acids, independently contributed to the differential methylation of 37 (23%) of these 159 CpG sites (p=0·0001 to 0·050), which could explain the adverse effect of early parenteral nutrition on neurocognitive development at 2-year follow-up (R<sup>2</sup> 0·61 [SD 0·01]). Early parenteral nutrition during paediatric critical illness altered DNA methylation, which suggests a plausible molecular basis for its negative effect on long-term neurocognitive development. Early administration of amino acids, rather than of glucose or lipids, mostly explained the aberrant DNA methylation-a finding that requires further investigation. European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and European Society for Clinical Nutrition and Metabolism.",
+Yes,20200316,ewas,32080920,Acute alcohol withdrawal and recovery in men lead to profound changes in DNA methylation profiles: a longitudinal clinical study.,Addiction,"Withdrawal is a serious and sometimes life-threatening event in alcohol-dependent individuals. It has been suggested that epigenetic processes may play a role in this context. This study aimed to identify genes and pathways involved in such processes which hint to relevant mechanisms underlying withdrawal. Cross-sectional case-control study and longitudinal within-cases study during alcohol withdrawal and after 2 weeks of recovery SETTING: Addiction medicine departments in two university hospitals in southern Germany. Ninety-nine alcohol-dependent male patients receiving in-patient treatment and suffering from severe withdrawal symptoms during detoxification and 95 age-matched male controls. Epigenome-wide methylation patterns were analyzed in patients during acute alcohol withdrawal and after 2 weeks of recovery, as well as in age-matched controls using Illumina EPIC bead chips. Methylation levels of patients and controls were tested for association with withdrawal status. Tests were adjusted for technical and batch effects, age, smoking and cell type distribution. Single-site analysis, as well as an analysis of differentially methylated regions and gene ontology analysis, were performed. We found pronounced epigenome-wide significant [false discovery rate (FDR) &lt; 0.05] differences between patients during withdrawal and after 2 weeks [2876 cytosine-phosphate-guanine (CpG) sites], as well as between patients and controls (9845 and 6094 CpG sites comparing patients at time-point 1 and patients at time-point 2 versus controls, respectively). Analysis of differentially methylated regions and involved pathways revealed an over-representation of gene ontology terms related to the immune system response. Differences between patients and controls diminished after recovery (&gt; 800 CpG sites less), suggesting a partial reversibility of alcohol- and withdrawal-related methylation. Acute alcohol withdrawal in severely dependent male patients appears to be associated with extensive changes in epigenome-wide methylation patterns. In particular, genes involved in immune system response seem to be affected by this condition.",
+Yes,20200316,ewas,32078381,Differential DNA Methylation in Placenta Associated With Maternal Blood Pressure During Pregnancy.,Hypertension,"Abnormal blood pressure during pregnancy is associated with impaired fetal growth, predisposing the offspring to cardiometabolic abnormalities over the life-course. Placental DNA methylation may be the regulatory pathway through which maternal blood pressure influences fetal and adult health outcomes. Epigenome-wide association study of 301 participants with placenta sample examined associations between DNA methylation and millimetre of mercury increases in systolic and diastolic blood pressure in each trimester. Findings were further examined using gene expression, gene pathway, and functional annotation analyses. Cytosine-(phosphate)-guanine (CpGs) known to be associated with cardiometabolic traits were evaluated. Increased maternal systolic and diastolic blood pressure were associated with methylation of 3 CpGs in the first, 6 CpGs in the second, and 15 CpGs in the third trimester at 5% false discovery rate (<i>P</i> values ranging from 6.6Ă—10<sup>-15</sup> to 2.3Ă—10<sup>-7</sup>). Several CpGs were enriched in pathways including cardiovascular-metabolic development (<i>P</i>=1.0Ă—10<sup>-45</sup>). Increased systolic and diastolic blood pressure were associated with increased CpG methylation and gene expression at <i>COL12A1</i>, a collagen family gene known for regulatory functions in the heart. Out of 304 previously reported CpGs known to be associated with cardiometabolic traits, 36 placental CpGs were associated with systolic and diastolic blood pressure in our data. The present study provides the first evidence for associations between placental DNA methylation and increased maternal blood pressure during pregnancy at genes implicated in cardiometabolic diseases. Identification of blood pressure-associated methylated sites in the placenta may provide clues to early origins of cardiometabolic dysfunction and inform guidelines for early prevention. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00912132.",
+No,20200316,mitochondria,32066501,Platelet mitochondrial DNA methylation predicts future cardiovascular outcome in adults with overweight and obesity.,Clin Epigenetics,"The association between obesity and cardiovascular disease (CVD) is proven, but why some adults with obesity develop CVD while others remain disease-free is poorly understood. Here, we investigated whether mitochondrial DNA (mtDNA) methylation in platelets is altered prior to CVD development in a population of adults with overweight and obesity. We devised a nested case-control study of 200 adults with overweight or obesity who were CVD-free at baseline, of whom 84 developed CVD within 5 years, while 116 remained CVD-free. Platelet mtDNA was isolated from plasma samples at baseline, and mtDNA methylation was quantified in mitochondrially encoded cytochrome-C-oxidase I (MT-CO1; nt6797 and nt6807), II (MT-CO2; nt8113 and nt8117), and III (MT-CO3; nt9444 and nt9449); tRNA leucine 1 (MT-TL1; nt3247 and nt3254); D-loop (nt16383); tRNA phenylalanine (MT-TF; nt624); and light-strand-origin-of-replication (MT-OLR; nt5737, nt5740, and nt5743) by bisulfite-pyrosequencing. Logistic regression was used to estimate the contribution of mtDNA methylation to future CVD risk. ROC curve analysis was used to identify the optimal mtDNA methylation threshold for future CVD risk prediction. A model was generated incorporating methylation at three loci (score 0, 1, or 2 according to 0, 1, or 2-3 hypermethylated loci, respectively), adjusted for potential confounders, such as diastolic and systolic blood pressure, fasting blood glucose, and cholesterol ratio. mtDNA methylation at MT-CO1 nt6807 (OR = 1.08, 95% CI 1.02-1.16; P = 0.014), MT-CO3 nt9444 (OR = 1.22, 95% CI 1.02-1.46, P = 0.042), and MT-TL1 nt3254 (OR = 1.30, 95% CI 1.05-1.61, P = 0.008) was higher at baseline in those who developed CVD by follow-up, compared with those who remained CVD-free. Combined use of the three loci significantly enhanced risk prediction, with hazard ratios of 1.38 (95% CI 0.68-2.78) and 2.68 (95% CI 1.41-5.08) for individuals with score 1 or 2, respectively (P = 0.003). Methylation at these sites was independent of conventional CVD risk factors, including inflammation markers, fasting blood glucose concentration, and blood pressure. Methylations of MT-CO1, MT-CO3, and MT-TL1 are, together, strong predictors of future CVD incidence. Since methylation of these mtDNA domains was independent of conventional CVD risk factors, these markers may represent a novel intrinsic predictor of CVD risk in adults with overweight and obesity.",
+No,20200323,prediction,32194204,Derivation of poly-methylomic profile scores for schizophrenia.,Prog Neuropsychopharmacol Biol Psychiatry,"Schizophrenia and bipolar disorder share biological features and environmental risk factors that may be associated with altered DNA methylation. In this study we sought to: 1) construct a novel 'Poly-Methylomic Profile Score (PMPS)' by transforming schizophrenia-associated epigenome-wide methylation from a previously published epigenome-wide association study (EWAS) into a single quantitative metric; and 2) examine associations between the PMPS and clinical status in an independent sample of 57 schizophrenia (SZ) cases, 59 bipolar disorder (BD) cases and 55 healthy controls (HC) for whom blood-derived DNA methylation was quantified using the Illumina 450 K methylation beadchip. We constructed five PMPSs at different p-value thresholds by summing methylation beta-values weighted by individual-CpG effect sizes from the meta-analysis of a previously published schizophrenia EWAS (comprising three separate cohorts with 675 [353 SZ and 322 HC] discovery cohort participants, 847 [414 SZ and 433 HC] replication cohort participants, and 96 monozygotic twin-pairs discordant for SZ). All SZ PMPSs were elevated in SZ participants relative to HCs, with the score calculated at a p-value threshold of 1 × 10<sup>-5</sup> accounting for the greatest amount of variance. All PMPSs were elevated in SZ relative to BD and none of the PMPSs were increased in BD, or in a combined cohort of BD and SZ cases, relative to HCs. PMPSs were also not associated with positive or negative symptom severity. That this SZ-derived PMPSs was elevated in SZ, but not BD, suggests that epigenome-wide methylation patterns may represent distinct pathophysiology that is yet to be elucidated.",
+Yes,20200323,ewas,32188935,Epigenome-wide association study for perceived discrimination among sub-Saharan African migrants in Europe - the RODAM study.,Sci Rep,"Sub-Saharan African (SSA) migrants in Europe experience psychosocial stressors, such as perceived discrimination (PD). The effect of such a stressor on health could potentially be mediated via epigenetics. In this study we performed an epigenome-wide association study (EWAS) to assess the association between levels of PD with genome-wide DNA methylation profiles in SSA migrants. The Illumina 450 K DNA-methylation array was used on whole blood samples of 340 Ghanaian adults residing in three European cities from the cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) study. PD was assessed using sum scores of the Everyday Discrimination Scale (EDS). Differentially methylated positions and regions (DMPs and DMRs) were identified through linear regression analysis. Two hypo-methylated DMPs, namely cg13986138 (CYFIP1) and cg10316525(ANKRD63), were found to be associated with PD. DMR analysis identified 47 regions associated with the PD. To the best of our knowledge, this survey is the first EWAS for PD in first generation SSA migrants. We identified two DMPs associated with PD. Whether these associations underlie a consequence or causal effect within the scope of biological functionality needs additional research.",
+Yes,20200323,ewas,32180791,Mendelian Randomization Identifies CpG Methylation Sites With Mediation Effects for Genetic Influences on BMD in Peripheral Blood Monocytes.,Front Genet,"Osteoporosis is mainly characterized by low bone mineral density (BMD) and is an increasingly serious public health concern. DNA methylation is a major epigenetic mechanism that may contribute to the variation in BMD and may mediate the effects of genetic and environmental factors of osteoporosis. In this study, we performed an epigenome-wide DNA methylation analysis in peripheral blood monocytes of 118 Caucasian women with extreme BMD values. Further, we developed and implemented a novel analytical framework that integrates Mendelian randomization with genetic fine mapping and colocalization to evaluate the causal relationships between DNA methylation and BMD phenotype. We identified 2,188 differentially methylated CpGs (DMCs) between the low and high BMD groups and distinguished 30 DMCs that may mediate the genetic effects on BMD. The causal relationship was further confirmed by eliminating the possibility of horizontal pleiotropy, linkage effect and reverse causality. The fine-mapping analysis determined 25 causal variants that are most likely to affect the methylation levels at these mediator DMCs. The majority of the causal methylation quantitative loci and DMCs reside within cell type-specific histone mark peaks, enhancers, promoters, promoter flanking regions and CTCF binding sites, supporting the regulatory potentials of these loci. The established causal pathways from genetic variant to BMD phenotype mediated by DNA methylation provide a gene list to aid in designing future functional studies and lead to a better understanding of the genetic and epigenetic mechanisms underlying the variation of BMD.",
+Yes,20200323,ewas,32171335,An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.,Clin Epigenetics,"Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10<sup>-7</sup>, p<sub>adj</sub> = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10<sup>-6</sup>), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10<sup>-5</sup>, p<sub>adj</sub> = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including &quot;Response to lipopolysaccharide&quot; (p = 6.97 × 10<sup>-6</sup>, p<sub>adj</sub> = 0.042). The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.",
+Yes,20200323,dnam age,32164769,Estimating breast tissue-specific DNA methylation age using next-generation sequencing data.,Clin Epigenetics,"DNA methylation (DNAm) age has been widely accepted as an epigenetic biomarker for biological aging. Emerging evidence suggests that DNAm age can be tissue-specific and female breast tissue ages faster than other parts of the body. The Horvath clock, which estimates DNAm age across multiple tissues, has been shown to be poorly calibrated in breast issue. We aim to develop a model to estimate breast tissue-specific DNAm age. Genome-wide DNA methylation sequencing data were generated for 459 normal, 107 tumor, and 45 paired adjacent-normal breast tissue samples. We determined a novel set of 286 breast tissue-specific clock CpGs using penalized linear regression and developed a model to estimate breast tissue-specific DNAm age. The model was applied to estimate breast tissue-specific DNAm age in different breast tissue types and in tumors with distinct clinical characteristics to investigate cancer-related aging effects. Our estimated breast tissue-specific DNAm age was highly correlated with chronological age (r = 0.88; p = 2.9 × 10<sup>-31</sup>) in normal breast tissue. Breast tumor tissue samples exhibited a positive epigenetic age acceleration, where DNAm age was on average 7 years older than respective chronological age (p = 1.8 × 10<sup>-8</sup>). In age-matched analyses, tumor breast tissue appeared 12 and 13 years older in DNAm age than adjacent-normal and normal breast tissue (p = 4.0 × 10<sup>-6</sup> and 1.0 × 10<sup>-6</sup>, respectively). Both HER2+ and hormone-receptor positive subtypes demonstrated significant acceleration in DNAm ages (p = 0.04 and 3.8 × 10<sup>-6</sup>, respectively), while no apparent DNAm age acceleration was observed for triple-negative breast tumors. We observed a non-linear pattern of epigenetic age acceleration with breast tumor grade. In addition, early-staged tumors showed a positive epigenetic age acceleration (p = 0.003) while late-staged tumors exhibited a non-significant negative epigenetic age acceleration (p = 0.10). The intended applications for this model are wide-spread and have been shown to provide biologically meaningful results for cancer-related aging effects in breast tumor tissue. Future studies are warranted to explore whether breast tissue-specific epigenetic age acceleration is predictive of breast cancer development, treatment response, and survival as well as the clinical utility of whether this model can be extended to blood samples.",
+No,20200323,eqtl,32149610,The single-cell eQTLGen consortium.,Elife,"In recent years, functional genomics approaches combining genetic information with bulk RNA-sequencing data have identified the downstream expression effects of disease-associated genetic risk factors through so-called expression quantitative trait locus (eQTL) analysis. Single-cell RNA-sequencing creates enormous opportunities for mapping eQTLs across different cell types and in dynamic processes, many of which are obscured when using bulk methods. Rapid increase in throughput and reduction in cost per cell now allow this technology to be applied to large-scale population genetics studies. To fully leverage these emerging data resources, we have founded the single-cell eQTLGen consortium (sc-eQTLGen), aimed at pinpointing the cellular contexts in which disease-causing genetic variants affect gene expression. Here, we outline the goals, approach and potential utility of the sc-eQTLGen consortium. We also provide a set of study design considerations for future single-cell eQTL studies.",
+Yes,20200330,ewas,32190749,Age at onset of different pubertal signs in boys and girls and differential DNA methylation at age 10 and 18 years: an epigenome-wide follow-up study.,Hum Reprod Open,"Is the age of onset of pubertal markers related to subsequent changes in DNA methylation (DNAm)? We identified 273 cytosine-phosphate-guanine (CpG) dinucleotides in girls and 67 CpGs in boys that were related to puberty and that were replicable in two other investigations. Previously, 457 CpGs (not gender-specific) and 347 (in girls) and 50 (in boys), respectively, were found to be associated with puberty, according to investigations of studies from Denmark (20 girls and 31 boys) and North America (30 girls and 25 boys). The study was based on a birth cohort of 1456 participants born in 1989/90, with follow-up at age 10 and 18 years. The follow-up included 470 participants with information on DNAm and age of pubertal onset (244 girls and 226 boys). Age of pubertal onset was ascertained retrospectively at age 18 years. Using the Pubertal Development Scale, both genders were asked about ages of onset of growth spurt, body hair growth and skin changes. Ages at voice deepening and growth of facial hair were inquired from boys; ages at breast development and menarche from girls. Blood samples were collected at 10 and 18 years of age. DNA was extracted using a standard salting out procedure. The methylation level for each CpG site was assessed using one of two different platforms. DNAm was measured by a ratio of intensities denoted as <i>β</i> values for each CpG site. After quality control, 349 455 CpG sites were available for analysis. <i>M</i> values were calculated (log2(<i>β</i>/(1-<i>β</i>)) to approximate a normal distribution, and their levels were adjusted for blood cell proportions. Linear mixed models were applied to test the association between age of pubertal markers and repeated measurement of DNAm at 10 and 18 years. In girls, a total of 63 019 CpGs statistically significantly changed after occurrence of any of the five pubertal events and 13 487 were changed subsequent to all five events: the respective number is boys were 3072 and 301. To further exclude false-positive findings, we investigated which CpGs were replicable in prior studies from Denmark or North America, resulting in 273 replicable CpG in girls and 67 CpGs in boys (236 and 68 genes, respectively). Most identified genes are known to be related to biological processes of puberty; however, genetic polymorphisms of only four of these genes were previously linked to pubertal markers in humans. The relative age of pubertal onset to the age of DNAm measurements does not allow causal inference, since DNAm at an earlier age may have affected the pubertal age or pubertal age may have altered later DNAm. This investigation concentrates on autosomes. CpGs on X and Y chromosomes are not included in the current study. Assessment of biological processes involved in pubertal transitions should include epigenetic information. Differential DNAm related to puberty needs to be investigated to determine whether it can act as an early marker for adult diseases known to be associated with puberty. This work was supported by NIH grants R03HD092776 (Epigenetic characterization of pubertal transitions) and R01AI121226. The 10-year follow-up of this study was funded by National Asthma Campaign, UK (Grant No 364), and the 18-year follow-up by a grant from the National Heart and Blood Institute (R01 HL082925). The authors have no conflicts to report.",
+No,20200406,ewas,32238836,Major surgery induces acute changes in measured DNA methylation associated with immune response pathways.,Sci Rep,"Surgery is an invasive procedure evoking acute inflammatory and immune responses that can influence risk for postoperative complications including cognitive dysfunction and delirium. Although the specific mechanisms driving these responses have not been well-characterized, they are hypothesized to involve the epigenetic regulation of gene expression. We quantified genome-wide levels of DNA methylation in peripheral blood mononuclear cells (PBMCs) longitudinally collected from a cohort of elderly patients undergoing major surgery, comparing samples collected at baseline to those collected immediately post-operatively and at discharge from hospital. We identified acute changes in measured DNA methylation at sites annotated to immune system genes, paralleling changes in serum-levels of markers including C-reactive protein (CRP) and Interleukin 6 (IL-6) measured in the same individuals. Many of the observed changes in measured DNA methylation were consistent across different types of major surgery, although there was notable heterogeneity between surgery types at certain loci. The acute changes in measured DNA methylation induced by surgery are relatively stable in the post-operative period, generally persisting until discharge from hospital. Our results highlight the dramatic alterations in gene regulation induced by invasive surgery, primarily reflecting upregulation of the immune system in response to trauma, wound healing and anaesthesia.",
+Yes,20200406,ewas,32237968,DNA methylation profiling identifies a high effect genetic variant for lipoprotein(a) levels.,Epigenetics,"Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF &lt;0.02) at the CpG site that largely explained the observed methylation effect. Rs76735376 is an expression quantitative trait loci for the LPA gene and could affect expression by altering enhancer activity. This EWAS for plasma Lp(a) identified a single CpG site within LPA. This association is due to an uncommon, but highly effective genetic variant, which was not in significant linkage disequilibrium with other variants known to influence Lp(a) levels or apo(a) isoform size. This study highlights the utility of CpG site methylation to identify potentially important genetic associations that would not be readily apparent in a comparable size genetic association study.",
+No,20200406,dnam score,32228717,The association of DNA methylation with body mass index: distinguishing between predictors and biomarkers.,Clin Epigenetics,"DNA methylation is associated with body mass index (BMI), but it is not clear if methylation scores are biomarkers for extant BMI or predictive of future BMI. Here, we explore the causal nature and predictive utility of DNA methylation measured in peripheral blood with BMI and cardiometabolic traits. Analyses were conducted across the life course using the ARIES cohort of mothers (n = 792) and children (n = 906), for whom DNA methylation and genetic profiles and BMI at multiple time points (3 in children at birth, in childhood and in adolescence; 2 in mothers during pregnancy and in middle age) were available. Genetic and DNA methylation scores for BMI were derived using published associations between BMI and DNA methylation and genotype. Causal relationships between methylation and BMI were assessed using Mendelian randomisation and cross-lagged models. The DNA methylation scores in adult women explained 10% of extant BMI variance. However, less extant variance was explained by scores generated in the same women during pregnancy (2% BMI variance) and in older children (15-17 years; 3% BMI variance). Similarly, little extant variance was explained in younger children (at birth and at 7 years; 1% and 2%, respectively). These associations remained following adjustment for smoking exposure and education levels. The DNA methylation score was found to be a poor predictor of future BMI using linear and cross-lagged models, suggesting that DNA methylation variation does not cause later variation in BMI. However, there was some evidence to suggest that BMI is predictive of later DNA methylation. Mendelian randomisation analyses also support this direction of effect, although evidence is weak. Finally, we find that DNA methylation scores for BMI are associated with extant cardiometabolic traits independently of BMI and genetic score. The age-specific nature of DNA methylation associations with BMI, lack of causal relationship and limited predictive ability of future BMI indicate that DNA methylation is likely influenced by BMI and might more accurately be considered a biomarker of BMI and related outcomes rather than a predictor. Future epigenome-wide association studies may benefit from further examining associations between early DNA methylation and later health outcomes.",
+No,20200406,epigenetics,32228436,The genome-wide landscape of C:G &gt; T:A polymorphism at the CpG contexts in the human population.,BMC Genomics,"The C:G &gt; T:A substitution at the CpG dinucleotide contexts is the most frequent substitution type in genome evolution. The mutational process is obviously ongoing in the human germline; however, its impact on common and rare genomic polymorphisms has not been comprehensively investigated yet. Here we observed the landscape and dynamics of C:G &gt; T:A substitutions from population-scale human genome sequencing datasets including ~ 4300 whole-genomes from the 1000 Genomes and the pan-cancer analysis of whole genomes (PCAWG) Project and ~ 60,000 whole-exomes from the Exome Aggregation Consortium (ExAC) database. Of the 28,084,558 CpG sites in the human reference genome, 26.0% show C:G &gt; T:A substitution in the dataset. Remarkably, CpGs in CpG islands (CGIs) have a much lower frequency of such mutations (5.6%). Interestingly, the mutation frequency of CGIs is not uniform with a significantly higher C:G &gt; T:A substitution rate for intragenic CGIs compared to other types. For non-CGI CpGs, the mutation rate was positively correlated with the distance from the nearest CGI up to 2 kb. Finally, we found the impact of negative selection for coding CpG mutations resulting in amino acid change. This study provides the first unbiased rate of C:G &gt; T:A substitution at the CpG dinucleotide contexts, using population-scale human genome sequencing data. Our findings provide insights into the dynamics of the mutation acquisition in the human genome.",
+No,20200406,epigenetics,32203468,DNA methylation disruption reshapes the hematopoietic differentiation landscape.,Nat Genet,"Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies<sup>1-3</sup> and clonal hematopoiesis<sup>4,5</sup>. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.",
+Yes,20200406,ewas,32202197,Identification of 20 novel loci associated to ischemic stroke. Epigenome-Wide Association Study.,Epigenetics,"<b>Rationale</b>. DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1-2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism.<b>Objective</b>. To detect epigenetic variants associated to stroke occurrence and stroke subtypes.<b>Methods and Results</b>. A two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N=226 and N=166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus <i>ZFHX3</i>, which includes known genetic variants associated with stroke. The pathways associated to these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways.<b>Conclusions</b>. We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.",
+No,20200406,sem,32216821,"DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936.",Clin Epigenetics,"DNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the inter-quartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples. Here, we showed an association between age and log<sub>10</sub>-transformed DNA methylation outlier burden in a large cross-sectional cohort, the Generation Scotland Family Health Study (N = 7010, β = 0.0091, p &lt; 2 × 10<sup>-16</sup>), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, β = 0.033, p = 7.9 × 10<sup>-4</sup>) and 1936 (N = 898, β = 0.0079, p = 0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, body mass index (BMI), smoking, and batch effects. In Generation Scotland, the increase in epigenetic outlier burden with age was not purely an artefact of an increase in DNA methylation level variability with age (epigenetic drift). Log<sub>10</sub>-transformed DNA methylation outlier burden in Generation Scotland was not related to self-reported, or family history of, age-related diseases, and it was not heritable (SNP-based heritability of 4.4%, p = 0.18). Finally, DNA methylation outlier burden was not significantly related to survival in either of the Lothian Birth Cohorts individually or in the meta-analysis after correction for multiple testing (HR<sub>meta</sub> = 1.12; 95% CI<sub>meta</sub> = [1.02; 1.21]; p<sub>meta</sub> = 0.021). These findings suggest that, while it does not associate with ageing-related health outcomes, DNA methylation outlier burden does track chronological ageing and may also relate to survival. DNA methylation outlier burden may thus be useful as a marker of biological ageing.",
+No,20200406,circulating,32221288,Mapping the breast cancer metastatic cascade onto ctDNA using genetic and epigenetic clonal tracking.,Nat Commun,"Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient's cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment.",
+No,20200406,epigenetics,32211199,Cannabis use and the sperm epigenome: a budding concern?,Environ Epigenet,"The United States is swiftly moving toward increased legalization of medical and recreational cannabis. Currently considered the most commonly used illicit psychoactive drug, recreational cannabis is legal in 11 states and Washington, DC, and male use is an important and understudied concern. Questions remain, however, about the potential long-term consequences of this exposure and how cannabis might impact the epigenetic integrity of sperm in such a way that could influence the health and development of offspring. This review summarizes cannabis use and potency in the USA, provides a brief overview of DNA methylation as an epigenetic mechanism that is vulnerable in sperm to environmental exposures including cannabis, and summarizes studies that have examined the effects of parental exposure to cannabis or delta-9 tetrahydrocannabinol (THC, the main psychoactive component of cannabis) on the epigenetic profile of the gametes and behavior of offspring. These studies have demonstrated significant changes to the sperm DNA methylome following cannabis use in humans, and THC exposure in rats. Furthermore, the use of rodent models has shown methylation and behavioral changes in rats born to fathers exposed to THC or synthetic cannabinoids, or to parents who were both exposed to THC. These data substantiate an urgent need for additional studies assessing the effects of cannabis exposure on childhood health and development. This is especially true given the current growing state of cannabis use in the USA.",
+No,20200504,ewas,32345361,Exploratory analysis of age and sex dependent DNA methylation patterns on the X-chromosome in whole blood samples.,Genome Med,"Large numbers of autosomal sites are found differentially methylated in the aging genome. Due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation (XCI) in females, this has not been explored for the X chromosome. Using data from middle age to elderly individuals (age 55+ years) from two Danish cohorts of monozygotic twins and the Scottish Lothian Birth Cohort 1921, we conducted an X-chromosome-wide analysis of age-associated DNA methylation patterns with consideration of stably inferred XCI status. Through analysing and comparing sex-specific X-linked DNA methylation changes over age late in life, we identified 123, 293 and 55 CpG sites significant (FDR &lt; 0.05) only in males, only in females and in both sexes of Danish twins. All findings were significantly replicated in the two Danish twin cohorts. CpG sites escaping XCI are predominantly de-methylated with increasing age across cohorts. In contrast, CpGs highly methylated in both sexes are methylated even further with increasing age. Among the replicated sites in Danish samples, 16 (13%), 24 (8.2%) and 3 (5.5%) CpGs were further validated in LBC1921 (FDR &lt; 0.05). The X-chromosome of whole blood leukocytes displays age- and sex-dependent DNA methylation patterns in relation to XCI across cohorts.",
+Yes,20200504,ewas,32343731,A genome-wide analysis of DNA methylation identifies a novel association signal for Lp(a) concentrations in the LPA promoter.,PLoS ONE,"Lipoprotein(a) [Lp(a)] is a major cardiovascular risk factor, which is largely genetically determined by one major gene locus, the LPA gene. Many aspects of the transcriptional regulation of LPA are poorly understood and the role of epigenetics has not been addressed yet. Therefore, we conducted an epigenome-wide analysis of DNA methylation on Lp(a) levels in two population-based studies (total n = 2208). We identified a CpG site in the LPA promoter which was significantly associated with Lp(a) concentrations. Surprisingly, the identified CpG site was found to overlap the SNP rs76735376. We genotyped this SNP de-novo in three studies (total n = 7512). The minor allele of rs76735376 (1.1% minor allele frequency) was associated with increased Lp(a) values (p = 1.01e-59) and explained 3.5% of the variation of Lp(a). Statistical mediation analysis showed that the effect on Lp(a) is rather originating from the base change itself and is not mediated by DNA methylation levels. This finding is supported by eQTL data from 208 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. To evaluate, whether the association signal at rs76735376 may actually be derived from a stronger eQTL signal in LD with this SNP, eQTL association results of all correlated SNPs (r2≥0.1) were integrated with genetic association results. This analysis pinpointed to rs10455872 as the potential trigger of the effect of rs76735376. Furthermore, both SNPs coincide with short apo(a) isoforms. Adjusting for both, rs10455872 and the apo(a) isoforms diminished the effect size of rs76735376 to 5.38 mg/dL (p = 0.0463). This indicates that the effect of rs76735376 can be explained by both an independent effect of the SNP and a strong correlation with rs10455872 and apo(a) isoforms.",
+Yes,20200504,ewas,32327964,A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins.,Front Neurosci,"Monozygotic twins are genetically identical but rarely phenotypically identical. Epigenetic and transcriptional variation could influence this phenotypic discordance. Investigation of intra-pair differences in molecular markers and a given phenotype in monozygotic twins controls most of the genetic contribution, enabling studies of the molecular features of the phenotype. This study aimed to identify genes associated with cognition in later life using integrated enrichment analyses of the results of blood-derived intra-pair epigenome-wide and transcriptome-wide association analyses of cognition in 452 middle-aged and old-aged monozygotic twins (56-80 years). Integrated analyses were performed with an unsupervised approach using KeyPathwayMiner, and a supervised approach using the KEGG and Reactome databases. The supervised approach identified several enriched gene sets, including &quot;neuroactive ligand receptor interaction&quot; (<i>p</i>-value = 1.62<sup>�</sup>10-2), &quot;Neurotrophin signaling&quot; (<i>p</i>-value = 2.52<sup>�</sup>10-3), &quot;Alzheimer's disease&quot; (<i>p</i>-value = 1.20<sup>�</sup>10-2), and &quot;long-term depression&quot; (<i>p</i>-value = 1.62<sup>�</sup>10-2). The unsupervised approach resulted in a 238 gene network, including the Alzheimer's disease gene <i>APP</i> (Amyloid Beta Precursor Protein) as an exception node, and several novel candidate genes. The strength of the unsupervised method is that it can reveal previously uncharacterized sub-pathways and detect interplay between biological processes, which remain undetected by the current supervised methods. In conclusion, this study identified several previously reported cognition genes and pathways and, additionally, puts forward novel candidates for further verification and validation.",
+No,20200504,dnam score,32308120,Epigenomic Assessment of Cardiovascular Disease Risk and Interactions With Traditional Risk Metrics.,J Am Heart Assoc,"Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics.",
+No,20200504,epigenetics,32275652,Stochastic modeling reveals kinetic heterogeneity in post-replication DNA methylation.,PLoS Comput Biol,"DNA methylation is a heritable epigenetic modification that plays an essential role in mammalian development. Genomic methylation patterns are dynamically maintained, with DNA methyltransferases mediating inheritance of methyl marks onto nascent DNA over cycles of replication. A recently developed experimental technique employing immunoprecipitation of bromodeoxyuridine labeled nascent DNA followed by bisulfite sequencing (Repli-BS) measures post-replication temporal evolution of cytosine methylation, thus enabling genome-wide monitoring of methylation maintenance. In this work, we combine statistical analysis and stochastic mathematical modeling to analyze Repli-BS data from human embryonic stem cells. We estimate site-specific kinetic rate constants for the restoration of methyl marks on &gt;10 million uniquely mapped cytosines within the CpG (cytosine-phosphate-guanine) dinucleotide context across the genome using Maximum Likelihood Estimation. We find that post-replication remethylation rate constants span approximately two orders of magnitude, with half-lives of per-site recovery of steady-state methylation levels ranging from shorter than ten minutes to five hours and longer. Furthermore, we find that kinetic constants of maintenance methylation are correlated among neighboring CpG sites. Stochastic mathematical modeling provides insight to the biological mechanisms underlying the inference results, suggesting that enzyme processivity and/or collaboration can produce the observed kinetic correlations. Our combined statistical/mathematical modeling approach expands the utility of genomic datasets and disentangles heterogeneity in methylation patterns arising from replication-associated temporal dynamics versus stable cell-to-cell differences.",
+No,20200504,dnam age,32264940,"Adverse childhood experiences, DNA methylation age acceleration, and cortisol in UK children: a prospective population-based cohort study.",Clin Epigenetics,"Epigenetic mechanisms may partly explain the persistent effects of adverse childhood experiences (ACEs) on health outcomes in later life. DNA methylation can predict chronological age, and advanced methylation-predicted age beyond chronological age (DNA methylation age acceleration) is associated with ACEs, adverse mental and physical health, and elevated diurnal and baseline salivary cortisol. Childhood adversity is also associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which produces the neuroendocrine hormone cortisol. It remains unknown whether these associations are specific to certain types of adversity. Herein, we investigate the associations of ACEs with DNA methylation age acceleration and plasma cortisol in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. In this study of the children in ALSPAC, we used multiple linear regression to examine associations of cumulative exposure to ACE, as well as exposure to ten individual types of ACEs, with Horvath-estimated DNA methylation age acceleration and with baseline plasma cortisol. The ten ACEs were those included in the World Health Organization's ACE International Questionnaire. Data on ACEs were prospectively collected from age 0-14 years. DNA methylation age acceleration and plasma cortisol were measured at mean 17.1 years and 15.5 years, respectively. We included 974 UK children in the present study. Exposure to four or more ACEs compared to zero was associated with DNA methylation age acceleration in girls (β, 95% CI = 1.65, 0.25 to 3.04 years) but not in boys (β, 95% CI = - 0.11, - 1.48 to 1.26 years). Also, in girls, emotional abuse and physical abuse were each associated with DNA methylation age acceleration (β, 95% CI = 1.20, 0.15 to 2.26 years and β, 95% CI = 1.22, 0.06 to 2.38 years, respectively). No other ACEs were associated with accelerated DNA methylation age in either sex. Associations were also null between ACE and cortisol, and cortisol and DNA methylation age acceleration. In this prospective population-based study of UK children, cumulative ACE exposure, emotional abuse, and physical abuse between age 0 and 14 years were each associated with Horvath-estimated DNA methylation age acceleration at age 17 years in girls but not in boys.",
+Yes,20200504,ewas,32264874,Changes of DNA methylation are associated with changes in lung function during adolescence.,Respir Res,"Adolescence is a significant period for the gender-dependent development of lung function. Prior studies have shown that DNA methylation (DNA-M) is associated with lung function and DNA-M at some cytosine-phosphate-guanine dinucleotide sites (CpGs) changes over time. This study examined whether changes of DNA-M at lung-function-related CpGs are associated with changes in lung function during adolescence for each gender, and if so, the biological significance of the detected CpGs. Genome-scale DNA-M was measured in peripheral blood samples at ages 10 (n = 330) and 18 years (n = 476) from the Isle of Wight (IOW) birth cohort in United Kingdom, using Illumina Infinium arrays (450 K and EPIC). Spirometry was conducted at both ages. A training and testing method was used to screen 402,714 CpGs for their potential associations with lung function. Linear regressions were applied to assess the association of changes in lung function with changes of DNA-M at those CpGs potentially related to lung function. Adolescence-related and personal and family-related confounders were included in the model. The analyses were stratified by gender. Multiple testing was adjusted by controlling false discovery rate of 0.05. Findings were further examined in two independent birth cohorts, the Avon Longitudinal Study of Children and Parents (ALSPAC) and the Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohort. Pathway analyses were performed on genes to which the identified CpGs were mapped. For females, 42 CpGs showed statistically significant associations with change in FEV<sub>1</sub>/FVC, but none for change in FEV<sub>1</sub> or FVC. No CpGs were identified for males. In replication analyses, 16 and 21 of the 42 CpGs showed the same direction of associations among the females in the ALSPAC and BAMSE cohorts, respectively, with 11 CpGs overlapping across all the three cohorts. Through pathway analyses, significant biological processes were identified that have previously been related to lung function development. The detected 11 CpGs in all three cohorts have the potential to serve as the candidate epigenetic markers for changes in lung function during adolescence in females.",
+No,20200504,prediction,32245523,Machine learning and clinical epigenetics: a review of challenges for diagnosis and classification.,Clin Epigenetics,"Machine learning is a sub-field of artificial intelligence, which utilises large data sets to make predictions for future events. Although most algorithms used in machine learning were developed as far back as the 1950s, the advent of big data in combination with dramatically increased computing power has spurred renewed interest in this technology over the last two decades. Within the medical field, machine learning is promising in the development of assistive clinical tools for detection of e.g. cancers and prediction of disease. Recent advances in deep learning technologies, a sub-discipline of machine learning that requires less user input but more data and processing power, has provided even greater promise in assisting physicians to achieve accurate diagnoses. Within the fields of genetics and its sub-field epigenetics, both prime examples of complex data, machine learning methods are on the rise, as the field of personalised medicine is aiming for treatment of the individual based on their genetic and epigenetic profiles. We now have an ever-growing number of reported epigenetic alterations in disease, and this offers a chance to increase sensitivity and specificity of future diagnostics and therapies. Currently, there are limited studies using machine learning applied to epigenetics. They pertain to a wide variety of disease states and have used mostly supervised machine learning methods.",
+No,20200504,epigenetics,32234052,Successful generation of epigenetic disease model mice by targeted demethylation of the epigenome.,Genome Biol,"Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders. We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain. We generate model mice for Silver-Russell syndrome (SRS), an imprinting disorder, by target-specific DNA demethylation in the H19 differentially methylated region. Like SRS patients, these mice show H19 upregulation and Igf2 downregulation, leading to severe intrauterine and postnatal growth retardation. This is the first report of an imprinting disease model animal generated by targeted demethylation of specific loci of the epigenome in fertilized eggs. Epigenome-edited animals are also useful for exploring the causative epimutations in epigenetic diseases.",
+No,20200504,epigenetics,32223889,Reversible promoter methylation determines fluctuating expression of acute phase proteins.,Elife,"Acute phase reactants (APRs) are secretory proteins exhibiting large expression changes in response to proinflammatory cytokines. Here we show that the expression pattern of a major human APR, that is <i>C-reactive protein</i> (<i>CRP</i>), is casually determined by DNMT3A and TET2-tuned promoter methylation status. <i>CRP</i> features a CpG-poor promoter with its CpG motifs located in binding sites of STAT3, C/EBP-β and NF-κB. These motifs are highly methylated at the resting state, but undergo STAT3- and NF-κB-dependent demethylation upon cytokine stimulation, leading to markedly enhanced recruitment of C/EBP-β that boosts <i>CRP</i> expression. Withdrawal of cytokines, by contrast, results in a rapid recovery of promoter methylation and termination of <i>CRP</i> induction. Further analysis suggests that reversible methylation also regulates the expression of highly inducible genes carrying CpG-poor promoters with APRs as representatives. Therefore, these CpG-poor promoters may evolve CpG-containing TF binding sites to harness dynamic methylation for prompt and reversible responses.",
+Yes,20200518,ewas,32398718,Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation.,Mol Psychiatry,"Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p &lt; 10<sup>-24</sup>). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.",
+Yes,20200518,ewas,32388307,Genome-wide DNA methylation analysis reveals significant impact of long-term ambient air pollution exposure on biological functions related to mitochondria and immune response.,Environ Pollut,"Exposure to long-term ambient air pollution is believed to have adverse effects on human health. However, the mechanisms underlying these impacts are poorly understood. DNA methylation, a crucial epigenetic modification, is susceptible to environmental factors and likely involved in these processes. We conducted a whole-genome bisulfite sequencing study on 120 participants from a highly polluted region (HPR) and a less polluted region (LPR) in China, where the HPR had much higher concentrations of five air pollutants (PM<sub>2.5</sub>, PM<sub>10</sub>, SO<sub>2</sub>, NO<sub>2</sub>, and CO) (fold difference 1.6 to 6.6 times; P value 1.80E-07 to 3.19E-23). Genome-wide methylation analysis revealed 371 DMRs in subjects from the two areas and these DMRs were located primarily in gene regulatory elements such as promoters and enhancers. Gene enrichment analysis showed that DMR-related genes were significantly enriched in diseases related to pulmonary disorders and cancers and in biological processes related to mitochondrial assembly and cytokine production. Further, HPR participants showed a higher mtDNA copy number. Of those identified DMRs, 15 were significantly correlated with mtDNA copy number. Finally, cytokine assay indicated that an increased plasma interleukin-5 level was associated with greater air pollution. Taken together, our findings suggest that exposure to long-term ambient air pollution can lead to alterations in DNA methylation whose functions relate to mitochondria and immune responses.",
+Yes,20200518,ewas,32381493,Epigenome-Wide Association Study of DNA Methylation and Adult Asthma in the Agricultural Lung Health Study.,Eur Respir J,"Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma. Studies in adults are rare, and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a U.S. agricultural cohort. Atopy was defined by serum specific immunoglobulin E. Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous CpGs were differentially methylated in non-atopic asthma (8 at family-wise error rate [FWER] p&lt;9Ă—10<sup>-8</sup>; 524 at False Discovery Rate [FDR]&lt;0.05) and implicated 382 novel genes. More CpGs were identified in atopic asthma (181 at FWER; 1086 at FDR) and implicated 569 novel genes. 104 FDR CpGs overlapped. 35% of CpGs in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpGs in non-atopic and atopic asthma. Many CpGs from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease and implicate novel genes associated with non-atopic and atopic asthma.",
+Yes,20200518,ewas,32361995,Genome-wide DNA methylation patterns associated with sleep and mental health in children: a population-based study.,J Child Psychol Psychiatry,"DNA methylation (DNAm) has been implicated in the biology of sleep. Yet, how DNAm patterns across the genome relate to different sleep outcomes, and whether these associations overlap with mental health is currently unknown. Here, we investigated associations of DNAm with sleep and mental health in a pediatric population. This cross-sectional study included 465 10-year-old children (51.3% female) from the Generation R Study. Genome-wide DNAm levels were measured using the Illumina 450K array (peripheral blood). Sleep problems were assessed from self-report and mental health outcomes from maternal questionnaires. Wrist actigraphy was used in 188 11-year-old children to calculate sleep duration and midpoint sleep. Weighted gene co-expression network analysis was used to identify highly comethylated DNAm 'modules', which were tested for associations with sleep and mental health outcomes. We identified 64 DNAm modules, one of which associated with sleep duration after covariate and multiple testing adjustment. This module included CpG sites spanning 9 genes on chromosome 17, including MAPT - a key regulator of Tau proteins in the brain involved in neuronal function - as well as genes previously implicated in sleep duration. Follow-up analyses suggested that DNAm variation in this region is under considerable genetic control and shows strong blood-brain concordance. DNAm modules associated with sleep did not overlap with those associated with mental health. We identified one DNAm region associated with sleep duration, including genes previously reported by recent GWAS studies. Further research is warranted to examine the functional role of this region and its longitudinal association with sleep.",
+Yes,20200518,ewas,32354366,Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis.,Clin Epigenetics,"Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p &gt; 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (&lt; 18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p &lt; 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways. Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363.",
+No,20200518,candidate,32346601,DNA methylation in APOE: The relationship with Alzheimer's and with cardiovascular health.,Alzheimers Dement (N Y),"Genetic variation in the apolipoprotein E (<i>APOE</i>) gene is associated with Alzheimer's disease (AD) and risk factors for cardiovascular disease (CVD). DNA methylationat <i>APOE</i> has been associated with altered cognition and AD. It is unclear if epigenetic marks could be used for predicting future disease. We assessed blood-based DNA methylation at 13 CpGs in the <i>APOE</i> gene in 5828 participants from the Generation Scotland (GS) cohort. Using linear mixed models regression, we examined the relationships among <i>APOE</i> methylation, cognition, cholesterol, the family history of AD and the risk for CVD. DNA methylation at two CpGs was associated with the ratio of total cholesterol and HDL cholesterol, but not with cognition, family history of AD, or the risk of CVD. <i>APOE</i> methylation is associated with the levels of blood cholesterol, but there is no evidence for the utility of <i>APOE</i> methylation as a biomarker for predicting AD or CVD.",
+No,20200518,chromatin interactions,32345984,Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data.,Nat Commun,"Promoter-anchored chromatin interactions (PAIs) play a pivotal role in transcriptional regulation. Current high-throughput technologies for detecting PAIs, such as promoter capture Hi-C, are not scalable to large cohorts. Here, we present an analytical approach that uses summary-level data from cohort-based DNA methylation (DNAm) quantitative trait locus (mQTL) studies to predict PAIs. Using mQTL data from human peripheral blood ([Formula: see text]), we predict 34,797 PAIs which show strong overlap with the chromatin contacts identified by previous experimental assays. The promoter-interacting DNAm sites are enriched in enhancers or near expression QTLs. Genes whose promoters are involved in PAIs are more actively expressed, and gene pairs with promoter-promoter interactions are enriched for co-expression. Integration of the predicted PAIs with GWAS data highlight interactions among 601 DNAm sites associated with 15 complex traits. This study demonstrates the use of mQTL data to predict PAIs and provides insights into the role of PAIs in complex trait variation.",
+No,20200518,ewas,31554518,Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation,Genome Biol,"BACKGROUND:
 DNA methylation (DNAm) is a critical regulator of both development and cellular identity and shows unique patterns in neurons. To better characterize maturational changes in DNAm patterns in these cells, we profile the DNAm landscape at single-base resolution across the first two decades of human neocortical development in NeuN+ neurons using whole-genome bisulfite sequencing and compare them to non-neurons (primarily glia) and prenatal homogenate cortex.
 
 RESULTS:
@@ -858,600 +858,600 @@ We show that DNAm changes more dramatically during the first 5 years of postnata
 
 CONCLUSIONS:
 By profiling DNAm changes in NeuN-sorted neurons over the span of human cortical development, we identify novel, dynamic regions of DNAm that would be masked in homogenate DNAm data; expand on the relationship between CpG methylation, CpH methylation, and gene expression; and find enrichment particularly for neuropsychiatric diseases in genomic regions with cell type-specific, developmentally dynamic DNAm patterns.",
-,Yes,20200601,ewas,32453742,Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago.,PLoS Genet,"Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.",
-,Yes,20200601,ewas,32448018,Replicated umbilical cord blood DNA methylation loci associated with gestational age at birth.,Epigenetics,"DNA methylation is highly sensitive to <i>in utero</i> perturbations and has an established role in both embryonic development and regulation of gene expression. The foetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behaviour of individual genes. The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for <i>cis</i> gene relationships in specimens with multi-omic data. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450 K BeadChip, was associated with GA for 2,372 CpG probes (5% FDR) in both the Pregnancy, Race, Environment, Genes (PREG) and Newborn Epigenetic Study (NEST) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. Gene pathways identified are consistent with the hypothesis of pathogen detection and response by the immune system to elicit premature labour as a consequence of unscheduled inflammation.",
-,Yes,20200601,ewas,32443666,Epigenome-Wide Association Study Reveals Duration of Breastfeeding Is Associated with Epigenetic Differences in Children.,Int J Environ Res Public Health,"Several small studies have shown associations between breastfeeding and genome-wide DNA methylation (DNAm). We performed a comprehensive Epigenome-Wide Association Study (EWAS) to identify associations between breastfeeding and DNAm patterns in childhood. We analysed DNAm data from the Isle of Wight Birth Cohort at birth, 10, 18 and 26 years. The feeding method was categorized as breastfeeding duration &gt;3 months and &gt;6 months, and exclusive breastfeeding duration &gt;3 months. EWASs using robust linear regression were performed to identify differentially methylated positions (DMPs) in breastfed and non-breastfed children at age 10 (false discovery rate of 5%). Differentially methylated regions (DMRs) were identified using comb-p. The persistence of significant associations was evaluated in neonates and individuals at 18 and 26 years. Two DMPs, in genes <i>SNX25</i> and <i>LINC00840</i>, were significantly associated with breastfeeding duration &gt;6 months at 10 years and was replicated for &gt;3 months of exclusive breastfeeding. Additionally, a significant DMR spanning the gene <i>FDFT1</i> was identified in 10-year-old children who were exposed to a breastfeeding duration &gt;3 months. None of these signals persisted to 18 or 26 years. This study lends further support for a suggestive role of DNAm in the known benefits of breastfeeding on a child's future health.",
-,No,20200601,mr,32429084,Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer's Disease.,J Clin Med,"Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specific associations with AD, respectively, suggesting a potential role for such epigenetic modifications in the heterogeneous nature of AD. Our analyses provided stronger evidence for possible roles of four genes (i.e., <i>AIM2</i>, <i>C16orf80</i>, <i>DGUOK</i>, and <i>ST14</i>) in AD pathogenesis as they were also transcriptionally associated with AD. The identified associations suggest a list of prioritized genes for follow-up functional studies and advance our understanding of AD pathogenesis.",
-,No,20200601,epigenetics,32423419,Protection from DNA re-methylation by transcription factors in primordial germ cells and pre-implantation embryos can explain trans-generational epigenetic inheritance.,Genome Biol,"A growing body of evidence suggests that certain epiphenotypes can be passed across generations via both the male and female germlines of mammals. These observations have been difficult to explain owing to a global loss of the majority of known epigenetic marks present in parental chromosomes during primordial germ cell development and after fertilization. By integrating previously published BS-seq, DNase-seq, ATAC-seq, and RNA-seq data collected during multiple stages of primordial germ cell and pre-implantation development, we find that the methylation status of the majority of CpGs genome-wide is restored after global de-methylation, despite the fact that global CpG methylation drops to 10% in primordial germ cells and 20% in the inner cell mass of the blastocyst. We estimate the proportion of such CpGs with preserved methylation status to be 78%. Further, we find that CpGs at sites bound by transcription factors during the global re-methylation phases of germline and embryonic development remain hypomethylated across all developmental stages observed. On the other hand, CpGs at sites not bound by transcription factors during the global re-methylation phase have high methylation levels prior to global de-methylation, become de-methylated during global de-methylation, and then become re-methylated. The results suggest that transcription factors can act as carriers of epigenetic information during germ cell and pre-implantation development by ensuring that the methylation status of CpGs is maintained. These findings provide the basis for a mechanistic description of trans-generational inheritance of epigenetic information in mammals.",
-,No,20200601,dnam age,32367804,"Quantification of the Pace of Biological Aging in Humans Through a Blood Test, The DunedinPoAm DNA Methylation Algorithm",Elife, ,
-,Yes,20200601,ewas,26822447,"Parenting, Socioeconomic Status Risk, and Later Young Adult Health: Exploration of Opposing Indirect Effects via DNA Methylation",Child Dev, ,
-,Yes,20200601,ewas,30351206,The biological embedding of early-life socioeconomic status and family adversity in children's genome-wide DNA methylation,Epigenomics, ,
-,Yes,20200601,ewas,28673994,Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood,Proc Natl Acad Sci USA, ,
-,Yes,20200601,ewas,27768648,Epigenetic Mediators Between Childhood Socioeconomic Disadvantage and Mid-Life Body Mass Index: The New England Family Study,Psychosome Med, ,
-,No,20200615,dnam score,32523041,Epigenetic prediction of major depressive disorder.,Mol. Psychiatry,"Variation in DNA methylation (DNAm) is associated with lifestyle factors such as smoking and body mass index (BMI) but there has been little research exploring its ability to identify individuals with major depressive disorder (MDD). Using penalised regression on genome-wide CpG methylation, we tested whether DNAm risk scores (MRS), trained on 1223 MDD cases and 1824 controls, could discriminate between cases (n = 363) and controls (n = 1417) in an independent sample, comparing their predictive accuracy to polygenic risk scores (PRS). The MRS explained 1.75% of the variance in MDD (β = 0.338, p = 1.17 × 10<sup>-7</sup>) and remained associated after adjustment for lifestyle factors (β = 0.219, p = 0.001, R<sup>2</sup> = 0.68%). When modelled alongside PRS (β = 0.384, p = 4.69 × 10<sup>-9</sup>) the MRS remained associated with MDD (β = 0.327, p = 5.66 × 10<sup>-7</sup>). The MRS was also associated with incident cases of MDD who were well at recruitment but went on to develop MDD at a later assessment (β = 0.193, p = 0.016, R<sup>2</sup> = 0.52%). Heritability analyses found additive genetic effects explained 22% of variance in the MRS, with a further 19% explained by pedigree-associated genetic effects and 16% by the shared couple environment. Smoking status was also strongly associated with MRS (β = 0.440, p ≤ 2 × 10<sup>-16</sup>). After removing smokers from the training set, the MRS strongly associated with BMI (β = 0.053, p = 0.021). We tested the association of MRS with 61 behavioural phenotypes and found that whilst PRS were associated with psychosocial and mental health phenotypes, MRS were more strongly associated with lifestyle and sociodemographic factors. DNAm-based risk scores of MDD significantly discriminated MDD cases from controls in an independent dataset and may represent an archive of exposures to lifestyle factors that are relevant to the prediction of MDD.",
-,Yes,20200615,ewas,32525743,Whole Blood DNA Methylation Signatures of Diet Are Associated with Cardiovascular Disease Risk Factors and All-cause Mortality.,Circ Genom Precis Med,"<b>Background</b> - DNA methylation patterns associated with habitual diet have not been well studied. <b>Methods</b> - Diet quality was characterized using a Mediterranean-style diet score (MDS) and the Alternative Healthy Eating Index score (AHEI). We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400,000 cytosine-guanine dinucleotides (CpGs) in five population-based cohorts including 6,662 European ancestry (EA), 2,702 African ancestry (AA), and 360 Hispanic ancestry (HA) participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease (CVD) risk factors and examined their longitudinal associations with all-cause mortality. <b>Results</b> - We identified 30 CpGs associated with either MDS or AHEI, or both, in EA participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected p-value &lt; 1.6Ă—10<sup>-3</sup>). Hypermethylation of cg18181703 (<i>SOCS3</i>) was associated with higher scores of both MDS and AHEI and lower risk for all-cause mortality (p-value = 5.7Ă—10<sup>-15</sup>). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (p-value &lt; 0.05). MR analysis revealed eight putatively causal associations for six CpGs with four CVD risk factors (BMI, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes; Bonferroni corrected MR p-value &lt; 4.5Ă—10<sup>-4</sup>). For example, hypermethylation of cg11250194 (<i>FADS2</i>) was associated with lower triglyceride concentrations (MR p-value = 1.5Ă—10<sup>-14</sup>) and hypermethylation of cg02079413 (<i>SNORA54</i>; <i>NAP1L4</i>) was associated with BMI (corrected MR p-value = 1Ă—10<sup>-6</sup>). <b>Conclusions</b> - Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in EA individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.",
-,Yes,20200615,ewas,32520614,"Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.",Hypertension,"We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with <i>P</i>&lt;1×10<sup>-5</sup>. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (<i>P</i>&lt;1×10<sup>-7</sup>) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with <i>P</i>&lt;0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (<i>TXNIP</i>) and cg00716257 (<i>JDP2</i>) determined by environmental effects acting on both systolic BP and methylation levels.",
-,Yes,20200615,ewas,32503626,Epigenome-wide association study in healthy individuals identifies significant associations with DNA methylation and PBMC extract VEGF-A concentration.,Clin Epigenetics,"Vascular endothelial growth factor A (VEGF-A) is a chemokine that induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis. It is known for its high heritability (&gt; 60%) and involvement in most common morbidities, which makes it a potentially interesting biomarker. Large GWAS studies have already assessed polymorphisms related to VEGF-A. However, no previous research has provided epigenome-wide insight in regulation of VEGF-A. VEGF-A concentrations of healthy participants from the STANISLAS Family Study (n = 201) were comprehensively assessed for association with DNA methylation. Genome-wide DNA methylation profiles were determined in whole blood DNA using the 450K Infinium BeadChip Array (Illumina). VEGF-A concentration in PBMC extracts was detected using a high-sensitivity multiplex Cytokine Array (Randox Laboratories, UK). Epigenome-wide association analysis identified 41 methylation sites significantly associated with VEGF-A concentrations derived from PBMC extracts. Twenty CpG sites within 13 chromosomes reached Holm-Bonferroni significance. Significant values ranged from P = 1.08 × 10<sup>-7</sup> to P = 5.64 × 10<sup>-15</sup>. This study exposed twenty significant CpG sites linking DNA methylation to VEGF-A concentration. Methylation detected in promoter regions, such as TPX2 and HAS-1, could explain previously reported associations with the VEGFA gene. Methylation may also help in the understanding of the regulatory mechanisms of other genes located in the vicinity of detected CpG sites.",
-,Yes,20200615,ewas,32496131,Sex-specific DNA methylation differences in people exposed to polybrominated biphenyl.,Epigenomics,"<b>Aim:</b> Michigan residents were exposed to polybrominated biphenyls (PBBs) when it was accidentally added to the food supply. Highly exposed individuals report sex-specific health problems, but the underlying biological mechanism behind these different health risks is not known. <b>Materials and methods:</b> DNA methylation in blood from 381 women and 277 men with PBB exposure was analyzed with the MethylationEPIC BeadChip. <b>Results:</b> 675 CpGs were associated with PBBs levels in males, while only 17 CpGs were associated in females (false discovery rate &lt;0.05). No CpGs were associated in both sexes. These CpGs were enriched in different functional regions and transcription factor binding sites in each sex. <b>Conclusion:</b> Exposure to PBBs may have sex-specific effects on the epigenome that may underlie sex-specific adverse health outcomes.",
-,Yes,20200615,ewas,32493484,DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases.,Clin Epigenetics,"Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) &lt; 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR &lt; 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. ClinicalTrials.gov, NCT00912132.",
-,Yes,20200615,ewas,32484729,Genome-Wide DNA Methylation in Peripheral Blood and Long-Term Exposure to Source-Specific Transportation Noise and Air Pollution: The SAPALDIA Study.,Environ. Health Perspect.,"BACKGROUND:Few epigenome-wide association studies (EWAS) on air pollutants exist, and none have been done on transportation noise exposures, which also contribute to environmental burden of disease. OBJECTIVE:We performed mutually independent EWAS on transportation noise and air pollution exposures. METHODS:We used data from two time points of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) from 1,389 participants contributing 2,542 observations. We applied multiexposure linear mixed-effects regressions with participant-level random intercept to identify significant Cytosine-phosphate-Guanine (CpG) sites and differentially methylated regions (DMRs) in relation to 1-y average aircraft, railway, and road traffic day-evening-night noise (Lden); nitrogen dioxide (NO2); and particulate matter (PM) with aerodynamic diameter <2.5?m (PM2.5). We performed candidate (CpG-based; cross-systemic phenotypes, combined into ""allostatic load"") and agnostic (DMR-based) pathway enrichment tests, and replicated previously reported air pollution EWAS signals. RESULTS:We found no statistically significant CpGs at false discovery rate <0.05. However, 14, 48, 183, 8, and 71 DMRs independently associated with aircraft, railway, and road traffic Lden; NO2; and PM2.5, respectively, with minimally overlapping signals. Transportation Lden and air pollutants tendentially associated with decreased and increased methylation, respectively. We observed significant enrichment of candidate DNA methylation related to C-reactive protein and body mass index (aircraft, road traffic Lden, and PM2.5), renal function and ""allostatic load"" (all exposures). Agnostic functional networks related to cellular immunity, gene expression, cell growth/proliferation, cardiovascular, auditory, embryonic, and neurological systems development were enriched. We replicated increased methylation in cg08500171 (NO2) and decreased methylation in cg17629796 (PM2.5). CONCLUSIONS:Mutually independent DNA methylation was associated with source-specific transportation noise and air pollution exposures, with distinct and shared enrichments for pathways related to inflammation, cellular development, and immune responses. These findings contribute in clarifying the pathways linking these exposures and age-related diseases but need further confirmation in the context of mediation analyses. https://doi.org/10.1289/EHP6174.",
-,Yes,20200615,ewas,32484362,"Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.",Environ. Health Perspect.,"The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45-74 years of age who participated in the Strong Heart Study in 1989-1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and <i>in silico</i> protein-protein interaction networks to explore the biological relevance of the findings. At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In <i>in silico</i> protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. https://doi.org/10.1289/EHP6345.",
-,Yes,20200615,ewas,32478847,Association of Neighborhood Disadvantage in Childhood With DNA Methylation in Young Adulthood.,JAMA Netw Open,"DNA methylation has been proposed as an epigenetic mechanism by which the childhood neighborhood environment may have implications for the genome that compromise adult health. To ascertain whether childhood neighborhood socioeconomic disadvantage is associated with differences in DNA methylation by age 18 years. This longitudinal cohort study analyzed data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative birth cohort of children born between 1994 and 1995 in England and Wales and followed up from age 5 to 18 years. Data analysis was performed from March 15, 2019, to June 30, 2019. High-resolution neighborhood data (indexing deprivation, dilapidation, disconnection, and dangerousness) collected across childhood. DNA methylation in whole blood was drawn at age 18 years. Associations between neighborhood socioeconomic disadvantage and methylation were tested using 3 prespecified approaches: (1) testing probes annotated to candidate genes involved in biological responses to growing up in socioeconomically disadvantaged neighborhoods and investigated in previous epigenetic research (stress reactivity-related and inflammation-related genes), (2) polyepigenetic scores indexing differential methylation in phenotypes associated with growing up in disadvantaged neighborhoods (obesity, inflammation, and smoking), and (3) a theory-free epigenome-wide association study. A total of 1619 participants (806 female individuals [50%]) had complete neighborhood and DNA methylation data. Children raised in socioeconomically disadvantaged neighborhoods exhibited differential DNA methylation in genes involved in inflammation (β = 0.12; 95% CI, 0.06-0.19; P &lt; .001) and smoking (β = 0.18; 95% CI, 0.11-0.25; P &lt; .001) but not obesity (β = 0.05; 95% CI, -0.01 to 0.11; P = .12). An epigenome-wide association study identified multiple CpG sites at an arraywide significance level of P &lt; 1.16 × 10-7 in genes involved in the metabolism of hydrocarbons. Associations between neighborhood disadvantage and methylation were small but robust to family-level socioeconomic factors and to individual-level tobacco smoking. Children raised in more socioeconomically disadvantaged neighborhoods appeared to enter young adulthood epigenetically distinct from their less disadvantaged peers. This finding suggests that epigenetic regulation may be a mechanism by which the childhood neighborhood environment alters adult health.",
-,Yes,20200615,ewas,32493224,Distinctions between sex and time in patterns of DNA methylation across puberty.,BMC Genomics,"There are significant sex differences in human physiology and disease; the genomic sources of these differences, however, are not well understood. During puberty, a drastic neuroendocrine shift signals physical changes resulting in robust sex differences in human physiology. Here, we explore how shifting patterns of DNA methylation may inform these pathways of biological plasticity during the pubertal transition. In this study we analyzed DNA methylation (DNAm) in saliva at two time points across the pubertal transition within the same individuals. Our purpose was to compare two domains of DNAm patterns that may inform processes of sexual differentiation 1) sex related sites, which demonstrated differences between males from females and 2) time related sites in which DNAm shifted significantly between timepoints. We further explored the correlated network structure sex and time related DNAm networks and linked these patterns to pubertal stage, assays of salivary testosterone, a reliable diagnostic of free, unbound hormone that is available to act on target tissues, and overlap with androgen response elements. Sites that differed by biological sex were largely independent of sites that underwent change across puberty. Time-related DNAm sites, but not sex-related sites, formed correlated networks that were associated with pubertal stage. Both time and sex DNAm networks reflected salivary testosterone levels that were enriched for androgen response elements, with sex-related DNAm networks being informative of testosterone levels above and beyond biological sex later in the pubertal transition. These results inform our understanding of the distinction between sex- and time-related differences in DNAm during the critical period of puberty and highlight a novel linkage between correlated patterns of sex-related DNAm and levels of salivary testosterone.",
-,No,20200615,mosaicism,32460841,The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues.,Genome Med,"Mosaic mutations acquired during early embryogenesis can lead to severe early-onset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate and mutational spectrum of embryonic mosaic mutations (EMMs) have only been studied in few tissues, and their contribution to genetic disorders is unknown. Therefore, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues. Mosaic mutation detection in 49 normal tissues from 570 individuals (Genotype-Tissue Expression (GTEx) cohort) was performed using a newly developed multi-tissue, multi-individual variant calling approach for RNA-seq data. Our method allows for reliable identification of EMMs and the developmental stage during which they appeared. The analysis of EMMs in 570 individuals revealed that newborns on average harbor 0.5-1 EMMs in the exome affecting multiple organs (1.3230 × 10<sup>-8</sup> per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multi-individual study design allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and adult life, as well as to provide insights into the rate and spectrum of mosaic mutations. We observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer. Investigation of the mutational spectrum of the gastrointestinal tract revealed a mutational pattern associated with the food-borne carcinogen aflatoxin, a signature that has so far only been reported in liver cancer. In summary, our multi-tissue, multi-individual study reveals a surprisingly high number of embryonic mosaic mutations in coding regions, implying novel hypotheses and diagnostic procedures for investigating genetic causes of disease and cancer predisposition.",
-,No,20200615,review,32514149,Unravelling the complex genetics of common kidney diseases: from variants to mechanisms.,Nat Rev Nephrol,"Genome-wide association studies (GWAS) have identified hundreds of loci associated with kidney-related traits such as glomerular filtration rate, albuminuria, hypertension, electrolyte and metabolite levels. However, these impressive, large-scale mapping approaches have not always translated into an improved understanding of disease or development of novel therapeutics. GWAS have several important limitations. Nearly all disease-associated risk loci are located in the non-coding region of the genome and therefore, their target genes, affected cell types and regulatory mechanisms remain unknown. Genome-scale approaches can be used to identify associations between DNA sequence variants and changes in gene expression (quantified through bulk and single-cell methods), gene regulation and other molecular quantitative trait studies, such as chromatin accessibility, DNA methylation, protein expression and metabolite levels. Data obtained through these approaches, used in combination with robust computational methods, can deliver robust mechanistic inferences for translational exploitation. Understanding the genetic basis of common kidney diseases means having a comprehensive picture of the genes that have a causal role in disease development and progression, of the cells, tissues and organs in which these genes act to affect the disease, of the cellular pathways and mechanisms that drive disease, and of potential targets for disease prevention, detection and therapy.",
-,No,20200615,single-cell rna-seq,32424074,"Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains.",Genome Res.,"Identification of gene expression traits unique to the human brain sheds light on the molecular mechanisms underlying human evolution. Here, we searched for uniquely human gene expression traits by analyzing 422 brain samples from humans, chimpanzees, bonobos, and macaques representing 33 anatomical regions, as well as 88,047 cell nuclei composing three of these regions. Among 33 regions, cerebral cortex areas, hypothalamus, and cerebellar gray and white matter evolved rapidly in humans. At the cellular level, astrocytes and oligodendrocyte progenitors displayed more differences in the human evolutionary lineage than the neurons. Comparison of the bulk tissue and single-nuclei sequencing revealed that conventional RNA sequencing did not detect up to two-thirds of cell-type-specific evolutionary differences.",
-,No,20200615,dnam age,32474592,A distinctive epigenetic ageing profile in human granulosa cells.,Hum. Reprod.,"Does women's age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells? Accumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile. The mechanisms underlying the decline in women's fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa). This study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden. Blood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package. Using established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7 years) compared to chronological age (average: 33.9 years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4 years) and leukocytes (average: 38.8 years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P = 0.003) but predicted telomere lengths unaffected by age (Pearson's correlation coefficient = -0.1, P = 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n = 335) and in leukocytes (n = 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P = 3.96 × 10-08) and gene expression (152 genes, P = 2.3 × 10-06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle. N/A. No gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found. Our findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age. This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest.",
-,No,20200713,biomarker,32580755,Refinement of cg05575921 demethylation response in nascent smoking.,Clin Epigenetics,"The initiation of adolescent smoking is difficult to detect using carbon monoxide or cotinine assays. Previously, we and others have shown that the methylation of cg05575921 is an accurate predictor of adult smoking status. But the dose and time dependency of the demethylation response to smoking initiation in adolescents is not yet well understood. To this end, we conducted three consecutive annual in-person interviews and biological samplings of 448 high school students (wave 1 (W1)-wave 3 (W3)). At W1 (n = 448), 62 subjects reported using tobacco and 72 subjects reported using cannabis at least once in their life-time with 38 and 20 subjects having a positive cotinine and cannabinoid levels, respectively, at W1 intake. At W3 (n = 383), 67 subjects reported using tobacco and 60 subjects reported using cannabis at least once with 75 and 60 subjects having positive cotinine and cannabinoid levels, respectively, at W3. Subjects with undetectable cotinine levels at all three-time waves had stable levels of cg05575921 methylation throughout the study (88.7% at W1 and 88.8% at W3, n = 149), while subjects with positive cotinine levels at all 3 time points manifested a steady decrease in cg05575921 methylation (81.8% at W1 and 71.3% at the W3, n = 12). In those subjects with an affirmative smoking self-report at W3 (n = 17), the amount of demethylation at cg05575921 was correlated with time and intensity of smoking. We conclude that cg05575921 methylation is a sensitive, dose-dependent indicator of early stages of smoking, and may help to identify smokers in the early stages of smoking.",
-,Yes,20200713,ewas,32539856,Harnessing peripheral DNA methylation differences in the Alzheimer's Disease Neuroimaging Initiative (ADNI) to reveal novel biomarkers of disease.,Clin Epigenetics,"Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer's disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multi-omics and phenotypic information on a well-phenotyped subset of ADNI participants. In this manuscript, we report cross-diagnosis differential peripheral DNA methylation in a cohort of AD, MCI, and age-matched CN individuals with longitudinal DNA methylation measurements. Epigenome-wide association studies (EWAS) were performed using a mixed model with repeated measures over time with a P value cutoff of 1 Ă— 10<sup>-5</sup> to test contrasts of pairwise differential peripheral methylation in AD vs CN, AD vs MCI, and MCI vs CN. The most highly significant differentially methylated loci also tracked with Mini Mental State Examination (MMSE) scores. Differentially methylated loci were enriched near brain and neurodegeneration-related genes (e.g., BDNF, BIN1, APOC1) validated using the genotype tissue expression project portal (GTex). Our work shows that peripheral differential methylation between age-matched subjects with AD relative to healthy controls will provide opportunities to further investigate and validate differential methylation as a surrogate of disease. Given the inaccessibility of brain tissue, the PB-associated methylation marks may help identify the stage of disease and progression phenotype, information that would be central to bringing forward successful drugs for AD.",
-,Yes,20200713,ewas,32561708,Epigenome-wide association study of attention-deficit/hyperactivity disorder in adults.,Transl Psychiatry,"Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that often persists into adulthood. There is growing evidence that epigenetic dysregulation participates in ADHD. Given that only a limited number of epigenome-wide association studies (EWASs) of ADHD have been conducted so far and they have mainly focused on pediatric and population-based samples, we performed an EWAS in a clinical sample of adults with ADHD. We report one CpG site and four regions differentially methylated between patients and controls, which are located in or near genes previously involved in autoimmune diseases, cancer or neuroticism. Our sensitivity analyses indicate that smoking status is not responsible for these results and that polygenic risk burden for ADHD does not greatly impact the signatures identified. Additionally, we show an overlap of our EWAS findings with genetic signatures previously described for ADHD and with epigenetic signatures for smoking behavior and maternal smoking. These findings support a role of DNA methylation in ADHD and emphasize the need for additional efforts in larger samples to clarify the role of epigenetic mechanisms on ADHD across the lifespan.",
-,Yes,20200713,ewas,32600451,Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer.,Clin Epigenetics,"Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to � 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival. Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (P<sub>Bonferroni</sub> &lt; 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10<sup>-05</sup>). Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.",
-,Yes,20200713,ewas,32603190,Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure.,Environ. Health Perspect.,"Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes. We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, <mml:math xmlns:mml=""http://www.w3.org/1998/Math/MathML""> <mml:mrow> <mml:mi>mean </mml:mi> <mml:mrow> <mml:mrow> <mml:mo>(</mml:mo> <mml:mrow> <mml:mo>±</mml:mo> <mml:mi>SD</mml:mi> </mml:mrow> <mml:mo>)</mml:mo> </mml:mrow> </mml:mrow> <mml:mi> μ</mml:mi> <mml:mi>g</mml:mi> <mml:mo>/</mml:mo> <mml:mi>g</mml:mi> </mml:mrow> </mml:math> creatinine: 11.7 (10.6)]. DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species. In adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (<mml:math xmlns:mml=""http://www.w3.org/1998/Math/MathML""> <mml:mrow> <mml:mtext>FDR</mml:mtext> <mml:mo>&lt;</mml:mo> <mml:mtext> </mml:mtext> <mml:mn>0.05</mml:mn> </mml:mrow> </mml:math>). After Bonferroni correction, 5 CpGs remained associated with total urinary As (<mml:math xmlns:mml=""http://www.w3.org/1998/Math/MathML""> <mml:mrow> <mml:msub> <mml:mi>p</mml:mi> <mml:mrow> <mml:mtext>Bonferroni</mml:mtext> </mml:mrow> </mml:msub> <mml:mo>&lt;</mml:mo> <mml:mn>0.05</mml:mn> </mml:mrow> </mml:math>), located in <i>SLC7A11</i>, <i>ANKS3</i>, <i>LINGO3</i>, <i>CSNK1D</i>, <i>ADAMTSL4</i>. We identified one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to <i>C11orf2</i>; <i>TSPAN32</i> genes. This is one of the first epigenome-wide association studies to investigate As exposure and locus-specific DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in <i>SLC7A11A</i>, a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As-induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As-related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. https://doi.org/10.1289/EHP6263.",
-,Yes,20200713,ewas,32629249,Dioxin-like compound exposures and DNA methylation in the Anniston Community Health Survey Phase II.,Sci. Total Environ.,"The Anniston Community Health Survey (ACHS-I) was initially conducted from 2005 to 2007 to assess polychlorinated biphenyl (PCB) exposures in Anniston, Alabama residents. In 2014, a follow-up study (ACHS-II) was conducted to measure the same PCBs as in ACHS-I and additional compounds e.g., polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like non-ortho (cPCBs) substituted PCBs. In this epigenome-wide association study (EWAS), we examined the associations between PCDD, PCDF, and PCB exposures and DNA methylation. Whole blood DNA methylation was measured using Illumina EPIC arrays (n=292). We modeled lipid-adjusted toxic equivalencies (TEQs) for: ΣDioxins (sum of 28 PCDDs, PCDFs, cPCBs, and mPCBs), PCDDs, PCDFs, cPCBs, and mPCBs using robust multivariable linear regression adjusting for age, race, sex, smoking, bisulfite conversion batch, and estimated percentages of six blood cell types. Among all exposures we identified 10 genome-wide (Bonferroni p≤6.74E-08) and 116 FDR (p≤5.00E-02) significant associations representing 10 and 113 unique CpGs, respectively. Of the 10 genome-wide associations, seven (70%) occurred in the PCDDs and four (40%) of these associations had an absolute differential methylation ≥1.00%, based on the methylation difference between the highest and lowest exposure quartiles. Most of the associations (six, 60%) represented hypomethylation changes. Of the 10 unique CpGs, eight (80%) were in genes shown to be associated with dioxins and/or PCBs based on data from the 2019 Comparative Toxicogenomics Database. In this study, we have identified a set of CpGs in blood DNA that may be particularly susceptible to dioxin, furan, and dioxin-like PCB exposures.",
-,Yes,20200713,ewas,32630231,Systemic Investigation of Promoter-wide Methylome and Genome Variations in Gout.,Int J Mol Sci,"Current knowledge of gout centers on hyperuricemia. Relatively little is known regarding the pathogenesis of gouty inflammation. To investigate the epigenetic background of gouty inflammation independent of hyperuricemia and its relationship to genetics, 69 gout patients and 1455 non-gout controls were included. Promoter-wide methylation was profiled with EPIC array. Whole-genome sequencing data were included for genetic and methylation quantitative trait loci (meQTL) analyses and causal inference tests. Identified loci were subjected to co-methylation analysis and functional localization with DNase hypersensitivity and histone marks analysis. An expression database was queried to clarify biologic functions of identified loci. A transcription factor dataset was integrated to identify transcription factors coordinating respective expression. In total, seven CpG loci involved in interleukin-1β production survived genetic/meQTL analyses, or causal inference tests. None had a significant relationship with various metabolic traits. Additional analysis suggested gouty inflammation, instead of hyperuricemia, provides the link between these CpG sites and gout. Six (<i>PGGT1B</i>, <i>INSIG1</i>, <i>ANGPTL2</i>, <i>JNK1</i>, <i>UBAP1</i>, and <i>RAPTOR</i>) were novel genes in the field of gout. One (<i>CNTN5</i>) was previously associated with gouty inflammation. Transcription factor mapping identified several potential transcription factors implicated in the link between differential methylation, interleukin-1β production, and gouty inflammation. In conclusion, this study revealed several novel genes specific to gouty inflammation and provided enhanced insight into the biological basis of gouty inflammation.",
-,Yes,20200713,ewas,32641083,Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults.,Genome Med,"The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets. In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn's disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.",
-,No,20200713,methods,32513961,Bayesian reassessment of the epigenetic architecture of complex traits.,Nat Commun,"Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. Here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. Implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (SNP) marker effects, improves association estimates and in 9,448 individuals, 75.7% (95% CI 71.70-79.3) of body mass index (BMI) variation and 45.6% (95% CI 37.3-51.9) of cigarette consumption variation was captured by whole blood methylation array data. Pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for BMI, and xenobiotic stimuli response for smoking, showed &gt;1.5 times larger associations with &gt;95% posterior inclusion probability. Prediction accuracy improved by 28.7% for BMI and 10.2% for smoking over a LASSO model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal.",
-,No,20200713,methods,32580727,New targeted approaches for epigenetic age predictions.,BMC Biol.,"Age-associated DNA methylation changes provide a promising biomarker for the aging process. While genome-wide DNA methylation profiles enable robust age-predictors by integration of many age-associated CG dinucleotides (CpGs), there are various alternative approaches for targeted measurements at specific CpGs that better support standardized and cost-effective high-throughput analysis. In this study, we utilized 4647 Illumina BeadChip profiles of blood to select CpG sites that facilitate reliable age-predictions based on pyrosequencing. We demonstrate that the precision of DNA methylation measurements can be further increased with droplet digital PCR (ddPCR). In comparison, bisulfite barcoded amplicon sequencing (BBA-seq) gave slightly lower correlation between chronological age and DNA methylation at individual CpGs, while the age-predictions were overall relatively accurate. Furthermore, BBA-seq data revealed that the correlation of methylation levels with age at neighboring CpG sites follows a bell-shaped curve, often associated with a CTCF binding site. We demonstrate that within individual BBA-seq reads the DNA methylation at neighboring CpGs is not coherently modified, but reveals a stochastic pattern. Based on this, we have developed a new approach for epigenetic age predictions based on the binary sequel of methylated and non-methylated sites in individual reads, which reflects heterogeneity in epigenetic aging within a sample. Targeted DNA methylation analysis at few age-associated CpGs by pyrosequencing, BBA-seq, and particularly ddPCR enables high precision of epigenetic age-predictions. Furthermore, we demonstrate that the stochastic evolution of age-associated DNA methylation patterns in BBA-seq data enables epigenetic clocks for individual DNA strands.",
-,No,20200713,methods,32605541,Simulating ComBat: how batch correction can lead to the systematic introduction of false positive results in DNA methylation microarray studies.,BMC Bioinformatics,"Systematic technical effects-also called batch effects-are a considerable challenge when analyzing DNA methylation (DNAm) microarray data, because they can lead to false results when confounded with the variable of interest. Methods to correct these batch effects are error-prone, as previous findings have shown. Here, we demonstrate how using the R function ComBat to correct simulated Infinium HumanMethylation450 BeadChip (450 K) and Infinium MethylationEPIC BeadChip Kit (EPIC) DNAm data can lead to a large number of false positive results under certain conditions. We further provide a detailed assessment of the consequences for the highly relevant problem of p-value inflation with subsequent false positive findings after application of the frequently used ComBat method. Using ComBat to correct for batch effects in randomly generated samples produced alarming numbers of false discovery rate (FDR) and Bonferroni-corrected (BF) false positive results in unbalanced as well as in balanced sample distributions in terms of the relation between the outcome of interest variable and the technical position of the sample during the probe measurement. Both sample size and number of batch factors (e.g. number of chips) were systematically simulated to assess the probability of false positive findings. The effect of sample size was simulated using n = 48 up to n = 768 randomly generated samples. Increasing the number of corrected factors led to an exponential increase in the number of false positive signals. Increasing the number of samples reduced, but did not completely prevent, this effect. Using the approach described, we demonstrate, that using ComBat for batch correction in DNAm data can lead to false positive results under certain conditions and sample distributions. Our results are thus contrary to previous publications, considering a balanced sample distribution as unproblematic when using ComBat. We do not claim completeness in terms of reporting all technical conditions and possible solutions of the occurring problems as we approach the problem from a clinician's perspective and not from that of a computer scientist. With our approach of simulating data, we provide readers with a simple method to assess the probability of false positive findings in DNAm microarray data analysis pipelines.",
-,No,20200713,review,32526941,Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease.,Int J Mol Sci,"Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications-histone methylation, acetylation and crotonylation-in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.",
-,No,20200713,dnam score,32552915,Individual and joint contributions of genetic and methylation risk scores for enhancing lung cancer risk stratification: data from a population-based cohort in Germany.,Clin Epigenetics,"Risk stratification for lung cancer (LC) screening is so far mostly based on smoking history. This study aimed to assess if and to what extent such risk stratification could be enhanced by additional consideration of genetic risk scores (GRSs) and epigenetic risk scores defined by DNA methylation. We conducted a nested case-control study of 143 incident LC cases and 1460 LC-free controls within a prospective cohort of 9949 participants aged 50-75 years with 14-year follow-up. Lifetime smoking history was obtained in detail at recruitment. We built a GRS based on 31 previously identified LC-associated single-nucleotide polymorphisms (SNPs) and a DNA methylation score (MRS) based on methylation of 151 previously identified smoking-associated cytosine-phosphate-guanine (CpG) loci. We evaluated associations of GRS and MRS with LC incidence by logistic regression models, controlling for age, sex, smoking status, and pack-years. We compared the predictive performance of models based on pack-years alone with models additionally including GRS and/or MRS using the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). GRS and MRS showed moderate and strong associations with LC risk even after comprehensive adjustment for smoking history (adjusted odds ratio [95% CI] comparing highest with lowest quartile 1.93 [1.05-3.71] and 5.64 [2.13-17.03], respectively). Similar associations were also observed within the risk groups of ever and heavy smokers. Addition of GRS and MRS furthermore strongly enhanced LC prediction beyond prediction by pack-years (increase of optimism-corrected AUC among heavy smokers from 0.605 to 0.654, NRI 26.7%, p = 0.0106, IDI 3.35%, p = 0.0036), the increase being mostly attributable to the inclusion of MRS. Consideration of MRS, by itself or in combination with GRS, may strongly enhance LC risk stratification.",
-,No,20200803,methods,32678018,Gene-methylation interactions: discovering region-wise DNA methylation levels that modify SNP-associated disease risk.,Clin Epigenetics,"Current technology allows rapid assessment of DNA sequences and methylation levels at a single-site resolution for hundreds of thousands of sites in the human genome, in thousands of individuals simultaneously. This has led to an increase in epigenome-wide association studies (EWAS) of complex traits, particularly those that are poorly explained by previous genome-wide association studies (GWAS). However, the genome and epigenome are intertwined, e.g., DNA methylation is known to affect gene expression through, for example, genomic imprinting. There is thus a need to go beyond single-omics data analyses and develop interaction models that allow a meaningful combination of information from EWAS and GWAS. We present two new methods for genetic association analyses that treat offspring DNA methylation levels as environmental exposure. Our approach searches for statistical interactions between SNP alleles and DNA methylation (G Ă—Me) and between parent-of-origin effects and DNA methylation (PoO Ă—Me), using case-parent triads or dyads. We use summarized methylation levels over nearby genomic region to ease biological interpretation. The methods were tested on a dataset of parent-offspring dyads, with EWAS data on the offspring. Our results showed that methylation levels around a SNP can significantly alter the estimated relative risk. Moreover, we show how a control dataset can identify false positives. The new methods, G Ă—Me and PoO Ă—Me, integrate DNA methylation in the assessment of genetic relative risks and thus enable a more comprehensive biological interpretation of genome-wide scans. Moreover, our strategy of condensing DNA methylation levels within regions helps overcome specific disadvantages of using sparse chip-based measurements. The methods are implemented in the freely available R package Haplin ( https://cran.r-project.org/package=Haplin ), enabling fast scans of multi-omics datasets.",
-,No,20200803,dnam score,32718350,Characterisation of an inflammation-related epigenetic score and its association with cognitive ability.,Clin Epigenetics,"Chronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear. The acute responses of many inflammatory biomarkers mean they may provide an unreliable picture of the chronicity of inflammation. Recently, a large-scale epigenome-wide association study identified DNA methylation correlates of C-reactive protein (CRP)-a widely used acute-phase inflammatory biomarker. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. We utilise a DNA methylation-based score for CRP and investigate its trajectories with age, and associations with cognitive ability in comparison with serum CRP and a genetic CRP score in a longitudinal study of older adults (n = 889) and a large, cross-sectional cohort (n = 7028). We identified no homogeneous trajectories of serum CRP with age across the cohorts, whereas the epigenetic CRP score was consistently found to increase with age (standardised β = 0.07 and 0.01) and to do so more rapidly in males compared to females. Additionally, the epigenetic CRP score had higher test-retest reliability compared to serum CRP, indicating its enhanced temporal stability. Higher serum CRP was not found to be associated with poorer cognitive ability (standardised β = - 0.08 and - 0.05); however, a consistent negative association was identified between cognitive ability and the epigenetic CRP score in both cohorts (standardised β = - 0.15 and - 0.08). An epigenetic proxy of CRP may provide a more reliable signature of chronic inflammation, allowing for more accurate stratification of individuals, and thus clearer inference of associations with incident health outcomes.",
-,Yes,20200803,dnam score,32711505,A panel of DNA methylation signature from peripheral blood may predict colorectal cancer susceptibility.,BMC Cancer,"Differential DNA methylation panel derived from peripheral blood could serve as biomarkers of CRC susceptibility. However, most of the previous studies utilized post-diagnostic blood DNA which may be markers of disease rather than susceptibility. In addition, only a few studies have evaluated the predictive potential of differential DNA methylation in CRC in a prospective cohort and on a genome-wide basis. The aim of this study was to identify a potential panel of DNA methylation biomarkers in peripheral blood that is associated with CRC risk and therefore serve as epigenetic biomarkers of disease susceptibility. DNA methylation profile of a nested case-control study with 166 CRC and 424 healthy normal subjects were obtained from the Gene Expression Omnibus (GEO) database. The differentially methylated markers were identified by moderated t-statistics. The DNA methylation panel was constructed by stepwise logistic regression and the least absolute shrinkage and selection operator in the training dataset. A methylation risk score (MRS) model was constructed and the association between MRS and CRC risk assessed. We identified 48 differentially methylated CpGs sites, of which 33 were hypomethylated. Of these, sixteen-CpG based MRS that was associated with CRC risk (OR = 2.68, 95% CI: 2.13, 3.38, P &lt;  0.0001) was constructed. This association is confirmed in the testing dataset (OR = 2.02, 95% CI: 1.48, 2.74, P &lt;  0.0001) and persisted in both males and females, younger and older subjects, short and long time-to-diagnosis. The MRS also predicted CRC with AUC 0.82 (95% CI: 0.76, 0.88), indicating high accuracy. Our study has identified a novel DNA methylation panel that is associated with CRC and could, if validated be useful for the prediction of CRC risk in the future.",
-,No,20200803,dnam score,32694610,Non-invasive early detection of cancer four years before conventional diagnosis using a blood test.,Nat Commun,"Early detection has the potential to reduce cancer mortality, but an effective screening test must demonstrate asymptomatic cancer detection years before conventional diagnosis in a longitudinal study. In the Taizhou Longitudinal Study (TZL), 123,115 healthy subjects provided plasma samples for long-term storage and were then monitored for cancer occurrence. Here we report the preliminary results of PanSeer, a noninvasive blood test based on circulating tumor DNA methylation, on TZL plasma samples from 605 asymptomatic individuals, 191 of whom were later diagnosed with stomach, esophageal, colorectal, lung or liver cancer within four years of blood draw. We also assay plasma samples from an additional 223 cancer patients, plus 200 primary tumor and normal tissues. We show that PanSeer detects five common types of cancer in 88% (95% CI: 80-93%) of post-diagnosis patients with a specificity of 96% (95% CI: 93-98%), We also demonstrate that PanSeer detects cancer in 95% (95% CI: 89-98%) of asymptomatic individuals who were later diagnosed, though future longitudinal studies are required to confirm this result. These results demonstrate that cancer can be non-invasively detected up to four years before current standard of care.",
-,Yes,20200803,ewas,32731254,Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers.,Neuropsychopharmacology,"Numerous DNA methylation (DNAm) biomarkers of cigarette smoking have been identified in peripheral blood studies, but because of tissue specificity, blood-based studies may not detect brain-specific smoking-related DNAm differences that may provide greater insight as neurobiological indicators of smoking and its exposure effects. We report the first epigenome-wide association study (EWAS) of smoking in human postmortem brain, focusing on nucleus accumbens (NAc) as a key brain region in developing and reinforcing addiction. Illumina HumanMethylation EPIC array data from 221 decedents (120 European American [23% current smokers], 101 African American [26% current smokers]) were analyzed. DNAm by smoking (current vs. nonsmoking) was tested within each ancestry group using robust linear regression models adjusted for age, sex, cell-type proportion, DNAm-derived negative control principal components (PCs), and genotype-derived PCs. The resulting ancestry-specific results were combined via meta-analysis. We extended our NAc findings, using published smoking EWAS results in blood, to identify DNAm smoking effects that are unique (tissue-specific) vs. shared between tissues (tissue-shared). We identified seven CpGs (false discovery rate &lt; 0.05), of which three CpGs are located near genes previously indicated with blood-based smoking DNAm biomarkers: ZIC1, ZCCHC24, and PRKDC. The other four CpGs are novel for smoking-related DNAm changes: ABLIM3, APCDD1L, MTMR6, and CTCF. None of the seven smoking-related CpGs in NAc are driven by genetic variants that share association signals with predisposing genetic risk variants for smoking, suggesting that the DNAm changes reflect consequences of smoking. Our results provide the first evidence for smoking-related DNAm changes in human NAc, highlighting CpGs that were undetected as peripheral biomarkers and may reflect brain-specific responses to smoking exposure.",
-,Yes,20200803,ewas,32728124,DNA methylation and adiposity phenotypes: an epigenome-wide association study among adults in the Strong Heart Study.,Int J Obes (Lond),"Elevated adiposity is often posited by medical and public health researchers to be a risk factor associated with cardiovascular disease, diabetes, and other diseases. These health challenges are now thought to be reflected in epigenetic modifications to DNA molecules, such as DNA methylation, which can alter gene expression. Here we report the results of three Epigenome Wide Association Studies (EWAS) in which we assessed the differential methylation of DNA (obtained from peripheral blood) associated with three adiposity phenotypes (BMI, waist circumference, and impedance-measured percent body fat) among American Indian adult participants in the Strong Heart Study. We found differential methylation at 8264 CpG sites associated with at least one of our three response variables. Of the three adiposity proxies we measured, waist circumference had the highest number of associated differentially methylated CpGs, while percent body fat was associated with the lowest. Because both waist circumference and percent body fat relate to physiology, we focused interpretations on these variables. We found a low degree of overlap between these two variables in our gene ontology enrichment and Differentially Methylated Region analyses, supporting that waist circumference and percent body fat measurements represent biologically distinct concepts. We interpret these general findings to indicate that highly significant regions of the genome (DMR) and synthesis pathways (GO) in waist circumference analyses are more likely to be associated with the presence of visceral/abdominal fat than more general measures of adiposity. Our findings confirmed numerous CpG sites previously found to be differentially methylated in association with adiposity phenotypes, while we also found new differentially methylated CpG sites and regions not previously identified.",
-,Yes,20200803,ewas,32697766,"Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.",Aging (Albany NY),"DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (<i>P</i> &lt; 9.3x10<sup>-7</sup>) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to <i>BMPR1B, MIR1973, IFITM3, NLRC5</i>, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to <i>SERINC2, CHST12</i>, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (<i>IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1</i>) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.",
-,Yes,20200803,ewas,32679516,An epigenome-wide association study of ambient pyrethroid pesticide exposures in California's central valley.,Int J Hyg Environ Health,"Pyrethroid pesticide use is increasing worldwide, although the full extent of associated health effects is unknown. An epigenome-wide association study (EWAS) with exploratory pathway analysis may help identify potential pyrethroid-related health effects. We performed an exploratory EWAS of chronic ambient pyrethroid exposure using control participants' blood in the Parkinson's Environment and Genes Study in the Central Valley of California (N = 237). We estimated associations of living and working near agricultural pyrethroid pesticide applications in the past 5 years (binary) with site-specific differential methylation, and used a false discovery rate (FDR) cut off of 0.05 for significance. We controlled for age, sex, education, cell count, and an ancestral marker for Hispanic ethnicity. We normalized methylation values for Type I/II probe bias using Beta-Mixture Quantile (BMIQ) normalization, filtered out cross-reactive probes, and evaluated for remaining bias with Surrogate Variable Analysis (SVA). We also evaluated the effects of controlling for cell count and normalizing for Type I/II probe bias by comparing changes in effect estimates and p-values for the top hits across BMIQ and GenomeStudio normalization methods, and controlling for cell count. To facilitate broader interpretation, we annotated genes to the CpG sites and performed gene set overrepresentation analysis, using genes annotated to CpG sites that were associated with pyrethroids at a raw p &lt; 0.05, and controlling for background representation of CpG sites on the chip. We did this for both a biological process context (Gene Ontology terms) using missMethyl, and a disease set context using WebGestalt. For these gene set overrepresentation analyses we also used an FDR cut off of 0.05 for significance of gene sets. After controlling for cell count and applying BMIQ normalization, 4 CpG sites were differentially methylated in relation to pyrethroid exposures. When using GenomeStudio's Illumina normalization, 415 CpG sites were differentially methylated, including all four identified with the BMIQ method. In the gene set overrepresentation analyses, we identified 6 GO terms using BMIQ normalization, and 76 using Illumina normalization, including the 6 identified by BMIQ. For disease sets, we identified signals for Alzheimer's disease, leukemia and several other cancers, diabetes, birth defects, and other diseases, for both normalization methods. We identified minimal changes in effect estimates after controlling for cell count, and controlling for cell count generally weakened p-values. BMIQ normalization, however, resulted in different beta coefficients and weakened p-values. Chronic ambient pyrethroid exposure is associated with differential methylation at CpG sites that annotate to a wide variety of disease states and biological mechanisms that align with prior research. However, this EWAS also implicates several novel diseases for future investigation, and highlights the relative importance of different background normalization methods in identifying associations.",
-,Yes,20200803,ewas,32677467,Early pregnancy dyslipidemia is associated with placental DNA methylation at loci relevant for cardiometabolic diseases.,Epigenomics,"<b>Aim:</b> To identify placental DNA methylation changes that are associated with early pregnancy maternal dyslipidemia. <b>Materials &amp; methods:</b> We analyzed placental genome-wide DNA methylation (n = 262). Genes annotating differentially methylated CpGs were evaluated for gene expression in placenta (n = 64). <b>Results:</b> We found 11 novel significant differentially methylated CpGs associated with high total cholesterol, low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol. High triglycerides were associated with decreased methylation of cg02785814 (<i>ALX4</i>) and decreased expression of <i>ALX4</i> in placenta. Genes annotating the differentially methylated CpGs play key roles in lipid metabolism and were enriched in dyslipidemia pathways. Functional annotation found <i>cis</i>-methylation quantitative trait loci for genetic loci in <i>ALX4</i> and <i>EXT2</i>. <b>Conclusion:</b> Our findings lend novel insights into potential placental epigenetic mechanisms linked with maternal dyslipidemia. <b>Trial Registration:</b> ClinicalTrials.gov, NCT00912132.",
-,Yes,20200803,ewas,32671182,Blood DNA methylation signatures to detect dementia prior to overt clinical symptoms.,Alzheimers Dement (Amst),"This study determined whether blood DNA methylation (DNAm) patterns differentiate individuals with presymptomatic dementia compared to controls. DNAm was measured in 73 individuals prior to dementia diagnosis and 87 cognitively healthy controls matched for age, sex, smoking, education, and baseline cognition. DNAm was also measured at 3 years follow-up in 25 dementia cases, and 24 controls. Cases and controls differed in DNAm (unadjusted <i>P</i> &lt; .01) at the time of diagnosis (n = 28,787 probes), and pre-diagnosis (n = 15,111 probes), with cg01404610 (<i>General transcription factor IIA subunit 1</i> gene) significant after correction for multiple testing. Overall, 1150 probes overlapped between analyses (methylation differences from -10.6% to +11.0%), and effect sizes increased from pre-diagnosis to diagnosis. Discernible blood DNAm signatures are in dementia cases before the appearance of overt clinical symptoms. Blood-based methylation may serve as a potential biomarker of dementia, but further investigation is needed to determine their true clinical utility.",
-,Yes,20200803,ewas,32661777,Genome-wide methylation association with current suicidal ideation in schizophrenia.,J Neural Transm (Vienna),"In this study, we investigate the epigenetic mechanisms associated with current suicidal ideation. Gene expression changes have been found in post-mortem brain of suicide victims. However, it is not clear how in-vivo gene expression change confers risk for suicide. DNA methylation is a form of epigenetic modification that regulates gene expression. Our primary aim is to investigate genome-wide methylation in conferring risk for current suicidal ideation (SI) in schizophrenia. The presence of current SI and genome-wide methylation patterns were assessed in 107 patients with schizophrenia. DNA methylation has been measured in white blood cells as a possible peripheral biomarker of SI. SI was the primary outcome variable in a model including methylation status of white blood cells using the Illumina 450 array. We have tested the association with genome-wide methylation levels in 19 subjects with current SI and 88 subjects without current SI and we found that higher methylation level in the CpG cg06121808 located in the gene SLC20A1 on chromosome 2 was associated with current SI (p = 0.000003; beta difference = 0.06). Furthermore, the distal promoter analysis showed that the gene SMPD2 was hypermethylated in suicide ideators (p = 0.0001; beta difference = 0.02). Thus, molecular biomarkers could advance our understanding of the molecular mechanisms of stress-related SI. Furthermore, the methylation sites that we have identified should be replicated in other suicide related phenotypes to generate robust biomarkers with high translational value for proof of concept interventions aiming at reducing SI.",
-,Yes,20200803,ewas,32660331,Genome-wide DNA methylation differences and polychlorinated biphenyl (PCB) exposure in a US population.,Epigenetics,"Exposure to polychlorinated biphenyls (PCBs), an endocrine-disrupting compound, is ubiquitous despite decades-old bans on the manufacture and use of PCBs. Increased exposure to PCBs is associated with adverse health consequences throughout life, including type 2 diabetes and cancer. PCB exposure is also associated with alterations in epigenetic marks and gene transcription, which could lead to adverse health outcomes, but many of these are population-specific. To further investigate the association between PCB and epigenetic marks, DNA methylation was measured at 787,684 CpG sites in 641 peripheral blood samples from the Michigan Polybrominated Biphenyl (PBB) Registry. 1345 CpGs were associated with increased total PCB level after controlling for age, sex, and 24 surrogate variables (FDR &lt; 0.05). These CpGs were enriched in active promoter and transcription associated regions (p &lt; 0.05), and in regions around the binding sites for transcription factors involved in xenobiotic metabolism and immune function (FDR &lt; 0.05). PCB exposure also associated with proportions of CD4T, NK, and granulocyte cell types, and with the neutrophil to lymphocyte ratio (NLR) (p &lt; 0.05), and the estimated effect sizes of PCB on the epigenome were correlated with the effect sizes previously reported in an epigenome-wide study of C-reactive protein (r = 0.29; p = 2.22e-5), supporting previous studies on the association between PCB and immune dysfunction. These results indicate that PCB exposure is associated with differences in epigenetic marks in active regions of the genome, and future work should investigate whether these may mediate the association between PCB and health consequences.",
-,Yes,20200803,ewas,32653021,Concentrations of persistent organic pollutants in maternal plasma and epigenome-wide placental DNA methylation.,Clin Epigenetics,"Prenatal maternal plasma persistent organic pollutant (POP) concentrations have been associated with neonatal outcomes. However, the underlying mechanisms remain unknown. Placental epigenetic mechanisms may be involved, but no prior epigenome-wide studies have investigated the impact of maternal POPs on placental DNA methylation. We studied the association between maternal plasma POP concentration in early pregnancy and epigenome-wide placental DNA methylation among 260 pregnant women from the NICHD Fetal Growth Studies. Our analysis focused on POPs with more than 80% plasma concentrations above the limit of quantification, including 3 organochlorine pesticides (hexachlorobenzene, trans-nonachlor, p,p'-dichlorodiphenyldichloroethylene), 1 polybrominated diphenyl ether (PBDE 47), 3 polychlorinated biphenyls (138/158, 153, 180), and 6 poly- and perfluorinated alkyl substances (PFASs) (perfluorodecanoic acid, perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluoroundecanoic acid (PFUnDA)). Using 5% false discovery rate, POPs were associated with a total of 214 differentially methylated CpG sites (nominal p values ranging from 2.61 Ă— 10<sup>-21</sup> to 2.11 Ă— 10<sup>-7</sup>). Out of the 214 CpG sites, 24 (11%) were significantly correlated with placental expression of 21 genes. Notably, higher PFUnDA was associated with increased methylation at 3 CpG sites (cg13996963, cg12089439, cg18145877) annotated to TUSC3, and increased methylation at those 3 CpG sites was correlated with decreased expression of TUSC3 in the placenta. Increased methylation at cg18145877 (TUSC3) and decreased expression of TUSC3 were correlated with shorter birth length. Out of the 214 CpG sites, methylation at 44 CpG sites was correlated (p value &lt; 0.10) with at least one neonatal anthropometry measure (i.e., birth weight, birth length, and head circumference). Seven CpG sites mediated (p value &lt; 0.05) the association between PBDE 47 and neonatal anthropometry measures. Genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (PBDE 47) and in pathways related to brain size and brain morphology (PFASs). DNA methylation changes in the placenta were significantly associated with maternal plasma POPs concentration. The findings suggest that placental DNA methylation and gene expression mechanism may be involved in the prenatal toxicity of POPs and their association with neonatal anthropometry measures.",
-,No,20200803,meqtl,32710526,A decade of epigenetic change in aging twins: Genetic and environmental contributions to longitudinal DNA methylation.,Aging Cell,"Epigenetic changes may result from the interplay of environmental exposures and genetic influences and contribute to differences in age-related disease, disability, and mortality risk. However, the etiologies contributing to stability and change in DNA methylation have rarely been examined longitudinally. We considered DNA methylation in whole blood leukocyte DNA across a 10-year span in two samples of same-sex aging twins: (a) Swedish Adoption Twin Study of Aging (SATSA; N = 53 pairs, 53% female; 62.9 and 72.5 years, SD = 7.2 years); (b) Longitudinal Study of Aging Danish Twins (LSADT; N = 43 pairs, 72% female, 76.2 and 86.1 years, SD=1.8 years). Joint biometrical analyses were conducted on 358,836 methylation probes in common. Bivariate twin models were fitted, adjusting for age, sex, and country. Overall, results suggest genetic contributions to DNA methylation across 358,836 sites tended to be small and lessen across 10 years (broad heritability M = 23.8% and 18.0%) but contributed to stability across time while person-specific factors explained emergent influences across the decade. Aging-specific sites identified from prior EWAS and methylation age clocks were more heritable than background sites. The 5037 sites that showed the greatest heritable/familial-environmental influences (p &lt; 1E-07) were enriched for immune and inflammation pathways while 2020 low stability sites showed enrichment in stress-related pathways. Across time, stability in methylation is primarily due to genetic contributions, while novel experiences and exposures contribute to methylation differences. Elevated genetic contributions at age-related methylation sites suggest that adaptions to aging and senescence may be differentially impacted by genetic background.",
-,No,20200803,dnam score,32736664,Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden,Clin Epigenetics,"Background: Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries (n ? 9537, Generation Scotland: Scottish Family Health Study).
+Yes,20200601,ewas,32453742,Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago.,PLoS Genet,"Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.",
+Yes,20200601,ewas,32448018,Replicated umbilical cord blood DNA methylation loci associated with gestational age at birth.,Epigenetics,"DNA methylation is highly sensitive to <i>in utero</i> perturbations and has an established role in both embryonic development and regulation of gene expression. The foetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behaviour of individual genes. The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for <i>cis</i> gene relationships in specimens with multi-omic data. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450 K BeadChip, was associated with GA for 2,372 CpG probes (5% FDR) in both the Pregnancy, Race, Environment, Genes (PREG) and Newborn Epigenetic Study (NEST) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. Gene pathways identified are consistent with the hypothesis of pathogen detection and response by the immune system to elicit premature labour as a consequence of unscheduled inflammation.",
+Yes,20200601,ewas,32443666,Epigenome-Wide Association Study Reveals Duration of Breastfeeding Is Associated with Epigenetic Differences in Children.,Int J Environ Res Public Health,"Several small studies have shown associations between breastfeeding and genome-wide DNA methylation (DNAm). We performed a comprehensive Epigenome-Wide Association Study (EWAS) to identify associations between breastfeeding and DNAm patterns in childhood. We analysed DNAm data from the Isle of Wight Birth Cohort at birth, 10, 18 and 26 years. The feeding method was categorized as breastfeeding duration &gt;3 months and &gt;6 months, and exclusive breastfeeding duration &gt;3 months. EWASs using robust linear regression were performed to identify differentially methylated positions (DMPs) in breastfed and non-breastfed children at age 10 (false discovery rate of 5%). Differentially methylated regions (DMRs) were identified using comb-p. The persistence of significant associations was evaluated in neonates and individuals at 18 and 26 years. Two DMPs, in genes <i>SNX25</i> and <i>LINC00840</i>, were significantly associated with breastfeeding duration &gt;6 months at 10 years and was replicated for &gt;3 months of exclusive breastfeeding. Additionally, a significant DMR spanning the gene <i>FDFT1</i> was identified in 10-year-old children who were exposed to a breastfeeding duration &gt;3 months. None of these signals persisted to 18 or 26 years. This study lends further support for a suggestive role of DNAm in the known benefits of breastfeeding on a child's future health.",
+No,20200601,mr,32429084,Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer's Disease.,J Clin Med,"Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specific associations with AD, respectively, suggesting a potential role for such epigenetic modifications in the heterogeneous nature of AD. Our analyses provided stronger evidence for possible roles of four genes (i.e., <i>AIM2</i>, <i>C16orf80</i>, <i>DGUOK</i>, and <i>ST14</i>) in AD pathogenesis as they were also transcriptionally associated with AD. The identified associations suggest a list of prioritized genes for follow-up functional studies and advance our understanding of AD pathogenesis.",
+No,20200601,epigenetics,32423419,Protection from DNA re-methylation by transcription factors in primordial germ cells and pre-implantation embryos can explain trans-generational epigenetic inheritance.,Genome Biol,"A growing body of evidence suggests that certain epiphenotypes can be passed across generations via both the male and female germlines of mammals. These observations have been difficult to explain owing to a global loss of the majority of known epigenetic marks present in parental chromosomes during primordial germ cell development and after fertilization. By integrating previously published BS-seq, DNase-seq, ATAC-seq, and RNA-seq data collected during multiple stages of primordial germ cell and pre-implantation development, we find that the methylation status of the majority of CpGs genome-wide is restored after global de-methylation, despite the fact that global CpG methylation drops to 10% in primordial germ cells and 20% in the inner cell mass of the blastocyst. We estimate the proportion of such CpGs with preserved methylation status to be 78%. Further, we find that CpGs at sites bound by transcription factors during the global re-methylation phases of germline and embryonic development remain hypomethylated across all developmental stages observed. On the other hand, CpGs at sites not bound by transcription factors during the global re-methylation phase have high methylation levels prior to global de-methylation, become de-methylated during global de-methylation, and then become re-methylated. The results suggest that transcription factors can act as carriers of epigenetic information during germ cell and pre-implantation development by ensuring that the methylation status of CpGs is maintained. These findings provide the basis for a mechanistic description of trans-generational inheritance of epigenetic information in mammals.",
+No,20200601,dnam age,32367804,"Quantification of the Pace of Biological Aging in Humans Through a Blood Test, The DunedinPoAm DNA Methylation Algorithm",Elife, ,
+Yes,20200601,ewas,26822447,"Parenting, Socioeconomic Status Risk, and Later Young Adult Health: Exploration of Opposing Indirect Effects via DNA Methylation",Child Dev, ,
+Yes,20200601,ewas,30351206,The biological embedding of early-life socioeconomic status and family adversity in children's genome-wide DNA methylation,Epigenomics, ,
+Yes,20200601,ewas,28673994,Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood,Proc Natl Acad Sci USA, ,
+Yes,20200601,ewas,27768648,Epigenetic Mediators Between Childhood Socioeconomic Disadvantage and Mid-Life Body Mass Index: The New England Family Study,Psychosome Med, ,
+No,20200615,dnam score,32523041,Epigenetic prediction of major depressive disorder.,Mol. Psychiatry,"Variation in DNA methylation (DNAm) is associated with lifestyle factors such as smoking and body mass index (BMI) but there has been little research exploring its ability to identify individuals with major depressive disorder (MDD). Using penalised regression on genome-wide CpG methylation, we tested whether DNAm risk scores (MRS), trained on 1223 MDD cases and 1824 controls, could discriminate between cases (n = 363) and controls (n = 1417) in an independent sample, comparing their predictive accuracy to polygenic risk scores (PRS). The MRS explained 1.75% of the variance in MDD (β = 0.338, p = 1.17 × 10<sup>-7</sup>) and remained associated after adjustment for lifestyle factors (β = 0.219, p = 0.001, R<sup>2</sup> = 0.68%). When modelled alongside PRS (β = 0.384, p = 4.69 × 10<sup>-9</sup>) the MRS remained associated with MDD (β = 0.327, p = 5.66 × 10<sup>-7</sup>). The MRS was also associated with incident cases of MDD who were well at recruitment but went on to develop MDD at a later assessment (β = 0.193, p = 0.016, R<sup>2</sup> = 0.52%). Heritability analyses found additive genetic effects explained 22% of variance in the MRS, with a further 19% explained by pedigree-associated genetic effects and 16% by the shared couple environment. Smoking status was also strongly associated with MRS (β = 0.440, p ≤ 2 × 10<sup>-16</sup>). After removing smokers from the training set, the MRS strongly associated with BMI (β = 0.053, p = 0.021). We tested the association of MRS with 61 behavioural phenotypes and found that whilst PRS were associated with psychosocial and mental health phenotypes, MRS were more strongly associated with lifestyle and sociodemographic factors. DNAm-based risk scores of MDD significantly discriminated MDD cases from controls in an independent dataset and may represent an archive of exposures to lifestyle factors that are relevant to the prediction of MDD.",
+Yes,20200615,ewas,32525743,Whole Blood DNA Methylation Signatures of Diet Are Associated with Cardiovascular Disease Risk Factors and All-cause Mortality.,Circ Genom Precis Med,"<b>Background</b> - DNA methylation patterns associated with habitual diet have not been well studied. <b>Methods</b> - Diet quality was characterized using a Mediterranean-style diet score (MDS) and the Alternative Healthy Eating Index score (AHEI). We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400,000 cytosine-guanine dinucleotides (CpGs) in five population-based cohorts including 6,662 European ancestry (EA), 2,702 African ancestry (AA), and 360 Hispanic ancestry (HA) participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease (CVD) risk factors and examined their longitudinal associations with all-cause mortality. <b>Results</b> - We identified 30 CpGs associated with either MDS or AHEI, or both, in EA participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected p-value &lt; 1.6Ă—10<sup>-3</sup>). Hypermethylation of cg18181703 (<i>SOCS3</i>) was associated with higher scores of both MDS and AHEI and lower risk for all-cause mortality (p-value = 5.7Ă—10<sup>-15</sup>). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (p-value &lt; 0.05). MR analysis revealed eight putatively causal associations for six CpGs with four CVD risk factors (BMI, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes; Bonferroni corrected MR p-value &lt; 4.5Ă—10<sup>-4</sup>). For example, hypermethylation of cg11250194 (<i>FADS2</i>) was associated with lower triglyceride concentrations (MR p-value = 1.5Ă—10<sup>-14</sup>) and hypermethylation of cg02079413 (<i>SNORA54</i>; <i>NAP1L4</i>) was associated with BMI (corrected MR p-value = 1Ă—10<sup>-6</sup>). <b>Conclusions</b> - Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in EA individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.",
+Yes,20200615,ewas,32520614,"Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.",Hypertension,"We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with <i>P</i>&lt;1×10<sup>-5</sup>. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (<i>P</i>&lt;1×10<sup>-7</sup>) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with <i>P</i>&lt;0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (<i>TXNIP</i>) and cg00716257 (<i>JDP2</i>) determined by environmental effects acting on both systolic BP and methylation levels.",
+Yes,20200615,ewas,32503626,Epigenome-wide association study in healthy individuals identifies significant associations with DNA methylation and PBMC extract VEGF-A concentration.,Clin Epigenetics,"Vascular endothelial growth factor A (VEGF-A) is a chemokine that induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis. It is known for its high heritability (&gt; 60%) and involvement in most common morbidities, which makes it a potentially interesting biomarker. Large GWAS studies have already assessed polymorphisms related to VEGF-A. However, no previous research has provided epigenome-wide insight in regulation of VEGF-A. VEGF-A concentrations of healthy participants from the STANISLAS Family Study (n = 201) were comprehensively assessed for association with DNA methylation. Genome-wide DNA methylation profiles were determined in whole blood DNA using the 450K Infinium BeadChip Array (Illumina). VEGF-A concentration in PBMC extracts was detected using a high-sensitivity multiplex Cytokine Array (Randox Laboratories, UK). Epigenome-wide association analysis identified 41 methylation sites significantly associated with VEGF-A concentrations derived from PBMC extracts. Twenty CpG sites within 13 chromosomes reached Holm-Bonferroni significance. Significant values ranged from P = 1.08 × 10<sup>-7</sup> to P = 5.64 × 10<sup>-15</sup>. This study exposed twenty significant CpG sites linking DNA methylation to VEGF-A concentration. Methylation detected in promoter regions, such as TPX2 and HAS-1, could explain previously reported associations with the VEGFA gene. Methylation may also help in the understanding of the regulatory mechanisms of other genes located in the vicinity of detected CpG sites.",
+Yes,20200615,ewas,32496131,Sex-specific DNA methylation differences in people exposed to polybrominated biphenyl.,Epigenomics,"<b>Aim:</b> Michigan residents were exposed to polybrominated biphenyls (PBBs) when it was accidentally added to the food supply. Highly exposed individuals report sex-specific health problems, but the underlying biological mechanism behind these different health risks is not known. <b>Materials and methods:</b> DNA methylation in blood from 381 women and 277 men with PBB exposure was analyzed with the MethylationEPIC BeadChip. <b>Results:</b> 675 CpGs were associated with PBBs levels in males, while only 17 CpGs were associated in females (false discovery rate &lt;0.05). No CpGs were associated in both sexes. These CpGs were enriched in different functional regions and transcription factor binding sites in each sex. <b>Conclusion:</b> Exposure to PBBs may have sex-specific effects on the epigenome that may underlie sex-specific adverse health outcomes.",
+Yes,20200615,ewas,32493484,DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases.,Clin Epigenetics,"Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) &lt; 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR &lt; 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. ClinicalTrials.gov, NCT00912132.",
+Yes,20200615,ewas,32484729,Genome-Wide DNA Methylation in Peripheral Blood and Long-Term Exposure to Source-Specific Transportation Noise and Air Pollution: The SAPALDIA Study.,Environ. Health Perspect.,"BACKGROUND:Few epigenome-wide association studies (EWAS) on air pollutants exist, and none have been done on transportation noise exposures, which also contribute to environmental burden of disease. OBJECTIVE:We performed mutually independent EWAS on transportation noise and air pollution exposures. METHODS:We used data from two time points of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) from 1,389 participants contributing 2,542 observations. We applied multiexposure linear mixed-effects regressions with participant-level random intercept to identify significant Cytosine-phosphate-Guanine (CpG) sites and differentially methylated regions (DMRs) in relation to 1-y average aircraft, railway, and road traffic day-evening-night noise (Lden); nitrogen dioxide (NO2); and particulate matter (PM) with aerodynamic diameter <2.5?m (PM2.5). We performed candidate (CpG-based; cross-systemic phenotypes, combined into ""allostatic load"") and agnostic (DMR-based) pathway enrichment tests, and replicated previously reported air pollution EWAS signals. RESULTS:We found no statistically significant CpGs at false discovery rate <0.05. However, 14, 48, 183, 8, and 71 DMRs independently associated with aircraft, railway, and road traffic Lden; NO2; and PM2.5, respectively, with minimally overlapping signals. Transportation Lden and air pollutants tendentially associated with decreased and increased methylation, respectively. We observed significant enrichment of candidate DNA methylation related to C-reactive protein and body mass index (aircraft, road traffic Lden, and PM2.5), renal function and ""allostatic load"" (all exposures). Agnostic functional networks related to cellular immunity, gene expression, cell growth/proliferation, cardiovascular, auditory, embryonic, and neurological systems development were enriched. We replicated increased methylation in cg08500171 (NO2) and decreased methylation in cg17629796 (PM2.5). CONCLUSIONS:Mutually independent DNA methylation was associated with source-specific transportation noise and air pollution exposures, with distinct and shared enrichments for pathways related to inflammation, cellular development, and immune responses. These findings contribute in clarifying the pathways linking these exposures and age-related diseases but need further confirmation in the context of mediation analyses. https://doi.org/10.1289/EHP6174.",
+Yes,20200615,ewas,32484362,"Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.",Environ. Health Perspect.,"The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45-74 years of age who participated in the Strong Heart Study in 1989-1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and <i>in silico</i> protein-protein interaction networks to explore the biological relevance of the findings. At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In <i>in silico</i> protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. https://doi.org/10.1289/EHP6345.",
+Yes,20200615,ewas,32478847,Association of Neighborhood Disadvantage in Childhood With DNA Methylation in Young Adulthood.,JAMA Netw Open,"DNA methylation has been proposed as an epigenetic mechanism by which the childhood neighborhood environment may have implications for the genome that compromise adult health. To ascertain whether childhood neighborhood socioeconomic disadvantage is associated with differences in DNA methylation by age 18 years. This longitudinal cohort study analyzed data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative birth cohort of children born between 1994 and 1995 in England and Wales and followed up from age 5 to 18 years. Data analysis was performed from March 15, 2019, to June 30, 2019. High-resolution neighborhood data (indexing deprivation, dilapidation, disconnection, and dangerousness) collected across childhood. DNA methylation in whole blood was drawn at age 18 years. Associations between neighborhood socioeconomic disadvantage and methylation were tested using 3 prespecified approaches: (1) testing probes annotated to candidate genes involved in biological responses to growing up in socioeconomically disadvantaged neighborhoods and investigated in previous epigenetic research (stress reactivity-related and inflammation-related genes), (2) polyepigenetic scores indexing differential methylation in phenotypes associated with growing up in disadvantaged neighborhoods (obesity, inflammation, and smoking), and (3) a theory-free epigenome-wide association study. A total of 1619 participants (806 female individuals [50%]) had complete neighborhood and DNA methylation data. Children raised in socioeconomically disadvantaged neighborhoods exhibited differential DNA methylation in genes involved in inflammation (β = 0.12; 95% CI, 0.06-0.19; P &lt; .001) and smoking (β = 0.18; 95% CI, 0.11-0.25; P &lt; .001) but not obesity (β = 0.05; 95% CI, -0.01 to 0.11; P = .12). An epigenome-wide association study identified multiple CpG sites at an arraywide significance level of P &lt; 1.16 × 10-7 in genes involved in the metabolism of hydrocarbons. Associations between neighborhood disadvantage and methylation were small but robust to family-level socioeconomic factors and to individual-level tobacco smoking. Children raised in more socioeconomically disadvantaged neighborhoods appeared to enter young adulthood epigenetically distinct from their less disadvantaged peers. This finding suggests that epigenetic regulation may be a mechanism by which the childhood neighborhood environment alters adult health.",
+Yes,20200615,ewas,32493224,Distinctions between sex and time in patterns of DNA methylation across puberty.,BMC Genomics,"There are significant sex differences in human physiology and disease; the genomic sources of these differences, however, are not well understood. During puberty, a drastic neuroendocrine shift signals physical changes resulting in robust sex differences in human physiology. Here, we explore how shifting patterns of DNA methylation may inform these pathways of biological plasticity during the pubertal transition. In this study we analyzed DNA methylation (DNAm) in saliva at two time points across the pubertal transition within the same individuals. Our purpose was to compare two domains of DNAm patterns that may inform processes of sexual differentiation 1) sex related sites, which demonstrated differences between males from females and 2) time related sites in which DNAm shifted significantly between timepoints. We further explored the correlated network structure sex and time related DNAm networks and linked these patterns to pubertal stage, assays of salivary testosterone, a reliable diagnostic of free, unbound hormone that is available to act on target tissues, and overlap with androgen response elements. Sites that differed by biological sex were largely independent of sites that underwent change across puberty. Time-related DNAm sites, but not sex-related sites, formed correlated networks that were associated with pubertal stage. Both time and sex DNAm networks reflected salivary testosterone levels that were enriched for androgen response elements, with sex-related DNAm networks being informative of testosterone levels above and beyond biological sex later in the pubertal transition. These results inform our understanding of the distinction between sex- and time-related differences in DNAm during the critical period of puberty and highlight a novel linkage between correlated patterns of sex-related DNAm and levels of salivary testosterone.",
+No,20200615,mosaicism,32460841,The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues.,Genome Med,"Mosaic mutations acquired during early embryogenesis can lead to severe early-onset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate and mutational spectrum of embryonic mosaic mutations (EMMs) have only been studied in few tissues, and their contribution to genetic disorders is unknown. Therefore, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues. Mosaic mutation detection in 49 normal tissues from 570 individuals (Genotype-Tissue Expression (GTEx) cohort) was performed using a newly developed multi-tissue, multi-individual variant calling approach for RNA-seq data. Our method allows for reliable identification of EMMs and the developmental stage during which they appeared. The analysis of EMMs in 570 individuals revealed that newborns on average harbor 0.5-1 EMMs in the exome affecting multiple organs (1.3230 × 10<sup>-8</sup> per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multi-individual study design allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and adult life, as well as to provide insights into the rate and spectrum of mosaic mutations. We observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer. Investigation of the mutational spectrum of the gastrointestinal tract revealed a mutational pattern associated with the food-borne carcinogen aflatoxin, a signature that has so far only been reported in liver cancer. In summary, our multi-tissue, multi-individual study reveals a surprisingly high number of embryonic mosaic mutations in coding regions, implying novel hypotheses and diagnostic procedures for investigating genetic causes of disease and cancer predisposition.",
+No,20200615,review,32514149,Unravelling the complex genetics of common kidney diseases: from variants to mechanisms.,Nat Rev Nephrol,"Genome-wide association studies (GWAS) have identified hundreds of loci associated with kidney-related traits such as glomerular filtration rate, albuminuria, hypertension, electrolyte and metabolite levels. However, these impressive, large-scale mapping approaches have not always translated into an improved understanding of disease or development of novel therapeutics. GWAS have several important limitations. Nearly all disease-associated risk loci are located in the non-coding region of the genome and therefore, their target genes, affected cell types and regulatory mechanisms remain unknown. Genome-scale approaches can be used to identify associations between DNA sequence variants and changes in gene expression (quantified through bulk and single-cell methods), gene regulation and other molecular quantitative trait studies, such as chromatin accessibility, DNA methylation, protein expression and metabolite levels. Data obtained through these approaches, used in combination with robust computational methods, can deliver robust mechanistic inferences for translational exploitation. Understanding the genetic basis of common kidney diseases means having a comprehensive picture of the genes that have a causal role in disease development and progression, of the cells, tissues and organs in which these genes act to affect the disease, of the cellular pathways and mechanisms that drive disease, and of potential targets for disease prevention, detection and therapy.",
+No,20200615,single-cell rna-seq,32424074,"Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains.",Genome Res.,"Identification of gene expression traits unique to the human brain sheds light on the molecular mechanisms underlying human evolution. Here, we searched for uniquely human gene expression traits by analyzing 422 brain samples from humans, chimpanzees, bonobos, and macaques representing 33 anatomical regions, as well as 88,047 cell nuclei composing three of these regions. Among 33 regions, cerebral cortex areas, hypothalamus, and cerebellar gray and white matter evolved rapidly in humans. At the cellular level, astrocytes and oligodendrocyte progenitors displayed more differences in the human evolutionary lineage than the neurons. Comparison of the bulk tissue and single-nuclei sequencing revealed that conventional RNA sequencing did not detect up to two-thirds of cell-type-specific evolutionary differences.",
+No,20200615,dnam age,32474592,A distinctive epigenetic ageing profile in human granulosa cells.,Hum. Reprod.,"Does women's age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells? Accumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile. The mechanisms underlying the decline in women's fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa). This study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden. Blood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package. Using established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7 years) compared to chronological age (average: 33.9 years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4 years) and leukocytes (average: 38.8 years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P = 0.003) but predicted telomere lengths unaffected by age (Pearson's correlation coefficient = -0.1, P = 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n = 335) and in leukocytes (n = 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P = 3.96 × 10-08) and gene expression (152 genes, P = 2.3 × 10-06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle. N/A. No gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found. Our findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age. This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest.",
+No,20200713,biomarker,32580755,Refinement of cg05575921 demethylation response in nascent smoking.,Clin Epigenetics,"The initiation of adolescent smoking is difficult to detect using carbon monoxide or cotinine assays. Previously, we and others have shown that the methylation of cg05575921 is an accurate predictor of adult smoking status. But the dose and time dependency of the demethylation response to smoking initiation in adolescents is not yet well understood. To this end, we conducted three consecutive annual in-person interviews and biological samplings of 448 high school students (wave 1 (W1)-wave 3 (W3)). At W1 (n = 448), 62 subjects reported using tobacco and 72 subjects reported using cannabis at least once in their life-time with 38 and 20 subjects having a positive cotinine and cannabinoid levels, respectively, at W1 intake. At W3 (n = 383), 67 subjects reported using tobacco and 60 subjects reported using cannabis at least once with 75 and 60 subjects having positive cotinine and cannabinoid levels, respectively, at W3. Subjects with undetectable cotinine levels at all three-time waves had stable levels of cg05575921 methylation throughout the study (88.7% at W1 and 88.8% at W3, n = 149), while subjects with positive cotinine levels at all 3 time points manifested a steady decrease in cg05575921 methylation (81.8% at W1 and 71.3% at the W3, n = 12). In those subjects with an affirmative smoking self-report at W3 (n = 17), the amount of demethylation at cg05575921 was correlated with time and intensity of smoking. We conclude that cg05575921 methylation is a sensitive, dose-dependent indicator of early stages of smoking, and may help to identify smokers in the early stages of smoking.",
+Yes,20200713,ewas,32539856,Harnessing peripheral DNA methylation differences in the Alzheimer's Disease Neuroimaging Initiative (ADNI) to reveal novel biomarkers of disease.,Clin Epigenetics,"Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer's disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multi-omics and phenotypic information on a well-phenotyped subset of ADNI participants. In this manuscript, we report cross-diagnosis differential peripheral DNA methylation in a cohort of AD, MCI, and age-matched CN individuals with longitudinal DNA methylation measurements. Epigenome-wide association studies (EWAS) were performed using a mixed model with repeated measures over time with a P value cutoff of 1 Ă— 10<sup>-5</sup> to test contrasts of pairwise differential peripheral methylation in AD vs CN, AD vs MCI, and MCI vs CN. The most highly significant differentially methylated loci also tracked with Mini Mental State Examination (MMSE) scores. Differentially methylated loci were enriched near brain and neurodegeneration-related genes (e.g., BDNF, BIN1, APOC1) validated using the genotype tissue expression project portal (GTex). Our work shows that peripheral differential methylation between age-matched subjects with AD relative to healthy controls will provide opportunities to further investigate and validate differential methylation as a surrogate of disease. Given the inaccessibility of brain tissue, the PB-associated methylation marks may help identify the stage of disease and progression phenotype, information that would be central to bringing forward successful drugs for AD.",
+Yes,20200713,ewas,32561708,Epigenome-wide association study of attention-deficit/hyperactivity disorder in adults.,Transl Psychiatry,"Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that often persists into adulthood. There is growing evidence that epigenetic dysregulation participates in ADHD. Given that only a limited number of epigenome-wide association studies (EWASs) of ADHD have been conducted so far and they have mainly focused on pediatric and population-based samples, we performed an EWAS in a clinical sample of adults with ADHD. We report one CpG site and four regions differentially methylated between patients and controls, which are located in or near genes previously involved in autoimmune diseases, cancer or neuroticism. Our sensitivity analyses indicate that smoking status is not responsible for these results and that polygenic risk burden for ADHD does not greatly impact the signatures identified. Additionally, we show an overlap of our EWAS findings with genetic signatures previously described for ADHD and with epigenetic signatures for smoking behavior and maternal smoking. These findings support a role of DNA methylation in ADHD and emphasize the need for additional efforts in larger samples to clarify the role of epigenetic mechanisms on ADHD across the lifespan.",
+Yes,20200713,ewas,32600451,Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer.,Clin Epigenetics,"Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to � 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival. Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (P<sub>Bonferroni</sub> &lt; 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10<sup>-05</sup>). Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.",
+Yes,20200713,ewas,32603190,Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure.,Environ. Health Perspect.,"Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes. We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, <mml:math xmlns:mml=""http://www.w3.org/1998/Math/MathML""> <mml:mrow> <mml:mi>mean </mml:mi> <mml:mrow> <mml:mrow> <mml:mo>(</mml:mo> <mml:mrow> <mml:mo>±</mml:mo> <mml:mi>SD</mml:mi> </mml:mrow> <mml:mo>)</mml:mo> </mml:mrow> </mml:mrow> <mml:mi> μ</mml:mi> <mml:mi>g</mml:mi> <mml:mo>/</mml:mo> <mml:mi>g</mml:mi> </mml:mrow> </mml:math> creatinine: 11.7 (10.6)]. DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species. In adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (<mml:math xmlns:mml=""http://www.w3.org/1998/Math/MathML""> <mml:mrow> <mml:mtext>FDR</mml:mtext> <mml:mo>&lt;</mml:mo> <mml:mtext> </mml:mtext> <mml:mn>0.05</mml:mn> </mml:mrow> </mml:math>). After Bonferroni correction, 5 CpGs remained associated with total urinary As (<mml:math xmlns:mml=""http://www.w3.org/1998/Math/MathML""> <mml:mrow> <mml:msub> <mml:mi>p</mml:mi> <mml:mrow> <mml:mtext>Bonferroni</mml:mtext> </mml:mrow> </mml:msub> <mml:mo>&lt;</mml:mo> <mml:mn>0.05</mml:mn> </mml:mrow> </mml:math>), located in <i>SLC7A11</i>, <i>ANKS3</i>, <i>LINGO3</i>, <i>CSNK1D</i>, <i>ADAMTSL4</i>. We identified one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to <i>C11orf2</i>; <i>TSPAN32</i> genes. This is one of the first epigenome-wide association studies to investigate As exposure and locus-specific DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in <i>SLC7A11A</i>, a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As-induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As-related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. https://doi.org/10.1289/EHP6263.",
+Yes,20200713,ewas,32629249,Dioxin-like compound exposures and DNA methylation in the Anniston Community Health Survey Phase II.,Sci. Total Environ.,"The Anniston Community Health Survey (ACHS-I) was initially conducted from 2005 to 2007 to assess polychlorinated biphenyl (PCB) exposures in Anniston, Alabama residents. In 2014, a follow-up study (ACHS-II) was conducted to measure the same PCBs as in ACHS-I and additional compounds e.g., polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like non-ortho (cPCBs) substituted PCBs. In this epigenome-wide association study (EWAS), we examined the associations between PCDD, PCDF, and PCB exposures and DNA methylation. Whole blood DNA methylation was measured using Illumina EPIC arrays (n=292). We modeled lipid-adjusted toxic equivalencies (TEQs) for: ΣDioxins (sum of 28 PCDDs, PCDFs, cPCBs, and mPCBs), PCDDs, PCDFs, cPCBs, and mPCBs using robust multivariable linear regression adjusting for age, race, sex, smoking, bisulfite conversion batch, and estimated percentages of six blood cell types. Among all exposures we identified 10 genome-wide (Bonferroni p≤6.74E-08) and 116 FDR (p≤5.00E-02) significant associations representing 10 and 113 unique CpGs, respectively. Of the 10 genome-wide associations, seven (70%) occurred in the PCDDs and four (40%) of these associations had an absolute differential methylation ≥1.00%, based on the methylation difference between the highest and lowest exposure quartiles. Most of the associations (six, 60%) represented hypomethylation changes. Of the 10 unique CpGs, eight (80%) were in genes shown to be associated with dioxins and/or PCBs based on data from the 2019 Comparative Toxicogenomics Database. In this study, we have identified a set of CpGs in blood DNA that may be particularly susceptible to dioxin, furan, and dioxin-like PCB exposures.",
+Yes,20200713,ewas,32630231,Systemic Investigation of Promoter-wide Methylome and Genome Variations in Gout.,Int J Mol Sci,"Current knowledge of gout centers on hyperuricemia. Relatively little is known regarding the pathogenesis of gouty inflammation. To investigate the epigenetic background of gouty inflammation independent of hyperuricemia and its relationship to genetics, 69 gout patients and 1455 non-gout controls were included. Promoter-wide methylation was profiled with EPIC array. Whole-genome sequencing data were included for genetic and methylation quantitative trait loci (meQTL) analyses and causal inference tests. Identified loci were subjected to co-methylation analysis and functional localization with DNase hypersensitivity and histone marks analysis. An expression database was queried to clarify biologic functions of identified loci. A transcription factor dataset was integrated to identify transcription factors coordinating respective expression. In total, seven CpG loci involved in interleukin-1β production survived genetic/meQTL analyses, or causal inference tests. None had a significant relationship with various metabolic traits. Additional analysis suggested gouty inflammation, instead of hyperuricemia, provides the link between these CpG sites and gout. Six (<i>PGGT1B</i>, <i>INSIG1</i>, <i>ANGPTL2</i>, <i>JNK1</i>, <i>UBAP1</i>, and <i>RAPTOR</i>) were novel genes in the field of gout. One (<i>CNTN5</i>) was previously associated with gouty inflammation. Transcription factor mapping identified several potential transcription factors implicated in the link between differential methylation, interleukin-1β production, and gouty inflammation. In conclusion, this study revealed several novel genes specific to gouty inflammation and provided enhanced insight into the biological basis of gouty inflammation.",
+Yes,20200713,ewas,32641083,Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults.,Genome Med,"The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets. In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn's disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.",
+No,20200713,methods,32513961,Bayesian reassessment of the epigenetic architecture of complex traits.,Nat Commun,"Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. Here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. Implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (SNP) marker effects, improves association estimates and in 9,448 individuals, 75.7% (95% CI 71.70-79.3) of body mass index (BMI) variation and 45.6% (95% CI 37.3-51.9) of cigarette consumption variation was captured by whole blood methylation array data. Pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for BMI, and xenobiotic stimuli response for smoking, showed &gt;1.5 times larger associations with &gt;95% posterior inclusion probability. Prediction accuracy improved by 28.7% for BMI and 10.2% for smoking over a LASSO model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal.",
+No,20200713,methods,32580727,New targeted approaches for epigenetic age predictions.,BMC Biol.,"Age-associated DNA methylation changes provide a promising biomarker for the aging process. While genome-wide DNA methylation profiles enable robust age-predictors by integration of many age-associated CG dinucleotides (CpGs), there are various alternative approaches for targeted measurements at specific CpGs that better support standardized and cost-effective high-throughput analysis. In this study, we utilized 4647 Illumina BeadChip profiles of blood to select CpG sites that facilitate reliable age-predictions based on pyrosequencing. We demonstrate that the precision of DNA methylation measurements can be further increased with droplet digital PCR (ddPCR). In comparison, bisulfite barcoded amplicon sequencing (BBA-seq) gave slightly lower correlation between chronological age and DNA methylation at individual CpGs, while the age-predictions were overall relatively accurate. Furthermore, BBA-seq data revealed that the correlation of methylation levels with age at neighboring CpG sites follows a bell-shaped curve, often associated with a CTCF binding site. We demonstrate that within individual BBA-seq reads the DNA methylation at neighboring CpGs is not coherently modified, but reveals a stochastic pattern. Based on this, we have developed a new approach for epigenetic age predictions based on the binary sequel of methylated and non-methylated sites in individual reads, which reflects heterogeneity in epigenetic aging within a sample. Targeted DNA methylation analysis at few age-associated CpGs by pyrosequencing, BBA-seq, and particularly ddPCR enables high precision of epigenetic age-predictions. Furthermore, we demonstrate that the stochastic evolution of age-associated DNA methylation patterns in BBA-seq data enables epigenetic clocks for individual DNA strands.",
+No,20200713,methods,32605541,Simulating ComBat: how batch correction can lead to the systematic introduction of false positive results in DNA methylation microarray studies.,BMC Bioinformatics,"Systematic technical effects-also called batch effects-are a considerable challenge when analyzing DNA methylation (DNAm) microarray data, because they can lead to false results when confounded with the variable of interest. Methods to correct these batch effects are error-prone, as previous findings have shown. Here, we demonstrate how using the R function ComBat to correct simulated Infinium HumanMethylation450 BeadChip (450 K) and Infinium MethylationEPIC BeadChip Kit (EPIC) DNAm data can lead to a large number of false positive results under certain conditions. We further provide a detailed assessment of the consequences for the highly relevant problem of p-value inflation with subsequent false positive findings after application of the frequently used ComBat method. Using ComBat to correct for batch effects in randomly generated samples produced alarming numbers of false discovery rate (FDR) and Bonferroni-corrected (BF) false positive results in unbalanced as well as in balanced sample distributions in terms of the relation between the outcome of interest variable and the technical position of the sample during the probe measurement. Both sample size and number of batch factors (e.g. number of chips) were systematically simulated to assess the probability of false positive findings. The effect of sample size was simulated using n = 48 up to n = 768 randomly generated samples. Increasing the number of corrected factors led to an exponential increase in the number of false positive signals. Increasing the number of samples reduced, but did not completely prevent, this effect. Using the approach described, we demonstrate, that using ComBat for batch correction in DNAm data can lead to false positive results under certain conditions and sample distributions. Our results are thus contrary to previous publications, considering a balanced sample distribution as unproblematic when using ComBat. We do not claim completeness in terms of reporting all technical conditions and possible solutions of the occurring problems as we approach the problem from a clinician's perspective and not from that of a computer scientist. With our approach of simulating data, we provide readers with a simple method to assess the probability of false positive findings in DNAm microarray data analysis pipelines.",
+No,20200713,review,32526941,Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease.,Int J Mol Sci,"Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications-histone methylation, acetylation and crotonylation-in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.",
+No,20200713,dnam score,32552915,Individual and joint contributions of genetic and methylation risk scores for enhancing lung cancer risk stratification: data from a population-based cohort in Germany.,Clin Epigenetics,"Risk stratification for lung cancer (LC) screening is so far mostly based on smoking history. This study aimed to assess if and to what extent such risk stratification could be enhanced by additional consideration of genetic risk scores (GRSs) and epigenetic risk scores defined by DNA methylation. We conducted a nested case-control study of 143 incident LC cases and 1460 LC-free controls within a prospective cohort of 9949 participants aged 50-75 years with 14-year follow-up. Lifetime smoking history was obtained in detail at recruitment. We built a GRS based on 31 previously identified LC-associated single-nucleotide polymorphisms (SNPs) and a DNA methylation score (MRS) based on methylation of 151 previously identified smoking-associated cytosine-phosphate-guanine (CpG) loci. We evaluated associations of GRS and MRS with LC incidence by logistic regression models, controlling for age, sex, smoking status, and pack-years. We compared the predictive performance of models based on pack-years alone with models additionally including GRS and/or MRS using the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). GRS and MRS showed moderate and strong associations with LC risk even after comprehensive adjustment for smoking history (adjusted odds ratio [95% CI] comparing highest with lowest quartile 1.93 [1.05-3.71] and 5.64 [2.13-17.03], respectively). Similar associations were also observed within the risk groups of ever and heavy smokers. Addition of GRS and MRS furthermore strongly enhanced LC prediction beyond prediction by pack-years (increase of optimism-corrected AUC among heavy smokers from 0.605 to 0.654, NRI 26.7%, p = 0.0106, IDI 3.35%, p = 0.0036), the increase being mostly attributable to the inclusion of MRS. Consideration of MRS, by itself or in combination with GRS, may strongly enhance LC risk stratification.",
+No,20200803,methods,32678018,Gene-methylation interactions: discovering region-wise DNA methylation levels that modify SNP-associated disease risk.,Clin Epigenetics,"Current technology allows rapid assessment of DNA sequences and methylation levels at a single-site resolution for hundreds of thousands of sites in the human genome, in thousands of individuals simultaneously. This has led to an increase in epigenome-wide association studies (EWAS) of complex traits, particularly those that are poorly explained by previous genome-wide association studies (GWAS). However, the genome and epigenome are intertwined, e.g., DNA methylation is known to affect gene expression through, for example, genomic imprinting. There is thus a need to go beyond single-omics data analyses and develop interaction models that allow a meaningful combination of information from EWAS and GWAS. We present two new methods for genetic association analyses that treat offspring DNA methylation levels as environmental exposure. Our approach searches for statistical interactions between SNP alleles and DNA methylation (G Ă—Me) and between parent-of-origin effects and DNA methylation (PoO Ă—Me), using case-parent triads or dyads. We use summarized methylation levels over nearby genomic region to ease biological interpretation. The methods were tested on a dataset of parent-offspring dyads, with EWAS data on the offspring. Our results showed that methylation levels around a SNP can significantly alter the estimated relative risk. Moreover, we show how a control dataset can identify false positives. The new methods, G Ă—Me and PoO Ă—Me, integrate DNA methylation in the assessment of genetic relative risks and thus enable a more comprehensive biological interpretation of genome-wide scans. Moreover, our strategy of condensing DNA methylation levels within regions helps overcome specific disadvantages of using sparse chip-based measurements. The methods are implemented in the freely available R package Haplin ( https://cran.r-project.org/package=Haplin ), enabling fast scans of multi-omics datasets.",
+No,20200803,dnam score,32718350,Characterisation of an inflammation-related epigenetic score and its association with cognitive ability.,Clin Epigenetics,"Chronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear. The acute responses of many inflammatory biomarkers mean they may provide an unreliable picture of the chronicity of inflammation. Recently, a large-scale epigenome-wide association study identified DNA methylation correlates of C-reactive protein (CRP)-a widely used acute-phase inflammatory biomarker. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. We utilise a DNA methylation-based score for CRP and investigate its trajectories with age, and associations with cognitive ability in comparison with serum CRP and a genetic CRP score in a longitudinal study of older adults (n = 889) and a large, cross-sectional cohort (n = 7028). We identified no homogeneous trajectories of serum CRP with age across the cohorts, whereas the epigenetic CRP score was consistently found to increase with age (standardised β = 0.07 and 0.01) and to do so more rapidly in males compared to females. Additionally, the epigenetic CRP score had higher test-retest reliability compared to serum CRP, indicating its enhanced temporal stability. Higher serum CRP was not found to be associated with poorer cognitive ability (standardised β = - 0.08 and - 0.05); however, a consistent negative association was identified between cognitive ability and the epigenetic CRP score in both cohorts (standardised β = - 0.15 and - 0.08). An epigenetic proxy of CRP may provide a more reliable signature of chronic inflammation, allowing for more accurate stratification of individuals, and thus clearer inference of associations with incident health outcomes.",
+Yes,20200803,dnam score,32711505,A panel of DNA methylation signature from peripheral blood may predict colorectal cancer susceptibility.,BMC Cancer,"Differential DNA methylation panel derived from peripheral blood could serve as biomarkers of CRC susceptibility. However, most of the previous studies utilized post-diagnostic blood DNA which may be markers of disease rather than susceptibility. In addition, only a few studies have evaluated the predictive potential of differential DNA methylation in CRC in a prospective cohort and on a genome-wide basis. The aim of this study was to identify a potential panel of DNA methylation biomarkers in peripheral blood that is associated with CRC risk and therefore serve as epigenetic biomarkers of disease susceptibility. DNA methylation profile of a nested case-control study with 166 CRC and 424 healthy normal subjects were obtained from the Gene Expression Omnibus (GEO) database. The differentially methylated markers were identified by moderated t-statistics. The DNA methylation panel was constructed by stepwise logistic regression and the least absolute shrinkage and selection operator in the training dataset. A methylation risk score (MRS) model was constructed and the association between MRS and CRC risk assessed. We identified 48 differentially methylated CpGs sites, of which 33 were hypomethylated. Of these, sixteen-CpG based MRS that was associated with CRC risk (OR = 2.68, 95% CI: 2.13, 3.38, P &lt;  0.0001) was constructed. This association is confirmed in the testing dataset (OR = 2.02, 95% CI: 1.48, 2.74, P &lt;  0.0001) and persisted in both males and females, younger and older subjects, short and long time-to-diagnosis. The MRS also predicted CRC with AUC 0.82 (95% CI: 0.76, 0.88), indicating high accuracy. Our study has identified a novel DNA methylation panel that is associated with CRC and could, if validated be useful for the prediction of CRC risk in the future.",
+No,20200803,dnam score,32694610,Non-invasive early detection of cancer four years before conventional diagnosis using a blood test.,Nat Commun,"Early detection has the potential to reduce cancer mortality, but an effective screening test must demonstrate asymptomatic cancer detection years before conventional diagnosis in a longitudinal study. In the Taizhou Longitudinal Study (TZL), 123,115 healthy subjects provided plasma samples for long-term storage and were then monitored for cancer occurrence. Here we report the preliminary results of PanSeer, a noninvasive blood test based on circulating tumor DNA methylation, on TZL plasma samples from 605 asymptomatic individuals, 191 of whom were later diagnosed with stomach, esophageal, colorectal, lung or liver cancer within four years of blood draw. We also assay plasma samples from an additional 223 cancer patients, plus 200 primary tumor and normal tissues. We show that PanSeer detects five common types of cancer in 88% (95% CI: 80-93%) of post-diagnosis patients with a specificity of 96% (95% CI: 93-98%), We also demonstrate that PanSeer detects cancer in 95% (95% CI: 89-98%) of asymptomatic individuals who were later diagnosed, though future longitudinal studies are required to confirm this result. These results demonstrate that cancer can be non-invasively detected up to four years before current standard of care.",
+Yes,20200803,ewas,32731254,Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers.,Neuropsychopharmacology,"Numerous DNA methylation (DNAm) biomarkers of cigarette smoking have been identified in peripheral blood studies, but because of tissue specificity, blood-based studies may not detect brain-specific smoking-related DNAm differences that may provide greater insight as neurobiological indicators of smoking and its exposure effects. We report the first epigenome-wide association study (EWAS) of smoking in human postmortem brain, focusing on nucleus accumbens (NAc) as a key brain region in developing and reinforcing addiction. Illumina HumanMethylation EPIC array data from 221 decedents (120 European American [23% current smokers], 101 African American [26% current smokers]) were analyzed. DNAm by smoking (current vs. nonsmoking) was tested within each ancestry group using robust linear regression models adjusted for age, sex, cell-type proportion, DNAm-derived negative control principal components (PCs), and genotype-derived PCs. The resulting ancestry-specific results were combined via meta-analysis. We extended our NAc findings, using published smoking EWAS results in blood, to identify DNAm smoking effects that are unique (tissue-specific) vs. shared between tissues (tissue-shared). We identified seven CpGs (false discovery rate &lt; 0.05), of which three CpGs are located near genes previously indicated with blood-based smoking DNAm biomarkers: ZIC1, ZCCHC24, and PRKDC. The other four CpGs are novel for smoking-related DNAm changes: ABLIM3, APCDD1L, MTMR6, and CTCF. None of the seven smoking-related CpGs in NAc are driven by genetic variants that share association signals with predisposing genetic risk variants for smoking, suggesting that the DNAm changes reflect consequences of smoking. Our results provide the first evidence for smoking-related DNAm changes in human NAc, highlighting CpGs that were undetected as peripheral biomarkers and may reflect brain-specific responses to smoking exposure.",
+Yes,20200803,ewas,32728124,DNA methylation and adiposity phenotypes: an epigenome-wide association study among adults in the Strong Heart Study.,Int J Obes (Lond),"Elevated adiposity is often posited by medical and public health researchers to be a risk factor associated with cardiovascular disease, diabetes, and other diseases. These health challenges are now thought to be reflected in epigenetic modifications to DNA molecules, such as DNA methylation, which can alter gene expression. Here we report the results of three Epigenome Wide Association Studies (EWAS) in which we assessed the differential methylation of DNA (obtained from peripheral blood) associated with three adiposity phenotypes (BMI, waist circumference, and impedance-measured percent body fat) among American Indian adult participants in the Strong Heart Study. We found differential methylation at 8264 CpG sites associated with at least one of our three response variables. Of the three adiposity proxies we measured, waist circumference had the highest number of associated differentially methylated CpGs, while percent body fat was associated with the lowest. Because both waist circumference and percent body fat relate to physiology, we focused interpretations on these variables. We found a low degree of overlap between these two variables in our gene ontology enrichment and Differentially Methylated Region analyses, supporting that waist circumference and percent body fat measurements represent biologically distinct concepts. We interpret these general findings to indicate that highly significant regions of the genome (DMR) and synthesis pathways (GO) in waist circumference analyses are more likely to be associated with the presence of visceral/abdominal fat than more general measures of adiposity. Our findings confirmed numerous CpG sites previously found to be differentially methylated in association with adiposity phenotypes, while we also found new differentially methylated CpG sites and regions not previously identified.",
+Yes,20200803,ewas,32697766,"Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.",Aging (Albany NY),"DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (<i>P</i> &lt; 9.3x10<sup>-7</sup>) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to <i>BMPR1B, MIR1973, IFITM3, NLRC5</i>, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to <i>SERINC2, CHST12</i>, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (<i>IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1</i>) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.",
+Yes,20200803,ewas,32679516,An epigenome-wide association study of ambient pyrethroid pesticide exposures in California's central valley.,Int J Hyg Environ Health,"Pyrethroid pesticide use is increasing worldwide, although the full extent of associated health effects is unknown. An epigenome-wide association study (EWAS) with exploratory pathway analysis may help identify potential pyrethroid-related health effects. We performed an exploratory EWAS of chronic ambient pyrethroid exposure using control participants' blood in the Parkinson's Environment and Genes Study in the Central Valley of California (N = 237). We estimated associations of living and working near agricultural pyrethroid pesticide applications in the past 5 years (binary) with site-specific differential methylation, and used a false discovery rate (FDR) cut off of 0.05 for significance. We controlled for age, sex, education, cell count, and an ancestral marker for Hispanic ethnicity. We normalized methylation values for Type I/II probe bias using Beta-Mixture Quantile (BMIQ) normalization, filtered out cross-reactive probes, and evaluated for remaining bias with Surrogate Variable Analysis (SVA). We also evaluated the effects of controlling for cell count and normalizing for Type I/II probe bias by comparing changes in effect estimates and p-values for the top hits across BMIQ and GenomeStudio normalization methods, and controlling for cell count. To facilitate broader interpretation, we annotated genes to the CpG sites and performed gene set overrepresentation analysis, using genes annotated to CpG sites that were associated with pyrethroids at a raw p &lt; 0.05, and controlling for background representation of CpG sites on the chip. We did this for both a biological process context (Gene Ontology terms) using missMethyl, and a disease set context using WebGestalt. For these gene set overrepresentation analyses we also used an FDR cut off of 0.05 for significance of gene sets. After controlling for cell count and applying BMIQ normalization, 4 CpG sites were differentially methylated in relation to pyrethroid exposures. When using GenomeStudio's Illumina normalization, 415 CpG sites were differentially methylated, including all four identified with the BMIQ method. In the gene set overrepresentation analyses, we identified 6 GO terms using BMIQ normalization, and 76 using Illumina normalization, including the 6 identified by BMIQ. For disease sets, we identified signals for Alzheimer's disease, leukemia and several other cancers, diabetes, birth defects, and other diseases, for both normalization methods. We identified minimal changes in effect estimates after controlling for cell count, and controlling for cell count generally weakened p-values. BMIQ normalization, however, resulted in different beta coefficients and weakened p-values. Chronic ambient pyrethroid exposure is associated with differential methylation at CpG sites that annotate to a wide variety of disease states and biological mechanisms that align with prior research. However, this EWAS also implicates several novel diseases for future investigation, and highlights the relative importance of different background normalization methods in identifying associations.",
+Yes,20200803,ewas,32677467,Early pregnancy dyslipidemia is associated with placental DNA methylation at loci relevant for cardiometabolic diseases.,Epigenomics,"<b>Aim:</b> To identify placental DNA methylation changes that are associated with early pregnancy maternal dyslipidemia. <b>Materials &amp; methods:</b> We analyzed placental genome-wide DNA methylation (n = 262). Genes annotating differentially methylated CpGs were evaluated for gene expression in placenta (n = 64). <b>Results:</b> We found 11 novel significant differentially methylated CpGs associated with high total cholesterol, low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol. High triglycerides were associated with decreased methylation of cg02785814 (<i>ALX4</i>) and decreased expression of <i>ALX4</i> in placenta. Genes annotating the differentially methylated CpGs play key roles in lipid metabolism and were enriched in dyslipidemia pathways. Functional annotation found <i>cis</i>-methylation quantitative trait loci for genetic loci in <i>ALX4</i> and <i>EXT2</i>. <b>Conclusion:</b> Our findings lend novel insights into potential placental epigenetic mechanisms linked with maternal dyslipidemia. <b>Trial Registration:</b> ClinicalTrials.gov, NCT00912132.",
+Yes,20200803,ewas,32671182,Blood DNA methylation signatures to detect dementia prior to overt clinical symptoms.,Alzheimers Dement (Amst),"This study determined whether blood DNA methylation (DNAm) patterns differentiate individuals with presymptomatic dementia compared to controls. DNAm was measured in 73 individuals prior to dementia diagnosis and 87 cognitively healthy controls matched for age, sex, smoking, education, and baseline cognition. DNAm was also measured at 3 years follow-up in 25 dementia cases, and 24 controls. Cases and controls differed in DNAm (unadjusted <i>P</i> &lt; .01) at the time of diagnosis (n = 28,787 probes), and pre-diagnosis (n = 15,111 probes), with cg01404610 (<i>General transcription factor IIA subunit 1</i> gene) significant after correction for multiple testing. Overall, 1150 probes overlapped between analyses (methylation differences from -10.6% to +11.0%), and effect sizes increased from pre-diagnosis to diagnosis. Discernible blood DNAm signatures are in dementia cases before the appearance of overt clinical symptoms. Blood-based methylation may serve as a potential biomarker of dementia, but further investigation is needed to determine their true clinical utility.",
+Yes,20200803,ewas,32661777,Genome-wide methylation association with current suicidal ideation in schizophrenia.,J Neural Transm (Vienna),"In this study, we investigate the epigenetic mechanisms associated with current suicidal ideation. Gene expression changes have been found in post-mortem brain of suicide victims. However, it is not clear how in-vivo gene expression change confers risk for suicide. DNA methylation is a form of epigenetic modification that regulates gene expression. Our primary aim is to investigate genome-wide methylation in conferring risk for current suicidal ideation (SI) in schizophrenia. The presence of current SI and genome-wide methylation patterns were assessed in 107 patients with schizophrenia. DNA methylation has been measured in white blood cells as a possible peripheral biomarker of SI. SI was the primary outcome variable in a model including methylation status of white blood cells using the Illumina 450 array. We have tested the association with genome-wide methylation levels in 19 subjects with current SI and 88 subjects without current SI and we found that higher methylation level in the CpG cg06121808 located in the gene SLC20A1 on chromosome 2 was associated with current SI (p = 0.000003; beta difference = 0.06). Furthermore, the distal promoter analysis showed that the gene SMPD2 was hypermethylated in suicide ideators (p = 0.0001; beta difference = 0.02). Thus, molecular biomarkers could advance our understanding of the molecular mechanisms of stress-related SI. Furthermore, the methylation sites that we have identified should be replicated in other suicide related phenotypes to generate robust biomarkers with high translational value for proof of concept interventions aiming at reducing SI.",
+Yes,20200803,ewas,32660331,Genome-wide DNA methylation differences and polychlorinated biphenyl (PCB) exposure in a US population.,Epigenetics,"Exposure to polychlorinated biphenyls (PCBs), an endocrine-disrupting compound, is ubiquitous despite decades-old bans on the manufacture and use of PCBs. Increased exposure to PCBs is associated with adverse health consequences throughout life, including type 2 diabetes and cancer. PCB exposure is also associated with alterations in epigenetic marks and gene transcription, which could lead to adverse health outcomes, but many of these are population-specific. To further investigate the association between PCB and epigenetic marks, DNA methylation was measured at 787,684 CpG sites in 641 peripheral blood samples from the Michigan Polybrominated Biphenyl (PBB) Registry. 1345 CpGs were associated with increased total PCB level after controlling for age, sex, and 24 surrogate variables (FDR &lt; 0.05). These CpGs were enriched in active promoter and transcription associated regions (p &lt; 0.05), and in regions around the binding sites for transcription factors involved in xenobiotic metabolism and immune function (FDR &lt; 0.05). PCB exposure also associated with proportions of CD4T, NK, and granulocyte cell types, and with the neutrophil to lymphocyte ratio (NLR) (p &lt; 0.05), and the estimated effect sizes of PCB on the epigenome were correlated with the effect sizes previously reported in an epigenome-wide study of C-reactive protein (r = 0.29; p = 2.22e-5), supporting previous studies on the association between PCB and immune dysfunction. These results indicate that PCB exposure is associated with differences in epigenetic marks in active regions of the genome, and future work should investigate whether these may mediate the association between PCB and health consequences.",
+Yes,20200803,ewas,32653021,Concentrations of persistent organic pollutants in maternal plasma and epigenome-wide placental DNA methylation.,Clin Epigenetics,"Prenatal maternal plasma persistent organic pollutant (POP) concentrations have been associated with neonatal outcomes. However, the underlying mechanisms remain unknown. Placental epigenetic mechanisms may be involved, but no prior epigenome-wide studies have investigated the impact of maternal POPs on placental DNA methylation. We studied the association between maternal plasma POP concentration in early pregnancy and epigenome-wide placental DNA methylation among 260 pregnant women from the NICHD Fetal Growth Studies. Our analysis focused on POPs with more than 80% plasma concentrations above the limit of quantification, including 3 organochlorine pesticides (hexachlorobenzene, trans-nonachlor, p,p'-dichlorodiphenyldichloroethylene), 1 polybrominated diphenyl ether (PBDE 47), 3 polychlorinated biphenyls (138/158, 153, 180), and 6 poly- and perfluorinated alkyl substances (PFASs) (perfluorodecanoic acid, perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluoroundecanoic acid (PFUnDA)). Using 5% false discovery rate, POPs were associated with a total of 214 differentially methylated CpG sites (nominal p values ranging from 2.61 Ă— 10<sup>-21</sup> to 2.11 Ă— 10<sup>-7</sup>). Out of the 214 CpG sites, 24 (11%) were significantly correlated with placental expression of 21 genes. Notably, higher PFUnDA was associated with increased methylation at 3 CpG sites (cg13996963, cg12089439, cg18145877) annotated to TUSC3, and increased methylation at those 3 CpG sites was correlated with decreased expression of TUSC3 in the placenta. Increased methylation at cg18145877 (TUSC3) and decreased expression of TUSC3 were correlated with shorter birth length. Out of the 214 CpG sites, methylation at 44 CpG sites was correlated (p value &lt; 0.10) with at least one neonatal anthropometry measure (i.e., birth weight, birth length, and head circumference). Seven CpG sites mediated (p value &lt; 0.05) the association between PBDE 47 and neonatal anthropometry measures. Genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (PBDE 47) and in pathways related to brain size and brain morphology (PFASs). DNA methylation changes in the placenta were significantly associated with maternal plasma POPs concentration. The findings suggest that placental DNA methylation and gene expression mechanism may be involved in the prenatal toxicity of POPs and their association with neonatal anthropometry measures.",
+No,20200803,meqtl,32710526,A decade of epigenetic change in aging twins: Genetic and environmental contributions to longitudinal DNA methylation.,Aging Cell,"Epigenetic changes may result from the interplay of environmental exposures and genetic influences and contribute to differences in age-related disease, disability, and mortality risk. However, the etiologies contributing to stability and change in DNA methylation have rarely been examined longitudinally. We considered DNA methylation in whole blood leukocyte DNA across a 10-year span in two samples of same-sex aging twins: (a) Swedish Adoption Twin Study of Aging (SATSA; N = 53 pairs, 53% female; 62.9 and 72.5 years, SD = 7.2 years); (b) Longitudinal Study of Aging Danish Twins (LSADT; N = 43 pairs, 72% female, 76.2 and 86.1 years, SD=1.8 years). Joint biometrical analyses were conducted on 358,836 methylation probes in common. Bivariate twin models were fitted, adjusting for age, sex, and country. Overall, results suggest genetic contributions to DNA methylation across 358,836 sites tended to be small and lessen across 10 years (broad heritability M = 23.8% and 18.0%) but contributed to stability across time while person-specific factors explained emergent influences across the decade. Aging-specific sites identified from prior EWAS and methylation age clocks were more heritable than background sites. The 5037 sites that showed the greatest heritable/familial-environmental influences (p &lt; 1E-07) were enriched for immune and inflammation pathways while 2020 low stability sites showed enrichment in stress-related pathways. Across time, stability in methylation is primarily due to genetic contributions, while novel experiences and exposures contribute to methylation differences. Elevated genetic contributions at age-related methylation sites suggest that adaptions to aging and senescence may be differentially impacted by genetic background.",
+No,20200803,dnam score,32736664,Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden,Clin Epigenetics,"Background: Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries (n ? 9537, Generation Scotland: Scottish Family Health Study).
 
 Results: DNAm GrimAge predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (COPD), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). DunedinPoAm predicted the incidence of COPD and lung cancer (hazard ratios = 2.02 and 1.45, respectively). DNAm PhenoAge predicted incidence of type 2 diabetes (hazard ratio = 1.54). DNAm Telomere Length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). DNAm GrimAge associated with all-cause mortality, the prevalence of COPD and spirometry measures at the study baseline. These associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent Bonferroni-corrected significance thresholds.
 
 Conclusions: Our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.",
-,No,20200907,candidate gene,32736658,AHRR cg05575921 methylation in relation to smoking and PM2.5 exposure among Taiwanese men and women,Clin Epigenetics,"BACKGROUND: Polycyclic aromatic hydrocarbon (PAH)-rich substances like cigarette smoke and PM2.5 induce aryl hydrocarbon receptor (AHR)-mediated aryl hydrocarbon receptor repressor (AHRR) methylation. AHRR cg05575921 and coagulation factor II (thrombin) receptor-like 3 (F2RL3) cg03636183 methylation patterns are well-established biomarkers for smoking. Even though AHRR cg05575921 methylation has recently been associated with PM2.5, the interaction between smoking and PM2.5 on AHRR methylation is yet to be fully explored. We evaluated AHRR and F2RL3 CpG sites to identify potential significant markers in relation to PM2.5 and smoking in Taiwanese adults.
+No,20200907,candidate gene,32736658,AHRR cg05575921 methylation in relation to smoking and PM2.5 exposure among Taiwanese men and women,Clin Epigenetics,"BACKGROUND: Polycyclic aromatic hydrocarbon (PAH)-rich substances like cigarette smoke and PM2.5 induce aryl hydrocarbon receptor (AHR)-mediated aryl hydrocarbon receptor repressor (AHRR) methylation. AHRR cg05575921 and coagulation factor II (thrombin) receptor-like 3 (F2RL3) cg03636183 methylation patterns are well-established biomarkers for smoking. Even though AHRR cg05575921 methylation has recently been associated with PM2.5, the interaction between smoking and PM2.5 on AHRR methylation is yet to be fully explored. We evaluated AHRR and F2RL3 CpG sites to identify potential significant markers in relation to PM2.5 and smoking in Taiwanese adults.
 METHODS: DNA methylation and smoking data of 948 participants aged 30-70 years were obtained from the Taiwan Biobank Database (2008-2015), while PM2.5 data were obtained from the Air Quality Monitoring Database (2006-2011).
 RESULTS: 
 CONCLUSION: Smoking and PM2.5 were independently associated with hypomethylation of cg05575921, cg23576855, cg03636183, and cg21911711. The most hypomethylated CpG site was cg05575921 and its association with smoking and PM2.5 was dose-dependent.",
-,No,20200907,chromatin interactions,32728247,Landscape of cohesin-mediated chromatin loops in the human genome,Nature,"Physical interactions between distal regulatory elements have a key role in regulating gene expression, but the extent to which these interactions vary between cell types and contribute to cell-type-specific gene expression remains unclear. Here, to address these questions as part of phase III of the Encyclopedia of DNA Elements (ENCODE), we mapped cohesin-mediated chromatin loops, using chromatin interaction analysis by paired-end tag sequencing (ChIA-PET), and analysed gene expression in 24 diverse human cell types, including core ENCODE cell lines. Twenty-eight per cent of all chromatin loops vary across cell types; these variations modestly correlate with changes in gene expression and are effective at grouping cell types according to their tissue of origin. The connectivity of genes corresponds to different functional classes, with housekeeping genes having few contacts, and dosage-sensitive genes being more connected to enhancer elements. This atlas of chromatin loops complements the diverse maps of regulatory architecture that comprise the ENCODE Encyclopedia, and will help to support emerging analyses of genome structure and function.",
-,No,20200907,circulating,32843700,Plasma cell-free DNA methylation marks for episodic memory impairment: a pilot twin study,Sci Rep,"Decline in episodic memory performance usually causes the first clinical symptoms of Alzheimer's disease. At present, Alzheimer's disease can only be diagnosed at a very late stage when neurodegeneration and cognitive impairment is already irreversible. New early disease markers are needed for earlier and more efficient Alzheimer's disease intervention. To identify early disease markers, we implemented a genome-wide bisulphite sequencing method for the analysis of plasma cell-free DNA methylation profiles and compared differences associated with episodic memory performance in Finnish twin pairs. A noticeable amount of cell-free DNA was present in plasma, however, the amounts as well as the genomic coverage of these fragments varied substantially between individuals. We found no significant markers associated with episodic memory performance in the twins' plasma cell-free DNA methylation profiles. Furthermore, our results indicate that due to the low genomic coverage of cell-free DNA fragments and the variety in these fragments between individuals, the implemented genome-wide bisulphite sequencing method is not optimal for comparing cell-free DNA methylation differences between large groups of individuals.",
-,No,20200907,circulating,32741373,Hypomethylation in HBV integration regions aids non-invasive surveillance to hepatocellular carcinoma by low-pass genome-wide bisulfite sequencing,BMC Med,"BACKGROUND: Circulating cell-free DNA (cfDNA) methylation has been demonstrated to be a promising approach for non-invasive cancer diagnosis. However, the high cost of whole genome bisulfite sequencing (WGBS) hinders the clinical implementation of a methylation-based cfDNA early detection biomarker. We proposed a novel strategy in low-pass WGBS (~ 5 million reads) to detect methylation changes in circulating cell-free DNA (cfDNA) from patients with liver diseases and hepatocellular carcinoma (HCC).
+No,20200907,chromatin interactions,32728247,Landscape of cohesin-mediated chromatin loops in the human genome,Nature,"Physical interactions between distal regulatory elements have a key role in regulating gene expression, but the extent to which these interactions vary between cell types and contribute to cell-type-specific gene expression remains unclear. Here, to address these questions as part of phase III of the Encyclopedia of DNA Elements (ENCODE), we mapped cohesin-mediated chromatin loops, using chromatin interaction analysis by paired-end tag sequencing (ChIA-PET), and analysed gene expression in 24 diverse human cell types, including core ENCODE cell lines. Twenty-eight per cent of all chromatin loops vary across cell types; these variations modestly correlate with changes in gene expression and are effective at grouping cell types according to their tissue of origin. The connectivity of genes corresponds to different functional classes, with housekeeping genes having few contacts, and dosage-sensitive genes being more connected to enhancer elements. This atlas of chromatin loops complements the diverse maps of regulatory architecture that comprise the ENCODE Encyclopedia, and will help to support emerging analyses of genome structure and function.",
+No,20200907,circulating,32843700,Plasma cell-free DNA methylation marks for episodic memory impairment: a pilot twin study,Sci Rep,"Decline in episodic memory performance usually causes the first clinical symptoms of Alzheimer's disease. At present, Alzheimer's disease can only be diagnosed at a very late stage when neurodegeneration and cognitive impairment is already irreversible. New early disease markers are needed for earlier and more efficient Alzheimer's disease intervention. To identify early disease markers, we implemented a genome-wide bisulphite sequencing method for the analysis of plasma cell-free DNA methylation profiles and compared differences associated with episodic memory performance in Finnish twin pairs. A noticeable amount of cell-free DNA was present in plasma, however, the amounts as well as the genomic coverage of these fragments varied substantially between individuals. We found no significant markers associated with episodic memory performance in the twins' plasma cell-free DNA methylation profiles. Furthermore, our results indicate that due to the low genomic coverage of cell-free DNA fragments and the variety in these fragments between individuals, the implemented genome-wide bisulphite sequencing method is not optimal for comparing cell-free DNA methylation differences between large groups of individuals.",
+No,20200907,circulating,32741373,Hypomethylation in HBV integration regions aids non-invasive surveillance to hepatocellular carcinoma by low-pass genome-wide bisulfite sequencing,BMC Med,"BACKGROUND: Circulating cell-free DNA (cfDNA) methylation has been demonstrated to be a promising approach for non-invasive cancer diagnosis. However, the high cost of whole genome bisulfite sequencing (WGBS) hinders the clinical implementation of a methylation-based cfDNA early detection biomarker. We proposed a novel strategy in low-pass WGBS (~ 5 million reads) to detect methylation changes in circulating cell-free DNA (cfDNA) from patients with liver diseases and hepatocellular carcinoma (HCC).
 METHODS: The effective small sequencing depth were determined by 5 pilot cfDNA samples with relative high-depth WGBS. CfDNA of 51 patients with hepatitis, cirrhosis, and HCC were conducted using low-pass WGBS. The strategy was validated in an independent WGBS cohort of 32 healthy individuals and 26 early-stage HCC patients. Fifteen paired tumor tissue and buffy coat samples were used to characterize the methylation of hepatitis B virus (HBV) integration regions and genome distribution of cfDNA.
 RESULTS: A significant enrichment of cfDNA in intergenic and repeat regions, especially in previously reported HBV integration sites were observed, as a feature of cfDNA and the bias of cfDNA release. Methylation profiles nearby HBV integration sites were a better indicator for hypomethylation of tumor genome comparing to Alu and LINE (long interspersed nuclear element) repeats, and were able to facilitate the cfDNA-based HCC prediction. Hypomethylation nearby HBV integration sites (5 kb flanking) was detected in HCC patients, but not in patients with hepatitis and cirrhosis (MethylHBV5k, median:0.61 vs 0.72, P = 0.0003). Methylation levels of integration sites certain candidate regions exhibited an area under the receiver operation curve (AUC) value > 0.85 to discriminate HCC from non-HCC samples. The validation cohort achieved the prediction performance with an AUC of 0.954.
 CONCLUSIONS: Hypomethylation around viral integration sites aids low-pass cfDNA WGBS to serve as a non-invasive approach for early HCC detection, and inspire future efforts on tumor surveillance for oncovirus with integration activity.",
-,No,20200907,cohort network,32705500,"The LifeCycle Project-EU Child Cohort Network: a federated analysis infrastructure and harmonized data of more than 250,000 children and parents",Eur J Epidemiol,"Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.",
-,Yes,20200907,ewas,32843619,An epigenome-wide association study of early-onset major depression in monozygotic twins,Transl Psychiatry,"Major depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome-wide examination of DNA methylation (DNAm) offers an attractive complement to studies of allelic risk given it can reflect the combined influence of genes and environment. The current study used monozygotic twins to identify differentially and variably methylated regions of the genome that distinguish twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins between the ages of 15 and 20 (73% female; Mage = 17.52 SD = 1.28) who were assessed during a developmental stage characterized by relatively distinct neurophysiological changes. All twins were generally healthy and currently free of medications with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450 K Array. MD associations with early-onset MD were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Genes and genomic regions involved neural circuitry formation, projection, functioning, and plasticity. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell-cell adhesion genes (e.g., PCDHA genes). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g., NRG3) also were identified. DNAm regions associated with early-onset MD were found to overlap genetic loci identified in the latest Psychiatric Genomics Consortium meta-analysis of depression. Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where changes in the DNA methylome may modulate individual differences in MD risk.",
-,Yes,20200907,ewas,32803843,Epigenome-wide analysis uncovers a blood-based DNA methylation biomarker of lifetime cannabis use,Am J Med Genet B Neuropsychiatr Genet,"Cannabis use is highly prevalent and is associated with adverse and beneficial effects. To better understand the full spectrum of health consequences, biomarkers that accurately classify cannabis use are needed. DNA methylation (DNAm) is an excellent candidate, yet no blood-based epigenome-wide association studies (EWAS) in humans exist. We conducted an EWAS of lifetime cannabis use (ever vs. never) using blood-based DNAm data from a case-cohort study within Sister Study, a prospective cohort of women at risk of developing breast cancer (Discovery N = 1,730 [855 ever users]; Replication N = 853 [392 ever users]). We identified and replicated an association with lifetime cannabis use at cg15973234 (CEMIP): combined p = 3.3 × 10-8 . We found no overlap between published blood-based cis-meQTLs of cg15973234 and reported lifetime cannabis use-associated single nucleotide polymorphism (SNPs; p < .05), suggesting that the observed DNAm difference was driven by cannabis exposure. We also developed a multi-CpG classifier of lifetime cannabis use using penalized regression of top EWAS CpGs. The resulting 50-CpG classifier produced an area under the curve (AUC) = 0.74 (95% CI [0.72, 0.76], p = 2.00 × 10-5 ) in the discovery sample and AUC = 0.54 ([0.51, 0.57], p = 2.87 × 10-2 ) in the replication sample. Our EWAS findings provide evidence that blood-based DNAm is associated with lifetime cannabis use.",
-,Yes,20200907,ewas,32799603,A genome-wide study of DNA methylation in white blood cells and asthma in Latino children and youth,Epigenetics,"Latinos are heavily affected with childhood asthma. Little is known about epigenetic mechanisms of asthma in Latino youth. We conducted a meta-analysis of two epigenome-wide association studies (EWAS) of asthma, using DNA from white blood cells (WBCs) from 1,136 Latino children and youth aged 6 to 20 years. Genes near the top CpG sites in this EWAS were examined in a pathway enrichment analysis, and we then assessed whether our results replicated those from publicly available data from three independent EWAS conducted in non-Latino populations. We found that DNA methylation profiles differed between subjects with and without asthma. After adjustment for covariates and multiple testing, two CpGs were differentially methylated at a false discovery rate (FDR)-adjusted P < 0.1, and 193 CpG sites were differentially methylated at FDR-adjusted P < 0.2. The two top CpGs are near genes relevant to inflammatory signalling, including CAMK1D (Calcium/Calmodulin Dependent Protein Kinase ID) and TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains). Moreover, 25 genomic regions were differentially methylated between subjects with and without asthma, at Šidák-corrected P < 0.10. An enrichment analysis then identified the TGF-beta pathway as most relevant to asthma in our analysis, and we replicated some of the top signals from publicly available EWAS datasets in non-Hispanic populations. In conclusion, we have identified novel epigenetic markers of asthma in WBCs from Latino children and youth, while also replicating previous results from studies conducted in non-Latinos.",
-,Yes,20200907,ewas,32795589,Integrated genetic and epigenetic analyses uncover MSI2 association with allergic inflammation,J Allergy Clin Immunol,"BACKGROUND: The relationship between allergic and eosinophilic inflammation, either systemic or local, remains unclear in allergic diseases.background OBJECTIVE: We performed combined genome-wide (GWAS) and epigenome-wide association studies (EWAS) for atopy and tissue eosinophilia to identify both genetic and epigenetic signatures between systemic and local allergic inflammation, and to capture global patterns of gene regulation.
+No,20200907,cohort network,32705500,"The LifeCycle Project-EU Child Cohort Network: a federated analysis infrastructure and harmonized data of more than 250,000 children and parents",Eur J Epidemiol,"Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.",
+Yes,20200907,ewas,32843619,An epigenome-wide association study of early-onset major depression in monozygotic twins,Transl Psychiatry,"Major depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome-wide examination of DNA methylation (DNAm) offers an attractive complement to studies of allelic risk given it can reflect the combined influence of genes and environment. The current study used monozygotic twins to identify differentially and variably methylated regions of the genome that distinguish twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins between the ages of 15 and 20 (73% female; Mage = 17.52 SD = 1.28) who were assessed during a developmental stage characterized by relatively distinct neurophysiological changes. All twins were generally healthy and currently free of medications with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450 K Array. MD associations with early-onset MD were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Genes and genomic regions involved neural circuitry formation, projection, functioning, and plasticity. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell-cell adhesion genes (e.g., PCDHA genes). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g., NRG3) also were identified. DNAm regions associated with early-onset MD were found to overlap genetic loci identified in the latest Psychiatric Genomics Consortium meta-analysis of depression. Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where changes in the DNA methylome may modulate individual differences in MD risk.",
+Yes,20200907,ewas,32803843,Epigenome-wide analysis uncovers a blood-based DNA methylation biomarker of lifetime cannabis use,Am J Med Genet B Neuropsychiatr Genet,"Cannabis use is highly prevalent and is associated with adverse and beneficial effects. To better understand the full spectrum of health consequences, biomarkers that accurately classify cannabis use are needed. DNA methylation (DNAm) is an excellent candidate, yet no blood-based epigenome-wide association studies (EWAS) in humans exist. We conducted an EWAS of lifetime cannabis use (ever vs. never) using blood-based DNAm data from a case-cohort study within Sister Study, a prospective cohort of women at risk of developing breast cancer (Discovery N = 1,730 [855 ever users]; Replication N = 853 [392 ever users]). We identified and replicated an association with lifetime cannabis use at cg15973234 (CEMIP): combined p = 3.3 × 10-8 . We found no overlap between published blood-based cis-meQTLs of cg15973234 and reported lifetime cannabis use-associated single nucleotide polymorphism (SNPs; p < .05), suggesting that the observed DNAm difference was driven by cannabis exposure. We also developed a multi-CpG classifier of lifetime cannabis use using penalized regression of top EWAS CpGs. The resulting 50-CpG classifier produced an area under the curve (AUC) = 0.74 (95% CI [0.72, 0.76], p = 2.00 × 10-5 ) in the discovery sample and AUC = 0.54 ([0.51, 0.57], p = 2.87 × 10-2 ) in the replication sample. Our EWAS findings provide evidence that blood-based DNAm is associated with lifetime cannabis use.",
+Yes,20200907,ewas,32799603,A genome-wide study of DNA methylation in white blood cells and asthma in Latino children and youth,Epigenetics,"Latinos are heavily affected with childhood asthma. Little is known about epigenetic mechanisms of asthma in Latino youth. We conducted a meta-analysis of two epigenome-wide association studies (EWAS) of asthma, using DNA from white blood cells (WBCs) from 1,136 Latino children and youth aged 6 to 20 years. Genes near the top CpG sites in this EWAS were examined in a pathway enrichment analysis, and we then assessed whether our results replicated those from publicly available data from three independent EWAS conducted in non-Latino populations. We found that DNA methylation profiles differed between subjects with and without asthma. After adjustment for covariates and multiple testing, two CpGs were differentially methylated at a false discovery rate (FDR)-adjusted P < 0.1, and 193 CpG sites were differentially methylated at FDR-adjusted P < 0.2. The two top CpGs are near genes relevant to inflammatory signalling, including CAMK1D (Calcium/Calmodulin Dependent Protein Kinase ID) and TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains). Moreover, 25 genomic regions were differentially methylated between subjects with and without asthma, at Šidák-corrected P < 0.10. An enrichment analysis then identified the TGF-beta pathway as most relevant to asthma in our analysis, and we replicated some of the top signals from publicly available EWAS datasets in non-Hispanic populations. In conclusion, we have identified novel epigenetic markers of asthma in WBCs from Latino children and youth, while also replicating previous results from studies conducted in non-Latinos.",
+Yes,20200907,ewas,32795589,Integrated genetic and epigenetic analyses uncover MSI2 association with allergic inflammation,J Allergy Clin Immunol,"BACKGROUND: The relationship between allergic and eosinophilic inflammation, either systemic or local, remains unclear in allergic diseases.background OBJECTIVE: We performed combined genome-wide (GWAS) and epigenome-wide association studies (EWAS) for atopy and tissue eosinophilia to identify both genetic and epigenetic signatures between systemic and local allergic inflammation, and to capture global patterns of gene regulation.
 METHODS: We included 126 subjects for atopy analysis and 147 for tissue eosinophilia analysis including 18 normal nasal tissues. We identified differentially methylated positions (DMPs) and genes associated with atopy and tissue eosinophilia. Furthermore, we performed Mendelian randomization analysis and penalized regression along with replication in an independent cohort.
 RESULTS: EWAS identified genes, including musashi RNA binding protein 2 (MSI2), associated with atopy, which contained enriched DMPs that that genetically affect atopy. A direct association was observed between MSI2 SNPs and atopy, as well as the causal effect of changes in MSI2 expression and methylation on atopy, which was replicated in a Costa Rican population. Regarding tissue eosinophilia, EWAS identified genes including CAMK1D with enriched DMPs directly contributing to tissue eosinophilia at the gene level. The GO terms of the identified genes for both phenotypes encompassed immune-related terms.results CONCLUSION: The EWAS combined with GWAS identified novel candidate genes, especially the methylation of MSI2, contributing to systemic allergic inflammation. Certain genes displayed a greater association with either systemic or local allergic inflammation; however, a harmonized effect of these genes is expected to influence immune responses.
 CONCLUSION: ",
-,Yes,20200907,ewas,32789163,Epigenome-wide analyses identify DNA methylation signatures of dementia risk,Alzheimers Dement (Amst),"Introduction: Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)-free participants.
+Yes,20200907,ewas,32789163,Epigenome-wide analyses identify DNA methylation signatures of dementia risk,Alzheimers Dement (Amst),"Introduction: Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)-free participants.
 Methods: Associations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland.
 Results: AD genetic risk and two dementia risk scores were associated with differential methylation. The GRS associated predominantly with methylation differences in cis but also identified a genomic region implicated in Parkinson disease. Loci associated with dementia risk scores were enriched for those previously associated with body mass index and alcohol consumption.
 Discussion: Dementia risk measures show widespread association with blood-based methylation, generating several hypotheses for assessment by future studies.",
-,Yes,20200907,ewas,32788176,Obesity susceptible novel DNA methylation marker on regulatory region of inflammation gene: results from the Korea Epigenome Study (KES),BMJ Open Diabetes Res Care,"INTRODUCTION: Obesity is growing global health concern and highly associated with increased risk of metabolic diseases including type 2 diabetes. We aimed to discover new differential DNA methylation patterns predisposing obesity and prioritize surrogate epigenetic markers in Koreans.
+Yes,20200907,ewas,32788176,Obesity susceptible novel DNA methylation marker on regulatory region of inflammation gene: results from the Korea Epigenome Study (KES),BMJ Open Diabetes Res Care,"INTRODUCTION: Obesity is growing global health concern and highly associated with increased risk of metabolic diseases including type 2 diabetes. We aimed to discover new differential DNA methylation patterns predisposing obesity and prioritize surrogate epigenetic markers in Koreans.
 RESEARCH DESIGN AND METHODS: We performed multistage epigenome-wide analyses to identify differentially expressed CpGs in obesity using the Illumina HumanMethylationEPIC array (EPIC). Forty-eight CpGs showed significant differences across three phases: 902 whole blood DNAs from two cohorts (phase 1: n=450, phase 2: n=377) and a hospital-based sample (phase 3: n=75). Samples from phase III participants were used to examine whether the 48 CpGs are significant in the fat tissue and influenced gene expression. Furthermore, we investigated the epigenetic effect of CpG loci in childhood obesity (n=94).
 RESULTS: Seven of the 48 CpGs exhibited similar changes in the fat tissue along with gene expression changes. In particular, hypomethylated CpG (cg13424229) on the GATA1 transcription factor cluster of CPA3 promoter was related to its increased gene expression and showed consistent effect in childhood obesity. Interestingly, subsequent analysis using RNA sequencing data from 21 preadipocytes and 26 adipocytes suggested CPA3 as a potential obesity-related gene. Moreover, expression patterns from RNA sequencing and public Gene Expression Omnibus showed the correlation between CPA3 and type 2 diabetes (T2D) and asthma.
 CONCLUSIONS: Our finding prioritizes influential genes in obesity and provides new evidence for the role of CPA3 linking obesity, T2D, and asthma.",
-,Yes,20200907,ewas,32787975,Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy,Clin Epigenetics,"BACKGROUND: Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes (T2D). Although the cellular and molecular mechanisms of DPN are poorly understood, we and others have shown that altered gene expression and DNA methylation are implicated in disease pathogenesis. However, how DNA methylation might functionally impact gene expression and contribute to nerve damage remains unclear. Here, we analyzed genome-wide transcriptomic and methylomic profiles of sural nerves from T2D patients with DPN.
+Yes,20200907,ewas,32787975,Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy,Clin Epigenetics,"BACKGROUND: Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes (T2D). Although the cellular and molecular mechanisms of DPN are poorly understood, we and others have shown that altered gene expression and DNA methylation are implicated in disease pathogenesis. However, how DNA methylation might functionally impact gene expression and contribute to nerve damage remains unclear. Here, we analyzed genome-wide transcriptomic and methylomic profiles of sural nerves from T2D patients with DPN.
 RESULTS: Unbiased clustering of transcriptomics data separated samples into groups, which correlated with HbA1c levels. Accordingly, we found 998 differentially expressed genes (DEGs) and 929 differentially methylated genes (DMGs) between the groups with the highest and lowest HbA1c levels. Functional enrichment analysis revealed that DEGs and DMGs were enriched for pathways known to play a role in DPN, including those related to the immune system, extracellular matrix (ECM), and axon guidance. To understand the interaction between the transcriptome and methylome in DPN, we performed an integrated analysis of the overlapping genes between DEGs and DMGs. Integrated functional and network analysis identified genes and pathways modulating functions such as immune response, ECM regulation, and PI3K-Akt signaling.
 CONCLUSION: These results suggest for the first time that DNA methylation is a mechanism regulating gene expression in DPN. Overall, DPN patients with high HbA1c have distinct alterations in sural nerve DNA methylome and transcriptome, suggesting that optimal glycemic control in DPN patients is an important factor in maintaining epigenetic homeostasis and nerve function.",
-,Yes,20200907,ewas,32754889,Association of Maternal DNA Methylation and Offspring Birthweight,Reprod Sci,"This study aims to evaluate the association of maternal DNA methylation (DNAm) during pregnancy and offspring birthweight. One hundred twenty-two newborn-mother dyads from the Isle of Wight (IOW) cohort were studied to identify differentially methylated cytosine-phosphate-guanine sites (CpGs) in maternal blood associated with offspring birthweight. Peripheral blood samples were drawn from mothers at 22-38 weeks of pregnancy for epigenome-wide DNAm assessment using the Illumina Infinium HumanMethylation450K array. Candidate CpGs were identified using a course of 100 repetitions of a training and testing process with robust regressions. CpGs were considered informative if they showed statistical significance in at least 80% of training and testing samples. Linear mixed models adjusting for covariates were applied to further assess the selected CpGs. The Swedish Born Into Life cohort was used to replicate our findings (n = 33). Eight candidate CpGs corresponding to the genes LMF1, KIF9, KLHL18, DAB1, VAX2, CD207, SCT, SCYL2, DEPDC4, NECAP1, and SFRS3 in mothers were identified as statistically significantly associated with their children's birthweight in the IOW cohort and confirmed by linear mixed models after adjusting for covariates. Of these, in the replication cohort, three CpGs (cg01816814, cg23153661, and cg17722033 with p values = 0.06, 0.175, and 0.166, respectively) associated with four genes (LMF1, VAX2, CD207, and NECAP1) were marginally significant. Biological pathway analyses of three of the genes revealed cellular processes such as endocytosis (possibly sustaining an adequate maternal-fetal interface) and metabolic processes such as regulation of lipoprotein lipase activity (involved in providing substrates for the developing fetus). Our results contribute to an epigenetic understanding of maternal involvement in offspring birthweight. Measuring DNAm levels of maternal CpGs may in the future serve as a diagnostic tool recognizing mothers at risk for pregnancies ending with altered birthweights.",
-,Yes,20200907,ewas,32745807,An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene,Neurobiol Aging,"A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.",
-,Yes,20200907,ewas,32745538,DNA methylation signature of passive smoke exposure is less pronounced than active smoking: The Understanding Society study,Environ Res,"INTRODUCTION: The extent of the biological impact of passive smoke exposure is unclear. We sought to investigate the association between passive smoke exposure and DNA methylation, which could serve as a biomarker of health risk.
+Yes,20200907,ewas,32754889,Association of Maternal DNA Methylation and Offspring Birthweight,Reprod Sci,"This study aims to evaluate the association of maternal DNA methylation (DNAm) during pregnancy and offspring birthweight. One hundred twenty-two newborn-mother dyads from the Isle of Wight (IOW) cohort were studied to identify differentially methylated cytosine-phosphate-guanine sites (CpGs) in maternal blood associated with offspring birthweight. Peripheral blood samples were drawn from mothers at 22-38 weeks of pregnancy for epigenome-wide DNAm assessment using the Illumina Infinium HumanMethylation450K array. Candidate CpGs were identified using a course of 100 repetitions of a training and testing process with robust regressions. CpGs were considered informative if they showed statistical significance in at least 80% of training and testing samples. Linear mixed models adjusting for covariates were applied to further assess the selected CpGs. The Swedish Born Into Life cohort was used to replicate our findings (n = 33). Eight candidate CpGs corresponding to the genes LMF1, KIF9, KLHL18, DAB1, VAX2, CD207, SCT, SCYL2, DEPDC4, NECAP1, and SFRS3 in mothers were identified as statistically significantly associated with their children's birthweight in the IOW cohort and confirmed by linear mixed models after adjusting for covariates. Of these, in the replication cohort, three CpGs (cg01816814, cg23153661, and cg17722033 with p values = 0.06, 0.175, and 0.166, respectively) associated with four genes (LMF1, VAX2, CD207, and NECAP1) were marginally significant. Biological pathway analyses of three of the genes revealed cellular processes such as endocytosis (possibly sustaining an adequate maternal-fetal interface) and metabolic processes such as regulation of lipoprotein lipase activity (involved in providing substrates for the developing fetus). Our results contribute to an epigenetic understanding of maternal involvement in offspring birthweight. Measuring DNAm levels of maternal CpGs may in the future serve as a diagnostic tool recognizing mothers at risk for pregnancies ending with altered birthweights.",
+Yes,20200907,ewas,32745807,An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene,Neurobiol Aging,"A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.",
+Yes,20200907,ewas,32745538,DNA methylation signature of passive smoke exposure is less pronounced than active smoking: The Understanding Society study,Environ Res,"INTRODUCTION: The extent of the biological impact of passive smoke exposure is unclear. We sought to investigate the association between passive smoke exposure and DNA methylation, which could serve as a biomarker of health risk.
 MATERIALS AND METHODS: We derived passive smoke exposure from self-reported questionnaire data among smoking and non-smoking partners of participants enrolled in the UK Household Longitudinal Study 'Understanding Society' (n=769). We performed an epigenome-wide association study (EWAS) of passive smoke exposure with DNA methylation in peripheral blood measured using the Illumina Infinium Methylation EPIC array.
 RESULTS: No CpG sites surpassed the epigenome-wide significance threshold of p<5.97 × 10-8 in relation to partner smoking, compared with 10 CpG sites identified in relation to own smoking. However, 10 CpG sites surpassed a less stringent threshold of p<1 × 10-5 in a model of partner smoking adjusted for own smoking (model 1), 7 CpG sites in a model of partner smoking restricted to non-smokers (model 2) and 16 CpGs in a model restricted to regular smokers (model 3). In addition, there was evidence for an interaction between own smoking status and partners' smoking status on DNA methylation levels at the majority of CpG sites identified in models 2 and 3. There was a clear lack of enrichment for previously identified smoking signals in the EWAS of passive smoke exposure compared with the EWAS of own smoking.
 CONCLUSION: The DNA methylation signature associated with passive smoke exposure is much less pronounced than that of own smoking, with no positive findings for 'expected' signals. It is unlikely that changes to DNA methylation serve as an important mechanism underlying the health risks of passive smoke exposure.",
-,Yes,20200907,ewas,32733030,Association between DNA methylation levels in brain tissue and late-life depression in community-based participants,Transl Psychiatry,"OBJECTIVE: Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD.
+Yes,20200907,ewas,32733030,Association between DNA methylation levels in brain tissue and late-life depression in community-based participants,Transl Psychiatry,"OBJECTIVE: Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD.
 METHODS: We performed a brain epigenome-wide association study (EWAS) of late-life MDD in 608 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex generated using the Illumina HumanMethylation450 Beadchip array. We also conducted an EWAS of MDD in each sex separately.
 RESULTS: We found epigenome-wide significant associations between brain tissue-based DNA methylation and late-life MDD. The most significant and robust association was found with altered methylation levels in the YOD1 locus (cg25594636, p value = 2.55 × 10-11; cg03899372, p value = 3.12 × 10-09; cg12796440, p value = 1.51 × 10-08, cg23982678, p value = 7.94 × 10-08). Analysis of differentially methylated regions (p value = 5.06 × 10-10) further confirmed this locus. Other significant loci include UGT8 (cg18921206, p value = 1.75 × 10-08), FNDC3B (cg20367479, p value = 4.97 × 10-08) and SLIT2 (cg10946669, p value = 8.01 × 10-08). Notably, brain tissue-based methylation levels were strongly associated with late-life MDD in men more than in women.
 CONCLUSIONS: We identified altered methylation in the YOD1, UGT8, FNDC3B, and SLIT2 loci as new epigenetic factors associated with late-life MDD. Furthermore, our study highlights the sex-specific molecular heterogeneity of MDD.",
-,Yes,20200907,ewas,32811491,In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children,BMC Med,"BACKGROUND: The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows.
+Yes,20200907,ewas,32811491,In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children,BMC Med,"BACKGROUND: The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows.
 METHODS: We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites.
 RESULTS: Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure.
 CONCLUSION: In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.",
-,Yes,20200907,ewas,32734142,Trimester-Specific Associations of Prenatal Lead Exposure With Infant Cord Blood DNA Methylation at Birth,Epigenet Insights,"Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within PDGFRL associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within TRHR with tibia bone Pb (adjusted P-value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted P-value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.",
-,No,20200907,fecal,32778176,Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review,Clin Epigenetics,"BACKGROUND: DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC.
+Yes,20200907,ewas,32734142,Trimester-Specific Associations of Prenatal Lead Exposure With Infant Cord Blood DNA Methylation at Birth,Epigenet Insights,"Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within PDGFRL associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within TRHR with tibia bone Pb (adjusted P-value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted P-value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.",
+No,20200907,fecal,32778176,Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review,Clin Epigenetics,"BACKGROUND: DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC.
 METHODS: We conducted a systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 14th January 2020. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, odds ratios (ORs), overall and stage-specific sensitivities, specificities, areas under the receiver operating characteristics curve, and p-values for statistical significance for OR and for association of methylation levels with stage.
 RESULTS: Twenty-seven studies that reported stage-specific associations or performances of fecal DNA methylation markers for detecting colorectal neoplasms were identified. All studies used methylation-specific polymerase chain reaction for assessing methylation levels in the promoter or exon 1 regions of targeted genes. However, most studies were underpowered and limited by their case-control design. Furthermore, the stage-specific associations or sensitivities were validated for two markers (hypermethylation of GATA4 and VIM) only.
 CONCLUSION: Methylation markers in stool may be useful for detection of CRC precursors or CRC staging, but promising candidate markers need to be validated in longitudinal studies on large screening populations, performing epigenome-wide analyses. Identification of stage-specific DNA methylation biomarkers in stool could boost current strategies towards early detection and enable different approaches to precision medicine for CRC.",
-,No,20200907,genetic dnam,32764609,An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk,Nat Commun,"It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes.",
-,No,20200907,methods,32805005,ipDMR: Identification of differentially methylated regions with interval p-values,Bioinformatics,"SUMMARY: ipDMR is an R software tool for identification of differentially methylated regions using auto-correlated P values for individual CpGs from epigenome-wide association analysis using array or bisulfite sequencing data. It summarizes p-values for adjacent CpGs, identifies association peaks, and then extends peaks to find boundaries of differentially methylated regions. ipDMR uses BED format files as input and is easy to use. Simulations guided by real data found that ipDMR outperformed current available methods and provided slightly higher true positive rates and much lower false discovery rates.
+No,20200907,genetic dnam,32764609,An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk,Nat Commun,"It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes.",
+No,20200907,methods,32805005,ipDMR: Identification of differentially methylated regions with interval p-values,Bioinformatics,"SUMMARY: ipDMR is an R software tool for identification of differentially methylated regions using auto-correlated P values for individual CpGs from epigenome-wide association analysis using array or bisulfite sequencing data. It summarizes p-values for adjacent CpGs, identifies association peaks, and then extends peaks to find boundaries of differentially methylated regions. ipDMR uses BED format files as input and is easy to use. Simulations guided by real data found that ipDMR outperformed current available methods and provided slightly higher true positive rates and much lower false discovery rates.
 AVAILABILITY: ipDMR is available at https://bioconductor.org/packages/release/bioc/html/ENmix.html.",
-,No,20200907,epigenetics,32859263,Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference,Genome Biol,"BACKGROUND: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data.
+No,20200907,epigenetics,32859263,Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference,Genome Biol,"BACKGROUND: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data.
 RESULTS: By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation.
 CONCLUSION: We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.",
-,No,20200907,omics,32803238,Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer's disease,Hum Mol Genet,"Alzheimer's disease (ad) is a devastating neurological disorder characterized by changes in cell-type proportions and consequently marked alterations of the transcriptome. Here we use a data-driven systems biology meta-analytical approach across three human ad cohorts, encompassing six cortical brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies, and quantitative trait loci to further characterize the genetic architecture of ad. We perform co-expression network analysis across more than twelve hundred human brain samples, identifying robust ad-associated dysregulation of the transcriptome, unaltered in normal human aging. We assess the cell-type specificity of ad gene co-expression changes and estimate cell-type proportion changes in human ad by integrating co-expression modules with single-cell transcriptome data generated from 27 321 nuclei from human postmortem prefrontal cortical tissue. We also show that genetic variants of ad are enriched in a microglial ad-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human ad gene expression datasets, which can be easily accessed using our online resource (https://swaruplab.bio.uci.edu/consensusAD).",
-,No,20200907,prediction,32762727,Genome-wide methylation patterns predict clinical benefit of immunotherapy in lung cancer,Clin Epigenetics,"BACKGROUND: It is crucial to unravel molecular determinants of responses to immune checkpoint blockade (ICB) therapy because only a small subset of advanced non-small cell lung cancer (NSCLC) patients responds to ICB therapy. Previous studies were concentrated on genomic and transcriptomic markers (e.g., mutation burden and immune gene expression). However, these markers are not sufficient to accurately predict a response to ICB therapy.
+No,20200907,omics,32803238,Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer's disease,Hum Mol Genet,"Alzheimer's disease (ad) is a devastating neurological disorder characterized by changes in cell-type proportions and consequently marked alterations of the transcriptome. Here we use a data-driven systems biology meta-analytical approach across three human ad cohorts, encompassing six cortical brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies, and quantitative trait loci to further characterize the genetic architecture of ad. We perform co-expression network analysis across more than twelve hundred human brain samples, identifying robust ad-associated dysregulation of the transcriptome, unaltered in normal human aging. We assess the cell-type specificity of ad gene co-expression changes and estimate cell-type proportion changes in human ad by integrating co-expression modules with single-cell transcriptome data generated from 27 321 nuclei from human postmortem prefrontal cortical tissue. We also show that genetic variants of ad are enriched in a microglial ad-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human ad gene expression datasets, which can be easily accessed using our online resource (https://swaruplab.bio.uci.edu/consensusAD).",
+No,20200907,prediction,32762727,Genome-wide methylation patterns predict clinical benefit of immunotherapy in lung cancer,Clin Epigenetics,"BACKGROUND: It is crucial to unravel molecular determinants of responses to immune checkpoint blockade (ICB) therapy because only a small subset of advanced non-small cell lung cancer (NSCLC) patients responds to ICB therapy. Previous studies were concentrated on genomic and transcriptomic markers (e.g., mutation burden and immune gene expression). However, these markers are not sufficient to accurately predict a response to ICB therapy.
 RESULTS: Here, we analyzed DNA methylomes of 141 advanced NSCLC samples subjected to ICB therapy (i.e., anti-programmed death-1) from two independent cohorts (60 and 81 patients from our and IDIBELL cohorts). Integrative analysis of patients with matched transcriptome data in our cohort (n = 28) at pathway level revealed significant overlaps between promoter hypermethylation and transcriptional repression in nonresponders relative to responders. Fifteen immune-related pathways, including interferon signaling, were identified to be enriched for both hypermethylation and repression. We built a reliable prognostic risk model based on eight genes using LASSO model and successfully validated the model in independent cohorts. Furthermore, we found 30 survival-associated molecular interaction networks, in which two or three hypermethylated genes showed significant mutual exclusion across nonresponders.
 CONCLUSIONS: Our study demonstrates that methylation patterns can provide insight into molecular determinants underlying the clinical benefit of ICB therapy.",
-,No,20200907,qc,32749174,Reliability of DNA methylation measures using Illumina methylation BeadChip,Epigenetics,"Illumina BeadChips are widely utilized in epigenome-wide association studies (EWAS). Several studies have reported that many probes on these arrays have poor reliability. Here, we compare different pre-processing methods to improve intra-class correlation coefficients (ICC). We describe the characteristics of ICC across the genome, within and between studies, and across different array platforms. Using technical duplicates from 128 subjects, we find that with raw data only 22.5% of the CpGs on 450 K array have 'acceptable' ICCs (>0.5). Data preprocessing steps, such as background correction and dye bias correction, can reduce technical noise and improve the percentage to 38.5%. Similar to previous studies, we found that ICC is associated with CpG methylation level such that 83% of CpGs with intermediate methylation (0.1< beta-value <0.9) have acceptable ICCs, whereas only 21% of CpGs with low or high methylation (beta-value <0.1 or >0.9) have acceptable ICCs. ICC is also correlated with CpG methylation variance; after mutual adjustment for beta-value and variance, only variance remains correlated. Many CpGs with poor ICCs (<0.5) are located in biologically important regulatory regions, including gene promoters and CpG islands. Poor ICC at these sites appears to be a consequence of low biologic variation among individuals rather than increased technical measurement variation. ICCs quality classifications are highly concordant across different array platforms and across different studies. We find that ICC can be reliably estimated with 30 pairs of duplicate samples. CpGs with acceptable ICC have higher study power and are more commonly reported in published epigenome-wide studies.",
-,No,20200907,review,32839576,The road ahead in genetics and genomics,Nat Rev Genet,"In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone.",
-,No,20200907,review,32860016,Genetics meets proteomics: perspectives for large population-based studies,Nat Rev Genet,"Proteomic analysis of cells, tissues and body fluids has generated valuable insights into the complex processes influencing human biology. Proteins represent intermediate phenotypes for disease and provide insight into how genetic and non-genetic risk factors are mechanistically linked to clinical outcomes. Associations between protein levels and DNA sequence variants that colocalize with risk alleles for common diseases can expose disease-associated pathways, revealing novel drug targets and translational biomarkers. However, genome-wide, population-scale analyses of proteomic data are only now emerging. Here, we review current findings from studies of the plasma proteome and discuss their potential for advancing biomedical translation through the interpretation of genome-wide association analyses. We highlight the challenges faced by currently available technologies and provide perspectives relevant to their future application in large-scale biobank studies.",
-,No,20200907,transcription factor binding,32814038,Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data across 27 Tissue Types,Cell Rep,"Characterizing the tissue-specific binding sites of transcription factors (TFs) is essential to reconstruct gene regulatory networks and predict functions for non-coding genetic variation. DNase-seq footprinting enables the prediction of genome-wide binding sites for hundreds of TFs simultaneously. Despite the public availability of high-quality DNase-seq data from hundreds of samples, a comprehensive, up-to-date resource for the locations of genomic footprints is lacking. Here, we develop a scalable footprinting workflow using two state-of-the-art algorithms: Wellington and HINT. We apply our workflow to detect footprints in 192 ENCODE DNase-seq experiments and predict the genomic occupancy of 1,515 human TFs in 27 human tissues. We validate that these footprints overlap true-positive TF binding sites from ChIP-seq. We demonstrate that the locations, depth, and tissue specificity of footprints predict effects of genetic variants on gene expression and capture a substantial proportion of genetic risk for complex traits.",
-,No,20200907,transcription factor binding,32728250,Global reference mapping of human transcription factor footprints,Nature,"Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, but it remains challenging to distinguish variants that affect regulatory function2. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin3-6. However, only a small fraction of such sites have been precisely resolved on the human genome sequence6. Here, to enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate about 4.5 million compact genomic elements that encode transcription factor occupancy at nucleotide resolution. We map the fine-scale structure within about 1.6 million DNase I-hypersensitive sites and show that the overwhelming majority are populated by well-spaced sites of single transcription factor-DNA interaction. Cell-context-dependent cis-regulation is chiefly executed by wholesale modulation of accessibility at regulatory DNA rather than by differential transcription factor occupancy within accessible elements. We also show that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions1,7 is almost entirely attributable to variants within footprints, and that functional variants that affect transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find increased density of human genetic variation within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation.",
-,Yes,20200914,ewas,32902349,Maternal atopy and offspring epigenome-wide methylation signature.,Epigenetics,,
-,Yes,20200914,ewas,32901515,Methylome-wide association study of central adiposity implicates genes involved in immune and endocrine systems.,Epigenomics,,
-,Yes,20200914,ewas,32889533,Effect of maternal preconceptional and pregnancy micronutrient interventions on children's DNA methylation: Findings from the EMPHASIS study.,Am J Clin Nutr,,
-,No,20200914,qc,32885222,Patterns of Reliability: Assessing the Reproducibility and Integrity of DNA Methylation Measurement.,Patterns (N Y),,
-,No,20200914,methods,32883324,EPISCORE: cell type deconvolution of bulk tissue DNA methylomes from single-cell RNA-Seq data.,Genome Biol,,
-,No,20200914,genetics,32859912,Sex differences in oncogenic mutational processes.,Nat Commun,,
-,No,20201026,atac-seq,32929078,Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder.,Nat Commun,FYN identified as heroine use disorder in rats and humans,
-,No,20201026,candidate,32962699,"AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality.",BMC Cancer,for ryan,
-,Yes,20201026,epigenetics,32963246,A cell-type deconvolution meta-analysis of whole blood EWAS reveals lineage-specific smoking-associated DNA methylation changes.,Nat Commun,another paper saying that smoking is better captured by granulocyte DNAm,
-,No,20201026,epigenetics,32988399,Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.,Genome Med,mitochondrial dna copy number is epigenetic 25237825,
-,"No (but we might include tissue comparisons, they would be useful)",20201026,epigenetics,33048947,The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations.,PLoS Genet,compares inter-individual variation between blood and sperm methylation,
-,No,20201026,epigenetics,33067439,Detection of haplotype-dependent allele-specific DNA methylation in WGBS data.,Nat Commun,A method for identifying allele-specific DNA methylation in WGBS methylomes,
-,Yes,20201026,ewas,32894192,Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns.,Clin Epigenetics,,
-,Yes,20201026,ewas,32913184,DNA methylation study of Huntington's disease and motor progression in patients and in animal models.,Nat Commun,inclusion of animal models,
-,Yes,20201026,ewas,32916427,An epigenome-wide association study identifies multiple DNA methylation markers of exposure to endocrine disruptors.,Environ Int,,
-,Yes,20201026,ewas,32917208,Epigenetic loci for blood pressure are associated with hypertensive target organ damage in older African Americans from the genetic epidemiology network of Arteriopathy (GENOA) study.,BMC Med Genomics,,
-,Yes,20201026,ewas,32928285,DNA methylation mediates the effect of cocaine use on HIV severity.,Clin Epigenetics,,
-,Yes,20201026,ewas,32951333,A germ cell-specific ageing pattern in otherwise healthy men.,Aging Cell,germ cells track age,
-,Yes,20201026,ewas,32958748,"Subjective mental health, incidence of depressive symptoms in later life, and the role of epigenetics: results from two longitudinal cohort studies.",Transl Psychiatry,,
-,No,20201026,ewas,32958812,DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity.,Sci Rep,physical activity reduces muscle age,
-,Yes,20201026,ewas,32967004,Epigenome-wide analysis identifies genes and pathways linked to acoustic cry variation in preterm infants.,Pediatr Res,,
-,No,20201026,ewas,32967728,Epigenetic approach in obesity: DNA methylation in a prepubertal population which underwent a lifestyle modification.,Clin Epigenetics,lifestyle change and DNAm,
-,No,20201026,ewas,32977850,Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci.,Genome Med,cd4+t cell isolation improves power?,
-,No,20201026,prediction,32991610,"Lower DNA methylation levels in CpG island shores of CR1, CLU, and PICALM in the blood of Japanese Alzheimer's disease patients.",PLoS One,AUC=0.8,
-,Yes,20201026,ewas,33003475,Placental Epigenome-Wide Association Study Identified Loci Associated with Childhood Adiposity at 3 Years of Age.,Int J Mol Sci,placenta and later adiposity,
-,Yes,20201026,ewas,33023569,Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.,BMC Med,prenatal smoking and placenta,
-,Yes,20201026,ewas,33054850,Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes.,Genome Med,152 WGBS methylomes contain DMRs that predict autism spectrum disorder,
-,Yes,20201026,ewas,33069246,Epigenome-wide association study of Alzheimer's disease replicates 22 differentially methylated positions and 30 differentially methylated regions.,Clin Epigenetics,,
-,Yes,20201026,ewas,33079621,Birth weight associations with DNA methylation differences in an adult population.,Epigenetics,One CpG site associated with birthweight in adults,
-,No,20201026,gxe,32967067,"Genes and environments, development and time.",Proc Natl Acad Sci U S A,"Collection of papers reviewing the latest research on GxE interactions and how they change over time (3,5,7 days after admission)",
-,No,20201026,longitudinal,33081814,Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU.,Clin Epigenetics,Investigating effects of delaying parenteral nutrition in the PICU (healthier) on DNA methylation,
-,No,20201026,methods,32894181,COCOA: coordinate covariation analysis of epigenetic heterogeneity.,Genome Biol,,
-,No,20201026,methods,33048617,Genome-wide DNA methylation profiling in human breast tissue by illumina TruSeq methyl capture EPIC sequencing and infinium methylationEPIC beadchip microarray.,Epigenetics,Compares TruSeq Methyl Capture to Methylation EPIC Beadchips,
-,No,20201026,methods,33070182,Integrative Analysis Of Multi-Omics Data For Discovering Low-Frequency Variants Associated With Low-Density Lipoprotein Cholesterol Levels.,Bioinformatics,Use DNA methylation and gene expression to increase power to discover associations with low-frequency variants.,
-,No,20201026,mqtl,33062306,Association of CNVs with methylation variation.,NPJ Genom Med,,
-,Yes,20201026,omics,32978376,Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism.,Nat Commun,is this a useful use of omics?,
-,No,20201026,prediction,32928150,From tobacco smoking to cancer mutational signature: a mediation analysis strategy to explore the role of epigenetic changes.,BMC Cancer,for ryan,
-,No,20201026,prediction,32930613,Machine Learning-Based DNA Methylation Score for Fetal Exposure to Maternal Smoking: Development and Validation in Samples Collected from Adolescents and Adults.,Environ Health Perspect,,
-,Yes,20201026,prediction,32958588,DNA methylation in peripheral blood and risk of gastric cancer: a prospective nested case-control study.,Cancer Prev Res (Phila),blood DNAm and cancer risk,
-,No,20201026,prediction,32973211,Improvements and inter-laboratory implementation and optimization of blood-based single-locus age prediction models using DNA methylation of the ELOVL2 promoter.,Sci Rep,will this approach work for improving prediction?,
-,No,20201026,prediction,33045984,Discrimination between human populations using a small number of differentially methylated CpG sites: a preliminary study using lymphoblastoid cell lines and peripheral blood samples of European and Chinese origin.,BMC Genomics,European vs Chinese ancestry differentiated by 8 CpG sites in both lymphoblastoid cell lines and blood,
-,No,20201026,methods,32949770,"Single-cell analyses of aging, inflammation and senescence.",Ageing Res Rev,inclusion of single-cell data,
-,No,20201026,methods,33045983,MethHaplo: combining allele-specific DNA methylation and SNPs for haplotype region identification.,BMC Bioinformatics,A method for identifying DNA 'methylation haplotype regions',
-,No,20201123,epigenetics,32273471,Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking,Science,,
-,Yes,20201123,ewas,33185669,Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.,Genome Biol Evol,"High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled Nitric Oxide (FeNO) also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.",
-,Yes,20201123,ewas,33184255,Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis.,Transl Psychiatry,"Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (� = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.",
-,Yes,20201123,ewas,33178681,DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA.,Front Cell Dev Biol,"A subset of individuals with type 1 diabetes will develop diabetic kidney disease (DKD). DKD is heritable and large-scale genome-wide association studies have begun to identify genetic factors that influence DKD. Complementary to genetic factors, we know that a person's epigenetic profile is also altered with DKD. This study reports analysis of DNA methylation, a major epigenetic feature, evaluating methylome-wide loci for association with DKD. Unique features (n= 485,577; 482,421 CpG probes) were evaluated in blood-derived DNA from carefully phenotyped White European individuals diagnosed with type 1 diabetes with (cases) or without (controls) DKD (n= 677 samples). Explicitly, 150 cases were compared to 100 controls using the 450K array, with subsequent analysis using data previously generated for a further 96 cases and 96 controls on the 27K array, andde novomethylation data generated for replication in 139 cases and 96 controls. Following stringent quality control, raw data were quantile normalized and beta values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls; resultantP-values for array-based data were adjusted for multiple testing. Genes with significantly increased (hypermethylated) and/or decreased (hypomethylated) levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways. Twenty-two loci demonstrated statistically significant fold changes associated with DKD and additional support for these associated loci was sought using independent samples derived from patients recruited with similar inclusion criteria. Markers associated withCCNL1andZNF187genes are supported as differentially regulated loci (P< 10-8), with evidence also presented forAFF3, which has been identified from a meta-analysis and subsequent replication of genome-wide association studies. Further supporting evidence for differential gene expression in CCNL1 and ZNF187 is presented from kidney biopsy and blood-derived RNA in people with and without kidney disease from NephroSeq. Evidence confirming that methylation sites influence the development of DKD may aid risk prediction tools and stimulate research to identify epigenomic therapies which might be clinically useful for this disease.Copyright © 2020 Smyth, Patterson, Swan, Maxwell and McKnight.",
-,Yes,20201123,ewas,33751861,"Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children.",Pediatr Pulmonol,"Exposure to violence (ETV) or stress may cause asthma through unclear mechanisms.Epigenome-wide association study (EWAS) of DNA methylation in nasal epithelium and four ETV or chronic stress measures in 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed measures of ETV or chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by P-value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA).In the EWAS of stress/violence in EVA-PR, gun violence was associated with methylation of cg18961589 inLINC01164(β=0.03,P=1.28×10-7), and maternal stress was associated with methylation of cg03402351 inSNN(β=0.04,P=1.69×10-7) and cg19064846 inPTPRN2(β=0.03,P=3.36×10-7). In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence in EVA-PR, CpGs inSTARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4andANAPC13were associated with atopic asthma at FDR-P< 0.05.ETV and chronic stress may increase the risk of atopic asthma through DNA methylation in airway epithelium, though this needs confirmation in future longitudinal studies.",
-,Yes,20201123,ewas,33152445,PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.,Brain Behav Immun,"Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.Copyright © 2020 Elsevier Inc. All rights reserved.",
-,Yes,20201123,ewas,33151971,"Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial.",PLoS Med,"Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders.Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings.ISRCTN89971375.",
-,Yes,20201123,ewas,33150670,Sex-specific associations of asthma acquisition with changes in DNA methylation during adolescence.,Clin Exp Allergy,"Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma.We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific.Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n=124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed.We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (p-values<1.0Ă—10-3). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (p-values<0.01 in both cohorts).Gender-reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence.This article is protected by copyright. All rights reserved.",
-,No,20201123,dnam age,33146735,Association of Neighborhood Deprivation With Epigenetic Aging Using 4 Clock Metrics.,JAMA Netw Open,"Neighborhood deprivation is associated with age-related disease, mortality, and reduced life expectancy. However, biological pathways underlying these associations are not well understood.To evaluate the association between neighborhood deprivation and epigenetic measures of age acceleration and genome-wide methylation.This cross-sectional study used data from the Sister Study, a prospective cohort study comprising 50 884 women living in the US and Puerto Rico aged 35 to 74 years at enrollment who had a sister with breast cancer but had not had breast cancer themselves. Cohort enrollment occurred between July 2003 and March 2009. Participants completed a computer-assisted telephone interview on demographic, socioeconomic, lifestyle, and residential factors and provided anthropometric measures and peripheral blood samples at a home examination. DNA methylation data obtained for 2630 non-Hispanic White women selected for a case-cohort study in 2014 were used in this cross-sectional analysis. DNA methylation was measured using the HumanMethylation450 BeadChips in whole blood samples collected at baseline. Data analysis for this study was performed from October 17, 2019, to August 27, 2020.Each participants' primary address was linked to an established index of neighborhood deprivation.Epigenetic age was estimated using 4 epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge). Age acceleration was determined using residuals from regressing chronologic age on each of the 4 epigenetic age metrics. Linear regression was used to estimate associations between neighborhood deprivation and epigenetic age acceleration as well as DNA methylation at individual cytosine-guanine sites across the genome.Mean (SD) age of the 2630 participants was 56.9 (8.7) years. Those with the greatest (>75th percentile) vs least (≤25th percentile) neighborhood deprivation had higher epigenetic age acceleration estimated by Hannum (β = 0.23; 95% CI, 0.01-0.45), PhenoAge (β = 0.28; 95% CI, 0.06-.50), and GrimAge (β = 0.37; 95% CI, 0.12-0.62). Increasing US quartiles of neighborhood deprivation exhibited a trend with Hannum, PhenoAge, and GrimAge. For example, GrimAge showed a significant dose-response (P test for trend <.001) as follows: level 2 vs level 1 (β = 0.30; 95% CI, 0.17-0.42), level 3 vs level 1 (β = 0.35; 95% CI, 0.19-0.50), and level 4 vs level 1 (β = 0.37; 95% CI, 0.12-0.62). Neighborhood deprivation was found to be associated with 3 cytosine-phosphate-guanine sites, with 1 of these annotated to a known gene MAOB (P = 9.71 × 10-08).The findings of this study suggest that residing in a neighborhood with a higher deprivation index appears to be reflected by methylation-based markers of aging.",
-,No,20201123,sem,33144501,Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease.,Proc Natl Acad Sci U S A,"Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.",
-,Yes,20201123,ewas,33137917,Association between Breastfeeding and DNA Methylation over the Life Course: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC).,Nutrients,"Breastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7 years, N = 640) and adolescence (age 15-17 years, N = 709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N = 702) was used as a negative control for potential pre-natal residual confounding.Two differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15-17 years, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15-17 years, but not between birth and age 7 years.Our findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations.",
-,Yes,20201123,ewas,33134824,Epigenome-Wide Association Study Using Prediagnostic Bloods Identifies New Genomic Regions Associated With Pancreatic Cancer Risk.,JNCI Cancer Spectr,"Epigenome-wide association studies using peripheral blood have identified specific sites of DNA methylation associated with risk of various cancers and may hold promise to identify novel biomarkers of risk; however, few studies have been performed for pancreatic cancer and none using a prospective study design.Using a nested case-control study design, incident pancreatic cancer cases and matched controls were identified from participants who provided blood at baseline in 3 prospective cohort studies. DNA methylation levels were measured in DNA extracted from leukocytes using the Illumina MethylationEPIC array. Average follow-up period for this analysis was 13 years.Several new genomic regions were identified as being differentially methylated in cases and controls; the 5 strongest associations were observed for CpGs located in genesTMEM204/IFT140,MFSD6L,FAM134B/RETREG1,KCNQ1D, andC6orf227. For some CpGs located in chromosome 16p13.3 (near genesTMEM204andIFT140), associations were stronger with shorter time to diagnosis (eg, odds ratio [OR] = 5.95, 95% confidence interval [CI] = 1.52 to 23.12, for top vs bottom quartile, for <5 years between blood draw and cancer diagnosis), but associations remained statistically significantly higher even when cases were diagnosed over 10 years after blood collection. Statistically significant differences in DNA methylation levels were also observed in the gastric secretion pathway using Gene Set Enrichment Analysis (GSEA) analysis.Changes in DNA methylation in peripheral blood may mark alterations in metabolic or immune pathways that play a role in pancreatic cancer. Identifying new biological pathways in carcinogenesis of pancreatic cancer using epigenome-wide association studies approach could provide new opportunities for improving treatment and prevention.© The Author(s) 2020. Published by Oxford University Press.",
-,No,20201123,methods,33125040,A Structured Approach to Evaluating Life Course Hypotheses: Moving Beyond Analyses of Exposed Versus Unexposed in the Omics Context.,Am J Epidemiol,"The structured life course modeling approach (SLCMA) is a theory-driven analytic method that empirically compares multiple prespecified life course hypotheses characterizing time-dependent exposure-outcome relationships to determine which theory best fits the observed data. In this study, we performed simulations and empirical analyses to evaluate the performance of the SLCMA when applied to genome-wide DNA methylation (DNAm). Using simulations, we compared five statistical inference tests used with SLCMA (n=700), assessing the family-wise error rate, statistical power, and confidence interval coverage to determine whether inference based on these tests was valid in the presence of substantial multiple testing and small effects, two hallmark challenges of inference from omics data. In the empirical analyses, we evaluated the time-dependent relationship of childhood abuse with genome-wide DNAm (n=703). In simulations, selective inference and max-|t|-test performed best: both controlled family-wise error rate and yielded moderate statistical power. Empirical analyses using SLCMA revealed time-dependent effects of childhood abuse on DNAm. Our findings show that SLCMA, applied and interpreted appropriately, can be used in high-throughput settings to examine time-dependent effects underlying exposure-outcome relationships over the life course. We provide recommendations for applying the SLCMA in omics settings and encourage researchers to move beyond analyses of exposed versus unexposed.© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
-,Yes,20201123,ewas,33100131,Epigenome-wide association study identifies DNA methylation sites associated with target organ damage in older African Americans.,Epigenetics,"Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 nearC7orf50, cg09155024, cg10254690 nearOAT, cg07660512, cg12661888 nearIFT43, and cg02264946 nearCATSPERD) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated withcis-gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.",
-,No,20201123,mediation,33092652,Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits.,Clin Epigenetics,"Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits.We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression.Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.",
-,No,20201123,prediction,33092459,DNA methylation biomarker selected by an ensemble machine learning approach predicts mortality risk in an HIV-positive veteran population.,Epigenetics,"Background: With the improved life expectancy of people living with HIV (PLWH), identifying vulnerable subpopulations at high mortality risk is important. Evidences showed that DNA methylation (DNAm) is associated with mortality in non-HIV populations. Here, we established a panel of DNAm biomarkers that can predict mortality risk among PLWH.Methods: 1,081 HIV-positive participants from the Veterans Ageing Cohort Study (VACS) were divided into training (N = 460), validation (N = 114), and testing (N = 507) sets. VACS index was used as a measure of mortality risk among PLWH. Model training and fine-tuning were conducted using the ensemble method in the training and validation sets and prediction performance was assessed in the testing set. The survival analysis comparing the predicted high and low mortality risk groups and the Gene Ontology enrichment analysis of the predictive CpG sites were performed.Results: We selected a panel of 393 CpGs for the ensemble prediction model that showed excellent performance in predicting high mortality risk with an auROC of 0.809 (95%CI: 0.767,0.851) and a balanced accuracy of 0.653 (95%CI: 0.611, 0.693) in the testing set. The high mortality risk group was significantly associated with 10-year mortality (hazard ratio = 1.79, p = 4E-05) compared with low risk group. These 393 CpGs were located in 280 genes enriched in immune and inflammation response pathways.Conclusions: We identified a panel of DNAm features associated with mortality risk in PLWH. These DNAm features may serve as predictive biomarkers for mortality risk among PLWH.Abbreviations: AUC: Area Under Curve; CI: Confidence interval; DMR: differentially methylated region; DNA: Deoxyribonucleic acid; DNAm: DNA methylation; DAVID: Database for Annotation, Visualization, and Integrated Discovery; EWA: epigenome-wide association; FDR: False discovery rate; FWER: Family-wise error rate; GLMNET: elastic-net-regularized generalized linear models; GO: Gene ontology; HIV: Human immunodeficiency virus; HM450K: Human Methylation 450 K BeadChip; k-NN: k-nearest neighbours; NK: Natural killer; PC: Principal component; PLWH: people living with HIV; QC: Quality control; SVM: Support Vector Machines; VACS: Veterans Ageing Cohort Study; XGBoost: Extreme Gradient Boosting Tree.",
-,No,20201123,dnam age,33109080,Blood-based epigenetic estimators of chronological age in human adults using DNA methylation data from the Illumina MethylationEPIC array.,BMC Genomics,"Epigenetic clocks have been recognized for their precise prediction of chronological age, age-related diseases, and all-cause mortality. Existing epigenetic clocks are based on CpGs from the Illumina HumanMethylation450 BeadChip (450 K) which has now been replaced by the latest platform, Illumina MethylationEPIC BeadChip (EPIC). Thus, it remains unclear to what extent EPIC contributes to increased precision and accuracy in the prediction of chronological age.We developed three blood-based epigenetic clocks for human adults using EPIC-based DNA methylation (DNAm) data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Gene Expression Omnibus (GEO) public repository: 1) an Adult Blood-based EPIC Clock (ABEC) trained on DNAm data from MoBa (n = 1592, age-span: 19 to 59 years), 2) an extended ABEC (eABEC) trained on DNAm data from MoBa and GEO (n = 2227, age-span: 18 to 88 years), and 3) a common ABEC (cABEC) trained on the same training set as eABEC but restricted to CpGs common to 450 K and EPIC. Our clocks showed high precision (Pearson correlation between chronological and epigenetic age (r) > 0.94) in independent cohorts, including GSE111165 (n = 15), GSE115278 (n = 108), GSE132203 (n = 795), and the Epigenetics in Pregnancy (EPIPREG) study of the STORK Groruddalen Cohort (n = 470). This high precision is unlikely due to the use of EPIC, but rather due to the large sample size of the training set.Our ABECs predicted adults' chronological age precisely in independent cohorts. As EPIC is now the dominant platform for measuring DNAm, these clocks will be useful in further predictions of chronological age, age-related diseases, and mortality.",
-,No,20201123,single cell,33098772,Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin.,Cell,"Cell differentiation and function are regulated across multiple layers of gene regulation, including modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of regulatory events leading to cell fate commitment. Here we developed simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq), a highly scalable approach for measurement of chromatin accessibility and gene expression in the same single cell, applicable to different tissues. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define domains of regulatory chromatin (DORCs) that significantly overlap with super-enhancers. During lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting that changes in chromatin accessibility may prime cells for lineage commitment. We computationally infer chromatin potential as a quantitative measure of chromatin lineage-priming and use it to predict cell fate outcomes. SHARE-seq is an extensible platform to study regulatory circuitry across diverse cells in tissues.Copyright © 2020 Elsevier Inc. All rights reserved.",
-,Yes,20201123,ewas,33076993,Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants.,Clin Epigenetics,"Infants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities.This study included 532 infants born < 30 weeks gestation, participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants study. We used a neonatal morbidity risk score, which was an additive index of the number of morbidities experienced during the NICU stay, including bronchopulmonary dysplasia (BPD), severe brain injury, serious neonatal infections, and severe retinopathy of prematurity. DNA was collected from buccal cells at discharge from the NICU, and DNAm was measured using the Illumina MethylationEPIC. We tested for differential methylation in association with the neonatal morbidity risk score then tested for differentially methylated regions (DMRs) and overrepresentation of biological pathways.We identified ten differentially methylated CpGs (α Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose-response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing.Neonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.",
-,No,20201123,single cell,33106633,Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases.,Nat Genet,"Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer's and Parkinson's diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson's disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.",
-,No,20201123,epigenetics,33099088,Integrated multi-omics reveal epigenomic disturbance of assisted reproductive technologies in human offspring.,EBioMedicine,"The births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the safety issue regarding ARTs has drawn growing attention with accumulating observations of rising health risks, and underlying epigenetic mechanisms are largely uncharacterized.In order to clarify epigenetic risks attributable to ARTs, we profiled DNA methylome on 137 umbilical cord blood (UCB) and 158 parental peripheral blood (PPB) samples, histone modifications (H3K4me3, H3K4me1, H3K27me3 and H3K27ac) on 33 UCB samples and transcriptome on 32 UCB samples by reduced representation bisulfite sequencing (RRBS), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq), respectively.We revealed that H3K4me3 was the most profoundly impacted by ICSI and freeze-thawing operation compared with the other three types of histone modifications. IVF-ET seemed to introduce less disturbance into infant epigenomes than IVF-FET or ICSI-ET did. ARTs also decreased the similarity of DNA methylome within twin pairs, and we confirmed that ART per se would introduce conservative changes locally through removal of parental effect. Importantly, those unique and common alterations induced by different ART procedures were highly enriched in the processes related to nervous system, cardiovascular system and glycolipid metabolism etc., which was in accordance with those findings in previous epidemiology studies and suggested some unexplored health issues, including in the immune system and skeletal system.Different ART procedures can induce local and functional epigenetic abnormalities, especially for DNA methylation and H3K4me3, providing an epigenetic basis for the potential long-term health risks in ART-conceived offspring.This study was funded by National Natural Science Foundation of China (81,730,038; 81,521,002), National Key Research and Development Program (2018YFC1004000; 2017YFA0103801; 2017YFA0105001) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020703). Yang Wang was supported by Postdoctoral Fellowship of Peking-Tsinghua Center for Life Science.Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.",
-,Yes,20201214,ewas,33290095,Maternal lipodome across pregnancy is associated with the neonatal DNA methylome.,Epigenomics,Aim:To classify the association between the maternal lipidome and DNA methylation in cord blood leukocytes.Materials & methods:Untargeted lipidomics was performed on first trimester maternal plasma (M1) and delivery maternal plasma (M3) in 100 mothers from the Michigan Mother-Infant Pairs cohort. Cord blood leukocyte DNA methylation was profiled using the Infinium EPIC bead array and empirical Bayes modeling identified differential DNA methylation related to maternal lipid groups.Results:M3-saturated lysophosphatidylcholine was associated with 45 differentially methylated loci and M3-saturated lysophosphatidylethanolamine was associated with 18 differentially methylated loci. Biological pathways enriched among differentially methylated loci by M3 saturated lysophosphatidylcholines were related to cell proliferation and growth.Conclusion:The maternal lipidome may be influential in establishing the infant epigenome.,
-,Yes,20201214,ewas,33227132,DNA methylation differences at birth after conception through ART.,Hum Reprod,"Is there a relation between ART and DNA methylation (DNAm) patterns in cord blood, including any differences between IVF and ICSI?DNAm at 19 CpGs was associated with conception via ART, with no difference found between IVF and ICSI.Prior studies on either IVF or ICSI show conflicting outcomes, as both widespread effects on DNAm and highly localized associations have been reported. No study on both IVF and ICSI and genome-wide neonatal DNAm has been performed.This was a cross-sectional study comprising 87 infants conceived with IVF or ICSI and 70 conceived following medically unassisted conception. The requirement for inclusion in the study was an understanding of the Swedish language and exclusion was the use of donor gametes.Participants were from the UppstART study, which was recruited from fertility and reproductive health clinics, and the Born into Life cohort, which is recruited from the larger LifeGene study. We measured DNAm from DNA extracted from cord blood collected at birth using a micro-array (450k array). Group differences in DNAm at individual CpG dinucleotides (CpGs) were determined using robust linear models and post-hoc Tukey's tests.We found no association of ART conception with global methylation levels, imprinted loci and meta-stable epialleles. In contrast, we identify 19 CpGs at which DNAm was associated with being conceived via ART (effect estimates: 0.5-4.9%, PFDR < 0.05), but no difference was found between IVF and ICSI. The associated CpGs map to genes related to brain function/development or genes connected to the plethora of conditions linked to subfertility, but functional annotation did not point to any likely functional consequences.We measured DNAm in cord blood and not at later ages or in other tissues. Given the number of tests performed, our study power is limited and the findings need to be replicated in an independent study.We find that ART is associated with DNAm differences in cord blood when compared to non-ART samples, but these differences are limited in number and effect size and have unknown functional consequences in adult blood. We did not find indications of differences between IVF and ICSI.E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128) and JPI-H2020 Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL) under proposal number 655 (PREcisE Project) through ZonMw (529051023). Financial support was provided from the European Union's Seventh Framework Program IDEAL (259679), the Swedish Research Council (K2011-69X-21871-01-6, 2011-3060, 2015-02434 and 2018-02640) and the Strategic Research Program in Epidemiology Young Scholar Awards, Karolinska Institute (to A.N.I.) and through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Strategic Research Program in Epidemiology at Karolinska Institutet and the Swedish Heart-Lung Foundation and Danderyd University Hospital (Stockholm, Sweden). The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. The authors declare no competing interests.N/A.© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.",
-,Yes,20201214,ewas,33214203,DNA methylation at birth is associated with lung function development till age 26 years.,Eur Respir J,"Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25-75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of 8 CpGs on genesGLUL, MYCN, HLX, LHX1, COBL, COL18A1, STRA6,andWNT11involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs onLHX1andCOL18A1were linked to gene expression in IOWBC-F2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.Copyright ©ERS 2020.",
-,Yes,20201214,ewas,33239103,DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.,Genome Med,"DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.",
-,No,20201214,ewas,33267929,Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children.,Psychol Med,"Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment.Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses.Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 Ă— 10-07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4.These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.",
-,Yes,20201214,ewas,33257653,Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer's disease.,Nat Commun,"DNA methylation differences in Alzheimer's disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. Using a uniform analysis pipeline, we identified 3751 CpGs and 119 differentially methylated regions (DMRs) significantly associated with Braak stage. Our analysis identified differentially methylated genes such as MAMSTR, AGAP2, and AZU1. The most significant DMR identified is located on the MAMSTR gene, which encodes a cofactor that stimulates MEF2C. Notably, MEF2C cooperates with another transcription factor, PU.1, a central hub in the AD gene network. Our enrichment analysis highlighted the potential roles of the immune system and polycomb repressive complex 2 in pathological AD. These results may help facilitate future mechanistic and biomarker discovery studies in AD.",
-,No,20201214,ewas,33298155,Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer's disease and implicate its dynamic role in disease progression.,Clin Epigenetics,"While Alzheimer's disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention.We analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters).When compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances.Our results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.",
-,Yes,20201214,ewas,33279932,Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population.,Mol Psychiatry,"Schizophrenia is a severe neuropsychiatric disorder with core features including hallucinations, delusions, and cognition deficits. Accumulating evidence has implicated abnormal DNA methylation in the development of schizophrenia. However, the mechanisms by which DNA methylation changes alter the risk for schizophrenia remain largely unknown. We recently carried out a DNA methylome study of peripheral blood samples from 469 first-episode patients with schizophrenia and 476 age- and gender-matched healthy controls of Han Chinese origin. Genomic DNA methylation patterns were quantified using an Illumina Infinium Human MethylationEPIC BeadChip. We identified multiple differentially methylated positions (DMPs) and regions between patients and controls. The most significant DMPs were annotated to genes C17orf53, THAP1 and KCNQ4 (KV7.4), with Bonferroni-adjusted P values of [Formula: see text], [Formula: see text], and [Formula: see text], respectively. In particular, KCNQ4 encodes a voltage-gated potassium channel of the KV7 family, which is linked to neuronal excitability. The genes associated with top-ranked DMPs also included many genes involved in nervous system development, such as LIMK2 and TMOD2. Gene ontology analysis of the differentially methylated genes further identified strong enrichment of neuronal networks, including neuron projection extension, axonogenesis and neuron apoptotic process. Finally, we provided evidence that schizophrenia-associated epigenetic alterations co-localize with genetic susceptibility loci. By focusing on first-episode schizophrenia patients, our investigation lends particularly strong support for an important role of DNA methylation in schizophrenia pathogenesis unconfounded by the effects of long-term antipsychotic medication or disease progression. The observed DNA methylation aberrations in schizophrenia patients could potentially provide a valuable resource for identifying diagnostic biomarkers and developing novel therapeutic targets to benefit schizophrenia patients.",
-,Yes,20201214,ewas,33235198,Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.,Nat Commun,"Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.",
-,Yes,20201214,ewas,33208194,Altered immune phenotype and DNA methylation in panic disorder.,Clin Epigenetics,"Multiple studies have related psychiatric disorders and immune alterations. Panic disorder (PD) has been linked with changes in leukocytes distributions in several small studies using different methods for immune characterization. Additionally, alterations in the methylation of repetitive DNA elements, such as LINE-1, have been associated with mental disorders. Here, we use peripheral blood DNA methylation data from two studies and an updated DNA methylation deconvolution library to investigate the relation of leukocyte proportions and methylation status of repetitive elements in 133 patients with panic disorder compared with 118 controls.We used DNA methylation data to deconvolute leukocyte cell-type proportions and to infer LINE-1 element methylation comparing PD cases and controls. We also identified differentially methylated CpGs associated with PD using an epigenome-wide association study approach (EWAS), with models adjusting for sex, age, and cell-type proportions. Individuals with PD had a lower proportion of CD8T cells (OR: 0.86, 95% CI: 0.78-0.96, P-adj = 0.030) when adjusting for age, sex, and study compared with controls. Also, PD cases had significantly lower LINE-1 repetitive element methylation than controls (P < 0.001). The EWAS identified 61 differentially methylated CpGs (58 hypo- and 3 hypermethylated) in PD (Bonferroni adjusted P < 1.33 × 10-7).These results suggest that those with panic disorder have changes to their immune system and dysregulation of repeat elements relative to controls.",
-,Yes,20201214,ewas,33277923,Associations of Alcohol Consumption with Epigenome-Wide DNA Methylation and Epigenetic Age Acceleration: Individual-Level and Co-twin Comparison Analyses.,Alcohol Clin Exp Res,"DNA methylation may play a role in progression from normative to problematic drinking and underlie adverse health outcomes associated with alcohol misuse. In the current study, we examined the association between alcohol consumption and DNA methylation patterns using three approaches: a conventional epigenome-wide association study (EWAS); a co-twin comparison design, which controls for genetic and environmental influences that twins share; and a regression of age acceleration, defined as a discrepancy between chronological age and DNA methylation age, on alcohol consumption.Participants came from the Finnish Twin Cohorts (FinnTwin12/FinnTwin16; N = 1004; 55% female; average age = 23 years). Individuals reported the number of alcoholic beverages consumed in the past week, and epigenome-wide DNA methylation was assessed in whole-blood using the Infinium HumanMethylation450 BeadChip.In the EWAS, alcohol consumption was significantly related to methylation at 24 CpG sites. When evaluating whether differences between twin siblings (185 monozygotic pairs) in alcohol consumption predicted differences in DNA methylation, co-twin comparisons replicated four CpG sites from the EWAS and identified 23 additional sites. However, when we examined qualitative differences in drinking patterns between twins (heavy drinker versus light drinker/abstainer or moderate drinker versus abstainer; 44 pairs), methylation patterns did not significantly differ within twin pairs. Finally, individuals who reported higher alcohol consumption also exhibited greater age acceleration, though results were no longer significant after controlling for genetic and environmental influences shared by co-twins.Our analyses offer insight into the associations between epigenetic variation and levels of alcohol consumption in young adulthood.This article is protected by copyright. All rights reserved.",
-,Yes,20201214,ewas,33215951,Childhood exposure to hunger: associations with health outcomes in later life and epigenetic markers.,Epigenomics,Aim:To assess associations of early exposure to hunger with depressive symptoms and cardiovascular disease (CVD) and to investigate possible epigenetic pathways.Patients & methods:Data were based on a German population-based cohort of older adults (n = 9631). Regression models were performed for health outcomes in later life. An epigenome-wide association study for early-life exposure to hunger was performed in a subgroup (n = 2221) with whole blood DNA methylation data.Results:Childhood exposure to hunger was associated with CVD and depressive symptoms in later life. Prenatal or infant exposure was strongly associated with depressive symptoms. No CpG reached epigenome-wide significance after multiple testing correction.Conclusion:Childhood hunger is a risk factor for depressive symptoms and CVD at older age. DNA methylation could not explain this association.,
-,Yes,20201214,ewas,33266012,DNA Methylation Profiles of Vegans and Non-Vegetarians in the Adventist Health Study-2 Cohort.,Nutrients,"We sought to determine if DNA methylation patterns differed between vegans and non-vegetarians in the Adventist Health Study-2 cohort. Genome-wide DNA methylation derived from buffy coat was profiled in 62 vegans and 142 non-vegetarians. Using linear regression, methylation of CpG sites and genes was categorized or summarized according to various genic/intergenic regions and CpG island-related regions, as well as the promoter. Methylation of genes was measured as the average methylation of available CpG's annotated to the nominated region of the respective gene. A permutation method defining the null distribution adapted from Storey et al. was used to adjust for false discovery. Differences in methylation of several CpG sites and genes were detected at a false discovery rate < 0.05 in region-specific and overall analyses. A vegan diet was associated predominantly with hypomethylation of genes, most notably methyltransferase-like 1 (METTL1). Although a limited number of differentially methylated features were detected in the current study, the false discovery method revealed that a much larger proportion of differentially methylated genes and sites exist, and could be detected with a larger sample size. Our findings suggest modest differences in DNA methylation in vegans and non-vegetarians, with a much greater number of detectable significant differences expected with a larger sample.",
-,Yes,20201214,ewas,33232214,Epigenome-wide association scan identifies methylation sites associated with HIV infection.,Epigenomics,"Aim:To investigate the role of epigenetics in HIV pathophysiology. Materials & methods:We conducted an epigenome-wide association scan on HIV infection status among people who inject drugs in the AIDS Linked to the IntraVenous Experience study with primary (n = 397) and validation samples (n = 390). DNA methylation from blood was measured by the Illumina EPIC BeadChip. We controlled for cell type heterogeneity by HIV status.Results:HIV infection status was associated (p < 10-8) with DNA methylation at 49 CpG sites. Sites were enriched in response to virus, interferon signaling pathway, etc. Among these sites, discovery and validation t-statistics were highly correlated (r = 0.96).Conclusion:In a cohort of people who inject drugs, HIV status was associated with differential DNA methylation at biologically meaningful sites.",
-,Yes,20201214,ewas,33228781,DNA methylation signatures to predict the cervicovaginal microbiome status.,Clin Epigenetics,"The composition of the microbiome plays an important role in human health and disease. Whether there is a direct association between the cervicovaginal microbiome and the host's epigenome is largely unexplored.Here we analyzed a total of 448 cervicovaginal smear samples and studied both the DNA methylome of the host and the microbiome using the Illumina EPIC array and next-generation sequencing, respectively. We found that those CpGs that are hypo-methylated in samples with non-lactobacilli (O-type) dominating communities are strongly associated with gastrointestinal differentiation and that a signature consisting of 819 CpGs was able to discriminate lactobacilli-dominating (L-type) from O-type samples with an area under the receiver operator characteristic curve (AUC) of 0.84 (95% CI = 0.77-0.90) in an independent validation set. The performance found in samples with more than 50% epithelial cells was further improved (AUC 0.87) and in women younger than 50 years of age was even higher (AUC 0.91). In a subset of 96 women, the buccal but not the blood cell DNA showed the same trend as the cervicovaginal samples in discriminating women with L- from O-type cervicovaginal communities.These findings strongly support the view that the epithelial epigenome plays an essential role in hosting specific microbial communities.",
-,Yes,20201214,ewas,33239708,An epigenome-wide association study of metabolic syndrome and its components.,Sci Rep,"The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP -previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P = 1.80 × 10-8). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P = 5.36 × 10-9) and waist circumference (P = 5.21 × 10-9). The previously identified type 2 diabetes-associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P = 2.24 × 10-7). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P = 7.81 × 10-8). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.",
-,Yes,20201214,ewas,33303027,Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium.,Clin Transl Allergy,"Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission.Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA).We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P < 0.05) and the same direction of effect in nasal brushes.We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway.",
-,No,20201214,dnam age,33279859,"DNA methylation-based biomarkers of age acceleration and all-cause death, myocardial infarction, stroke, and cancer in two cohorts: The NAS, and KORA F4.",EBioMedicine,"DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints.We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing.The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer.From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions.National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.",
-,No,20201214,dnam age,33210602,Plasma proteomic biomarker signature of age predicts health and life span.,Elife,"Older age is a strong shared risk factor for many chronic diseases, and there is increasing interest in identifying aging biomarkers. Here, a proteomic analysis of 1301 plasma proteins was conducted in 997 individuals between 21 and 102 years of age. We identified 651 proteins associated with age (506 over-represented, 145 underrepresented with age). Mediation analysis suggested a role for partialcis-epigenetic control of protein expression with age. Of the age-associated proteins, 33.5% and 45.3%, were associated with mortality and multimorbidity, respectively. There was enrichment of proteins associated with inflammation and extracellular matrix as well as senescence-associated secretory proteins. A 76-protein proteomic age signature predicted accumulation of chronic diseases and all-cause mortality. These data support the use of proteomic biomarkers to monitor aging trajectories and to identify individuals at higher risk of disease to be targeted for in depth diagnostic procedures and early interventions.",
-,No,20201214,epigenetics,33239447,KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.,Proc Natl Acad Sci U S A,"Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. However, a subset of TEs exhibit variable methylation levels in genetically identical individuals, and this is associated with epigenetically conferred phenotypic differences, environmental adaptability, and transgenerational epigenetic inheritance. The evolutionary origins and molecular mechanisms underlying interindividual epigenetic variability remain unknown. Using a repertoire of murine variably methylated intracisternal A-particle (VM-IAP) epialleles as a model, we demonstrate that variable DNA methylation states at TEs are highly susceptible to genetic background effects. Taking a classical genetics approach coupled with genome-wide analysis, we harness these effects and identify a cluster of KRAB zinc finger protein (KZFP) genes that modifies VM-IAPs intransin a sequence-specific manner. Deletion of the cluster results in decreased DNA methylation levels and altered histone modifications at the targeted VM-IAPs. In some cases, these effects are accompanied by dysregulation of neighboring genes. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators. These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance.Copyright © 2020 the Author(s). Published by PNAS.",
-,No,20201214,epigenetics,33257808,Female human primordial germ cells display X-chromosome dosage compensation despite the absence of X-inactivation.,Nat Cell Biol,"X-chromosome dosage compensation in female placental mammals is achieved by X-chromosome inactivation (XCI). Human pre-implantation embryos are an exception, in which dosage compensation occurs by X-chromosome dampening (XCD). Here, we examined whether XCD extends to human prenatal germ cells given their similarities to naive pluripotent cells. We found that female human primordial germ cells (hPGCs) display reduced X-linked gene expression before entering meiosis. Moreover, in hPGCs, both X chromosomes are active and express the long non-coding RNAs X active coating transcript (XACT) and X inactive specific transcript (XIST)-the master regulator of XCI-which are silenced after entry into meiosis. We find that XACT is a hPGC marker, describe XCD associated with XIST expression in hPGCs and suggest that XCD evolved in humans to regulate X-linked genes in pre-implantation embryos and PGCs. Furthermore, we found a unique mechanism of X-chromosome regulation in human primordial oocytes. Therefore, future studies of human germline development must consider the sexually dimorphic X-chromosome dosage compensation mechanisms in the prenatal germline.",
-,No,20201214,meqtl,33216750,Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles.,PLoS Genet,"Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.",
-,No,20201214,methods,33205092,Patterns of Reliability: Assessing the Reproducibility and Integrity of DNA Methylation Measurement.,Patterns (N Y),"DNA methylation plays an important role in both normal human development and risk of disease. The most utilized method of assessing DNA methylation uses BeadChips, generating an epigenome-wide ""snapshot"" of >450,000 observations (probe measurements) per assay. However, the reliability of each of these measurements is not equal, and little consideration is paid to consequences for research. We correlated repeat measurements of the same DNA samples using the Illumina HumanMethylation450K and the Infinium MethylationEPIC BeadChips in 350 blood DNA samples. Probes that were reliably measured were more heritable and showed consistent associations with environmental exposures, gene expression, and greater cross-tissue concordance. Unreliable probes were less replicable and generated an unknown volume of false negatives. This serves as a lesson for working with DNA methylation data, but the lessons are equally applicable to working with other data: as we advance toward generating increasingly greater volumes of data, failure to document reliability risks harming reproducibility.© 2020 The Authors.",
-,No,20201214,methods,33230324,Simultaneous profiling of chromatin accessibility and methylation on human cell lines with nanopore sequencing.,Nat Methods,"Probing epigenetic features on DNA has tremendous potential to advance our understanding of the phased epigenome. In this study, we use nanopore sequencing to evaluate CpG methylation and chromatin accessibility simultaneously on long strands of DNA by applying GpC methyltransferase to exogenously label open chromatin. We performed nanopore sequencing of nucleosome occupancy and methylome (nanoNOMe) on four human cell lines (GM12878, MCF-10A, MCF-7 and MDA-MB-231). The single-molecule resolution allows footprinting of protein and nucleosome binding, and determination of the combinatorial promoter epigenetic signature on individual molecules. Long-read sequencing makes it possible to robustly assign reads to haplotypes, allowing us to generate a fully phased human epigenome, consisting of chromosome-level allele-specific profiles of CpG methylation and chromatin accessibility. We further apply this to a breast cancer model to evaluate differential methylation and accessibility between cancerous and noncancerous cells.",
-,No,20201214,prediction,33256852,Whole blood DNA methylation aging markers predict colorectal cancer survival: a prospective cohort study.,Clin Epigenetics,"Blood DNA methylation-based aging algorithms predict mortality in the general population. We investigated the prognostic value of five established DNA methylation aging algorithms for patients with colorectal cancer (CRC).AgeAccelHorvath, AgeAccelHannum, DNAmMRscore, AgeAccelPheno and AgeAccelGrim were constructed using whole blood epi-genomic data from 2206 CRC patients. After a median follow-up of 6.2 years, 1079 deaths were documented, including 596 from CRC. Associations of the aging algorithms with survival outcomes were evaluated using the Cox regression and survival curves. Harrell's C-statistics were computed to investigate predictive performance.Adjusted hazard ratios (95% confidence intervals) of all-cause mortality for patients in the third compared to the first tertile were 1.66 (1.32, 2.09) for the DNAmMRscore, 1.35 (1.14, 1.59) for AgeAccelPheno and 1.65 (1.37, 2.00) for AgeAccelGrim, even after adjustment for age, sex and stage. AgeAccelHorvath and AgeAccelHannum were not associated with all-cause or CRC-specific mortality. In stage-specific analyses, associations were much stronger for patients with early or intermediate stage cancers (stages I, II and III) than for patients with metastatic (stage IV) cancers. Associations were weaker and less often statistically significant for CRC-specific mortality. Adding DNAmMRscore, AgeAccelPheno or AgeAccelGrim to models including age, sex and tumor stage improved predictive performance moderately.DNAmMRscore, AgeAccelPheno and AgeAccelGrim could serve as non-invasive CRC prognostic biomarkers independent of other commonly used markers. Further research should aim for tailoring and refining such algorithms for CRC patients and to explore their value for enhanced prediction of treatment success and treatment decisions.",
-,No,20201214,prediction,33213499,A pitfall for machine learning methods aiming to predict across cell types.,Genome Biol,"Machine learning models that predict genomic activity are most useful when they make accurate predictions across cell types. Here, we show that when the training and test sets contain the same genomic loci, the resulting model may falsely appear to perform well by effectively memorizing the average activity associated with each locus across the training cell types. We demonstrate this phenomenon in the context of predicting gene expression and chromatin domain boundaries, and we suggest methods to diagnose and avoid the pitfall. We anticipate that, as more data becomes available, future projects will increasingly risk suffering from this issue.",
-,No,20201214,reference,33268789,A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation.,Nat Commun,"DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers.",
-,No,20201214,wgbs,33228774,Comparison of methylation capture sequencing and Infinium MethylationEPIC array in peripheral blood mononuclear cells.,Epigenetics Chromatin,"Epigenome-wide association studies (EWAS) have been widely applied to identify methylation CpG sites associated with human disease. To date, the Infinium MethylationEPIC array (EPIC) is commonly used for high-throughput DNA methylation profiling. However, the EPIC array covers only 30% of the human methylome. Methylation Capture bisulfite sequencing (MC-seq) captures target regions of methylome and has advantages of extensive coverage in the methylome at an affordable price.Epigenome-wide DNA methylation in four peripheral blood mononuclear cell samples was profiled by using SureSelectXT Methyl-Seq for MC-seq and EPIC platforms separately. CpG site-based reproducibility of MC-seq was assessed with DNA sample inputs ranging in quantity of high (> 1000 ng), medium (300-1000 ng), and low (150 ng-300 ng). To compare the performance of MC-seq and the EPIC arrays, we conducted a Pearson correlation and methylation value difference at each CpG site that was detected by both MC-seq and EPIC. We compared the percentage and counts in each CpG island and gene annotation between MC-seq and the EPIC array.After quality control, an average of 3,708,550 CpG sites per sample were detected by MC-seq with DNA quantity > 1000 ng. Reproducibility of DNA methylation in MC-seq-detected CpG sites was high among samples with high, medium, and low DNA inputs (r > 0.96). The EPIC array captured an average of 846,464 CpG sites per sample. Compared with the EPIC array, MC-seq detected more CpGs in coding regions and CpG islands. Among the 472,540 CpG sites captured by both platforms, methylation of a majority of CpG sites was highly correlated in the same sample (r: 0.98-0.99). However, methylation for a small proportion of CpGs (N = 235) differed significantly between the two platforms, with differences in beta values of greater than 0.5.Our results show that MC-seq is an efficient and reliable platform for methylome profiling with a broader coverage of the methylome than the array-based platform. Although methylation measurements in majority of CpGs are highly correlated, a number of CpG sites show large discrepancy between the two platforms, which warrants further investigation and needs cautious interpretation.",
-,No,20201214,cancer,33288854,Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression.,Commun Biol,"Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. In the current study we examine whether tumour DNA methylation (DNAme) profiling combined with genomic data is able to identify cell of origin and to reveal pathways involved in PanNET progression. We analyse genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confirm cell identity, we investigate ARX and PDX1 expression. Based on epigenetic similarities, PanNETs cluster in α-like, β-like and intermediate tumours. The epigenetic similarity to α-cells progressively decreases in the intermediate tumours, which present unclear differentiation. Specific transcription factor methylation and expression vary in the respective α/β-tumour groups. Depending on DNAme similarity to α/β-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.",
-,No,20210111,dnam age,33377907,Racial Disparities in Epigenetic Aging of the Right vs Left Colon.,J Natl Cancer Inst,"There are well-documented racial differences in age-of-onset and laterality of colorectal cancer. Epigenetic age acceleration is postulated to be an underlying factor. However, comparative studies of side-specific colonic tissue epigenetic aging are lacking. Here, we performed DNA methylation analysis of matched right and left biopsies of normal colon from 128 individuals. Among African Americans (n = 88), the right colon showed accelerated epigenetic aging as compared to individual-matched left colon (1.51 years; 95% CI = 0.62 to 2.40 years; two-sided P = .001). In contrast, among European Americans (n = 40), the right colon shows remarkable age deceleration (1.93 years; 95% CI = 0.65 to 3.21 years; two-sided P = .004). Further, epigenome-wide analysis of DNA methylation identifies a unique pattern of hypermethylation in African American right colon. Our study is the first to report such race and side-specific differences in epigenetic aging of normal colon, providing novel insight into the observed younger age-of-onset and relative preponderance of right-side colon neoplasia in African Americans.© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
-,No,20210111,dnamage,33384442,Targeted methods for epigenetic age predictions in mice.,Sci Rep,"Age-associated DNA methylation reflects aspect of biological aging-therefore epigenetic clocks for mice can elucidate how the aging process in this model organism is affected by specific treatments or genetic background. Initially, age-predictors for mice were trained for genome-wide DNA methylation profiles and we have recently described a targeted assay based on pyrosequencing of DNA methylation at only three age-associated genomic regions. Here, we established alternative approaches using droplet digital PCR (ddPCR) and barcoded bisulfite amplicon sequencing (BBA-seq). At individual CG dinucleotides (CpGs) the correlation of DNA methylation with chronological age was slightly higher for pyrosequencing and ddPCR as compared to BBA-seq. On the other hand, BBA-seq revealed that neighboring CpGs tend to be stochastically modified at murine age-associated regions. Furthermore, the binary sequel of methylated and non-methylated CpGs in individual reads can be used for single-read predictions, which may reflect heterogeneity in epigenetic aging. In comparison to C57BL/6 mice the single-read age-predictions using BBA-seq were also accelerated in the shorter-lived DBA/2 mice, and in C57BL/6 mice with a lifespan quantitative trait locus of DBA/2 mice. Taken together, we describe alternative targeted methods for epigenetic age predictions that provide new perspectives for aging-intervention studies in mice.",
-,No,20210111,cell types,33407091,Cell-specific characterization of the placental methylome.,BMC Genomics,"DNA methylation (DNAm) profiling has emerged as a powerful tool for characterizing the placental methylome. However, previous studies have focused primarily on whole placental tissue, which is a mixture of epigenetically distinct cell populations. Here, we present the first methylome-wide analysis of first trimester (n = 9) and term (n = 19) human placental samples of four cell populations: trophoblasts, Hofbauer cells, endothelial cells, and stromal cells, using the Illumina EPIC methylation array, which quantifies DNAm at > 850,000 CpGs.The most distinct DNAm profiles were those of placental trophoblasts, which are central to many pregnancy-essential functions, and Hofbauer cells, which are a rare fetal-derived macrophage population. Cell-specific DNAm occurs at functionally-relevant genes, including genes associated with placental development and preeclampsia. Known placental-specific methylation marks, such as those associated with genomic imprinting, repetitive element hypomethylation, and placental partially methylated domains, were found to be more pronounced in trophoblasts and often absent in Hofbauer cells. Lastly, we characterize the cell composition and cell-specific DNAm dynamics across gestation.Our results provide a comprehensive analysis of DNAm in human placental cell types from first trimester and term pregnancies. This data will serve as a useful DNAm reference for future placental studies, and we provide access to this data via download from GEO (GSE159526), through interactive exploration from the web browser ( https://robinsonlab.shinyapps.io/Placental_Methylome_Browser/ ), and through the R package planet, which allows estimation of cell composition directly from placental DNAm data.",
-,Yes,20210111,ewas,33317634,High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations.,Clin Epigenetics,"Children of aged fathers are at a higher risk of developing mental disorders. Alterations in sperm DNA methylation have been implicated as a potential cause. However, age-dependent modifications of the germ cells' epigenome remain poorly understood. Our objective was to assess the DNA methylation profile of human spermatozoa during aging.We used a high throughput, customized methylC-capture sequencing (MCC-seq) approach to characterize the dynamic DNA methylation in spermatozoa from 94 fertile and infertile men, who were categorized as young, 48 men between 18-38 years or old 46 men between 46-71 years. We identified more than 150,000 age-related CpG sites that are significantly differentially methylated among 2.65 million CpG sites covered. We conducted machine learning using our dataset to predict the methylation age of subjects; the age prediction accuracy based on our assay provided a more accurate prediction than that using the 450 K chip approach. In addition, we found that there are more hypermethylated (62%) than hypomethylated (38%) CpG sites in sperm of aged men, corresponding to 798 of total differential methylated regions (DMRs), of which 483 are hypermethylated regions (HyperDMR), and 315 hypomethylated regions (HypoDMR). Moreover, the distribution of age-related hyper- and hypomethylated CpGs in sperm is not random; the CpG sites that were hypermethylated with advanced age were frequently located in the distal region to genes, whereas hypomethylated sites were near to gene transcription start sites (TSS). We identified a high density of age-associated CpG changes in chromosomes 4 and 16, particularly HyperDMRs with localized clusters, the chr4 DMR cluster overlaps PGC1α locus, a protein involved in metabolic aging and the chr16 DMR cluster overlaps RBFOX1 locus, a gene implicated in neurodevelopmental disease. Gene ontology analysis revealed that the most affected genes by age were associated with development, neuron projection, differentiation and recognition, and behaviour, suggesting a potential link to the higher risk of neurodevelopmental disorders in children of aged fathers.We identified thousands of age-related and sperm-specific epigenetic alterations. These findings provide novel insight in understanding human sperm DNA methylation dynamics during paternal aging, and the subsequently affected genes potentially related to diseases in offspring.",
-,Yes,20210111,ewas,33319642,Epigenome-wide association study and network analysis for IgA Nephropathy from CD19<sup>+</sup> B-cell in Chinese Population.,Epigenetics,"IgA nephropathy (IgAN) is the most common primary glomerular disease in China and worldwide. The proliferation of B cells is known to be associated with both risk and prognosis of IgAN, but the epigenetic mechanism underlying this association is unknown. In this study we carried out the first Epigenome-wide Association Study (EWAS) by using the latest Infinium Methylation EPIC BeadChip on 184 B cell-specific samples (92 case/control pairs) for Chinese IgAN population. After rigorous data normalization and residual batch effect correction, linear mixed effect model was used to detect methylation CpG sites associated with IgAN adjusting for age, gender and smoking. False discovery rate (FDR) less than 10% was used to account for multiple testing. Weighted gene co-methylation networks were generated to identify gene modules highly correlated with IgAN. A permutation test was performed to account for the potential effect of overfitting. After adjusting clinical covariates and potential technical batch effects, three CpGs corresponding toPCDH17, TERT, WDR82genes and three in the intergenic regions passed the genome-wide significant threshold. Methylation network analysis identified an additional IgAN associated gene module, containing 72 significant CpGs includingGALNT6, IQSEC1, CDC16 and SYS1, involved in the pathway related to tubular atrophy/interstitial fibrosis of IgAN. These results suggested important DNA methylation and gene targets in CD19+ B cells for the pathogenesis of IgAN.",
-,Yes,20210111,ewas,33324494,Prenatal lead exposure and cord blood DNA methylation in PROGRESS: an epigenome-wide association study.,Environ Epigenet,"The effects of prenatal lead exposure on child development include impaired growth and cognitive function. DNA methylation might be involved in the underlying mechanisms and previous epigenome-wide association studies reported associations between lead exposure during pregnancy and cord blood methylation levels. However, it is unclear during which developmental stage lead exposure is most harmful. Cord blood methylation levels were assayed in 420 children from a Mexican pre-birth cohort using the Illumina Infinium MethylationEPIC microarray. Lead concentrations were measured in umbilical cord blood as well as in blood samples from the mothers collected at 2nd and 3rd trimester and delivery using inductively coupled plasma-mass spectrometry. In addition, maternal bone lead levels were measured in tibia and patella using X-ray fluorescence. Comprehensive quality control and preprocessing of microarray data was followed by an unbiased restriction to methylation sites with substantial variance. Methylation levels at 202 111 cytosine-phosphate-guanine sites were regressed on each exposure adjusting for child sex, leukocyte composition, batch variables, gestational age, birthweight-for-gestational-age, maternal age, maternal education and mode of delivery. We find no association between prenatal lead exposure and cord blood methylation. This null result is strengthened by a sensitivity analysis showing that in the same dataset known biomarkers for birthweight-for-gestational-age can be recovered and the fact that phenotypic associations with lead exposure have been described in the same cohort.© The Author(s) 2020. Published by Oxford University Press.",
-,Yes,20210111,ewas,33331245,Maternal haemoglobin levels in pregnancy and child DNA methylation: a study in the Pregnancy And Childhood Epigenetics Consortium.,Epigenetics,"Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analysed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 child and 1,962 adolescent whole-blood samples derived from ten cohorts. DNA methylation was measured using Illumina Infinium Methylation450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.",
-,Yes,20210111,ewas,33338541,Shared DNA methylation signatures in childhood allergy: the MeDALL study.,J Allergy Clin Immunol,"Differential DNA methylation associated with allergy might provide novel insights into shared or unique etiology of asthma, rhinitis and eczema.We sought to identify DNA methylation profiles associated with childhood allergy.Within the European Mechanisms of the Development of ALLergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation using a cross-sectional design. Allergy is defined as having symptoms from at least one allergic disease (asthma/rhinitis/eczema) and positive serum specific IgE to common aeroallergens. The discovery study included 219 cases and 417 controls at age 4 and 228 cases and 593 controls at age 8 from three birth cohorts, with replication analyses in 325 cases and 1,111 controls. We performed additional analyses on 21 replicated sites in 785 cases and 2,124 controls by allergic symptoms only from eight cohorts, three not previously included in analyses.We identified 80 differentially methylated CpG sites (CpGs) which showed 1-3% methylation difference in the discovery phase, of which 21, including five novel CpGs, passed genome-wide significance after meta-analysis. All 21 CpGs were also significantly differentially methylated with allergic symptoms, and shared between asthma, rhinitis and eczema. The 21 CpGs mapped to relevant genes, including ACOT7, LMAN3 and CLDN23. All 21 CpGs were differently methylated in asthma in isolated eosinophils, and ten were replicated in respiratory epithelium.Reduced whole blood DNA methylation at 21 CpGs was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis and eczema.Copyright © 2020. Published by Elsevier Inc.",
-,Yes,20210111,ewas,33339956,Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males.,Mol Psychiatry,"Post-traumatic stress disorder (PTSD) is a heterogeneous condition evidenced by the absence of objective physiological measurements applicable to all who meet the criteria for the disorder as well as divergent responses to treatments. This study capitalized on biological diversity observed within the PTSD group observed following epigenome-wide analysis of a well-characterized Discovery cohort (N = 166) consisting of 83 male combat exposed veterans with PTSD, and 83 combat veterans without PTSD in order to identify patterns that might distinguish subtypes. Computational analysis of DNA methylation (DNAm) profiles identified two PTSD biotypes within the PTSD+ group, G1 and G2, associated with 34 clinical features that are associated with PTSD and PTSD comorbidities. The G2 biotype was associated with an increased PTSD risk and had higher polygenic risk scores and a greater methylation compared to the G1 biotype and healthy controls. The findings were validated at a 3-year follow-up (N = 59) of the same individuals as well as in two independent, veteran cohorts (N = 54 and N = 38), and an active duty cohort (N = 133). In some cases, for example Dopamine-PKA-CREB and GABA-PKC-CREB signaling pathways, the biotypes were oppositely dysregulated, suggesting that the biotypes were not simply a function of a dimensional relationship with symptom severity, but may represent distinct biological risk profiles underpinning PTSD. The identification of two novel distinct epigenetic biotypes for PTSD may have future utility in understanding biological and clinical heterogeneity in PTSD and potential applications in risk assessment for active duty military personnel under non-clinician-administered settings, and improvement of PTSD diagnostic markers.",
-,Yes,20210111,ewas,33354722,Epigenome-wide association study of diet quality in the Women's Health Initiative and TwinsUK cohort.,Int J Epidemiol,"Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445 548 loci in the Women's Health Initiative (WHI) and the TwinsUK cohort.The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models that regressed methylation on AHEI-2010, adjusting for cell composition, chip number and location, study characteristics, principal components of genetic relatedness, age, smoking status, race/ethnicity and body mass index (BMI). Statistical significance was defined as a false discovery rate < 0.05. Significant sites were tested for replication in the TwinsUK cohort, with significant replication defined by P < 0.05 and a consistent direction.Diet quality was significantly associated with differential DNA methylation at 428 cytosine-phosphate-guanine (CpG) sites in the discovery cohort. A total of 24 CpG sites were consistent with replication in the TwinsUK cohort, more than would be expected by chance (P = 2.7x10-4), with one site replicated in both the blood and adipose tissue (cg16379999 located in the body of SEL1L).Diet quality was associated with methylation at 24 CpG sites, several of which have been associated with adiposity, inflammation and dysglycaemia. These findings may provide insight into pathways through which diet influences chronic disease.© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.",
-,Yes,20210111,ewas,33356526,"Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study.",Environ Health Perspect,"Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype.We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators.Among 583 mother-infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate(FDR)<0.05and differentially methylated regions (DMRs) were identified using comb-p (Šidák-adjustedp<0.05). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin.Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations (�=0.28-0.76). Methylation at one DMP (cg18587484), annotated to the geneTJAP1, was associated with perfluorooctanoate (PFOA) atFDR< 0.05. Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth (RPTOR), lipid homeostasis (PON1,PON3,CIDEB,NR1H2), inflammation and immune activity (RASL11B,RNF39), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively (FDR< 0.1).DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. https://doi.org/10.1289/EHP6888.",
-,Yes,20210111,ewas,33371772,DNA methylation signatures of adolescent victimization: analysis of a longitudinal monozygotic twin sample.,Epigenetics,"Accumulating evidence suggests that individuals exposed to victimization at key developmental stages may have different epigenetic fingerprints compared to those exposed to no/minimal stressful events, however results are inconclusive. This study aimed to strengthen causal inference regarding the impact of adolescent victimization on the epigenome by controlling for genetic variation, age, gender, and shared environmental exposures. We conducted longitudinal epigenome-wide association analyses (EWAS) on DNA methylation (DNAm) profiles of 118 monozygotic (MZ) twin pairs from the Environmental Risk study with and without severe adolescent victimization generated using buccal DNA collected at ages 5, 10 and 18, and the Illumina EPIC array. Additionally, we performed cross-sectional EWAS on age-18 blood and buccal DNA from the same individuals to elucidate tissue-specific signatures of severe adolescent victimization. Our analyses identified 20 suggestive differentially methylated positions (DMPs) (P< 5e-05), with altered DNAm trajectories between ages 10-18 associated with severe adolescent victimization (�Beta range = -5.5%-5.3%). Age-18 cross-sectional analyses revealed 72 blood (�Beta range = -2.2%-3.4%) and 42 buccal (�Beta range = -3.6%-4.6%) suggestive severe adolescent victimization-associated DMPs, with some evidence of convergent signals between these two tissue types. Downstream regional analysis identified significant differentially methylated regions (DMRs) inLGR6andANK3(ŠidákP = 5e-09 and 4.07e-06), and one upstream ofCCL27(ŠidákP = 2.80e-06) in age-18 blood and buccal EWAS, respectively. Our study represents the first longitudinal MZ twin analysis of DNAm and severe adolescent victimization, providing initial evidence for altered DNA methylomic signatures in individuals exposed to adolescent victimization.",
-,Yes,20210111,ewas,33396735,Epigenome-Wide Association of Infant Feeding and Changes in DNA Methylation from Birth to 10 Years.,Nutrients,"Epigenetic factors have been suggested as mediators of early-life nutrition to future health. Prior studies focused on breastfeeding effects on DNA methylation (DNAm), ignoring other feeding modes. In this analysis of the Isle of Wight birth cohort, feeding modes were categorized as exclusive breastfeeding (EBF), exclusive formula feeding (EFF), and mixed feeding based on whether the respective feeding mode lasted for at least 3 months. In addition, in the past, infant feeding modes were assessed using DNAm at one time point in childhood, not changes of DNAm. In this paper, methylation differences (delta DNAm) were calculated by subtracting residual methylation values at birth from age 10 years (adjusting for cell types and season of blood collection at both ages). These deltas were estimated for all methylation sites where cytosine was followed by guanine (cytosine guanine dinucleotide (CpG) sites). Then, we performed an epigenome-wide association study contrasting EBF, EFF, and mixed feeding with delta DNAm that represents changes in methylation from birth to 10 years. A total of 87 CpGs (EBF: 27 CpGs, EFF: 48 CpGs, mixed: 12 CpGs) were identified using separate linear regression models adjusting for confounders and multiple testing. The sum of all changes in methylation from birth to age 10 years was significantly lower in the EFF group. Correspondingly, the number of CpGs with a methylation decline was 4.7% higher reflecting 13,683 CpGs. Lower methylation related to exclusive formula feeding and its adverse potential for the child's development needs future research to reduce adverse health effects.",
-,Yes,20210111,ewas,33397400,Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles.,Genome Med,"The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer's disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses.We obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10-100 ≤ P ≤ 2.44 × 10-8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10-4 ≤ P ≤ 3.01 × 10-2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24.APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.",
-,Yes,20210111,ewas,33400784,Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa.,J Infect Dis,"Tuberculosis (TB) is the most deadly infectious disease globally and highly prevalent in the developing world. For individuals infected with both Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV), the risk of active TB is 10% or more annually. Previously, we identified in a genome-wide association study (GWAS) a region on chromosome 5 associated with resistance to TB, which included epigenetic marks that could influence gene regulation. We hypothesized that HIV-infected individuals exposed to Mtb, who remain disease free, carry epigenetic changes that strongly protect them from active TB.We conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania and integrated data from our GWAS.We identified 3 regions of interest that included markers that were differentially methylated between TB cases and LTBI controls: chromosome 1 (RNF220, p=4x10 -5), chromosome 2 (between COPS8 and COL6A3, p=2.7x10 -5), and chromosome 5 (CEP72, p=1.3x10 -5). These methylation results co-localized with associated SNPs, methylation QTLs, and methylation x SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung.Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.",
-,Yes,20210111,ewas,33406918,Epigenome-wide association study of maternal hemoglobin A1c in pregnancy and cord blood DNA methylation.,Epigenomics,"Background:Gestational hyperglycemia is associated with adverse perinatal outcomes and long-term offspring metabolic programming, likely through dysregulation of DNA methylation (DNAm).Materials & methods:We tested associations between maternal HbA1c and cord blood DNAm among 412 mother-child pairs in the genetics of glucose regulation in gestation and growth (Gen3G) and implemented Mendelian randomization to infer causality. We sought replication in an independent sample from Healthy Start.Results:Higher second trimester HbA1c levels were associated with lower DNAm at cg21645848 (p = 3.9 × 10-11) nearURGCP. Mendelian randomization and replication analyses showed same direction of effect between HbA1c and DNAm at cg21645848, but did not reach statistical significance.Conclusion:We found that higher maternal glycemia reflected by HbA1c is associated with cord blood DNAm atURGCP, a gene related with inflammatory pathways.",
-,Yes,20210111,ewas,33407823,Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood.,Clin Epigenetics,"The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood.DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex.High and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases.The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.",
-,No,20210111,global,33317014,Prenatal Multivitamin Use and <i>MTHFR</i> Genotype Are Associated with Newborn Cord Blood DNA Methylation.,Int J Environ Res Public Health,"Fetal development involves cellular differentiation and epigenetic changes-complex processes that are sensitive to environmental factors. Maternal nutrient levels during pregnancy affect development, and methylene tetrahydrofolate reductase (MTHFR) is important for processing the nutrient folate.We hypothesize that supplement intake before pregnancy and maternal genotype are associated with DNA methylation in newborns.In the pregnancy cohort, Early Autism Risk Longitudinal Investigation (EARLI), health history, and genotype information was obtained (n = 249 families). Cord blood DNA methylation (n = 130) was measured using the Illumina HumanMethylation450k array and global DNA methylation levels were computed over 455,698 sites. Supplement use preconception and during pregnancy were surveyed at visits during pregnancy. We evaluated associations between maternal preconception supplement intake and global DNA methylation or DNA methylation density distributions of newborn cord blood, stratified by the presence of a variant maternalMTHFRC677T allele.Maternal preconceptional multivitamin intake was associated with cord blood methylation, dependent on maternalMTHFRgenotype (interaction termp= 0.013). For mothers without theMTHFRvariant allele, multivitamin intake was associated with 0.96% (95% CI: 0.09, 1.83) higher global cord blood methylation (p= 0.04) and was also associated with the cumulative density distribution of methylation (p= 0.03). For mothers with at least one variant allele, multivitamin intake had a null -0.06% (95% CI: -0.45, 0.33) association with global cord blood DNA methylation, and was not associated with the cumulative density distribution (p= 0.37).We observed that cord blood DNA methylation was associated with maternal supplement exposure preconception and maternal genotype. Genetic context should be considered when assessing DNA methylation effects of modifiable risk factors around the time of pregnancy.",
-,No,20210111,methods,33335112,Detecting methylation signatures in neurodegenerative disease by density-based clustering of applications with reducing noise.,Sci Rep,"There have been numerous genetic and epigenetic datasets generated for the study of complex disease including neurodegenerative disease. However, analysis of such data often suffers from detecting the outliers of the samples, which subsequently affects the extraction of the true biological signals involved in the disease. To address this critical issue, we developed a novel framework for identifying methylation signatures using consecutive adaptation of a well-known outlier detection algorithm, density based clustering of applications with reducing noise (DBSCAN) followed by hierarchical clustering. We applied the framework to two representative neurodegenerative diseases, Alzheimer's disease (AD) and Down syndrome (DS), using DNA methylation datasets from public sources (Gene Expression Omnibus, GEO accession ID: GSE74486). We first applied DBSCAN algorithm to eliminate outliers, and then used Limma statistical method to determine differentially methylated genes. Next, hierarchical clustering technique was applied to detect gene modules. Our analysis identified a methylation signature comprising 21 genes for AD and a methylation signature comprising 89 genes for DS, respectively. Our evaluation indicated that these two signatures could lead to high classification accuracy values (92% and 70%) for these two diseases. In summary, this framework will be useful to better detect outlier-free genetic and epigenetic signatures in various complex diseases and their developmental stages.",
-,No,20210111,methods,33350870,Estimating cell-type-specific DNA methylation effects in heterogeneous cellular populations.,Epigenomics,Aim:To develop a method for estimating cell-specific effects in epigenomic association studies in the presence of cell type heterogeneity.Materials & methods:We utilized Monte Carlo Expectation-Maximization (MCEM) algorithm with Metropolis-Hastings sampler to reconstruct the 'missing' cell-specific methylations and to estimate their associations with phenotypes free of confounding by cell type proportions.Results:Simulations showed reliable performance of the method under various settings including when the cell type is rare. Application to a real dataset recapitulated the directly measured cell-specific methylation pattern in whole blood.Conclusion:This work provides a framework to identify important cell groups and account for cell type composition useful for studying the role of epigenetic changes in human traits and diseases.,
-,No,20210111,variation,33402197,Equivalent DNA methylation variation between monozygotic co-twins and unrelated individuals reveals universal epigenetic inter-individual dissimilarity.,Genome Biol,"Although the genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. Particularly for young and healthy monozygotic twins, DNA methylation divergence, if any, may be restricted to stochastic processes occurring post-twinning during embryonic development and early life. However, to what extent such stochastic mechanisms can systematically provide a stable source of inter-individual epigenetic variation remains uncertain until now.We enriched for inter-individual stochastic variation by using an equivalence testing-based statistical approach on whole blood methylation microarray data from healthy adolescent monozygotic twins. As a result, we identified 333 CpGs displaying similarly large methylation variation between monozygotic co-twins and unrelated individuals. Although their methylation variation surpasses measurement error and is stable in a short timescale, susceptibility to aging is apparent in the long term. Additionally, 46% of these CpGs were replicated in adipose tissue. The identified sites are significantly enriched at the clustered protocadherin loci, known for stochastic methylation in developing neurons. We also confirmed an enrichment in monozygotic twin DNA methylation discordance at these loci in whole genome bisulfite sequencing data from blood and adipose tissue.We have isolated a component of stochastic methylation variation, distinct from genetic influence, measurement error, and epigenetic drift. Biomarkers enriched in this component may serve in the future as the basis for universal epigenetic fingerprinting, relevant for instance in the discrimination of monozygotic twin individuals in forensic applications, currently impossible with standard DNA profiling.",
-,No,20210111,mitochondria,33385171,Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance.,Hum Genet,"Mitochondrial (MT) dysfunction is a hallmark of aging and has been associated with most aging-related diseases as well as immunological processes. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial DNA (mtDNA) abundance. In this study, mtDNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that the abundance of mtDNA was significantly elevated in women compared to men, was negatively correlated with advanced age, higher smoking exposure, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and lower mortality. In addition, several biochemistry markers in blood-related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with mtDNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with mtDNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of mtDNA abundance to be around 8%. To investigate the consequence of altered mtDNA abundance, we performed a phenome-wide association study and found that mtDNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating mtDNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease-relevant processes, particularly those related to immunity and established mitochondrial functions.",
-,No,20210111,prediction,33337494,Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.,JAMA Netw Open,"Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies.To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB.This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019.Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites.The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation.Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways.This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.",
-,No,20210111,prediction,33308293,Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm.,Mol Autism,"Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes.We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS.Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case-control status.The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited.Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.",
-,No,20210111,prediction,33344728,A polyepigenetic glucocorticoid exposure score at birth and childhood mental and behavioral disorders.,Neurobiol Stress,"Maternal depression and anxiety during pregnancy may enhance fetal exposure to glucocorticoids (GCs) and harm neurodevelopment. We tested whether a novel cross-tissue polyepigenetic biomarker indicative ofin uteroexposure to GC is associated with mental and behavioral disorders and their severity in children, possibly mediating the associations between maternal prenatal depressive and anxiety symptoms and these child outcomes.Children (n = 814) from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study were followed-up from birth to age 7.1-10.7 years. A weighted polyepigenetic GC exposure score was calculated based on the methylation profile of 24 CpGs from umbilical cord blood. Child diagnosis of mental and behavioral disorder (n = 99) and its severity, defined as the number of days the child had received treatment (all 99 had received outpatient treatment and 8 had been additionally in inpatient treatment) for mental or behavioral disorder as the primary diagnosis, came from the Care Register for Health Care. Mothers (n = 408) reported on child total behavior problems at child's age of 2.3-5.8 years and their own depressive and anxiety symptoms during pregnancy (n = 583).The fetal polyepigenetic GC exposure score at birth was not associated with child hazard of mental and behavioral disorder (HR = 0.82, 95% CI 0.54; 1.24, p = 0.35) or total behavior problems (unstandardized beta = -0.10, 95% CI -0.31; 0.10, p = 0.33). However, for one standard deviation decrease in the polyepigenetic score, the child had spent 2.94 (95%CI 1.59; 5.45, p < 0.001) more days in inpatient or outpatient treatment with any mental and behavioral disorder as the primary diagnosis. Criteria for mediation tests were not met.These findings suggest that fetal polyepigenetic GC exposure score at birth was not associated with any mental or behavioral disorder diagnosis or mother-rated total behavior problems, but it may contribute to identifying children at birth who are at risk for more severe mental or behavioral disorders.© 2020 The Authors.",
-,No,20210125,omics,33481009,Multi-omics analyses of cognitive traits and psychiatric disorders highlights brain-dependent mechanisms.,Hum Mol Genet,"Integrating findings from genome-wide association studies with molecular datasets can develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied the principles of Mendelian randomization (MR) to investigate whether brain-derived gene expression (n = 1194) may be responsible for mediating the effect of genetic variants on eight cognitive and psychological outcomes (attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, bipolar disorder, depression, intelligence, insomnia, neuroticism and schizophrenia). Transcriptome-wide analyses identified 83 genes associated with at least one outcome (PBonferroni < 6.72 × 10-6), with multiple-trait colocalization also implicating changes to brain-derived DNA methylation at nine of these loci. Comparing effects between outcomes identified evidence of enrichment which may reflect putative causal relationships, such as an inverse relationship between genetic liability towards schizophrenia risk and cognitive ability in later life. Repeating these analyses in whole blood (n = 31 684), we replicated 58.2% of brain-derived effects (based on P < 0.05). Finally, we undertook phenome-wide evaluations at associated loci to investigate pleiotropic effects with 700 complex traits. This highlighted pleiotropic loci such as FURIN (initially implicated in schizophrenia risk (P = 1.05 × 10-7)) which had evidence of an effect on 28 other outcomes, as well as genes which may have a more specific role in disease pathogenesis (e.g. SLC12A5 which only provided evidence of an effect on depression (P = 7.13 × 10-10)). Our results support the utility of whole blood as a valuable proxy for informing initial target identification but also suggest that gene discovery in a tissue-specific manner may be more informative. Finally, non-pleiotropic loci highlighted by our study may be of use for therapeutic translational endeavours.© The Author(s) 2021. Published by Oxford University Press.",
-,Yes,20210125,ewas,33468710,DNA methylation perturbations may link altered development and aging in the lung.,Aging (Albany NY),"Fetal perturbations in DNA methylation during lung development may reveal insights into the enduring impacts on adult lung health and disease during aging that have not been explored altogether before. We studied the association between genome-wide DNA-methylation and post-conception age in fetal-lung (n=78, 42 exposed to in-utero-smoke (IUS)) tissue and chronological age in adult-lung tissue (n=160, 114 with Chronic Obstructive Pulmonary Disease) using multi-variate linear regression models with covariate adjustment and tested for effect modification by phenotypes. Overlapping age-associations were evaluated for functional and tissue-specific enrichment using the Genotype-Tissue-Expression (GTEx) project. We identified 244 age-associated differentially methylated positions and 878 regions overlapping between fetal and adult-lung tissues. Hyper-methylated CpGs (96%) were enriched in transcription factor activity (FDR adjusted P=2x10-33) and implicated in developmental processes including embryonic organ morphogenesis, neurogenesis and growth delay. Hypo-methylated CpGs (2%) were enriched in oxido-reductase activity and VEGFA-VEGFR2 Signaling. Twenty-one age-by-sex and eleven age-by-pack-years interactions were statistically significant (FDR<0.05) in adult-lung tissue. DNA methylation in transcription factors during development in fetal lung recapitulates in adult-lung tissue with aging. These findings reveal molecular mechanisms and pathways that may link disrupted development in early-life and age-associated lung diseases.",
-,Yes,20210125,ewas,33450751,Epigenome-wide change and variation in DNA methylation in childhood: Trajectories from birth to late adolescence.,Hum Mol Genet,"DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for nonlinear change and inter-individual variation in nonlinear trajectories was somewhat less common (11% and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. By contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often nonlinear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.© The Author(s) 2021. Published by Oxford University Press.",
-,Yes,20210125,ewas,33448462,"High blood pressure in pregnancy, DNA methylation, and later blood pressure in African American women enrolled in the InterGEN Study.",Birth,"Few studies have examined the effects of high blood pressure (BP) in pregnancy, preeclampsia, or eclampsia on later BP, and the epigenetics of this phenomenon is similarly poorly understood, especially among African Americans. The purpose of this study was to examine the association between high BP in pregnancy, epigenomics, and later BP in African American women in the InterGEN Study (n = 250).In cross-sectional analyses, regression and linear mixed-effects models were employed to examine the effects of high BP in pregnancy on: (a) epigenetic associations (DNA methylation) and (b) BP 3-5 years after birth. The 850K Illumina EPIC BeadChip was used for evaluating epigenome-wide DNA methylation. High BP in pregnancy, preeclampsia, or eclampsia was self-reported by women, and BP was measured 3-5 years after birth, per JNC-7 guidelines. DNA methylation and clinical BP were the main outcomes.Mean age of enrolled women was 31.2 years, 21.8% were smokers, 58% had some college or higher education, 46.6% reported an annual income <$15 000, and 13.6% reported high BP in pregnancy. After adjustment for obesity, smoking, and age, women with a history of high BP in pregnancy had significantly higher BP than those who did not report this complication (5.39 ± 2.4 mm Hg, P = .030). Epigenome-wide analysis revealed no significant sites after multiple testing correction.We observed a small, but clinically significant, increase in BP in women who reported high BP in pregnancy 3-5 years after that pregnancy. Future studies with larger sample sizes should examine epigenetic contributions to this finding.© 2020 Wiley Periodicals LLC.",
-,Yes,20210125,ewas,33443234,DNA methylation is associated with airflow obstruction in patients living with HIV.,Thorax,"People living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.Using blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV1, FEV1/FVC ratio and FEV1decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.Airflow obstruction as defined by a FEV1/FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV1/FVC<lower limit of normal. These DMPs were enriched for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV1and FEV1/FVC, respectively. No positions were associated with FEV1decline.A large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
-,Yes,20210125,omics,33436383,"Genetic variants shape rheumatoid arthritis-specific transcriptomic features in CD4<sup>+</sup> T cells through differential DNA methylation, explaining a substantial proportion of heritability.",Ann Rheum Dis,"CD4+T cells have been suggested as the most disease-relevant cell type in rheumatoid arthritis (RA) in which RA-risk non-coding variants exhibit allele-specific effects on regulation of RA-driving genes. This study aimed to understand RA-specific signatures in CD4+T cells using multi-omics data, interpreting inter-omics relationships in shaping the RA transcriptomic landscape.We profiled genome-wide variants, gene expression and DNA methylation in CD4+T cells from 82 patients with RA and 40 healthy controls using high-throughput technologies. We investigated differentially expressed genes (DEGs) and differential methylated regions (DMRs) in RA and localised quantitative trait loci (QTLs) for expression and methylation. We then integrated these based on individual-level correlations to inspect DEG-regulating sources and investigated the potential regulatory roles of RA-risk variants by a partitioned-heritability enrichment analysis with RA genome-wide association summary statistics.A large number of RA-specific DEGs were identified (n=2575), highlighting T cell differentiation and activation pathways. RA-specific DMRs, preferentially located in T cell regulatory regions, were correlated with the expression levels of 548 DEGs mostly in the same topologically associating domains. In addition, expressional variances in 771 and 83 DEGs were partially explained by expression QTLs for DEGs and methylation QTLs (meQTLs) for DEG-correlated DMRs, respectively. A large number of RA variants were moderately to strongly correlated with meQTLs. DEG-correlated DMRs, enriched with meQTLs, had strongly enriched heritability of RA.Our findings revealed that the methylomic changes, driven by RA heritability-explaining variants, shape the differential expression of a substantial fraction of DEGs in CD4+T cells in patients with RA, reinforcing the importance of a multidimensional approach in disease-relevant tissues.© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.",
-,Yes,20210125,ewas,33436068,Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight.,Clin Epigenetics,"High early postnatal weight gain has been associated with childhood adiposity; however, the mechanism remains unknown. DNA methylation is a hypothesised mechanism linking early life exposures and subsequent disease. However, epigenetic changes associated with high early weight gain have not previously been investigated. Our aim was to investigate the associations between early weight gain, peripheral blood DNA methylation, and subsequent overweight/obese. Data from the UK Avon Longitudinal study of Parents and Children (ALSPAC) cohort were used to estimate associations between early postnatal weight gain and epigenome-wide DNA CpG site methylation (Illumina 450 K Methylation Beadchip) in blood in childhood (n = 125) and late adolescence (n = 96). High weight gain in the first year (a change in weight z-scores > 0.67), both unconditional (rapid weight gain) and conditional on birthweight (rapid thrive), was related to individual CpG site methylation and across regions using the meffil pipeline, with and without adjustment for cell type proportions, and with 5% false discovery rate correction. Variation in methylation at high weight gain-associated CpG sites was then examined with regard to body composition measures in childhood and adolescence. Replication of the differentially methylated CpG sites was sought using whole-blood DNA samples from 104 children from the UK Southampton Women's Survey.Rapid infant weight gain was associated with small (+ 1% change) increases in childhood methylation (age 7) for two distinct CpG sites (cg01379158 (NT5M) and cg11531579 (CHFR)). Childhood methylation at one of these CpGs (cg11531579) was also higher in those who experienced rapid weight gain and were subsequently overweight/obese in adolescence (age 17). Rapid weight gain was not associated with differential DNA methylation in adolescence. Childhood methylation at the cg11531579 site was also suggestively associated with rapid weight gain in the replication cohort.This study identified associations between rapid weight gain in infancy and small increases in childhood methylation at two CpG sites, one of which was replicated and was also associated with subsequent overweight/obese. It will be important to determine whether loci are markers of early rapid weight gain across different, larger populations. The mechanistic relevance of these differentially methylated sites requires further investigation.",
-,No,20210125,reference,33434283,A comprehensive epigenome atlas reveals DNA methylation regulating skeletal muscle development.,Nucleic Acids Res,"DNA methylation is important for the epigenetic regulation of gene expression and plays a critical role in mammalian development. However, the dynamic regulation of genome-wide DNA methylation in skeletal muscle development remains largely unknown. Here, we generated the first single-base resolution DNA methylome and transcriptome maps of porcine skeletal muscle across 27 developmental stages. The overall methylation level decreased from the embryo to the adult, which was highly correlated with the downregulated expression of DNMT1 and an increase in partially methylated domains. Notably, we identified over 40 000 developmentally differentially methylated CpGs (dDMCs) that reconstitute the developmental trajectory of skeletal muscle and associate with muscle developmental genes and transcription factors (TFs). The dDMCs were significantly under-represented in promoter regulatory regions but strongly enriched as enhancer histone markers and in chromatin-accessible regions. Integrative analysis revealed the negative regulation of both promoter and gene body methylation in genes associated with muscle contraction and insulin signaling during skeletal muscle development. Mechanistically, DNA methylation affected the expression of muscle-related genes by modulating the accessibly of upstream myogenesis TF binding, indicating the involvement of the DNA methylation/SP1/IGF2BP3 axis in skeletal myogenesis. Our results highlight the function and regulation of dynamic DNA methylation in skeletal muscle development.© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",
-,Yes,20210125,ewas,33431374,Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood DNA Methylation Which Associates With Body Composition in the Offspring.,Diabetes,"Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the TOP-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus controls (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus controls (FDR<5%) when using the Houseman reference-free method to correct for cell composition and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared to controls. Methylation at 17 sites, annotated to e.g.DISC1,GBX2,HERC2andHUWE1, partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR<5%). Moreover, 22 methylation sites were associated with offspring BMI z-scores during the first 3 years of life (p<0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring's lean mass and early growth.© 2021 by the American Diabetes Association.",
-,Yes,20210125,ewas,33420481,DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.,Mol Psychiatry,"DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.",
-,Yes,20210125,ewas,33414500,Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.,Mol Psychiatry,"Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.",
-,Yes,20210125,ewas,33414392,A genome-wide methylation study reveals X chromosome and childhood trauma methylation alterations associated with borderline personality disorder.,Transl Psychiatry,"Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with (N = 49) and without (N = 47) childhood traumas and in a control group (N = 44). Results were confirmed in a replication cohort (N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome (PQBP1, ZNF41, RPL10, cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes (POU5F1, GGT6, TNFRSF13C and FAM113B), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.",
-,Yes,20210125,ewas,33413638,DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures.,Clin Epigenetics,"The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10-10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.",
-,No,20210125,dnam age,33442664,Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study.,JNCI Cancer Spectr,"We previously investigated the association between 5 ""first-generation"" measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging:PhenoAge,GrimAge, and predicted telomere length.We estimated rate ratios (RRs) for the association between these 3 age-adjusted measures and risk of colorectal (N = 813), gastric (N = 165), kidney (N = 139), lung (N = 327), mature B-cell (N = 423), prostate (N = 846), and urothelial (N = 404) cancer using conditional logistic regression models. We also assessed associations by time since blood draw and by cancer subtype, and we investigated potential nonlinearity.We observed relatively strong associations of age-adjustedPhenoAgewith risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers (RR per SD was approximately 1.2-1.3). Similar findings were obtained for age-adjustedGrimAge, but the association with lung cancer risk was much larger (RR per SD = 1.82, 95% confidence interval [CI] = 1.44 to 2.30), after adjustment for smoking status, pack-years, starting age, time since quitting, and other cancer risk factors. Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle, and anthropometric variables. For cancer overall, the comprehensively adjusted rate ratio per SD was 1.13 (95% CI = 1.07 to 1.19) forPhenoAgeand 1.12 (95% CI = 1.05 to 1.20) forGrimAgeand appeared larger within 5 years of blood draw (RR = 1.29, 95% CI = 1.15 to 1.44 and 1.19, 95% CI = 1.06 to 1.33, respectively).The methylation-based measuresPhenoAgeandGrimAgemay provide insights into the relationship between biological aging and cancer and be useful to predict cancer risk, particularly for lung cancer.© The Author(s) 2020. Published by Oxford University Press.",
-,No,20210125,gene expression,33436844,Gene expression in blood reflects smoking exposure among cancer-free women in the Norwegian Women and Cancer (NOWAC) postgenome cohort.,Sci Rep,"Active smoking has been linked to modulated gene expression in blood. However, there is a need for a more thorough understanding of how quantitative measures of smoking exposure relate to differentially expressed genes (DEGs) in whole-blood among ever smokers. This study analysed microarray-based gene expression profiles from whole-blood samples according to smoking status and quantitative measures of smoking exposure among cancer-free women (n = 1708) in the Norwegian Women and Cancer postgenome cohort. When compared with never smokers and former smokers, current smokers had 911 and 1082 DEGs, respectively and their biological functions could indicate systemic impacts of smoking. LRRN3 was associated with smoking status with the lowest FDR-adjusted p-value. When never smokers and all former smokers were compared, no DEGs were observed, but LRRN3 was differentially expressed when never smokers were compared with former smokers who quit smoking ≤ 10 years ago. Further, LRRN3 was positively associated with smoking intensity, pack-years, and comprehensive smoking index score among current smokers; and negatively associated with time since cessation among former smokers. Consequently, LRRN3 expression in whole-blood is a molecular signal of smoking exposure that could supplant self-reported smoking data in further research targeting blood-based markers related to the health effects of smoking.",
-,No,20210125,methods,33452255,Cellular Heterogeneity-Adjusted cLonal Methylation (CHALM) improves prediction of gene expression.,Nat Commun,"Promoter DNA methylation is a well-established mechanism of transcription repression, though its global correlation with gene expression is weak. This weak correlation can be attributed to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity-Adjusted cLonal Methylation (CHALM) as a methylation quantification method. CHALM improves understanding of the functional consequences of DNA methylation, including its correlations with gene expression and H3K4me3. When applied to different methylation datasets, the CHALM method enables detection of differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms.",
-,No,20210125,gene expression,33436912,Longitudinal saliva omics responses to immune perturbation: a case study.,Sci Rep,"Saliva omics has immense potential for non-invasive diagnostics, including monitoring very young or elderly populations, or individuals in remote locations. In this study, multiple saliva omics from an individual were monitored over three periods (100 timepoints) involving: (1) hourly sampling over 24 h without intervention, (2) hourly sampling over 24 h including immune system activation using the standard 23-valent pneumococcal polysaccharide vaccine, (3) daily sampling for 33 days profiling the post-vaccination response. At each timepoint total saliva transcriptome and proteome, and small RNA from salivary extracellular vesicles were profiled, including mRNA, miRNA, piRNA and bacterial RNA. The two 24-h periods were used in a paired analysis to remove daily variation and reveal vaccination responses. Over 18,000 omics longitudinal series had statistically significant temporal trends compared to a healthy baseline. Various immune response and regulation pathways were activated following vaccination, including interferon and cytokine signaling, and MHC antigen presentation. Immune response timeframes were concordant with innate and adaptive immunity development, and coincided with vaccination and reported fever. Overall, mRNA results appeared more specific and sensitive (timewise) to vaccination compared to other omics. The results suggest saliva omics can be consistently assessed for non-invasive personalized monitoring and immune response diagnostics.",
-,No,20210125,imprinting,33441584,Imprinting methylation predicts hippocampal volumes and hyperintensities and the change with age in later life.,Sci Rep,"Epigenetic imprinting is important for neurogenesis and brain function. Hippocampal volumes and brain hyperintensities in late life have been associated with early life circumstances. Epigenetic imprinting may underpin these associations. Methylation was measured at 982 sites in 13 imprinted locations in blood samples from a longitudinal cohort by bisulphite amplicon sequencing. Hippocampal volumes and hyperintensities were determined at age 64y and 72y using MRI. Hyperintensities were determined in white matter, grey matter and infratentorial regions. Permutation methods were used to adjust for multiple testing. At 64y, H19/IGF2 and NESPAS methylation predicted hippocampal volumes. PEG3 predicted hyperintensities in hippocampal grey matter, and white matter. GNASXL predicted grey matter hyperintensities. Changes with age were predicted for hippocampal volume (MEST1, KvDMR, L3MBTL, GNASXL), white matter (MEST1, PEG3) and hippocampal grey matter hyperintensities (MCTS2, GNASXL, NESPAS, L3MBTL, MCTS2, SNRPN, MEST1). Including childhood cognitive ability, years in education, or socioeconomic status as additional explanatory variables in regression analyses did not change the overall findings. Imprinting methylation in multiple genes predicts brain structures, and their change over time. These findings are potentially relevant to the development of novel tests of brain structure and function across the life-course, strategies to improve cognitive outcomes, and our understanding of early influences on brain development and function.",
-,No,20210125,organoids,33436582,A logical network-based drug-screening platform for Alzheimer's disease representing pathological features of human brain organoids.,Nat Commun,"Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.",
-,No,20210222,biomarker,33560371,A serum-based DNA methylation assay provides accurate detection of glioma.,Neuro Oncol,"The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a non-invasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with non-invasive approaches.Genome-wide DNA methylation profiling of tumor tissue and serum cell-free DNA of glioma patients.Here, we developed a non-invasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the ""glioma epigenetic liquid biopsy score"" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (e.g., progression, pseudoprogression or response to standard or experimental treatment).Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
-,No,20210222,omics,33523105,"Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets.",JAMA Neurol,"Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD.To investigate what genes and genomic processes underlie the risk of sporadic PD.This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks.It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role.Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance.Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies.",
-,No,20210222,dnam age,33558008,An integrative study of five biological clocks in somatic and mental health.,Elife,"Biological clocks have been developed at different molecular levels and were found to be more advanced in the presence of somatic illness and mental disorders. However, it is unclear whether different biological clocks reflect similar aging processes and determinants. In ~3000 subjects, we examined whether five biological clocks (telomere length, epigenetic, transcriptomic, proteomic, and metabolomic clocks) were interrelated and associated to somatic and mental health determinants. Correlations between biological aging indicators were small (allr< 0.2), indicating little overlap. The most consistent associations of advanced biological aging were found for male sex, higher body mass index (BMI), metabolic syndrome, smoking, and depression. As compared to the individual clocks, a composite index of all five clocks showed most pronounced associations with health determinants. The large effect sizes of the composite index and the low correlation between biological aging indicators suggest that one's biological age is best reflected by combining aging measures from multiple cellular levels.© 2021, Jansen et al.",
-,No,20210222,epigenetics,33542217,An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine.,Nat Commun,"Epigenetic modifications of DNA play important roles in many biological processes. Identifying readers of these epigenetic marks is a critical step towards understanding the underlying mechanisms. Here, we present an all-to-all approach, dubbed digital affinity profiling via proximity ligation (DAPPL), to simultaneously profile human TF-DNA interactions using mixtures of random DNA libraries carrying different epigenetic modifications (i.e., 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine) on CpG dinucleotides. Many proteins that recognize consensus sequences carrying these modifications in symmetric and/or hemi-modified forms are identified. We further demonstrate that the modifications in different sequence contexts could either enhance or suppress TF binding activity. Moreover, many modifications can affect TF binding specificity. Furthermore, symmetric modifications show a stronger effect in either enhancing or suppressing TF-DNA interactions than hemi-modifications. Finally, in vivo evidence suggests that USF1 and USF2 might regulate transcription via hydroxymethylcytosine-binding activity in weak enhancers in human embryonic stem cells.",
-,No,20210222,epigenetics,33505025,Systematic analysis of binding of transcription factors to noncoding variants.,Nature,"Many sequence variants have been linked to complex human traits and diseases1, but deciphering their biological functions remains challenging, as most of them reside in noncoding DNA. Here we have systematically assessed the binding of 270 human transcription factors to 95,886 noncoding variants in the human genome using an ultra-high-throughput multiplex protein-DNA binding assay, termed single-nucleotide polymorphism evaluation by systematic evolution of ligands by exponential enrichment (SNP-SELEX). The resulting 828 million measurements of transcription factor-DNA interactions enable estimation of the relative affinity of these transcription factors to each variant in vitro and evaluation of the current methods to predict the effects of noncoding variants on transcription factor binding. We show that the position weight matrices of most transcription factors lack sufficient predictive power, whereas the support vector machine combined with the gapped k-mer representation show much improved performance, when assessed on results from independent SNP-SELEX experiments involving a new set of 61,020 sequence variants. We report highly predictive models for 94 human transcription factors and demonstrate their utility in genome-wide association studies and understanding of the molecular pathways involved in diverse human traits and diseases.",
-,No,20210222,cancer,33536596,An epigenetic tipping point in cancer comes under the microscope.,Nature,NA,
-,No,20210222,reference,33536621,Regulatory genomic circuitry of human disease loci by integrative epigenomics.,Nature,"Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete1-3. Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits4, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits.",
-,Yes,20210222,ewas,33566097,Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.,Genome Biol Evol,"High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.",
-,Yes,20210222,ewas,33564054,Identification of epigenetic memory candidates associated with gestational age at birth through analysis of methylome and transcriptional data.,Sci Rep,"Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23-41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.",
-,Yes,20210222,ewas,33554115,Cross-reactive probes on Illumina DNA methylation arrays: a large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies.,NAR Genom Bioinform,"Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of theC9orf72repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to theC9orf72locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS.© The Author(s) 2020. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
-,Yes,20210222,ewas,33550919,Adiposity associated DNA methylation signatures in adolescents are related to leptin and perinatal factors.,Epigenetics,"Epigenetics links perinatal influences with later obesity. We identifed differentially methylated CpG (dmCpG) loci measured at 17 years associated with concurrent adiposity measures and examined whether these were associated with hsCRP, adipokines, and early life environmental factors. Genome-wide DNA methylation from 1192 Raine Study participants at 17 years, identified 29 dmCpGs (Bonferroni corrected p < 1.06E-07) associated with body mass index (BMI), 10 with waist circumference (WC) and 9 with subcutaneous fat thickness. DmCpGs within Ras Association (RalGDS/AF-6), Pleckstrin Homology Domains 1 (RAPH1), Musashi RNA-Binding Protein 2 (MSI2), and solute carrier family 25 member 10 (SLC25A10) are associated with both BMI and WC. Validation by pyrosequencing confirmed these associations and showed thatMSI2,SLC25A10, andRAPH1methylation was positively associated with serum leptin. These were  also associated with the early environment;MSI2methylation (β = 0.81, p = 0.0004) was associated with pregnancy maternal smoking,SLC25A10(CpG2 β = 0.12, p = 0.002) with pre- and early pregnancy BMI, andRAPH1(β = -1.49, p = 0.036) with gestational weight gain. Adjusting for perinatal factors, methylation of the dmCpGs withinMSI2, RAPH1,andSLC25A10independently predicted BMI, accounting for 24% of variance.MSI2methylation was additionally associated with BMI over time (17 years old β = 0.026, p = 0.0025; 20 years old β = 0.027, p = 0.0029) and between generations (mother β = 0.044, p = 7.5e-04). Overall findings suggest that DNA methylation inMSI2,RAPH1, andSLC25A10in blood may be robust markers, mediating through early life factors.",
-,Yes,20210222,ewas,33547282,The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.,Nat Commun,"Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10-8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.",
-,Yes,20210222,ewas,33542190,DNA methylation differences associated with social anxiety disorder and early life adversity.,Transl Psychiatry,"Social anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genes SLC43A2 and TNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within the SLC17A3 promoter region and the SIAH3 gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions within C2CD2L and MRPL28 showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.",
-,Yes,20210222,ewas,33528912,Novel DNA methylation marker discovery by assumption-free genome-wide association analysis of cognitive function in twins.,Aging Cell,"Privileged by rapid increase in available epigenomic data, epigenome-wide association studies (EWAS) are to make a profound contribution to understand the molecular mechanism of DNA methylation in cognitive aging. Current statistical methods used in EWAS are dominated by models based on multiple assumptions, for example, linear relationship between molecular profiles and phenotype, normal distribution for the methylation data and phenotype. In this study, we applied an assumption-free method, the generalized correlation coefficient (GCC), and compare it to linear models, namely the linear mixed model and kinship model. We use DNA methylation associated with a cognitive score in 400 and 206 twins as discovery and replication samples respectively. DNA methylation associated with cognitive function using GCC, linear mixed model, and kinship model, identified 65 CpGs (p < 1e-04) from discovery sample displaying both nonlinear and linear correlations. Replication analysis successfully replicated 9 of these top CpGs. When combining results of GCC and linear models to cover diverse patterns of relationships, we identified genes like KLHDC4, PAPSS2, and MRPS18B as well as pathways including focal adhesion, axon guidance, and some neurological signaling. Genomic region-based analysis found 15 methylated regions harboring 11 genes, with three verified in gene expression analysis, also the 11 genes were related to top functional clusters including neurohypophyseal hormone and maternal aggressive behaviors. The GCC approach detects valuable methylation sites missed by traditional linear models. A combination of methylation markers from GCC and linear models enriched biological pathways sensible in neurological function that could implicate cognitive performance and cognitive aging.© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",
-,Yes,20210222,ewas,33517419,Paternal body mass index and offspring DNA methylation: findings from the PACE consortium.,Int J Epidemiol,"Accumulating evidence links paternal adiposity in the periconceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans.In the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of coordinated epigenome-wide association studies (EWAS) of paternal prenatal body mass index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 data sets; total n = 4894) and in childhood (6 data sets; total n = 1982).We found little evidence of an association at either time point: at all CpGs, the false-discovery-rate-adjusted P-values were >0.05. In secondary sex-stratified analyses, we found just four CpGs for which there was robust evidence of an association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes.Our findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring-blood DNA methylation, even at imprinted regions.© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.",
-,Yes,20210222,ewas,33515580,Prenatal lead exposure and cord blood DNA methylation in the Korean Exposome Study.,Environ Res,"Prenatal lead exposure has been reported to affect infant growth and nervous system development, as well as to influence DNA methylation. We conducted an epigenome-wide association study to identify associations between prenatal lead exposure and cord blood DNA methylation in Korean infants.Cord blood samples were assayed with the Illumina HumanMethylationEPIC BeadChip kits, and maternal blood lead levels during early and late pregnancy, as well as cord blood lead level, were measured. The association between CpG methylation and lead level was analyzed using the limma package, with adjusting for infant sex, maternal pre-pregnancy body mass index, and estimated leukocyte composition.Among 364 blood samples (182 males and 182 females), those for which maternal and cord blood lead concentrations during early and later pregnancy was known were used for analysis. Maternal lead concentration in blood during early pregnancy was significantly associated with the methylation status of specific positions. After data stratification by infant sex, we found that, in males, the level of maternal blood lead was associated with 18 CpG sites during early pregnancy, and with one CpG site near the NBAS gene, during late pregnancy. In female samples, there was no significant association between DNA methylation and lead concentrations.Prenatal lead exposure was associated with altered, gender-specific patterns of DNA methylation in Korean infants.Copyright © 2021 Elsevier Inc. All rights reserved.",
-,Yes,20210222,ewas,33499918,Profile of copper-associated DNA methylation and its association with incident acute coronary syndrome.,Clin Epigenetics,"Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear.We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study.We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02-1.48; P = 0.03).We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.",
-,Yes,20210222,ewas,33494854,"Epigenetic profiling of social communication trajectories and co-occurring mental health problems: a prospective, methylome-wide association study.",Dev Psychopathol,"While previous studies suggest that both genetic and environmental factors play an important role in the development of autism-related traits, little is known about potential biological mechanisms underlying these associations. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined prospective associations between DNA methylation (DNAm: nbirth = 804, nage 7 = 877) and trajectories of social communication deficits at age 8-17 years. Methylomic variation at three loci across the genome (false discovery rate = 0.048) differentiated children following high (n = 80) versus low (n = 724) trajectories of social communication deficits. This differential DNAm was specific to the neonatal period and not observed at 7 years of age. Associations between DNAm and trajectory membership remained robust after controlling for co-occurring mental health problems (i.e., hyperactivity/inattention, conduct problems). The three loci identified at birth were not replicated in the Generation R Study. However, to the best of our knowledge, ALSPAC is the only study to date that is prospective enough to examine DNAm in relation to longitudinal trajectories of social communication deficits from childhood to adolescence. Although the present findings might point to potentially novel sites that differentiate between a high versus low trajectory of social communication deficits, the results should be considered tentative until further replicated.",
-,Yes,20210222,ewas,33484127,Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L.,J Clin Endocrinol Metab,"Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited.To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts.We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed.We identified 2 DMPs with epigenome-wide significant (P < 2.4E-7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E-10) and cg04173586 in DOT1L (P = 2.09E-16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH.This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
-,Yes,20210222,ewas,33526782,Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.,Transl Psychiatry,"Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.",
-,Yes,20210222,ewas,33466918,DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life.,Int J Mol Sci,"DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidakp≤ 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.",
-,Yes,20210222,ewas,33542415,Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies.,Sci Rep,"Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.",
-,Yes,20210222,ewas,33593402,Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects.,Clin Epigenetics,"Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers.A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA).Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results.This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.",
-,No ,20210308,dnam age,33656257,BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy.,Aging Cell,"Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional, or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such as Caenorhabditis elegans and it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy. Here, we devised an approach that uses temporal scaling and binarization of C. elegans transcriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments, and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this binarized transcriptomic aging (BiT age) clock can also be applied to human age prediction with high accuracy. The BiT age clock could therefore find wide application in genetic, nutritional, environmental, and therapeutic interventions in the aging process.© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
-,No ,20210308,methods,33623021,Single-cell multiomics sequencing reveals the functional regulatory landscape of early embryos.,Nat Commun,"Extensive epigenetic reprogramming occurs during preimplantation embryo development. However, it remains largely unclear how the drastic epigenetic reprogramming contributes to transcriptional regulatory network during this period. Here, we develop a single-cell multiomics sequencing technology (scNOMeRe-seq) that enables profiling of genome-wide chromatin accessibility, DNA methylation and RNA expression in the same individual cell. We apply this method to depict a single-cell multiomics map of mouse preimplantation development. We find that genome-wide DNA methylation remodeling facilitates the reconstruction of genetic lineages in early embryos. Further, we construct a zygotic genome activation (ZGA)-associated regulatory network and reveal coordination among multiple epigenetic layers, transcription factors and repeat elements that instruct proper ZGA. Cell fates associated cis-regulatory elements are activated stepwise in post-ZGA stages. Trophectoderm (TE)-specific transcription factors play dual roles in promoting the TE program while repressing the inner cell mass (ICM) program during the ICM/TE separation.",
-,No ,20210308,prediction,33608029,Genome-wide cell-free DNA methylation analyses improve accuracy of non-invasive diagnostic imaging for early-stage breast cancer.,Mol Cancer,"Early detection is crucial to improve breast cancer (BC) patients' outcomes and survival. Mammogram and ultrasound adopting the Breast Imaging Reporting and Data System (BI-RADS) categorization are widely used for BC early detection, while suffering high false-positive rate leading to unnecessary biopsy, especially in BI-RADS category-4 patients. Plasma cell-free DNA (cfDNA) carrying on DNA methylation information has emerged as a non-invasive approach for cancer detection. Here we present a prospective multi-center study with whole-genome bisulfite sequencing data to address the clinical utility of cfDNA methylation markers from 203 female patients with breast lesions suspected for malignancy. The cfDNA is enriched with hypo-methylated genomic regions. A practical computational framework was devised to excavate optimal cfDNA-rich DNA methylation markers, which significantly improved the early diagnosis of BI-RADS category-4 patients (AUC from 0.78-0.79 to 0.93-0.94). As a proof-of-concept study, we performed the first blood-based whole-genome DNA methylation study for detecting early-stage breast cancer from benign tumors at single-base resolution, which suggests that combining the liquid biopsy with the traditional diagnostic imaging can improve the current clinical practice, by reducing the false-positive rate and avoiding unnecessary harms.",
-,No ,20210308,dnam age,33606025,Epigenetic Age Acceleration and Cognitive Decline: A Twin Study.,J Gerontol A Biol Sci Med Sci,"Little is known about the role of DNA methylation (DNAm) epigenetic age acceleration in cognitive decline. Using a twin study design, we examined whether DNAm age acceleration is related to cognitive decline measured longitudinally in persons without a clinical diagnosis of dementia.We studied 266 paired male twins (133 pairs) with a mean age of 56 years at baseline. Of these, 114 paired twins returned for a follow-up after an average of 11.5 years. We obtained six indices of DNAm age acceleration based on epigenome-wide data from peripheral blood lymphocytes. At both baseline and follow-up, we administered a battery of cognitive measures and constructed two composite scores, one for executive function and one for memory function. We fitted multivariable mixed regression models to examine the association of DNAm age acceleration markers with cognitive function within pairs.In cross sectional analyses at baseline, there was no association between DNAm age acceleration and cognitive function scores. In longitudinal analyses, however, comparing twins within pairs, each additional year of age acceleration using the Horvath's method was associated with a 3% decline (95% CI, 1% to 5%) in the composite executive function score and a 2.5% decline (95% CI, 0.01% to 4.9%) in the memory function score. These results did not attenuate after adjusting for education and other risk factors.Middle-aged men who had older DNAm age relative to their brothers of the same demographic age, showed a faster rate of cognitive decline in the subsequent 11.5 years. These results point to the role of epigenetic modifications in cognitive aging.© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
-,No ,20210308,epigenetics,33619309,Skewness of X-chromosome inactivation increases with age and varies across birth cohorts in elderly Danish women.,Sci Rep,"Mosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2-7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917-1923 and 1931-1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7-29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917-1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.",
-,No,20210308,prediction,33632303,DNA methylation and cancer incidence: lymphatic-hematopoietic versus solid cancers in the Strong Heart Study.,Clin Epigenetics,"Epigenetic alterations may contribute to early detection of cancer. We evaluated the association of blood DNA methylation with lymphatic-hematopoietic cancers and, for comparison, with solid cancers. We also evaluated the predictive ability of DNA methylation for lymphatic-hematopoietic cancers.Blood DNA methylation was measured using the Illumina Infinium methylationEPIC array in 2324 Strong Heart Study participants (41.4% men, mean age 56 years). 788,368 CpG sites were available for differential DNA methylation analysis for lymphatic-hematopoietic, solid and overall cancers using elastic-net and Cox regression models. We conducted replication in an independent population: the Framingham Heart Study. We also analyzed differential variability and conducted bioinformatic analyses to assess for potential biological mechanisms.Over a follow-up of up to 28 years (mean 15), we identified 41 lymphatic-hematopoietic and 394 solid cancer cases. A total of 126 CpGs for lymphatic-hematopoietic cancers, 396 for solid cancers, and 414 for overall cancers were selected as predictors by the elastic-net model. For lymphatic-hematopoietic cancers, the predictive ability (C index) increased from 0.58 to 0.87 when adding these 126 CpGs to the risk factor model in the discovery set. The association was replicated with hazard ratios in the same direction in 28 CpGs in the Framingham Heart Study. When considering the association of variability, rather than mean differences, we found 432 differentially variable regions for lymphatic-hematopoietic cancers.This study suggests that differential methylation and differential variability in blood DNA methylation are associated with lymphatic-hematopoietic cancer risk. DNA methylation data may contribute to early detection of lymphatic-hematopoietic cancers.",
-,Yes,20210308,ewas,33661023,Comparative epigenome-wide analysis highlights placenta-specific differentially methylated regions.,Epigenomics,Aim:The placenta undergoes DNA methylation (DNAm) programming that is unique compared with all other fetal tissues. We aim to decipher some of the physiologic roles of the placenta by comparing its DNAm profile with that of another fetal tissue.Materials & methods:We performed a comparative analysis of genome-wide DNAm of 444 placentas paired with cord blood samples collected at birth. Gene ontology term analyses were conducted on the resulting differentially methylated regions.Results:Genomic regions upstream of transcription start sites showing lower DNAm in the placenta were enriched with terms related to miRNA functions and genes encoding G protein-coupled receptors.Conclusion:These results highlight genomic regions that are differentially methylated in the placenta in contrast to fetal blood.,
-,Yes,20210308,ewas,33646943,DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.,Elife,"We performed a systematic analysis of blood DNA methylation profiles from 4,483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1,048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.© 2021, Hannon et al.",
-,Yes,20210308,ewas,33622391,DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts.,Clin Epigenetics,"Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones.We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%).This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.",
-,No,20210329,cancer,33762478,Genome-wide association analysis reveals regulation of at-risk loci by DNA methylation in prostate cancer.,Asian J Androl,"Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations. Prostate cancer (PCa) is characterized by variable clinical manifestations and frequently unpredictable outcomes. We performed an expression quantitative trait loci (eQTL) analysis to identify the genomic regions that regulate gene expression in PCa and identified a relationship between DNA methylation and clinical information. Using multi-level information published in The Cancer Genome Atlas, we performed eQTL-based analyses on DNA methylation and gene expression. To better interpret these data, we correlated loci and clinical indexes to identify the important loci for both PCa development and progression. Our data demonstrated that although only a small proportion of genes are regulated via DNA methylation in PCa, these genes are enriched in important cancer-related groups. In addition, single nucleotide polymorphism analysis identified the locations of CpG sites and genes within at-risk loci, including the 19q13.2-q13.43 and 16q22.2-q23.1 loci. Further, an epigenetic association study of clinical indexes detected risk loci and pyrosequencing for site validation. Although DNA methylation-regulated genes across PCa samples are a small proportion, the associated genes play important roles in PCa carcinogenesis.",
-,No,20210329,cancer,33666134,DNA-methylation for the detection and distinction of 19 human malignancies.,Epigenetics,"The contribution of DNA-methylation based gene silencing to carcinogenesis is well established. Increasingly, DNA-methylation is examined using genome-wide techniques, with recent public efforts yielding immense data sets of diverse malignancies representing the vast majority of human cancer related disease burden. Whereas mutation events may group preferentially or in high frequency with a given histology, mutations are poor classifiers of tumour type. Here we examine the hypothesis that cancer-specific DNA-methylation reflects the tissue of origin or carcinogenic risk factor, and these methylation abnormalities may be used to faithfully classify tumours according to histology. We present an analysis of 7427 tumours representing 19 human malignancies and 708 normal samples demonstrating that specific tumour changes in methylation can correctly determine site of origin and tumour histology with 86% overall accuracy. Examination of misclassified tumours reveals underlying shared biology as the source of misclassifications, including common cell of origin or risk factors.",
-,No,20210329,cancer,33707228,DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia.,Genome Res,"Acute myeloid leukemia (AML) is a molecularly complex disease characterized by heterogeneous tumor genetic profiles and involving numerous pathogenic mechanisms and pathways. Integration of molecular data types across multiple patient cohorts may advance current genetic approaches for improved sub-classification and understanding of the biology of the disease. Here we analyzed genome-wide DNA methylation in 649 AML patients using Illumina arrays and identified a configuration of 13 subtypes (termed 'epitypes') using unbiased clustering. Integration of genetic data revealed that most epitypes were associated with a certain recurrent mutation (or combination) in a majority of patients, yet other epitypes were largely independent. Epitypes demonstrated developmental blockage at discrete stages of myeloid differentiation, revealing epitypes that retain arrested hematopoietic stem cell-like phenotypes. Detailed analyses of DNA methylation patterns identified unique patterns of aberrant hyper- and hypomethylation among epitypes, with variable involvement of transcription factors influencing promoter, enhancer, and repressed regions. Patients in epitypes with stem cell-like methylation features showed inferior overall survival along with upregulated stem cell gene expression signatures. We further identified a DNA methylation signature involving STAT motifs associated withFLT3-ITD mutations. Finally, DNA methylation signatures were stable at relapse for the large majority of patients, and rare epitype switching accompanied loss of the dominant epitype mutations and reversion to stem cell-like methylation patterns. These results demonstrate that DNA methylation-based classification integrates important molecular features of AML to reveal the diverse pathogenic and biological aspects of the disease.Published by Cold Spring Harbor Laboratory Press.",
-,No,20210329,cell lines,33676569,Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines.,Clin Epigenetics,"Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents.We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta-values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epigenome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxygenases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes affecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlapping effects of each epigenetic factor on methylation of specific targets and the importance of such influences in tumor response to individual agents require further investigation.Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may affect response to therapeutic agents. Our findings suggest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly affect response to chemotherapy.",
-,No,20210329,dnam age,33653394,Weight management intervention identifies association of decreased DNA methylation age with improved functional age measures in older adults with obesity.,Clin Epigenetics,"Assessing functional ability is an important component of understanding healthy aging. Objective measures of functional ability include grip strength, gait speed, sit-to-stand time, and 6-min walk distance. Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Peripheral blood DNA methylation was measured (pre/post) with the Illumina HumanMethylationEPIC array and the Hannum, Horvath, and PhenoAge DNA methylation age clocks were used. Linear regression models adjusted for chronological age and sex tested the relationship between DNA methylation age and grip strength, gait speed, sit-to-stand, and 6-min walk.Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively. Mean grip strength increased 3.2 kg. Decreased Hannum methylation age was significantly associated with increased grip strength (β = -0.30, p = 0.04), and increased gait speed (β = 0.02, p = 0.05), in adjusted models. Similarly, decreased methylation age using the PhenoAge clock was associated with significantly increased gait speed (β = 0.02, p = 0.04). A decrease in Horvath DNA methylation age and increase in physical functional ability did not demonstrate a significant association.The observed relationship between increased physical functional ability and decreased biological age using DNA methylation clocks demonstrate the potential utility of DNA methylation clocks to assess interventional approaches to improve health in older obese adults.National Institute on Aging (NIA), NCT03104192. Posted April 7, 2017, https://clinicaltrials.gov/ct2/show/NCT03104192.",
-,No,20210329,dnam age,33726838,Epigenetic age acceleration is associated with cardiometabolic risk factors and clinical cardiovascular disease risk scores in African Americans.,Clin Epigenetics,"Cardiovascular disease (CVD) is the leading cause of mortality among US adults. African Americans have higher burden of CVD morbidity and mortality compared to any other racial group. Identifying biomarkers for clinical risk prediction of CVD offers an opportunity for precision prevention and earlier intervention.Using linear mixed models, we investigated the cross-sectional association between four measures of epigenetic age acceleration (intrinsic (IEAA), extrinsic (EEAA), PhenoAge (PhenoAA), and GrimAge (GrimAA)) and ten cardiometabolic markers of hypertension, insulin resistance, and dyslipidemia in 1,100 primarily hypertensive African Americans from sibships in the Genetic Epidemiology Network of Arteriopathy (GENOA). We then assessed the association between epigenetic age acceleration and time to self-reported incident CVD using frailty hazard models and investigated CVD risk prediction improvement compared to models with clinical risk scores (Framingham risk score (FRS) and the atherosclerotic cardiovascular disease (ASCVD) risk equation). After adjusting for sex and chronological age, increased epigenetic age acceleration was associated with higher systolic blood pressure (IEAA), higher pulse pressure (EEAA and GrimAA), higher fasting glucose (PhenoAA and GrimAA), higher fasting insulin (EEAA), lower low density cholesterol (GrimAA), and higher triglycerides (GrimAA). A five-year increase in GrimAA was associated with CVD incidence with a hazard ratio of 1.54 (95% CI 1.22-2.01) and remained significant after adjusting for CVD risk factors. The addition of GrimAA to risk score models improved model fit using likelihood ratio tests (P = 0.013 for FRS and P = 0.008 for ASCVD), but did not improve C statistics (P > 0.05). Net reclassification index (NRI) showed small but significant improvement in reassignment of risk categories with the addition of GrimAA to FRS (NRI: 0.055, 95% CI 0.040-0.071) and the ASCVD equation (NRI: 0.029, 95% CI 0.006-0.064).Epigenetic age acceleration measures are associated with traditional CVD risk factors in an African-American cohort with a high prevalence of hypertension. GrimAA was associated with CVD incidence and slightly improved prediction of CVD events over clinical risk scores.",
-,No,20210329,dnam age,33712580,DNA methylation predicts age and provides insight into exceptional longevity of bats.,Nat Commun,"Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.",
-,No,20210329,dnam age,33663610,Lifestyle weight-loss intervention may attenuate methylation aging: the CENTRAL MRI randomized controlled trial.,Clin Epigenetics,"DNA methylation age (mAge), a methylation biomarker for the aging process, might serve as a more accurate predictor of morbidity and aging status than chronological age. We evaluated the role of multiple factors, including fat deposition, cardiometabolic risk factors and lifestyle weight-loss intervention, on the deviation of mAge from chronological age (mAge deviation) or 18-month change in mAge (�mAge). In this sub-study of the CENTRAL magnetic resonance imaging weight-loss trial, we evaluated mAge by a validated 240-CpG-based prediction formula at baseline and after 18-month intervention of either low fat (LF) or mediterranean/low carbohydrate (MED/LC) diets.Among 120 CENTRAL participants with abdominal obesity or dyslipidemia, mAge (mean ± SD: 60.3 ± 7.5 years) was higher than the chronological age (48.6 ± 9.3 years) but strongly correlated (r = 0.93; p = 3.1 × 10-53). Participants in the lowest tertile of mAge deviation from their chronological age had significantly lower waist-circumference, visceral adipose tissue, intrahepatic fat (IHF) content, fasting-glucose and HOMA-IR, as compared with participants in the highest sex-specific residual tertile (p < 0.05 for all). IHF% remained associated with greater mAge deviation after further adjustments (β = 0.23; p = 0.02). After 18-month weight-loss lifestyle intervention, mAge remained significantly correlated with chronological age (r = 0.94, p = 1.5 × 10-55). mAging occurred, with no difference between lifestyle intervention groups (� = 0.9 ± 1.9 years in MED/LC vs. � = 1.3 ± 1.9 years in LF; p = 0.2); however, we observed a mAging attenuation in successful weight losers (> 5% weight loss) vs. weight-loss failures ( � = 0.6 years vs. � = 1.1 years; p = 0.04), and in participants who completed the trial with healthy liver fat content (< 5% IHF) vs. participants with fatty liver (� = 0.6 years vs. � = 1.8 years; p = 0.003). Overall, 18 months of weight-loss lifestyle intervention attenuated the mAging of the men, mainly the older, by 7.1 months than the expected (p < 0.05).Lifestyle weight-loss intervention may attenuate mAging. Deviation of mAge from chronological age might be related to body fat distribution and glycemic control and could indicate biological age, health status and the risk for premature cardiometabolic diseases.ClinicalTrials.gov NCT01530724. Registered 10 February 2012, https://clinicaltrials.gov/ct2/show/study/NCT01530724 .",
-,No,20210329,dnam age,33749330,Epigenetic age associates with psychosocial stress and resilience in children of Latinx immigrants.,Epigenomics,"Aim:To investigate associations of psychosocial stressors and resilience factors with DNA methylation age in saliva of Latinx children of immigrants before and after the 2016 presidential election (2015-2018).Materials & methods:We compared psychosocial exposures with four distinct measures of epigenetic age assessed in saliva of children (6-13 years, n = 71 pre-election; n = 35 post-election). Exploratory genome-wide analyses were also conducted.Results:We found distinct associations across epigenetic clocks and time points: for example, greater maternal social status pre-election and fear of parent deportation post-election both associated with decreased Hannum Age (p ≤ 0.01).Conclusion:Though limited in size, our unique study design provides novel hypotheses regarding how the social environment may influence epigenetic aging and genome-wide methylation, potentially contributing to racial/ethnic health inequalities.",
-,No,20210329,metastable epialleles,33680493,Rationale and design of the Baylor Infant Twin Study-A study assessing obesity-related risk factors from infancy.,Obes Sci Pract,"Early childhood (0-3 years) is a critical period for obesity prevention, when tendencies in eating behaviors and physical activity are established. Yet, little is understood about how the environment shapes children's genetic predisposition for these behaviors during this time. The Baylor Infant Twin Study (BITS) is a two phase study, initiated to study obesity risk factors from infancy. Data collection has been completed for Phase 1 in which three sub-studies pilot central measures for Phase 2. A novel infant temperament assessment, based on observations made by trained researchers was piloted inBehavior Observation Pilot Protocol(BOPP) study, a new device for measuring infant feeding parameters (the ""orometer"") in theBaylor Infant Orometer(BIO), and methods for analyzing DNA methylation in twins of unknown chorionicity inEpiTwin.EpiTwin was a cross-sectional study of neonatal twins, while up to three study visits occurred for the other studies, at 4- (BOPP, BIO), 6- (BOPP), and 12- (BOPP, BIO) of age. Measurements for BOPP and BIO included temperament observations, feeding observations, and body composition assessments while EpiTwin focused on collecting samples of hair, urine, nails, and blood for quantifying methylation levels at 10 metastable epialleles. Additional data collected include demographic information, zygosity, chorionicity, and questionnaire-based measures of infant behaviors.Recruitment for all three studies was completed in early 2020. EpiTwin recruited 80 twin pairs (50% monochorionic), 31 twin pairs completed the BOPP protocol, and 68 singleton infants participated in BIO.The psychometric properties of the data from all three studies are being analyzed currently. The resulting findings will inform the development of the full BITS protocol, with the goal of completing assessments at 4-, 6-, 12-, and 14-month of age for 400 twin pairs.© 2020 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.",
-,No,20210329,methods,33707472,EMeth: An EM algorithm for cell type decomposition based on DNA methylation data.,Sci Rep,"We introduce a new computational method named EMeth to estimate cell type proportions using DNA methylation data. EMeth is a reference-based method that requires cell type-specific DNA methylation data from relevant cell types. EMeth improves on the existing reference-based methods by detecting the CpGs whose DNA methylation are inconsistent with the deconvolution model and reducing their contributions to cell type decomposition. Another novel feature of EMeth is that it allows a cell type with known proportions but unknown reference and estimates its methylation. This is motivated by the case of studying methylation in tumor cells while bulk tumor samples include tumor cells as well as other cell types such as infiltrating immune cells, and tumor cell proportion can be estimated by copy number data. We demonstrate that EMeth delivers more accurate estimates of cell type proportions than several other methods using simulated data and in silico mixtures. Applications in cancer studies show that the proportions of T regulatory cells estimated by DNA methylation have expected associations with mutation load and survival time, while the estimates from gene expression miss such associations.",
-,No,20210329,methods,33722199,Correction for both common and rare cell types in blood is important to identify genes that correlate with age.,BMC Genomics,"Aging is a multifactorial process that affects multiple tissues and is characterized by changes in homeostasis over time, leading to increased morbidity. Whole blood gene expression signatures have been associated with aging and have been used to gain information on its biological mechanisms, which are still not fully understood. However, blood is composed of many cell types whose proportions in blood vary with age. As a result, previously observed associations between gene expression levels and aging might be driven by cell type composition rather than intracellular aging mechanisms. To overcome this, previous aging studies already accounted for major cell types, but the possibility that the reported associations are false positives driven by less prevalent cell subtypes remains.Here, we compared the regression model from our previous work to an extended model that corrects for 33 additional white blood cell subtypes. Both models were applied to whole blood gene expression data from 3165 individuals belonging to the general population (age range of 18-81 years). We evaluated that the new model is a better fit for the data and it identified fewer genes associated with aging (625, compared to the 2808 of the initial model; P ≤ 2.5⨯10-6). Moreover, 511 genes (~ 18% of the 2808 genes identified by the initial model) were found using both models, indicating that the other previously reported genes could be proxies for less abundant cell types. In particular, functional enrichment of the genes identified by the new model highlighted pathways and GO terms specifically associated with platelet activity.We conclude that gene expression analyses in blood strongly benefit from correction for both common and rare blood cell types, and recommend using blood-cell count estimates as standard covariates when studying whole blood gene expression.",
-,No,20210329,methods,33752591,Nonlinear ridge regression improves cell-type-specific differential expression analysis.,BMC Bioinformatics,"Epigenome-wide association studies (EWAS) and differential gene expression analyses are generally performed on tissue samples, which consist of multiple cell types. Cell-type-specific effects of a trait, such as disease, on the omics expression are of interest but difficult or costly to measure experimentally. By measuring omics data for the bulk tissue, cell type composition of a sample can be inferred statistically. Subsequently, cell-type-specific effects are estimated by linear regression that includes terms representing the interaction between the cell type proportions and the trait. This approach involves two issues, scaling and multicollinearity.First, although cell composition is analyzed in linear scale, differential methylation/expression is analyzed suitably in the logit/log scale. To simultaneously analyze two scales, we applied nonlinear regression. Second, we show that the interaction terms are highly collinear, which is obstructive to ordinary regression. To cope with the multicollinearity, we applied ridge regularization. In simulated data, nonlinear ridge regression attained well-balanced sensitivity, specificity and precision. Marginal model attained the lowest precision and highest sensitivity and was the only algorithm to detect weak signal in real data.Nonlinear ridge regression performed cell-type-specific association test on bulk omics data with well-balanced performance. The omicwas package for R implements nonlinear ridge regression for cell-type-specific EWAS, differential gene expression and QTL analyses. The software is freely available from https://github.com/fumi-github/omicwas.",
-,No,20210329,reference,33739972,Assessing the co-variability of DNA methylation across peripheral cells and tissues: Implications for the interpretation of findings in epigenetic epidemiology.,PLoS Genet,"Most epigenome-wide association studies (EWAS) quantify DNA methylation (DNAm) in peripheral tissues such as whole blood to identify positions in the genome where variation is statistically associated with a trait or exposure. As whole blood comprises a mix of cell types, it is unclear whether trait-associated DNAm variation is specific to an individual cellular population. We collected three peripheral tissues (whole blood, buccal epithelial and nasal epithelial cells) from thirty individuals. Whole blood samples were subsequently processed using fluorescence-activated cell sorting (FACS) to purify five constituent cell-types (monocytes, granulocytes, CD4+ T cells, CD8+ T cells, and B cells). DNAm was profiled in all eight sample-types from each individual using the Illumina EPIC array. We identified significant differences in both the level and variability of DNAm between different sample types, and DNAm data-derived estimates of age and smoking were found to differ dramatically across sample types from the same individual. We found that for the majority of loci variation in DNAm in individual blood cell types was only weakly predictive of variance in DNAm measured in whole blood, although the proportion of variance explained was greater than that explained by either buccal or nasal epithelial samples. Covariation across sample types was much higher for DNAm sites influenced by genetic factors. Overall, we observe that DNAm variation in whole blood is additively influenced by a combination of the major blood cell types. For a subset of sites, however, variable DNAm detected in whole blood can be attributed to variation in a single blood cell type providing potential mechanistic insight about EWAS findings. Our results suggest that associations between whole blood DNAm and traits or exposures reflect differences in multiple cell types and our data will facilitate the interpretation of findings in epigenetic epidemiology.",
-,No,20210329,reference,33669975,Extensive Placental Methylation Profiling in Normal Pregnancies.,Int J Mol Sci,"The placental methylation pattern is crucial for the regulation of genes involved in trophoblast invasion and placental development, both key events for fetal growth. We investigated LINE-1 methylation and methylome profiling using a methylation EPIC array and the targeted methylation sequencing of 154 normal, full-term pregnancies, stratified by birth weight percentiles. LINE-1 methylation showed evidence of a more pronounced hypomethylation in small neonates compared with normal and large for gestational age. Genome-wide methylation, performed in two subsets of pregnancies, showed very similar methylation profiles among cord blood samples while placentae from different pregnancies appeared very variable. A unique methylation profile emerged in each placenta, which could represent the sum of adjustments that the placenta made during the pregnancy to preserve the epigenetic homeostasis of the fetus. Investigations into the 1000 most variable sites between cord blood and the placenta showed that promoters and gene bodies that are hypermethylated in the placenta are associated with blood-specific functions, whereas those that are hypomethylated belong mainly to pathways involved in cancer. These features support the functional analogies between a placenta and cancer. Our results, which provide a comprehensive analysis of DNA methylation profiling in the human placenta, suggest that its peculiar dynamicity can be relevant for understanding placental plasticity in response to the environment.",
-,No,20210329,twas,33693414,The Human Blood Transcriptome in a Large Population Cohort and Its Relation to Aging and Health.,Front Big Data,"Background:The blood transcriptome is expected to provide a detailed picture of an organism's physiological state with potential outcomes for applications in medical diagnostics and molecular and epidemiological research. We here present the analysis of blood specimens of 3,388 adult individuals, together with phenotype characteristics such as disease history, medication status, lifestyle factors, and body mass index (BMI). The size and heterogeneity of this data challenges analytics in terms of dimension reduction, knowledge mining, feature extraction, and data integration.Methods:Self-organizing maps (SOM)-machine learning was applied to study transcriptional states on a population-wide scale. This method permits a detailed description and visualization of the molecular heterogeneity of transcriptomes and of their association with different phenotypic features.Results:The diversity of transcriptomes is described by personalized SOM-portraits, which specify the samples in terms of modules of co-expressed genes of different functional context. We identified two major blood transcriptome types where type 1 was found more in men, the elderly, and overweight people and it upregulated genes associated with inflammation and increased heme metabolism, while type 2 was predominantly found in women, younger, and normal weight participants and it was associated with activated immune responses, transcriptional, ribosomal, mitochondrial, and telomere-maintenance cell-functions. We find a striking overlap of signatures shared by multiple diseases, aging, and obesity driven by an underlying common pattern, which was associated with the immune response and the increase of inflammatory processes.Conclusions:Machine learning applications for large and heterogeneous omics data provide a holistic view on the diversity of the human blood transcriptome. It provides a tool for comparative analyses of transcriptional signatures and of associated phenotypes in population studies and medical applications.Copyright © 2020 Schmidt, Hopp, Arakelyan, Kirsten, Engel, Wirkner, Krohn, Burkhardt, Thiery, Loeffler, Loeffler-Wirth and Binder.",
-,Yes,20210329,ewas,33752734,Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases.,Clin Epigenetics,"DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases.We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data.Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.",
-,Yes,20210329,ewas,33751861,"Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children.",Pediatr Pulmonol,"Exposure to violence (ETV) or chronic stress may influence asthma through unclear mechanisms.Epigenome-wide association study (EWAS) of ETV or chronic stress measures and DNA methylation in nasal epithelium from 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed four measures of ETV and chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by p value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA).Three CpGs (in SNN, PTPRN2, and LINC01164) were associated with maternal perceived stress or gun violence (p = 1.28-3.36 × 10-7), but not with atopic asthma, in EVA-PR. In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence measures in EVA-PR, 12 CpGs (in STARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4, and ANAPC13) were associated with atopic asthma at FDR-p < .05.Pending confirmation in longitudinal studies, our findings suggest that nasal epithelial methylation markers associated with measures of ETV and chronic stress may be linked to atopic asthma in children and adolescents.© 2021 Wiley Periodicals LLC.",
-,Yes,20210329,ewas,33748261,Epigenome-wide association study on diffusing capacity of the lung.,ERJ Open Res,"Epigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung.To identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (DLCO)).An epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) (asDLCO/VA), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the ""discovery panel"") and the Framingham Heart Study (FHS, the ""replication panel""). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression.We identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated withDLCO/VAand one (cg05575921) suggestively associated withDLCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression ofEXOC3in lung tissue is positively associated withDLCO/VAandDLCO.We report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation ofAHRRmight affect pulmonary gas exchange.Copyright ©ERS 2021.",
-,Yes,20210329,ewas,33741061,Birthweight DNA methylation signatures in infant saliva.,Clin Epigenetics,"Low birthweight has been repeatedly associated with long-term adverse health outcomes and many non-communicable diseases. Our aim was to look-up cord blood birthweight-associated CpG sites identified by the PACE Consortium in infant saliva, and to explore saliva-specific DNA methylation signatures of birthweight.DNA methylation was assessed using Infinium HumanMethylation450K array in 135 saliva samples collected from children of the NINFEA birth cohort at an average age of 10.8 (range 7-17) months. The association analyses between birthweight and DNA methylation variations were carried out using robust linear regression models both in the exploratory EWAS analyses and in the look-up of the PACE findings in infant saliva.None of the cord blood birthweight-associated CpGs identified by the PACE Consortium was associated with birthweight when analysed in infant saliva. In saliva EWAS analyses, considering a false discovery rate p-values < 0.05, birthweight as continuous variable was associated with DNA methylation in 44 CpG sites; being born small for gestational age (SGA, lower 10thpercentile of birthweight for gestational age according to WHO reference charts) was associated with DNA methylation in 44 CpGs, with only one overlapping CpG between the two analyses. Despite no overlap with PACE results at the CpG level, two of the top saliva birthweight CpGs mapped at genes associated with birthweight with the same direction of the effect also in the PACE Consortium (MACROD1 and RPTOR).Our study provides an indication of the birthweight and SGA epigenetic salivary signatures in children around 10 months of age. DNA methylation signatures in cord blood may not be comparable with saliva DNA methylation signatures at about 10 months of age, suggesting that the birthweight epigenetic marks are likely time and tissue specific.",
-,Yes,20210329,ewas,33729499,Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT study.,Int J Epidemiol,"It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development.We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer.The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P < 5 × 10-8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer.DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.",
-,Yes,20210329,ewas,33667780,Epigenome-wide study of brain DNA methylation following acute opioid intoxication.,Drug Alcohol Depend,"Opioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of opioid abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. To clarify the association between opioid abuse and DNA methylation, we conducted an epigenome-wide analysis of DNA methylation in brain samples of individuals who died from acute opioid intoxication and group-matched controls.Tissue samples were extracted from the dorsolateral prefrontal cortex of 153 deceased individuals (Mage= 35.42; 62 % male; 77 % European ancestry). The study included 72 opioid samples, 53 psychiatric controls, and 28 normal controls. The epigenome-wide analysis was implemented using the Illumina MethylationEPIC BeadChip; analyses adjusted for sociodemographic characteristics, negative control principal components, ancestry principal components, cellular composition, and surrogate variables. Horvath's epigenetic age and Levine's PhenoAge were calculated, and gene set enrichment analyses were performed.Although no CpG sites survived false-discovery rate correction for multiple testing, 13 sites surpassed a relaxed significance threshold (p < 1.0 × 10-5). One of these sites was located within Netrin-1, a gene implicated in kappa opioid receptor activity. There was an association between opioid use and accelerated PhenoAge (b = 2.24, se = 1.11, p = .045). Gene set enrichment analyses revealed enrichment of differential methylation in GO and KEGG pathways broadly related to substance use.Netrin-1 may be associated with opioid overdose, and future research with larger samples across stages of opioid use will elucidate the complex genomics of opioid abuse.Copyright © 2021 Elsevier B.V. All rights reserved.",
-,Yes,20210329,ewas,33663600,DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother-newborn pairs.,Clin Epigenetics,"Maternal smoking affects more than half a million pregnancies each year in the US and is known to result in fetal growth restriction as measured by lower birthweight and its associated long-term consequences. Maternal smoking also has been linked to altered fetal DNA methylation (DNAm). However, what remains largely unexplored is whether these DNAm alterations are merely markers of smoking exposure or if they also have implications for health outcomes. This study tested the hypothesis that fetal DNAm mediates the effect of maternal smoking on newborn birthweight.This study included mother-newborn pairs from a US predominantly urban, low-income multi-ethnic birth cohort. DNAm in cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip. After standard quality control and normalization procedures, an epigenome-wide association study (EWAS) of maternal smoking was performed using linear regression models, controlling for maternal age, education, race, parity, pre-pregnancy body mass index, alcohol consumption, gestational age, maternal pregestational/gestational diabetes, child sex, cord blood cell compositions and batch effects. To quantify the degree to which cord DNAm mediates the smoking-birthweight association, the VanderWeele-Vansteelandt approach for single mediator and structural equational model for multiple mediators were used, adjusting for pertinent covariates.The study included 954 mother-newborn pairs. Among mothers, 165 (17.3%) ever smoked before or during pregnancy. Newborns with smoking exposure had on average 258 g lower birthweight than newborns without exposure (P < 0.001). Using a false discovery rate (FDR) < 0.05 as the significance cutoff, the EWAS identified 38 differentially methylated CpG sites associated with maternal smoking. Of those, 17 CpG sites were mapped to previously reported genes: GFI1, AHRR, CYP1A1, and CNTNAP2; 8 of those, located in the first three genes, were Bonferroni significantly associated with newborn birthweight and mediated the smoking-birthweight association. The combined mediation effect of the three genes explained 67.8% of the smoking-birthweight association.Our study not only lends further support that maternal smoking alters fetal DNAm in a multiethnic population, but also suggests that fetal DNAm substantially mediates the maternal smoking-birthweight association. Our findings, if further validated, indicate that DNAm modification is likely an important pathway by which maternal smoking impairs fetal growth and, perhaps, even long-term health outcomes.",
-,Yes,20210416,ewas,33845866,DNA methylation in cord blood in association with prenatal depressive symptoms.,Clin Epigenetics,"Prenatal symptoms of depression (PND) and anxiety affect up to every third pregnancy. Children of mothers with mental health problems are at higher risk of developmental problems, possibly through epigenetic mechanisms together with other factors such as genetic and environmental. We investigated DNA methylation in cord blood in relation to PND, taking into consideration a history of depression, co-morbidity with anxiety and selective serotonin reuptake inhibitors (SSRI) use, and stratified by sex of the child. Mothers (N = 373) prospectively filled out web-based questionnaires regarding mood symptoms and SSRI use throughout pregnancy. Cord blood was collected at birth and DNA methylation was measured using Illumina MethylationEPIC array at 850 000 CpG sites throughout the genome. Differentially methylated regions were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p-values < 0.05 were considered significant.No differential DNA methylation was associated with PND alone; however, differential DNA methylation was observed in children exposed to comorbid PND with anxiety symptoms compared with healthy controls in ABCF1 (log twofold change - 0.2), but not after stratification by sex of the child. DNA methylation in children exposed to PND without SSRI treatment and healthy controls both differed in comparison with SSRI exposed children at several sites and regions, among which hypomethylation was observed in CpGs in the promoter region of CRBN (log2 fold change - 0.57), involved in brain development, and hypermethylation in MDFIC (log2 fold change 0.45), associated with the glucocorticoid stress response.Although it is not possible to assess if these methylation differences are due to SSRI treatment itself or to more severe depression, our findings add on to existing knowledge that there might be different biological consequences for the child depending on whether maternal PND was treated with SSRIs or not.",
-,No,20210416,epigenetics,33844406,The interplay between DNA and histone methylation: molecular mechanisms and disease implications.,EMBO Rep,"Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome-wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA- and histone-modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.© 2021 The Authors.",
-,Yes,20210416,ewas,33838873,Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline.,Biol Psychiatry,"Cognitive trajectory varies widely and can distinguish people who develop dementia from people who remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. We sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human postmortem brain.We performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains simultaneously.We found an epigenome-wide association for differential methylation of sites in the CLDN5 locus and cognitive trajectory (p = 9.96 × 10-7) that was robust to adjustment for cell type proportions (p = 8.52 × 10-7). This association was primarily driven by association with declines in episodic (p = 4.65 × 10-6) and working (p = 2.54 × 10-7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs of amyloid-β and neurofibrillary tangle pathology.Differential methylation of CLDN5, a gene that encodes an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimer's disease pathologies. The association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer's disease.Copyright © 2021 Society of Biological Psychiatry. All rights reserved.",
-,No,20210416,methods,33838111,Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing.,Cell,"A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff-a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing. We identify single guide RNAs (sgRNAs) capable of silencing the large majority of genes including those lacking canonical CpG islands (CGIs) and reveal a wide targeting window extending beyond annotated CGIs. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.Copyright © 2021 Elsevier Inc. All rights reserved.",
-,Yes,20210416,ewas,33823916,Persistent variations of blood DNA methylation associated with treatment exposures and risk for cardiometabolic outcomes in long-term survivors of childhood cancer in the St. Jude Lifetime Cohort.,Genome Med,"It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions.We included 2052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA.By performing multiple treatment-specific EWAS, we identified 935 5'-cytosine-phosphate-guanine-3' (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p < 9 × 10-8). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (false discovery rate-adjusted p < 0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with a 32.9% mediation effect, and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA).In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.",
-,Yes,20210416,ewas,33818294,Epigenome-wide analysis of long-term air pollution exposure and DNA methylation in monocytes: results from the Multi-Ethnic Study of Atherosclerosis.,Epigenetics,"Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals andcis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants' homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals andcis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or nearSDHAP3, ZFP57, HOXA5, andPRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5(p = 1.4×10-6) and NOX(p = 7.7×10-6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (nearTOMM20) had the smallest p-value (p = 5.6×10-8). NOXsignificantly associated with cg11756214 withinZNF347(p = 5.6×10-8). Several differentially methylated signals were also associated withcis-gene expression. The DMR located on chromosome 7 was associated with the expression ofHOXA5, HOXA9, andHOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression ofMRPL36andDEXI, respectively. The CpG cg05926640 was associated with expression ofARID4B, IRF2BP2, andTOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.",
-,No,20210416,epigenetics,33808774,Identification of a Minimal 3-Transcript Signature to Differentiate Viral from Bacterial Infection from Best Genome-Wide Host RNA Biomarkers: A Multi-Cohort Analysis.,Int J Mol Sci,"The fight against the spread of antibiotic resistance is one of the most important challenges facing health systems worldwide. Given the limitations of current diagnostic methods, the development of fast and accurate tests for the diagnosis of viral and bacterial infections would improve patient management and treatment, as well as contribute to reducing antibiotic misuse in clinical settings. In this scenario, analysis of host transcriptomics constitutes a promising target to develop new diagnostic tests based on the host-specific response to infections. We carried out a multi-cohort meta-analysis of blood transcriptomic data available in public databases, including 11 different studies and 1209 samples from virus- (n= 695) and bacteria- (n= 514) infected patients. We applied a Parallel Regularized Regression Model Search (PReMS) on a set of previously reported genes that distinguished viral from bacterial infection to find a minimum gene expression bio-signature. This strategy allowed us to detect three genes, namelyBAFT,ISG15andDNMT1, that clearly differentiate groups of infection with high accuracy (training set: area under the curve (AUC) 0.86 (sensitivity: 0.81; specificity: 0.87); testing set: AUC 0.87 (sensitivity: 0.82; specificity: 0.86)).BAFTandISG15are involved in processes related to immune response, whileDNMT1is related to the preservation of methylation patterns, and its expression is modulated by pathogen infections. We successfully tested this three-transcript signature in the 11 independent studies, demonstrating its high performance under different scenarios. The main advantage of this three-gene signature is the low number of genes needed to differentiate both groups of patient categories.",
-,Yes,20210416,ewas,33784941,"DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake.",Epigenetics,"Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at both the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human MethylationEPIC array we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women's Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p≤6.45x10-8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195g (95%CI: -241, -149g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin releasing hormone binding protein (CRHBP).. Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p=1.37x10-255), maternal smoking (7.71%, p=1.50x10-57) and maternal plasma folate levels during pregnancy (0.33%, p=0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and/or suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs.",
-,Yes,20210416,ewas,33771206,Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.,Genome Biol,"People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.",
-,No,20210416,ewas,33766110,Pre-adolescence DNA methylation is associated with BMI status change from pre- to post-adolescence.,Clin Epigenetics,"Previous studies have shown that DNA methylation (DNAm) is associated with body mass index (BMI). However, it is unknown whether DNAm at pre-adolescence is associated with BMI status transition from pre- to post-adolescence. In the Isle of Wight (IoW) birth cohort, genome-wide DNA methylation in whole blood was measured using Illumina Infinium Human450 and EPIC BeadChip arrays in n = 325 subjects, and pre- to post-adolescence BMI transition was classified into four groups: (1) normal to normal, (2) normal to overweight or obese, (3) overweight or obese to normal, and (4) persistent overweight or obese. We used recursive random forest to screen genome-wide Cytosine-phosphate-Guanine (CpG) sites with DNAm potentially associated with BMI transition for each gender, and the association of BMI status transition with DNAm at an earlier age was assessed via logistic regressions. To evaluate gender specificity, interactions between DNAm and gender were included in the model. Findings in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC).In total, 174 candidate CpGs were selected including CpGs from screening and CpGs previously associated correctionally with BMI in children and adults. Of these 174 CpGs, pre-adolescent DNAm of 38 CpGs in the IoW cohort was associated with BMI status transition, including 30 CpGs showing gender-specific associations. Thirteen CpGs showed consistent associations between the IoW cohort and the ALSPAC cohort (11 of which were gender-specific).Pre-adolescence DNAm is associated with the change in BMI status from pre- to post-adolescence and such associations are likely to be gender-specific.",
-,No,20210416,y,33744870,Male-specific age estimation based on Y-chromosomal DNA methylation.,Aging (Albany NY),"Although DNA methylation variation of autosomal CpGs provides robust age predictive biomarkers, no male-specific age predictor exists based on Y-CpGs yet. Since sex chromosomes play an important role in aging, a Y-chromosome-based age predictor would allow studying male-specific aging effects and would also be useful in forensics. Here, we used blood-based DNA methylation microarray data of 1,057 males from six cohorts aged 15-87 and identified 75 Y-CpGs with an interquartile range of ≥0.1. Of these, 22 and six were significantly hyper- and hypomethylated with age (p(cor)<0.05, Bonferroni), respectively. Amongst several machine learning algorithms, a model based on support vector machines with radial kernel performed best in male-specific age prediction. We achieved a mean absolute deviation (MAD) between true and predicted age of 7.54 years (cor=0.81, validation) when using all 75 Y-CpGs, and a MAD of 8.46 years (cor=0.73, validation) based on the most predictive 19 Y-CpGs. The accuracies of both age predictors did not worsen with increased age, in contrast to autosomal CpG-based age predictors that are known to predict age with reduced accuracy in the elderly. Overall, we introduce the first-of-its-kind male-specific epigenetic age predictor for future applications in aging research and forensics.",
-,No,20210416,omics,33836805,DNA methylation and gene expression integration in cardiovascular disease.,Clin Epigenetics,"The integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event.Four independent latent factors (9, 19, 21-only in women-and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination.Unsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.",
-,No,20210416,epigenetics,33795684,Evolution of DNA methylation in the human brain.,Nat Commun,"DNA methylation is a critical regulatory mechanism implicated in development, learning, memory, and disease in the human brain. Here we have elucidated DNA methylation changes during recent human brain evolution. We demonstrate dynamic evolutionary trajectories of DNA methylation in cell-type and cytosine-context specific manner. Specifically, DNA methylation in non-CG context, namely CH methylation, has increased (hypermethylation) in neuronal gene bodies during human brain evolution, contributing to human-specific down-regulation of genes and co-expression modules. The effects of CH hypermethylation is particularly pronounced in early development and neuronal subtypes. In contrast, DNA methylation in CG context shows pronounced reduction (hypomethylation) in human brains, notably in cis-regulatory regions, leading to upregulation of downstream genes. We show that the majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and harbors strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage since the divergence from the chimpanzee lineage and carries significant genetic risk for schizophrenia. Therefore, recent epigenetic evolution of human cortex has shaped the cellular regulatory landscape and contributed to the increased vulnerability to neuropsychiatric diseases.",
-,No,20210416,twas,33795786,Transcriptomic signals in blood prior to lung cancer focusing on time to diagnosis and metastasis.,Sci Rep,Recent studies have indicated that there are functional genomic signals that can be detected in blood years before cancer diagnosis. This study aimed to assess gene expression in prospective blood samples from the Norwegian Women and Cancer cohort focusing on time to lung cancer diagnosis and metastatic cancer using a nested case-control design. We employed several approaches to statistically analyze the data and the methods indicated that the case-control differences were subtle but most distinguishable in metastatic case-control pairs in the period 0-3 years prior to diagnosis. The genes of interest along with estimated blood cell populations could indicate disruption of immunological processes in blood. The genes identified from approaches focusing on alterations with time to diagnosis were distinct from those focusing on the case-control differences. Our results support that explorative analyses of prospective blood samples could indicate circulating signals of disease-related processes.,
-,No,20210416,prediction,33785068,Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside.,Clin Epigenetics,"Despite impressive efforts invested in epigenetic research in the last 50 years, clinical applications are still lacking. Only a few university hospital centers currently use epigenetic biomarkers at the bedside. Moreover, the overall concept of precision medicine is not widely recognized in routine medical practice and the reductionist approach remains predominant in treating patients affected by major diseases such as cancer and cardiovascular diseases. By its' very nature, epigenetics is integrative of genetic networks. The study of epigenetic biomarkers has led to the identification of numerous drugs with an increasingly significant role in clinical therapy especially of cancer patients. Here, we provide an overview of clinical epigenetics within the context of network analysis. We illustrate achievements to date and discuss how we can move from traditional medicine into the era of network medicine (NM), where pathway-informed molecular diagnostics will allow treatment selection following the paradigm of precision medicine.",
-,No,20210416,vntr,33824302,Variable number tandem repeats mediate the expression of proximal genes.,Nat Commun,"Variable number tandem repeats (VNTRs) account for significant genetic variation in many organisms. In humans, VNTRs have been implicated in both Mendelian and complex disorders, but are largely ignored by genomic pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks to genotype a VNTR in 18 seconds on 55X whole genome data, while maintaining high accuracy. We use adVNTR-NN to genotype 10,264 VNTRs in 652 GTEx individuals. Associating VNTR length with gene expression in 46 tissues, we identify 163 ""eVNTRs"". Of the 22 eVNTRs in blood where independent data is available, 21 (95%) are replicated in terms of significance and direction of association. 49% of the eVNTR loci show a strong and likely causal impact on the expression of genes and 80% have maximum effect size at least 0.3. The impacted genes are involved in diseases including Alzheimer's, obesity and familial cancers, highlighting the importance of VNTRs for understanding the genetic basis of complex diseases.",
-,No,20210416,epigenetics,33828297,Genome-wide enhancer maps link risk variants to disease genes.,Nature,"Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.",
-,No,20210416,cell-free dna,33752803,"Applications of genetic-epigenetic tissue mapping for plasma DNA in prenatal testing, transplantation and oncology.",Elife,"We developed genetic-epigenetic tissue mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung transplant recipients, we showed that, at 72 hr after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles, and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring, and cancer screening.",
-,No,20210416,ewas,33785011,The impact of cesarean delivery on infant DNA methylation.,BMC Pregnancy Childbirth,"Mounting evidence suggests that cesarean delivery may have a long-lasting effect on infant health. But the underlying mechanisms remain unclear. This study aims to examine whether cesarean delivery on maternal request without any medical indications (CDMR) impacts DNA methylation status in the umbilical cord blood of the infant.A cross-sectional study was conducted in Shanghai, China. A total of 70 CDMR and 70 vaginal deliveries (VD) were recruited in 2012. The cord blood DNA methylation status was measured in 30 CDMR and 30 VD newborns using Illumina Infinium Human Methylation 450 K BeadChip. To validate the results, the cord blood DNA methylation status was measured in another 40 CDMR and 40 VD newborns using targeted bisulfite sequencing assay. A total of 497 CpG sites from 40 genes were included in the analysis.A total of 165 differentially methylated positions (DMPs) exhibited differences in DNA methylation by 10% or more between the CDMR and VD groups, many of which were related to the development of the immune system. Based on the targeted bisulfite sequencing assay, 16 genes (16/22, 72.7%) had higher methylation level in the CDMR group than the VD group. Among them, 5 genes were related to the immune system. After considering the estimation of cell type proportions, there was few significant differences in DNA methylation between CDMR and VD groups.The DMPs identified between CDMR and VD groups might be largely explained by the cell type proportions. Further studies are needed to examine DNA methylation in each cell type separately.",
-,No,20210416,epigenetics,33758175,Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level.,Nat Commun,"To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.",
-,No,20210416,prediction,33752746,DNA methylation biomarker for cumulative lead exposure is associated with Parkinson's disease.,Clin Epigenetics,"Lead, a known neurotoxicant, has previously received attention in Parkinson's disease (PD) research, but epidemiologic studies have been limited in sample size and findings are equivocal. We generated two methylation-based biomarkers for cumulative tibia and patella bone-measured lead exposure in 1528 PD patients and 1169 controls. PD status was associated with increased levels of the DNAm biomarker for tibia-lead levels. We estimated a meta-OR for PD of 1.89 per unit DNAm tibia-lead increase (95% CI 1.59, 2.24; p = 8.1E-13). The current study supports the notion that chronic and long-term lead exposure tracked via DNAm may contribute to PD pathogenesis.",
-,No,20210416,epigenetics,33828295,"The structure, function and evolution of a complete human chromosome 8.",Nature,"The complete assembly of each human chromosome is essential for understanding human biology and evolution1,2. Here we use complementary long-read sequencing technologies to complete the linear assembly of human chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08-Mb centromeric α-satellite array, a 644-kb copy number polymorphism in the β-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order α-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confirm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the flanking sequence.",
-,No,20210510,dnam age,33903745,Origins of human disease: the chrono-epigenetic perspective.,Nat Rev Genet,"Epigenetics has enriched human disease studies by adding new interpretations to disease features that cannot be explained by genetic and environmental factors. However, identifying causal mechanisms of epigenetic origin has been challenging. New opportunities have risen from recent findings in intra-individual and cyclical epigenetic variation, which includes circadian epigenetic oscillations. Cytosine modifications display deterministic temporal rhythms, which may drive ageing and complex disease. Temporality in the epigenome, or the 'chrono' dimension, may help the integration of epigenetic, environmental and genetic disease studies, and reconcile several disparities stemming from the arbitrarily delimited research fields. The ultimate goal of chrono-epigenetics is to predict disease risk, age of onset and disease dynamics from within individual-specific temporal dynamics of epigenomes.",
-,No,20210510,dnam age,33911272,The central role of DNA damage in the ageing process.,Nature,"Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level-for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.",
-,No,20210510,dnam age,33926514,Characteristics of epigenetic aging across gestational and perinatal tissues.,Clin Epigenetics,"Epigenetic clocks have been used to indicate differences in biological states between individuals of same chronological age. However, so far, only few studies have examined epigenetic aging in newborns-especially regarding different gestational or perinatal tissues. In this study, we investigated which birth- and pregnancy-related variables are most important in predicting gestational epigenetic age acceleration or deceleration (i.e., the deviation between gestational epigenetic age estimated from the DNA methylome and chronological gestational age) in chorionic villus, placenta and cord blood tissues from two independent study cohorts (ITU, n = 639 and PREDO, n = 966). We further characterized the correspondence of epigenetic age deviations between these tissues.Among the most predictive factors of epigenetic age deviations in single tissues were child sex, birth length, maternal smoking during pregnancy, maternal mental disorders until childbirth, delivery mode and parity. However, the specific factors related to epigenetic age deviation and the direction of association differed across tissues. In individuals with samples available from more than one tissue, relative epigenetic age deviations were not correlated across tissues.Gestational epigenetic age acceleration or deceleration was not related to more favorable or unfavorable factors in one direction in the investigated tissues, and the relative epigenetic age differed between tissues of the same person. This indicates that epigenetic age deviations associate with distinct, tissue specific, factors during the gestational and perinatal period. Our findings suggest that the epigenetic age of the newborn should be seen as a characteristic of a specific tissue, and less as a general characteristic of the child itself.",
-,No,20210510,dnam age,33870444,Ageing affects subtelomeric DNA methylation in blood cells from a large European population enrolled in the MARK-AGE study.,Geroscience,"Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated.",
-,No,20210510,dnam age,33821798,High social status males experience accelerated epigenetic aging in wild baboons.,Elife,"Aging, for virtually all life, is inescapable. However, within populations, biological aging rates vary. Understanding sources of variation in this process is central to understanding the biodemography of natural populations. We constructed a DNA methylation-based age predictor for an intensively studied wild baboon population in Kenya. Consistent with findings in humans, the resulting 'epigenetic clock' closely tracks chronological age, but individuals are predicted to be somewhat older or younger than their known ages. Surprisingly, these deviations are not explained by the strongest predictors of lifespan in this population, early adversity and social integration. Instead, they are best predicted by male dominance rank: high-ranking males are predicted to be older than their true ages, and epigenetic age tracks changes in rank over time. Our results argue that achieving high rank for male baboons - the best predictor of reproductive success - imposes costs consistent with a 'live fast, die young' life-history strategy.© 2021, Anderson et al.",
-,No,20210510,dnam age,33875015,An EPIC predictor of gestational age and its application to newborns conceived by assisted reproductive technologies.,Clin Epigenetics,"Gestational age is a useful proxy for assessing developmental maturity, but correct estimation of gestational age is difficult using clinical measures. DNA methylation at birth has proven to be an accurate predictor of gestational age. Previous predictors of epigenetic gestational age were based on DNA methylation data from the Illumina HumanMethylation 27 K or 450 K array, which have subsequently been replaced by the Illumina MethylationEPIC 850 K array (EPIC). Our aims here were to build an epigenetic gestational age clock specific for the EPIC array and to evaluate its precision and accuracy using the embryo transfer date of newborns from the largest EPIC-derived dataset to date on assisted reproductive technologies (ART).We built an epigenetic gestational age clock using Lasso regression trained on 755 randomly selected non-ART newborns from the Norwegian Study of Assisted Reproductive Technologies (START)-a substudy of the Norwegian Mother, Father, and Child Cohort Study (MoBa). For the ART-conceived newborns, the START dataset had detailed information on the embryo transfer date and the specific ART procedure used for conception. The predicted gestational age was compared to clinically estimated gestational age in 200 non-ART and 838 ART newborns using MM-type robust regression. The performance of the clock was compared to previously published gestational age clocks in an independent replication sample of 148 newborns from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restrictions (PREDO) study-a prospective pregnancy cohort of Finnish women.Our new epigenetic gestational age clock showed higher precision and accuracy in predicting gestational age than previous gestational age clocks (R2 = 0.724, median absolute deviation (MAD) = 3.14 days). Restricting the analysis to CpGs shared between 450 K and EPIC did not reduce the precision of the clock. Furthermore, validating the clock on ART newborns with known embryo transfer date confirmed that DNA methylation is an accurate predictor of gestational age (R2 = 0.767, MAD = 3.7 days).We present the first EPIC-based predictor of gestational age and demonstrate its robustness and precision in ART and non-ART newborns. As more datasets are being generated on the EPIC platform, this clock will be valuable in studies using gestational age to assess neonatal development.",
-,No,20210510,epigenetics,33956822,Comparative analysis reveals distinctive epigenetic features of the human cerebellum.,PLoS Genet,"Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution.",
-,No,20210510,ewas,33870089,DNA Methylation at Birth is Associated with Childhood Serum Immunoglobulin E Levels.,Epigenet Insights,"Immunoglobulin E (IgE) is known to play an important role in allergic diseases. Epigenetic traits acquired due to modification of deoxyribonucleic acid (DNA) methylation (DNAm) in early life may have phenotypic consequences through their role in transcriptional regulation with relevance to the developmental origins of diseases including allergy. However, epigenome-scale studies on the longitudinal association of cord blood DNAm with IgE over time are lacking. Our study aimed to examine the association of DNAm at birth with childhood serum IgE levels during early life. Genome-scale DNAm and total serum IgE measured at birth, 5, 8, and 11 years of children in the Taiwan Maternal and Infant Cohort Study were included in the study in the discovery stage. Linear mixed models were implemented to assess the association between cord blood DNAm at ~310K 5'-cytosine-phosphate-guanine-3' (CpG) sites with repeated IgE measurements, adjusting for cord blood IgE. Identified statistically significant CpGs (at a false discovery rate, FDR, of 0.05) were further tested in an independent replication cohort, the Isle of Wight (IoW) birth cohort. We mapped replicated CpGs to genes and conducted gene ontology analysis using ToppFun to identify significantly enriched pathways and biological processes of the genes. Cord blood DNAm of 273 CpG sites were significantly (FDR = 0.05) associated with IgE levels longitudinally. Among the identified CpGs available in both cohorts (184 CpGs), 92 CpGs (50%) were replicated in the IoW in terms of consistency in direction of associations between DNA methylation and IgE levels later in life, and 16 of the 92 CpGs showed statistically significant associations (P < .05). Gene ontology analysis identified 4 pathways (FDR = 0.05). The identified 16 CpG sites had the potential to serve as epigenetic markers associated with later IgE production, beneficial to allergic disease prevention and intervention.© The Author(s) 2021.",x
-,No,20210510,ewas,33940396,Blood lead levels in Peruvian adults are associated with proximity to mining and DNA methylation.,Environ Int,"Inorganic lead (Pb) is common in the environment, and is toxic to neurological, renal, and cardiovascular systems. Pb exposure influences the epigenome with documented effects on DNA methylation (DNAm). We assessed the impact of low levels of Pb exposure on DNAm among non-miner individuals from two locations in Peru: Lima, the capital, and Cerro de Pasco, a highland mining town, to study the effects of Pb exposure on physiological outcomes and DNAm.Pb levels were measured in whole blood (n = 305). Blood leukocyte DNAm was determined for 90 DNA samples using the Illumina MethylationEPIC chip. An epigenome-wide association study was performed to assess the relationship between Pb and DNAm.Individuals from Cerro de Pasco had higher Pb than individuals from Lima (p-value = 2.00E-16). Males had higher Pb than females (p-value = 2.36E-04). Pb was positively associated with hemoglobin (p-value = 8.60E-04). In Cerro de Pasco, blood Pb decreased with the distance from the mine (p-value = 0.04), and association with soil Pb was approaching significance (p-value = 0.08). We identified differentially methylated positions (DMPs) associated with genes SOX18, ZMIZ1, and KDM1A linked to neurological function. We also found 45 differentially methylated regions (DMRs), seven of which were associated with genes involved in metal ion binding and nine to neurological function and development.Our results demonstrate that even low levels of Pb can have a significant impact on the body including changes to DNAm. We report associations between Pb and hemoglobin, Pb and distance from mining, and between blood and soil Pb. We also report associations between loci- and region-specific DNAm and Pb.Copyright © 2021. Published by Elsevier Ltd.",
-,Yes,20210510,ewas,33939316,DNA methylome analysis identifies BMI-related epigenetic changes associated with non-small cell lung cancer susceptibility.,Cancer Med,"Body mass index (BMI) has been reported to be inversely associated with incident risk of non-small cell lung cancer (NSCLC). However, the underlying mechanism is still unclear. This study aimed to investigate the role of DNA methylation in the relationship between BMI and NSCLC.We carried out a genome-wide DNA methylation study of BMI in peripheral blood among 2266 Chinese participants by using Illumina Methylation arrays. For the BMI-related DNA methylation changes, their associations with NSCLC risk were further analyzed and their mediation effects on BMI-NSCLC association were also evaluated.The methylation levels of four CpGs (cg12593793, cg17061862, cg11024682, and cg06500161, annotated to LMNA, ZNF143, SREBF1, and ABCG1, respectively) were found to be significantly associated with BMI. Methylation levels of cg12593793, cg11024682, and cg06500161 were observed to be inversely associated with NSCLC risk [OR (95%CI) =0.22 (0.16, 0.31), 0.39 (0.30, 0.50), and 0.66 (0.53, 0.82), respectively]. Additionally, cg11024682 in SREBF1 and cg06500161 in ABCG1 mediated 45.3% and 19.5% of the association between BMI and decreased NSCLC risk, respectively.In this study, we identified four DNA methylation sites associated with BMI in the Chinese populations at the genome-wide significant level. We also found that the BMI-related methylations of SREBF1 and ABCG1 could mediate about a quintile-to-half of the effect of BMI on reduced NSCLC risk, which adds a potential mechanism underlying this association.© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",
-,Yes,20210510,ewas,33931109,Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.,Genome Med,"DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.",
-,Yes,20210510,ewas,33902726,Sex-specific DNA methylation differences in Alzheimer's disease pathology.,Acta Neuropathol Commun,"Sex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer's disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation differences in AD neuropathology, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort, we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with the AD Braak stage in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated genes in AD neuropathology, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation differences were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Our study implicated multiple new loci and biological processes that affected AD neuropathology in a sex-specific manner.",
-,Yes,20210510,ewas,33890633,DNA methylation patterns within whole blood of adolescents born from assisted reproductive technology are not different from adolescents born from natural conception.,Hum Reprod,"Do the epigenome-wide DNA methylation profiles of adolescents born from ART differ from the epigenome of naturally conceived counterparts?No significant differences in the DNA methylation profiles of adolescents born from ART [IVF or ICSI] were observed when compared to their naturally conceived, similar aged counterparts.Short-term and longer-term studies have investigated the general health outcomes of children born from IVF treatment, albeit without common agreement as to the cause and underlying mechanisms of these adverse health findings. Growing evidence suggests that the reported adverse health outcomes in IVF-born offspring might have underlying epigenetic mechanisms.The Growing Up Healthy Study (GUHS) is a prospective study that recruited 303 adolescents and young adults, conceived through ART, to compare various long-term health outcomes and DNA methylation profiles with similar aged counterparts from Generation 2 from the Raine Study. GUHS assessments were conducted between 2013 and 2017. The effect of ART on DNA methylation levels of 231 adolescents mean age 15.96 ± 1.59 years (52.8% male) was compared to 1188 naturally conceived counterparts, 17.25 ± 0.58 years (50.9% male) from the Raine Study.DNA methylation profiles from a subset of 231 adolescents (13-19.9 years) from the GUHS, generated using the Infinium Methylation Epic Bead Chip (EPIC) array were compared to 1188 profiles from the Raine Study previously measured using the Illumina 450K array. We conducted epigenome-wide association approach (EWAS) and tested for an association between the cohorts applying Firth's bias reduced logistic regression against the outcome of ART versus naturally conceived offspring. Additionally, within the GUHS cohort, we investigated differences in methylation status in fresh versus frozen embryo transfers, cause of infertility as well as IVF versus ICSI conceived offspring. Following the EWAS analysis we investigated nominally significant probes using Gene Set Enrichment Analysis (GSEA) to identify enriched biological pathways. Finally, within GUHS we compared four estimates (Horvath, Hanuum, PhenoAge [Levine], and skin Horvath) of epigenetic age and their correlation with chronological age.Between the two cohorts, we did not identify any DNA methylation probes that reached a Bonferroni corrected P-value < 1.24E-0.7. When comparing IVF versus ICSI conceived adolescents within the GUHS cohort, after adjustment for participant age, sex, maternal smoking, multiple births, and batch effect, three methylation probes (cg15016734, cg26744878 and cg20233073) reached a Bonferroni correction of 6.31E-08. After correcting for cell count heterogeneity, two of the aforementioned probes remained significant and an additional two probes (cg 0331628 and cg 20235051) were identified. A general trend towards hypomethylation in the ICSI offspring was observed. All four measures of epigenetic age were highly correlated with chronological age and showed no evidence of accelerated epigenetic aging within their whole blood.The small sample size coupled with the use of whole blood, where epigenetic differences may occur in other tissue. This was corrected by the utilized statistical method that accounts for imbalanced sample size between groups and adjusting for cell count heterogeneity. Only a small portion of the methylome was analysed and rare individual differences may be missed.Our findings provide further reassurance that the effects of the ART manipulations occurring during early embryogenesis, existing in the neonatal period are indeed of a transient nature and do not persist into adolescence. However, we have not excluded that alternative epigenetic mechanisms may be at play.This project was supported by NHMRC project Grant no. 1042269 and R.J.H. received funding support from Ferring Pharmaceuticals Pty Ltd. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from Merck Sharp & Dohme Corp.- Australia, Merck-Serono Australia Pty Ltd and Ferring Pharmaceuticals Pty Ltd. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. The remaining authors have no conflicts of interest.© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
-,Yes,20210510,ewas,33890479,DNA methylation as the link between migration and the major noncommunicable diseases: the RODAM study.,Epigenomics,"Aim:We assessed epigenome-wide DNA methylation (DNAm) differences between migrant and non-migrant Ghanaians.Materials & methods:We used the Illumina Infinium®HumanMethylation450 BeadChip to profile DNAm of 712 Ghanaians in whole blood. We used linear models to detect differentially methylated positions (DMPs) associated with migration. We performed multiple post hoc analyses to validate our findings.Results:We identified 13 DMPs associated with migration (delta-beta values: 0.2-4.5%). Seven DMPs inCPLX2,EIF4E3,MEF2D,TLX3,ST8SIA1,ANGandCHRM3were independent of extrinsic genomic influences in public databases. Two DMPs inNLRC5were associated with duration of stay in Europe among migrants. All DMPs were biologically linked to migration-related factors.Conclusion:Our findings provide the first insights into DNAm differences between migrants and non-migrants.",
-,Yes,20210510,ewas,33883019,Epigenome-wide association study of level and change in cognitive abilities from midlife through late life.,Clin Epigenetics,"Epigenetic mechanisms are important in aging and may be involved in late-life changes in cognitive abilities. We conducted an epigenome-wide association study of leukocyte DNA methylation in relation to level and change in cognitive abilities, from midlife through late life in 535 Swedish twins.Methylation levels were measured with the Infinium Human Methylation 450 K or Infinium MethylationEPIC array, and all sites passing quality control on both arrays were selected for analysis (n = 250,816). Empirical Bayes estimates of individual intercept (age 65), linear, and quadratic change were obtained from latent growth curve models of cognitive traits and used as outcomes in linear regression models. Significant sites (p < 2.4 × 10-7) were followed up in between-within twin pair models adjusting for familial confounding and full-growth modeling. We identified six significant associations between DNA methylation and level of cognitive abilities at age 65: cg18064256 (PPP1R13L) with processing speed and spatial ability; cg04549090 (NRXN3) with spatial ability; cg09988380 (POGZ), cg25651129 (-), and cg08011941 (ENTPD8) with working memory. The genes are involved in neuroinflammation, neuropsychiatric disorders, and ATP metabolism. Within-pair associations were approximately half that of between-pair associations across all sites. In full-growth curve models, associations between DNA methylation and cognitive level at age 65 were of small effect sizes, and associations between DNA methylation and longitudinal change in cognitive abilities of very small effect sizes.Leukocyte DNA methylation was associated with level, but not change in cognitive abilities. The associations were substantially attenuated in within-pair analyses, indicating they are influenced in part by genetic factors.",
-,Yes,20210510,ewas,33883000,DNA methylation biomarkers of myocardial infarction and cardiovascular disease.,Clin Epigenetics,"The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identified biomarkers is still limited. We aimed to identify differentially methylated loci associated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers.We designed a case-control, two-stage, epigenome-wide association study on AMI (ndiscovery = 391, nvalidation = 204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. We performed a fixed-effects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n ~ 1800 and n ~ 2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infinium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic influence and therefore the results were not conclusive.We have identified 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.",
-,Yes,20210510,ewas,33872906,Effect of prenatal exposure to phthalates on epigenome-wide DNA methylations in cord blood and implications for fetal growth: The Hokkaido Study on Environment and Children's Health.,Sci Total Environ,"Prenatal exposure to phthalates negatively affects the offspring's health. In particular, epigenetic alterations, such as DNA methylation, may connect phthalate exposure with health outcomes. Here, we evaluated the association of di-2-ethylhexyl phthalate (DEHP) exposure in utero with cord blood epigenome-wide DNA methylation in 203 mother-child pairs enrolled in the Hokkaido Study on Environment and Children's Health, using the Illumina HumanMethylation450 BeadChip. Epigenome-wide association analysis demonstrated the predominant positive associations between the levels of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), in maternal blood and DNA methylation levels in cord blood. The genes annotated to the CpGs positively associated with MEHP levels were enriched for pathways related to metabolism, the endocrine system, and signal transduction. Among them, methylation levels of CpGs involved in metabolism were inversely associated with the offspring's ponderal index (PI). Further, clustering and mediation analyses suggested that multiple increased methylation changes may jointly mediate the association of DEHP exposure in utero with the offspring's PI at birth. Although further studies are required to assess the impact of these changes, this study suggests that differential DNA methylation may link phthalate exposure in utero to fetal growth and further imply that DNA methylation has predictive value for the offspring's obesity.Copyright © 2021. Published by Elsevier B.V.",
-,Yes,20210510,ewas,33867313,Epigenome-wide association study of COVID-19 severity with respiratory failure.,EBioMedicine,"Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities.Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients.The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease.We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2.The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.",
-,Yes,20210510,ewas,33862401,Residential surrounding greenness and DNA methylation: An epigenome-wide association study.,Environ Int,"DNA methylation is a potential biological mechanism through which residential greenness affects health, but little is known about its association with greenness and whether the association could be modified by genetic background. We aimed to evaluate the association between surrounding greenness and genome-wide DNA methylation and potential gene-greenness interaction effects on DNA methylation.We measured blood-derived DNA methylation using the HumanMethylation450 BeadChip array (Illumina) for 479 Australian women, including 66 monozygotic, 66 dizygotic twin pairs, and 215 sisters of these twins. Surrounding greenness was represented by Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI) within 300, 500, 1000 or 2000 m surrounding participants' home addresses. For each cytosine-guanine dinucleotide (CpG), the associations between its methylation level and NDVI or EVI were evaluated by generalized estimating equations, after adjusting for age, education, marital status, area-level socioeconomic status, smoking behavior, cell-type proportions, and familial clustering. We used comb-p and DMRcate to identify significant differentially methylated regions (DMRs). For each significant CpG, we evaluated the interaction effects of greenness and single-nucleotide polymorphisms (SNPs) within ±1 Mb window on its methylation level.We found associations between surrounding greenness and blood DNA methylation for one CpG (cg04720477, mapped to the promoter region of CNP gene) with false discovery rate [FDR] < 0.05, and for another 9 CpGs with 0.05 ≤ FDR < 0.10. For two of these CpGs, we found 33 SNPs significantly (FDR < 0.05) modified the greenness-methylation association. There were 35 significant DMRs related to surrounding greenness that were identified by both comb-p (Sidak p-value < 0.01) and DMRcate (FDR < 0.01). Those CpGs and DMRs were mapped to genes related to many human diseases, such as mental health disorders and neoplasms as well as nutritional and metabolic diseases.Surrounding greenness was associated with blood DNA methylation of many loci across human genome, and this association could be modified by genetic variations.Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.",
-,No,20210510,dnam age,33926538,"Associations of circulating folate, vitamin B12 and homocysteine concentrations in early pregnancy and cord blood with epigenetic gestational age: the Generation R Study.",Clin Epigenetics,"Circulating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration.Up to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin's training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin's method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight's training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(- 0.16 weeks, 95% CI - 0.30, - 0.02) and (- 0.15 weeks, 95% CI - 0.29, - 0.01), respectively] by Knight's method.We found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.",
-,No,20210510,meqtls,33931130,Genetic impacts on DNA methylation: research findings and future perspectives.,Genome Biol,"Multiple recent studies highlight that genetic variants can have strong impacts on a significant proportion of the human DNA methylome. Methylation quantitative trait loci, or meQTLs, allow for the exploration of biological mechanisms that underlie complex human phenotypes, with potential insights for human disease onset and progression. In this review, we summarize recent milestones in characterizing the human genetic basis of DNA methylation variation over the last decade, including heritability findings and genome-wide identification of meQTLs. We also discuss challenges in this field and future areas of research geared to generate insights into molecular processes underlying human complex traits.",
-,No,20210510,methods,33926513,Estimands in epigenome-wide association studies.,Clin Epigenetics,"In DNA methylation analyses like epigenome-wide association studies, effects in differentially methylated CpG sites are assessed. Two kinds of outcomes can be used for statistical analysis: Beta-values and M-values. M-values follow a normal distribution and help to detect differentially methylated CpG sites. As biological effect measures, differences of M-values are more or less meaningless. Beta-values are of more interest since they can be interpreted directly as differences in percentage of DNA methylation at a given CpG site, but they have poor statistical properties. Different frameworks are proposed for reporting estimands in DNA methylation analysis, relying on Beta-values, M-values, or both.We present and discuss four possible approaches of achieving estimands in DNA methylation analysis. In addition, we present the usage of M-values or Beta-values in the context of bioinformatical pipelines, which often demand a predefined outcome. We show the dependencies between the differences in M-values to differences in Beta-values in two data simulations: a analysis with and without confounder effect. Without present confounder effects, M-values can be used for the statistical analysis and Beta-values statistics for the reporting. If confounder effects exist, we demonstrate the deviations and correct the effects by the intercept method. Finally, we demonstrate the theoretical problem on two large human genome-wide DNA methylation datasets to verify the results.The usage of M-values in the analysis of DNA methylation data will produce effect estimates, which cannot be biologically interpreted. The parallel usage of Beta-value statistics ignores possible confounder effects and can therefore not be recommended. Hence, if the differences in Beta-values are the focus of the study, the intercept method is recommendable. Hyper- or hypomethylated CpG sites must then be carefully evaluated. If an exploratory analysis of possible CpG sites is the aim of the study, M-values can be used for inference.",x
-,No,20210510,review,33895575,Air pollution and DNA methylation in adults: A systematic review and meta-analysis of observational studies.,Environ Pollut,"This systematic review and meta-analysis aimed to investigate the association between air pollution and DNA methylation in adults from published observational studies. PubMed, Web of Science and Embase databases were systematically searched for available studies on the association between air pollution and DNA methylation published up to March 9, 2021. Three DNA methylation approaches were considered: global methylation, candidate-gene, and epigenome-wide association studies (EWAS). Meta-analysis was used to summarize the combined estimates for the association between air pollutants and global DNA methylation levels. Heterogeneity was assessed with the Cochran Q test and quantified with the I2statistic. In total, 38 articles were included in this study: 16 using global methylation, 18 using candidate genes, and 11 using EWAS, with 7 studies using more than one approach. Meta-analysis revealed an imprecise but inverse association between exposure to PM2.5and global DNA methylation (for each 10-μg/m3PM2.5, combined estimate: 0.39; 95% confidence interval: 0.97 - 0.19). The candidate-gene results were consistent for the ERCC3 and SOX2 genes, suggesting hypermethylation in ERCC3 associated with benzene and that in SOX2 associated with PM2.5exposure. EWAS identified 201 CpG sites and 148 differentially methylated regions that showed differential methylation associated with air pollution. Among the 307 genes investigated in 11 EWAS, a locus in nucleoredoxin gene was found to be positively associated with PM2.5in two studies. Current meta-analysis indicates that PM2.5is imprecisely and inversely associated with DNA methylation. The candidate-gene results consistently suggest hypermethylation in ERCC3 associated with benzene exposure and that in SOX2 associated with PM2.5exposure. The Kyoto Encyclopedia of Genes and Genomes (KEGG) network analyses revealed that these genes were associated with African trypanosomiasis, Malaria, Antifolate resistance, Graft-versus-host disease, and so on. More evidence is needed to clarify the association between air pollution and DNA methylation.Copyright © 2021 Elsevier Ltd. All rights reserved.",x
-,Yes,20210510,variance,33937763,Human methylome variation across Infinium 450K data on the Gene Expression Omnibus.,NAR Genom Bioinform,"While DNA methylation (DNAm) is the most-studied epigenetic mark, few recent studies probe the breadth of publicly available DNAm array samples. We collectively analyzed 35 360 Illumina Infinium HumanMethylation450K DNAm array samples published on the Gene Expression Omnibus. We learned a controlled vocabulary of sample labels by applying regular expressions to metadata and used existing models to predict various sample properties including epigenetic age. We found approximately two-thirds of samples were from blood, one-quarter were from brain and one-third were from cancer patients. About 19% of samples failed at least one of Illumina's 17 prescribed quality assessments; signal distributions across samples suggest modifying manufacturer-recommended thresholds for failure would make these assessments more informative. We further analyzed DNAm variances in seven tissues (adipose, nasal, blood, brain, buccal, sperm and liver) and characterized specific probes distinguishing them. Finally, we compiled DNAm array data and metadata, including our learned and predicted sample labels, into database files accessible via the recountmethylation R/Bioconductor companion package. Its vignettes walk the user through some analyses contained in this paper.© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
-,No,20210607,aging,33813140,Clinical biomarkers and associations with healthspan and lifespan: Evidence from observational and genetic data,EBioMedicine,"Background: Biomarker-disease relationships are extensively investigated. However, associations between common clinical biomarkers and healthspan, the disease-free lifespan, are largely unknown. We aimed to explore the predictive values of ten biomarkers on healthspan and lifespan, and to identify putative causal mechanisms.
+No,20200907,qc,32749174,Reliability of DNA methylation measures using Illumina methylation BeadChip,Epigenetics,"Illumina BeadChips are widely utilized in epigenome-wide association studies (EWAS). Several studies have reported that many probes on these arrays have poor reliability. Here, we compare different pre-processing methods to improve intra-class correlation coefficients (ICC). We describe the characteristics of ICC across the genome, within and between studies, and across different array platforms. Using technical duplicates from 128 subjects, we find that with raw data only 22.5% of the CpGs on 450 K array have 'acceptable' ICCs (>0.5). Data preprocessing steps, such as background correction and dye bias correction, can reduce technical noise and improve the percentage to 38.5%. Similar to previous studies, we found that ICC is associated with CpG methylation level such that 83% of CpGs with intermediate methylation (0.1< beta-value <0.9) have acceptable ICCs, whereas only 21% of CpGs with low or high methylation (beta-value <0.1 or >0.9) have acceptable ICCs. ICC is also correlated with CpG methylation variance; after mutual adjustment for beta-value and variance, only variance remains correlated. Many CpGs with poor ICCs (<0.5) are located in biologically important regulatory regions, including gene promoters and CpG islands. Poor ICC at these sites appears to be a consequence of low biologic variation among individuals rather than increased technical measurement variation. ICCs quality classifications are highly concordant across different array platforms and across different studies. We find that ICC can be reliably estimated with 30 pairs of duplicate samples. CpGs with acceptable ICC have higher study power and are more commonly reported in published epigenome-wide studies.",
+No,20200907,review,32839576,The road ahead in genetics and genomics,Nat Rev Genet,"In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone.",
+No,20200907,review,32860016,Genetics meets proteomics: perspectives for large population-based studies,Nat Rev Genet,"Proteomic analysis of cells, tissues and body fluids has generated valuable insights into the complex processes influencing human biology. Proteins represent intermediate phenotypes for disease and provide insight into how genetic and non-genetic risk factors are mechanistically linked to clinical outcomes. Associations between protein levels and DNA sequence variants that colocalize with risk alleles for common diseases can expose disease-associated pathways, revealing novel drug targets and translational biomarkers. However, genome-wide, population-scale analyses of proteomic data are only now emerging. Here, we review current findings from studies of the plasma proteome and discuss their potential for advancing biomedical translation through the interpretation of genome-wide association analyses. We highlight the challenges faced by currently available technologies and provide perspectives relevant to their future application in large-scale biobank studies.",
+No,20200907,transcription factor binding,32814038,Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data across 27 Tissue Types,Cell Rep,"Characterizing the tissue-specific binding sites of transcription factors (TFs) is essential to reconstruct gene regulatory networks and predict functions for non-coding genetic variation. DNase-seq footprinting enables the prediction of genome-wide binding sites for hundreds of TFs simultaneously. Despite the public availability of high-quality DNase-seq data from hundreds of samples, a comprehensive, up-to-date resource for the locations of genomic footprints is lacking. Here, we develop a scalable footprinting workflow using two state-of-the-art algorithms: Wellington and HINT. We apply our workflow to detect footprints in 192 ENCODE DNase-seq experiments and predict the genomic occupancy of 1,515 human TFs in 27 human tissues. We validate that these footprints overlap true-positive TF binding sites from ChIP-seq. We demonstrate that the locations, depth, and tissue specificity of footprints predict effects of genetic variants on gene expression and capture a substantial proportion of genetic risk for complex traits.",
+No,20200907,transcription factor binding,32728250,Global reference mapping of human transcription factor footprints,Nature,"Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, but it remains challenging to distinguish variants that affect regulatory function2. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin3-6. However, only a small fraction of such sites have been precisely resolved on the human genome sequence6. Here, to enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate about 4.5 million compact genomic elements that encode transcription factor occupancy at nucleotide resolution. We map the fine-scale structure within about 1.6 million DNase I-hypersensitive sites and show that the overwhelming majority are populated by well-spaced sites of single transcription factor-DNA interaction. Cell-context-dependent cis-regulation is chiefly executed by wholesale modulation of accessibility at regulatory DNA rather than by differential transcription factor occupancy within accessible elements. We also show that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions1,7 is almost entirely attributable to variants within footprints, and that functional variants that affect transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find increased density of human genetic variation within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation.",
+Yes,20200914,ewas,32902349,Maternal atopy and offspring epigenome-wide methylation signature.,Epigenetics,,
+Yes,20200914,ewas,32901515,Methylome-wide association study of central adiposity implicates genes involved in immune and endocrine systems.,Epigenomics,,
+Yes,20200914,ewas,32889533,Effect of maternal preconceptional and pregnancy micronutrient interventions on children's DNA methylation: Findings from the EMPHASIS study.,Am J Clin Nutr,,
+No,20200914,qc,32885222,Patterns of Reliability: Assessing the Reproducibility and Integrity of DNA Methylation Measurement.,Patterns (N Y),,
+No,20200914,methods,32883324,EPISCORE: cell type deconvolution of bulk tissue DNA methylomes from single-cell RNA-Seq data.,Genome Biol,,
+No,20200914,genetics,32859912,Sex differences in oncogenic mutational processes.,Nat Commun,,
+No,20201026,atac-seq,32929078,Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder.,Nat Commun,FYN identified as heroine use disorder in rats and humans,
+No,20201026,candidate,32962699,"AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality.",BMC Cancer,for ryan,
+Yes,20201026,epigenetics,32963246,A cell-type deconvolution meta-analysis of whole blood EWAS reveals lineage-specific smoking-associated DNA methylation changes.,Nat Commun,another paper saying that smoking is better captured by granulocyte DNAm,
+No,20201026,epigenetics,32988399,Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.,Genome Med,mitochondrial dna copy number is epigenetic 25237825,
+"No (but we might include tissue comparisons, they would be useful)",20201026,epigenetics,33048947,The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations.,PLoS Genet,compares inter-individual variation between blood and sperm methylation,
+No,20201026,epigenetics,33067439,Detection of haplotype-dependent allele-specific DNA methylation in WGBS data.,Nat Commun,A method for identifying allele-specific DNA methylation in WGBS methylomes,
+Yes,20201026,ewas,32894192,Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns.,Clin Epigenetics,,
+Yes,20201026,ewas,32913184,DNA methylation study of Huntington's disease and motor progression in patients and in animal models.,Nat Commun,inclusion of animal models,
+Yes,20201026,ewas,32916427,An epigenome-wide association study identifies multiple DNA methylation markers of exposure to endocrine disruptors.,Environ Int,,
+Yes,20201026,ewas,32917208,Epigenetic loci for blood pressure are associated with hypertensive target organ damage in older African Americans from the genetic epidemiology network of Arteriopathy (GENOA) study.,BMC Med Genomics,,
+Yes,20201026,ewas,32928285,DNA methylation mediates the effect of cocaine use on HIV severity.,Clin Epigenetics,,
+Yes,20201026,ewas,32951333,A germ cell-specific ageing pattern in otherwise healthy men.,Aging Cell,germ cells track age,
+Yes,20201026,ewas,32958748,"Subjective mental health, incidence of depressive symptoms in later life, and the role of epigenetics: results from two longitudinal cohort studies.",Transl Psychiatry,,
+No,20201026,ewas,32958812,DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity.,Sci Rep,physical activity reduces muscle age,
+Yes,20201026,ewas,32967004,Epigenome-wide analysis identifies genes and pathways linked to acoustic cry variation in preterm infants.,Pediatr Res,,
+No,20201026,ewas,32967728,Epigenetic approach in obesity: DNA methylation in a prepubertal population which underwent a lifestyle modification.,Clin Epigenetics,lifestyle change and DNAm,
+No,20201026,ewas,32977850,Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci.,Genome Med,cd4+t cell isolation improves power?,
+No,20201026,prediction,32991610,"Lower DNA methylation levels in CpG island shores of CR1, CLU, and PICALM in the blood of Japanese Alzheimer's disease patients.",PLoS One,AUC=0.8,
+Yes,20201026,ewas,33003475,Placental Epigenome-Wide Association Study Identified Loci Associated with Childhood Adiposity at 3 Years of Age.,Int J Mol Sci,placenta and later adiposity,
+Yes,20201026,ewas,33023569,Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.,BMC Med,prenatal smoking and placenta,
+Yes,20201026,ewas,33054850,Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes.,Genome Med,152 WGBS methylomes contain DMRs that predict autism spectrum disorder,
+Yes,20201026,ewas,33069246,Epigenome-wide association study of Alzheimer's disease replicates 22 differentially methylated positions and 30 differentially methylated regions.,Clin Epigenetics,,
+Yes,20201026,ewas,33079621,Birth weight associations with DNA methylation differences in an adult population.,Epigenetics,One CpG site associated with birthweight in adults,
+No,20201026,gxe,32967067,"Genes and environments, development and time.",Proc Natl Acad Sci U S A,"Collection of papers reviewing the latest research on GxE interactions and how they change over time (3,5,7 days after admission)",
+No,20201026,longitudinal,33081814,Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU.,Clin Epigenetics,Investigating effects of delaying parenteral nutrition in the PICU (healthier) on DNA methylation,
+No,20201026,methods,32894181,COCOA: coordinate covariation analysis of epigenetic heterogeneity.,Genome Biol,,
+No,20201026,methods,33048617,Genome-wide DNA methylation profiling in human breast tissue by illumina TruSeq methyl capture EPIC sequencing and infinium methylationEPIC beadchip microarray.,Epigenetics,Compares TruSeq Methyl Capture to Methylation EPIC Beadchips,
+No,20201026,methods,33070182,Integrative Analysis Of Multi-Omics Data For Discovering Low-Frequency Variants Associated With Low-Density Lipoprotein Cholesterol Levels.,Bioinformatics,Use DNA methylation and gene expression to increase power to discover associations with low-frequency variants.,
+No,20201026,mqtl,33062306,Association of CNVs with methylation variation.,NPJ Genom Med,,
+Yes,20201026,omics,32978376,Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism.,Nat Commun,is this a useful use of omics?,
+No,20201026,prediction,32928150,From tobacco smoking to cancer mutational signature: a mediation analysis strategy to explore the role of epigenetic changes.,BMC Cancer,for ryan,
+No,20201026,prediction,32930613,Machine Learning-Based DNA Methylation Score for Fetal Exposure to Maternal Smoking: Development and Validation in Samples Collected from Adolescents and Adults.,Environ Health Perspect,,
+Yes,20201026,prediction,32958588,DNA methylation in peripheral blood and risk of gastric cancer: a prospective nested case-control study.,Cancer Prev Res (Phila),blood DNAm and cancer risk,
+No,20201026,prediction,32973211,Improvements and inter-laboratory implementation and optimization of blood-based single-locus age prediction models using DNA methylation of the ELOVL2 promoter.,Sci Rep,will this approach work for improving prediction?,
+No,20201026,prediction,33045984,Discrimination between human populations using a small number of differentially methylated CpG sites: a preliminary study using lymphoblastoid cell lines and peripheral blood samples of European and Chinese origin.,BMC Genomics,European vs Chinese ancestry differentiated by 8 CpG sites in both lymphoblastoid cell lines and blood,
+No,20201026,methods,32949770,"Single-cell analyses of aging, inflammation and senescence.",Ageing Res Rev,inclusion of single-cell data,
+No,20201026,methods,33045983,MethHaplo: combining allele-specific DNA methylation and SNPs for haplotype region identification.,BMC Bioinformatics,A method for identifying DNA 'methylation haplotype regions',
+No,20201123,epigenetics,32273471,Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking,Science,,
+Yes,20201123,ewas,33185669,Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.,Genome Biol Evol,"High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled Nitric Oxide (FeNO) also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.",
+Yes,20201123,ewas,33184255,Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis.,Transl Psychiatry,"Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (� = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.",
+Yes,20201123,ewas,33178681,DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA.,Front Cell Dev Biol,"A subset of individuals with type 1 diabetes will develop diabetic kidney disease (DKD). DKD is heritable and large-scale genome-wide association studies have begun to identify genetic factors that influence DKD. Complementary to genetic factors, we know that a person's epigenetic profile is also altered with DKD. This study reports analysis of DNA methylation, a major epigenetic feature, evaluating methylome-wide loci for association with DKD. Unique features (n= 485,577; 482,421 CpG probes) were evaluated in blood-derived DNA from carefully phenotyped White European individuals diagnosed with type 1 diabetes with (cases) or without (controls) DKD (n= 677 samples). Explicitly, 150 cases were compared to 100 controls using the 450K array, with subsequent analysis using data previously generated for a further 96 cases and 96 controls on the 27K array, andde novomethylation data generated for replication in 139 cases and 96 controls. Following stringent quality control, raw data were quantile normalized and beta values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls; resultantP-values for array-based data were adjusted for multiple testing. Genes with significantly increased (hypermethylated) and/or decreased (hypomethylated) levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways. Twenty-two loci demonstrated statistically significant fold changes associated with DKD and additional support for these associated loci was sought using independent samples derived from patients recruited with similar inclusion criteria. Markers associated withCCNL1andZNF187genes are supported as differentially regulated loci (P< 10-8), with evidence also presented forAFF3, which has been identified from a meta-analysis and subsequent replication of genome-wide association studies. Further supporting evidence for differential gene expression in CCNL1 and ZNF187 is presented from kidney biopsy and blood-derived RNA in people with and without kidney disease from NephroSeq. Evidence confirming that methylation sites influence the development of DKD may aid risk prediction tools and stimulate research to identify epigenomic therapies which might be clinically useful for this disease.Copyright © 2020 Smyth, Patterson, Swan, Maxwell and McKnight.",
+Yes,20201123,ewas,33751861,"Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children.",Pediatr Pulmonol,"Exposure to violence (ETV) or stress may cause asthma through unclear mechanisms.Epigenome-wide association study (EWAS) of DNA methylation in nasal epithelium and four ETV or chronic stress measures in 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed measures of ETV or chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by P-value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA).In the EWAS of stress/violence in EVA-PR, gun violence was associated with methylation of cg18961589 inLINC01164(β=0.03,P=1.28×10-7), and maternal stress was associated with methylation of cg03402351 inSNN(β=0.04,P=1.69×10-7) and cg19064846 inPTPRN2(β=0.03,P=3.36×10-7). In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence in EVA-PR, CpGs inSTARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4andANAPC13were associated with atopic asthma at FDR-P< 0.05.ETV and chronic stress may increase the risk of atopic asthma through DNA methylation in airway epithelium, though this needs confirmation in future longitudinal studies.",
+Yes,20201123,ewas,33152445,PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.,Brain Behav Immun,"Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.Copyright © 2020 Elsevier Inc. All rights reserved.",
+Yes,20201123,ewas,33151971,"Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial.",PLoS Med,"Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders.Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings.ISRCTN89971375.",
+Yes,20201123,ewas,33150670,Sex-specific associations of asthma acquisition with changes in DNA methylation during adolescence.,Clin Exp Allergy,"Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma.We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific.Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n=124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed.We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (p-values<1.0Ă—10-3). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (p-values<0.01 in both cohorts).Gender-reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence.This article is protected by copyright. All rights reserved.",
+No,20201123,dnam age,33146735,Association of Neighborhood Deprivation With Epigenetic Aging Using 4 Clock Metrics.,JAMA Netw Open,"Neighborhood deprivation is associated with age-related disease, mortality, and reduced life expectancy. However, biological pathways underlying these associations are not well understood.To evaluate the association between neighborhood deprivation and epigenetic measures of age acceleration and genome-wide methylation.This cross-sectional study used data from the Sister Study, a prospective cohort study comprising 50 884 women living in the US and Puerto Rico aged 35 to 74 years at enrollment who had a sister with breast cancer but had not had breast cancer themselves. Cohort enrollment occurred between July 2003 and March 2009. Participants completed a computer-assisted telephone interview on demographic, socioeconomic, lifestyle, and residential factors and provided anthropometric measures and peripheral blood samples at a home examination. DNA methylation data obtained for 2630 non-Hispanic White women selected for a case-cohort study in 2014 were used in this cross-sectional analysis. DNA methylation was measured using the HumanMethylation450 BeadChips in whole blood samples collected at baseline. Data analysis for this study was performed from October 17, 2019, to August 27, 2020.Each participants' primary address was linked to an established index of neighborhood deprivation.Epigenetic age was estimated using 4 epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge). Age acceleration was determined using residuals from regressing chronologic age on each of the 4 epigenetic age metrics. Linear regression was used to estimate associations between neighborhood deprivation and epigenetic age acceleration as well as DNA methylation at individual cytosine-guanine sites across the genome.Mean (SD) age of the 2630 participants was 56.9 (8.7) years. Those with the greatest (>75th percentile) vs least (≤25th percentile) neighborhood deprivation had higher epigenetic age acceleration estimated by Hannum (β = 0.23; 95% CI, 0.01-0.45), PhenoAge (β = 0.28; 95% CI, 0.06-.50), and GrimAge (β = 0.37; 95% CI, 0.12-0.62). Increasing US quartiles of neighborhood deprivation exhibited a trend with Hannum, PhenoAge, and GrimAge. For example, GrimAge showed a significant dose-response (P test for trend <.001) as follows: level 2 vs level 1 (β = 0.30; 95% CI, 0.17-0.42), level 3 vs level 1 (β = 0.35; 95% CI, 0.19-0.50), and level 4 vs level 1 (β = 0.37; 95% CI, 0.12-0.62). Neighborhood deprivation was found to be associated with 3 cytosine-phosphate-guanine sites, with 1 of these annotated to a known gene MAOB (P = 9.71 × 10-08).The findings of this study suggest that residing in a neighborhood with a higher deprivation index appears to be reflected by methylation-based markers of aging.",
+No,20201123,sem,33144501,Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease.,Proc Natl Acad Sci U S A,"Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.",
+Yes,20201123,ewas,33137917,Association between Breastfeeding and DNA Methylation over the Life Course: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC).,Nutrients,"Breastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7 years, N = 640) and adolescence (age 15-17 years, N = 709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N = 702) was used as a negative control for potential pre-natal residual confounding.Two differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15-17 years, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15-17 years, but not between birth and age 7 years.Our findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations.",
+Yes,20201123,ewas,33134824,Epigenome-Wide Association Study Using Prediagnostic Bloods Identifies New Genomic Regions Associated With Pancreatic Cancer Risk.,JNCI Cancer Spectr,"Epigenome-wide association studies using peripheral blood have identified specific sites of DNA methylation associated with risk of various cancers and may hold promise to identify novel biomarkers of risk; however, few studies have been performed for pancreatic cancer and none using a prospective study design.Using a nested case-control study design, incident pancreatic cancer cases and matched controls were identified from participants who provided blood at baseline in 3 prospective cohort studies. DNA methylation levels were measured in DNA extracted from leukocytes using the Illumina MethylationEPIC array. Average follow-up period for this analysis was 13 years.Several new genomic regions were identified as being differentially methylated in cases and controls; the 5 strongest associations were observed for CpGs located in genesTMEM204/IFT140,MFSD6L,FAM134B/RETREG1,KCNQ1D, andC6orf227. For some CpGs located in chromosome 16p13.3 (near genesTMEM204andIFT140), associations were stronger with shorter time to diagnosis (eg, odds ratio [OR] = 5.95, 95% confidence interval [CI] = 1.52 to 23.12, for top vs bottom quartile, for <5 years between blood draw and cancer diagnosis), but associations remained statistically significantly higher even when cases were diagnosed over 10 years after blood collection. Statistically significant differences in DNA methylation levels were also observed in the gastric secretion pathway using Gene Set Enrichment Analysis (GSEA) analysis.Changes in DNA methylation in peripheral blood may mark alterations in metabolic or immune pathways that play a role in pancreatic cancer. Identifying new biological pathways in carcinogenesis of pancreatic cancer using epigenome-wide association studies approach could provide new opportunities for improving treatment and prevention.© The Author(s) 2020. Published by Oxford University Press.",
+No,20201123,methods,33125040,A Structured Approach to Evaluating Life Course Hypotheses: Moving Beyond Analyses of Exposed Versus Unexposed in the Omics Context.,Am J Epidemiol,"The structured life course modeling approach (SLCMA) is a theory-driven analytic method that empirically compares multiple prespecified life course hypotheses characterizing time-dependent exposure-outcome relationships to determine which theory best fits the observed data. In this study, we performed simulations and empirical analyses to evaluate the performance of the SLCMA when applied to genome-wide DNA methylation (DNAm). Using simulations, we compared five statistical inference tests used with SLCMA (n=700), assessing the family-wise error rate, statistical power, and confidence interval coverage to determine whether inference based on these tests was valid in the presence of substantial multiple testing and small effects, two hallmark challenges of inference from omics data. In the empirical analyses, we evaluated the time-dependent relationship of childhood abuse with genome-wide DNAm (n=703). In simulations, selective inference and max-|t|-test performed best: both controlled family-wise error rate and yielded moderate statistical power. Empirical analyses using SLCMA revealed time-dependent effects of childhood abuse on DNAm. Our findings show that SLCMA, applied and interpreted appropriately, can be used in high-throughput settings to examine time-dependent effects underlying exposure-outcome relationships over the life course. We provide recommendations for applying the SLCMA in omics settings and encourage researchers to move beyond analyses of exposed versus unexposed.© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
+Yes,20201123,ewas,33100131,Epigenome-wide association study identifies DNA methylation sites associated with target organ damage in older African Americans.,Epigenetics,"Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 nearC7orf50, cg09155024, cg10254690 nearOAT, cg07660512, cg12661888 nearIFT43, and cg02264946 nearCATSPERD) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated withcis-gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.",
+No,20201123,mediation,33092652,Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits.,Clin Epigenetics,"Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits.We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression.Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.",
+No,20201123,prediction,33092459,DNA methylation biomarker selected by an ensemble machine learning approach predicts mortality risk in an HIV-positive veteran population.,Epigenetics,"Background: With the improved life expectancy of people living with HIV (PLWH), identifying vulnerable subpopulations at high mortality risk is important. Evidences showed that DNA methylation (DNAm) is associated with mortality in non-HIV populations. Here, we established a panel of DNAm biomarkers that can predict mortality risk among PLWH.Methods: 1,081 HIV-positive participants from the Veterans Ageing Cohort Study (VACS) were divided into training (N = 460), validation (N = 114), and testing (N = 507) sets. VACS index was used as a measure of mortality risk among PLWH. Model training and fine-tuning were conducted using the ensemble method in the training and validation sets and prediction performance was assessed in the testing set. The survival analysis comparing the predicted high and low mortality risk groups and the Gene Ontology enrichment analysis of the predictive CpG sites were performed.Results: We selected a panel of 393 CpGs for the ensemble prediction model that showed excellent performance in predicting high mortality risk with an auROC of 0.809 (95%CI: 0.767,0.851) and a balanced accuracy of 0.653 (95%CI: 0.611, 0.693) in the testing set. The high mortality risk group was significantly associated with 10-year mortality (hazard ratio = 1.79, p = 4E-05) compared with low risk group. These 393 CpGs were located in 280 genes enriched in immune and inflammation response pathways.Conclusions: We identified a panel of DNAm features associated with mortality risk in PLWH. These DNAm features may serve as predictive biomarkers for mortality risk among PLWH.Abbreviations: AUC: Area Under Curve; CI: Confidence interval; DMR: differentially methylated region; DNA: Deoxyribonucleic acid; DNAm: DNA methylation; DAVID: Database for Annotation, Visualization, and Integrated Discovery; EWA: epigenome-wide association; FDR: False discovery rate; FWER: Family-wise error rate; GLMNET: elastic-net-regularized generalized linear models; GO: Gene ontology; HIV: Human immunodeficiency virus; HM450K: Human Methylation 450 K BeadChip; k-NN: k-nearest neighbours; NK: Natural killer; PC: Principal component; PLWH: people living with HIV; QC: Quality control; SVM: Support Vector Machines; VACS: Veterans Ageing Cohort Study; XGBoost: Extreme Gradient Boosting Tree.",
+No,20201123,dnam age,33109080,Blood-based epigenetic estimators of chronological age in human adults using DNA methylation data from the Illumina MethylationEPIC array.,BMC Genomics,"Epigenetic clocks have been recognized for their precise prediction of chronological age, age-related diseases, and all-cause mortality. Existing epigenetic clocks are based on CpGs from the Illumina HumanMethylation450 BeadChip (450 K) which has now been replaced by the latest platform, Illumina MethylationEPIC BeadChip (EPIC). Thus, it remains unclear to what extent EPIC contributes to increased precision and accuracy in the prediction of chronological age.We developed three blood-based epigenetic clocks for human adults using EPIC-based DNA methylation (DNAm) data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Gene Expression Omnibus (GEO) public repository: 1) an Adult Blood-based EPIC Clock (ABEC) trained on DNAm data from MoBa (n = 1592, age-span: 19 to 59 years), 2) an extended ABEC (eABEC) trained on DNAm data from MoBa and GEO (n = 2227, age-span: 18 to 88 years), and 3) a common ABEC (cABEC) trained on the same training set as eABEC but restricted to CpGs common to 450 K and EPIC. Our clocks showed high precision (Pearson correlation between chronological and epigenetic age (r) > 0.94) in independent cohorts, including GSE111165 (n = 15), GSE115278 (n = 108), GSE132203 (n = 795), and the Epigenetics in Pregnancy (EPIPREG) study of the STORK Groruddalen Cohort (n = 470). This high precision is unlikely due to the use of EPIC, but rather due to the large sample size of the training set.Our ABECs predicted adults' chronological age precisely in independent cohorts. As EPIC is now the dominant platform for measuring DNAm, these clocks will be useful in further predictions of chronological age, age-related diseases, and mortality.",
+No,20201123,single cell,33098772,Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin.,Cell,"Cell differentiation and function are regulated across multiple layers of gene regulation, including modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of regulatory events leading to cell fate commitment. Here we developed simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq), a highly scalable approach for measurement of chromatin accessibility and gene expression in the same single cell, applicable to different tissues. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define domains of regulatory chromatin (DORCs) that significantly overlap with super-enhancers. During lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting that changes in chromatin accessibility may prime cells for lineage commitment. We computationally infer chromatin potential as a quantitative measure of chromatin lineage-priming and use it to predict cell fate outcomes. SHARE-seq is an extensible platform to study regulatory circuitry across diverse cells in tissues.Copyright © 2020 Elsevier Inc. All rights reserved.",
+Yes,20201123,ewas,33076993,Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants.,Clin Epigenetics,"Infants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities.This study included 532 infants born < 30 weeks gestation, participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants study. We used a neonatal morbidity risk score, which was an additive index of the number of morbidities experienced during the NICU stay, including bronchopulmonary dysplasia (BPD), severe brain injury, serious neonatal infections, and severe retinopathy of prematurity. DNA was collected from buccal cells at discharge from the NICU, and DNAm was measured using the Illumina MethylationEPIC. We tested for differential methylation in association with the neonatal morbidity risk score then tested for differentially methylated regions (DMRs) and overrepresentation of biological pathways.We identified ten differentially methylated CpGs (α Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose-response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing.Neonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.",
+No,20201123,single cell,33106633,Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases.,Nat Genet,"Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer's and Parkinson's diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson's disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.",
+No,20201123,epigenetics,33099088,Integrated multi-omics reveal epigenomic disturbance of assisted reproductive technologies in human offspring.,EBioMedicine,"The births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the safety issue regarding ARTs has drawn growing attention with accumulating observations of rising health risks, and underlying epigenetic mechanisms are largely uncharacterized.In order to clarify epigenetic risks attributable to ARTs, we profiled DNA methylome on 137 umbilical cord blood (UCB) and 158 parental peripheral blood (PPB) samples, histone modifications (H3K4me3, H3K4me1, H3K27me3 and H3K27ac) on 33 UCB samples and transcriptome on 32 UCB samples by reduced representation bisulfite sequencing (RRBS), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq), respectively.We revealed that H3K4me3 was the most profoundly impacted by ICSI and freeze-thawing operation compared with the other three types of histone modifications. IVF-ET seemed to introduce less disturbance into infant epigenomes than IVF-FET or ICSI-ET did. ARTs also decreased the similarity of DNA methylome within twin pairs, and we confirmed that ART per se would introduce conservative changes locally through removal of parental effect. Importantly, those unique and common alterations induced by different ART procedures were highly enriched in the processes related to nervous system, cardiovascular system and glycolipid metabolism etc., which was in accordance with those findings in previous epidemiology studies and suggested some unexplored health issues, including in the immune system and skeletal system.Different ART procedures can induce local and functional epigenetic abnormalities, especially for DNA methylation and H3K4me3, providing an epigenetic basis for the potential long-term health risks in ART-conceived offspring.This study was funded by National Natural Science Foundation of China (81,730,038; 81,521,002), National Key Research and Development Program (2018YFC1004000; 2017YFA0103801; 2017YFA0105001) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020703). Yang Wang was supported by Postdoctoral Fellowship of Peking-Tsinghua Center for Life Science.Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.",
+Yes,20201214,ewas,33290095,Maternal lipodome across pregnancy is associated with the neonatal DNA methylome.,Epigenomics,Aim:To classify the association between the maternal lipidome and DNA methylation in cord blood leukocytes.Materials & methods:Untargeted lipidomics was performed on first trimester maternal plasma (M1) and delivery maternal plasma (M3) in 100 mothers from the Michigan Mother-Infant Pairs cohort. Cord blood leukocyte DNA methylation was profiled using the Infinium EPIC bead array and empirical Bayes modeling identified differential DNA methylation related to maternal lipid groups.Results:M3-saturated lysophosphatidylcholine was associated with 45 differentially methylated loci and M3-saturated lysophosphatidylethanolamine was associated with 18 differentially methylated loci. Biological pathways enriched among differentially methylated loci by M3 saturated lysophosphatidylcholines were related to cell proliferation and growth.Conclusion:The maternal lipidome may be influential in establishing the infant epigenome.,
+Yes,20201214,ewas,33227132,DNA methylation differences at birth after conception through ART.,Hum Reprod,"Is there a relation between ART and DNA methylation (DNAm) patterns in cord blood, including any differences between IVF and ICSI?DNAm at 19 CpGs was associated with conception via ART, with no difference found between IVF and ICSI.Prior studies on either IVF or ICSI show conflicting outcomes, as both widespread effects on DNAm and highly localized associations have been reported. No study on both IVF and ICSI and genome-wide neonatal DNAm has been performed.This was a cross-sectional study comprising 87 infants conceived with IVF or ICSI and 70 conceived following medically unassisted conception. The requirement for inclusion in the study was an understanding of the Swedish language and exclusion was the use of donor gametes.Participants were from the UppstART study, which was recruited from fertility and reproductive health clinics, and the Born into Life cohort, which is recruited from the larger LifeGene study. We measured DNAm from DNA extracted from cord blood collected at birth using a micro-array (450k array). Group differences in DNAm at individual CpG dinucleotides (CpGs) were determined using robust linear models and post-hoc Tukey's tests.We found no association of ART conception with global methylation levels, imprinted loci and meta-stable epialleles. In contrast, we identify 19 CpGs at which DNAm was associated with being conceived via ART (effect estimates: 0.5-4.9%, PFDR < 0.05), but no difference was found between IVF and ICSI. The associated CpGs map to genes related to brain function/development or genes connected to the plethora of conditions linked to subfertility, but functional annotation did not point to any likely functional consequences.We measured DNAm in cord blood and not at later ages or in other tissues. Given the number of tests performed, our study power is limited and the findings need to be replicated in an independent study.We find that ART is associated with DNAm differences in cord blood when compared to non-ART samples, but these differences are limited in number and effect size and have unknown functional consequences in adult blood. We did not find indications of differences between IVF and ICSI.E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128) and JPI-H2020 Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL) under proposal number 655 (PREcisE Project) through ZonMw (529051023). Financial support was provided from the European Union's Seventh Framework Program IDEAL (259679), the Swedish Research Council (K2011-69X-21871-01-6, 2011-3060, 2015-02434 and 2018-02640) and the Strategic Research Program in Epidemiology Young Scholar Awards, Karolinska Institute (to A.N.I.) and through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Strategic Research Program in Epidemiology at Karolinska Institutet and the Swedish Heart-Lung Foundation and Danderyd University Hospital (Stockholm, Sweden). The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. The authors declare no competing interests.N/A.© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.",
+Yes,20201214,ewas,33214203,DNA methylation at birth is associated with lung function development till age 26 years.,Eur Respir J,"Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25-75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of 8 CpGs on genesGLUL, MYCN, HLX, LHX1, COBL, COL18A1, STRA6,andWNT11involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs onLHX1andCOL18A1were linked to gene expression in IOWBC-F2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.Copyright ©ERS 2020.",
+Yes,20201214,ewas,33239103,DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.,Genome Med,"DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.",
+No,20201214,ewas,33267929,Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children.,Psychol Med,"Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment.Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses.Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 Ă— 10-07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4.These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.",
+Yes,20201214,ewas,33257653,Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer's disease.,Nat Commun,"DNA methylation differences in Alzheimer's disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. Using a uniform analysis pipeline, we identified 3751 CpGs and 119 differentially methylated regions (DMRs) significantly associated with Braak stage. Our analysis identified differentially methylated genes such as MAMSTR, AGAP2, and AZU1. The most significant DMR identified is located on the MAMSTR gene, which encodes a cofactor that stimulates MEF2C. Notably, MEF2C cooperates with another transcription factor, PU.1, a central hub in the AD gene network. Our enrichment analysis highlighted the potential roles of the immune system and polycomb repressive complex 2 in pathological AD. These results may help facilitate future mechanistic and biomarker discovery studies in AD.",
+No,20201214,ewas,33298155,Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer's disease and implicate its dynamic role in disease progression.,Clin Epigenetics,"While Alzheimer's disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention.We analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters).When compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances.Our results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.",
+Yes,20201214,ewas,33279932,Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population.,Mol Psychiatry,"Schizophrenia is a severe neuropsychiatric disorder with core features including hallucinations, delusions, and cognition deficits. Accumulating evidence has implicated abnormal DNA methylation in the development of schizophrenia. However, the mechanisms by which DNA methylation changes alter the risk for schizophrenia remain largely unknown. We recently carried out a DNA methylome study of peripheral blood samples from 469 first-episode patients with schizophrenia and 476 age- and gender-matched healthy controls of Han Chinese origin. Genomic DNA methylation patterns were quantified using an Illumina Infinium Human MethylationEPIC BeadChip. We identified multiple differentially methylated positions (DMPs) and regions between patients and controls. The most significant DMPs were annotated to genes C17orf53, THAP1 and KCNQ4 (KV7.4), with Bonferroni-adjusted P values of [Formula: see text], [Formula: see text], and [Formula: see text], respectively. In particular, KCNQ4 encodes a voltage-gated potassium channel of the KV7 family, which is linked to neuronal excitability. The genes associated with top-ranked DMPs also included many genes involved in nervous system development, such as LIMK2 and TMOD2. Gene ontology analysis of the differentially methylated genes further identified strong enrichment of neuronal networks, including neuron projection extension, axonogenesis and neuron apoptotic process. Finally, we provided evidence that schizophrenia-associated epigenetic alterations co-localize with genetic susceptibility loci. By focusing on first-episode schizophrenia patients, our investigation lends particularly strong support for an important role of DNA methylation in schizophrenia pathogenesis unconfounded by the effects of long-term antipsychotic medication or disease progression. The observed DNA methylation aberrations in schizophrenia patients could potentially provide a valuable resource for identifying diagnostic biomarkers and developing novel therapeutic targets to benefit schizophrenia patients.",
+Yes,20201214,ewas,33235198,Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.,Nat Commun,"Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.",
+Yes,20201214,ewas,33208194,Altered immune phenotype and DNA methylation in panic disorder.,Clin Epigenetics,"Multiple studies have related psychiatric disorders and immune alterations. Panic disorder (PD) has been linked with changes in leukocytes distributions in several small studies using different methods for immune characterization. Additionally, alterations in the methylation of repetitive DNA elements, such as LINE-1, have been associated with mental disorders. Here, we use peripheral blood DNA methylation data from two studies and an updated DNA methylation deconvolution library to investigate the relation of leukocyte proportions and methylation status of repetitive elements in 133 patients with panic disorder compared with 118 controls.We used DNA methylation data to deconvolute leukocyte cell-type proportions and to infer LINE-1 element methylation comparing PD cases and controls. We also identified differentially methylated CpGs associated with PD using an epigenome-wide association study approach (EWAS), with models adjusting for sex, age, and cell-type proportions. Individuals with PD had a lower proportion of CD8T cells (OR: 0.86, 95% CI: 0.78-0.96, P-adj = 0.030) when adjusting for age, sex, and study compared with controls. Also, PD cases had significantly lower LINE-1 repetitive element methylation than controls (P < 0.001). The EWAS identified 61 differentially methylated CpGs (58 hypo- and 3 hypermethylated) in PD (Bonferroni adjusted P < 1.33 × 10-7).These results suggest that those with panic disorder have changes to their immune system and dysregulation of repeat elements relative to controls.",
+Yes,20201214,ewas,33277923,Associations of Alcohol Consumption with Epigenome-Wide DNA Methylation and Epigenetic Age Acceleration: Individual-Level and Co-twin Comparison Analyses.,Alcohol Clin Exp Res,"DNA methylation may play a role in progression from normative to problematic drinking and underlie adverse health outcomes associated with alcohol misuse. In the current study, we examined the association between alcohol consumption and DNA methylation patterns using three approaches: a conventional epigenome-wide association study (EWAS); a co-twin comparison design, which controls for genetic and environmental influences that twins share; and a regression of age acceleration, defined as a discrepancy between chronological age and DNA methylation age, on alcohol consumption.Participants came from the Finnish Twin Cohorts (FinnTwin12/FinnTwin16; N = 1004; 55% female; average age = 23 years). Individuals reported the number of alcoholic beverages consumed in the past week, and epigenome-wide DNA methylation was assessed in whole-blood using the Infinium HumanMethylation450 BeadChip.In the EWAS, alcohol consumption was significantly related to methylation at 24 CpG sites. When evaluating whether differences between twin siblings (185 monozygotic pairs) in alcohol consumption predicted differences in DNA methylation, co-twin comparisons replicated four CpG sites from the EWAS and identified 23 additional sites. However, when we examined qualitative differences in drinking patterns between twins (heavy drinker versus light drinker/abstainer or moderate drinker versus abstainer; 44 pairs), methylation patterns did not significantly differ within twin pairs. Finally, individuals who reported higher alcohol consumption also exhibited greater age acceleration, though results were no longer significant after controlling for genetic and environmental influences shared by co-twins.Our analyses offer insight into the associations between epigenetic variation and levels of alcohol consumption in young adulthood.This article is protected by copyright. All rights reserved.",
+Yes,20201214,ewas,33215951,Childhood exposure to hunger: associations with health outcomes in later life and epigenetic markers.,Epigenomics,Aim:To assess associations of early exposure to hunger with depressive symptoms and cardiovascular disease (CVD) and to investigate possible epigenetic pathways.Patients & methods:Data were based on a German population-based cohort of older adults (n = 9631). Regression models were performed for health outcomes in later life. An epigenome-wide association study for early-life exposure to hunger was performed in a subgroup (n = 2221) with whole blood DNA methylation data.Results:Childhood exposure to hunger was associated with CVD and depressive symptoms in later life. Prenatal or infant exposure was strongly associated with depressive symptoms. No CpG reached epigenome-wide significance after multiple testing correction.Conclusion:Childhood hunger is a risk factor for depressive symptoms and CVD at older age. DNA methylation could not explain this association.,
+Yes,20201214,ewas,33266012,DNA Methylation Profiles of Vegans and Non-Vegetarians in the Adventist Health Study-2 Cohort.,Nutrients,"We sought to determine if DNA methylation patterns differed between vegans and non-vegetarians in the Adventist Health Study-2 cohort. Genome-wide DNA methylation derived from buffy coat was profiled in 62 vegans and 142 non-vegetarians. Using linear regression, methylation of CpG sites and genes was categorized or summarized according to various genic/intergenic regions and CpG island-related regions, as well as the promoter. Methylation of genes was measured as the average methylation of available CpG's annotated to the nominated region of the respective gene. A permutation method defining the null distribution adapted from Storey et al. was used to adjust for false discovery. Differences in methylation of several CpG sites and genes were detected at a false discovery rate < 0.05 in region-specific and overall analyses. A vegan diet was associated predominantly with hypomethylation of genes, most notably methyltransferase-like 1 (METTL1). Although a limited number of differentially methylated features were detected in the current study, the false discovery method revealed that a much larger proportion of differentially methylated genes and sites exist, and could be detected with a larger sample size. Our findings suggest modest differences in DNA methylation in vegans and non-vegetarians, with a much greater number of detectable significant differences expected with a larger sample.",
+Yes,20201214,ewas,33232214,Epigenome-wide association scan identifies methylation sites associated with HIV infection.,Epigenomics,"Aim:To investigate the role of epigenetics in HIV pathophysiology. Materials & methods:We conducted an epigenome-wide association scan on HIV infection status among people who inject drugs in the AIDS Linked to the IntraVenous Experience study with primary (n = 397) and validation samples (n = 390). DNA methylation from blood was measured by the Illumina EPIC BeadChip. We controlled for cell type heterogeneity by HIV status.Results:HIV infection status was associated (p < 10-8) with DNA methylation at 49 CpG sites. Sites were enriched in response to virus, interferon signaling pathway, etc. Among these sites, discovery and validation t-statistics were highly correlated (r = 0.96).Conclusion:In a cohort of people who inject drugs, HIV status was associated with differential DNA methylation at biologically meaningful sites.",
+Yes,20201214,ewas,33228781,DNA methylation signatures to predict the cervicovaginal microbiome status.,Clin Epigenetics,"The composition of the microbiome plays an important role in human health and disease. Whether there is a direct association between the cervicovaginal microbiome and the host's epigenome is largely unexplored.Here we analyzed a total of 448 cervicovaginal smear samples and studied both the DNA methylome of the host and the microbiome using the Illumina EPIC array and next-generation sequencing, respectively. We found that those CpGs that are hypo-methylated in samples with non-lactobacilli (O-type) dominating communities are strongly associated with gastrointestinal differentiation and that a signature consisting of 819 CpGs was able to discriminate lactobacilli-dominating (L-type) from O-type samples with an area under the receiver operator characteristic curve (AUC) of 0.84 (95% CI = 0.77-0.90) in an independent validation set. The performance found in samples with more than 50% epithelial cells was further improved (AUC 0.87) and in women younger than 50 years of age was even higher (AUC 0.91). In a subset of 96 women, the buccal but not the blood cell DNA showed the same trend as the cervicovaginal samples in discriminating women with L- from O-type cervicovaginal communities.These findings strongly support the view that the epithelial epigenome plays an essential role in hosting specific microbial communities.",
+Yes,20201214,ewas,33239708,An epigenome-wide association study of metabolic syndrome and its components.,Sci Rep,"The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP -previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P = 1.80 × 10-8). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P = 5.36 × 10-9) and waist circumference (P = 5.21 × 10-9). The previously identified type 2 diabetes-associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P = 2.24 × 10-7). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P = 7.81 × 10-8). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.",
+Yes,20201214,ewas,33303027,Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium.,Clin Transl Allergy,"Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission.Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA).We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P < 0.05) and the same direction of effect in nasal brushes.We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway.",
+No,20201214,dnam age,33279859,"DNA methylation-based biomarkers of age acceleration and all-cause death, myocardial infarction, stroke, and cancer in two cohorts: The NAS, and KORA F4.",EBioMedicine,"DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints.We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing.The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer.From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions.National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.",
+No,20201214,dnam age,33210602,Plasma proteomic biomarker signature of age predicts health and life span.,Elife,"Older age is a strong shared risk factor for many chronic diseases, and there is increasing interest in identifying aging biomarkers. Here, a proteomic analysis of 1301 plasma proteins was conducted in 997 individuals between 21 and 102 years of age. We identified 651 proteins associated with age (506 over-represented, 145 underrepresented with age). Mediation analysis suggested a role for partialcis-epigenetic control of protein expression with age. Of the age-associated proteins, 33.5% and 45.3%, were associated with mortality and multimorbidity, respectively. There was enrichment of proteins associated with inflammation and extracellular matrix as well as senescence-associated secretory proteins. A 76-protein proteomic age signature predicted accumulation of chronic diseases and all-cause mortality. These data support the use of proteomic biomarkers to monitor aging trajectories and to identify individuals at higher risk of disease to be targeted for in depth diagnostic procedures and early interventions.",
+No,20201214,epigenetics,33239447,KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.,Proc Natl Acad Sci U S A,"Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. However, a subset of TEs exhibit variable methylation levels in genetically identical individuals, and this is associated with epigenetically conferred phenotypic differences, environmental adaptability, and transgenerational epigenetic inheritance. The evolutionary origins and molecular mechanisms underlying interindividual epigenetic variability remain unknown. Using a repertoire of murine variably methylated intracisternal A-particle (VM-IAP) epialleles as a model, we demonstrate that variable DNA methylation states at TEs are highly susceptible to genetic background effects. Taking a classical genetics approach coupled with genome-wide analysis, we harness these effects and identify a cluster of KRAB zinc finger protein (KZFP) genes that modifies VM-IAPs intransin a sequence-specific manner. Deletion of the cluster results in decreased DNA methylation levels and altered histone modifications at the targeted VM-IAPs. In some cases, these effects are accompanied by dysregulation of neighboring genes. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators. These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance.Copyright © 2020 the Author(s). Published by PNAS.",
+No,20201214,epigenetics,33257808,Female human primordial germ cells display X-chromosome dosage compensation despite the absence of X-inactivation.,Nat Cell Biol,"X-chromosome dosage compensation in female placental mammals is achieved by X-chromosome inactivation (XCI). Human pre-implantation embryos are an exception, in which dosage compensation occurs by X-chromosome dampening (XCD). Here, we examined whether XCD extends to human prenatal germ cells given their similarities to naive pluripotent cells. We found that female human primordial germ cells (hPGCs) display reduced X-linked gene expression before entering meiosis. Moreover, in hPGCs, both X chromosomes are active and express the long non-coding RNAs X active coating transcript (XACT) and X inactive specific transcript (XIST)-the master regulator of XCI-which are silenced after entry into meiosis. We find that XACT is a hPGC marker, describe XCD associated with XIST expression in hPGCs and suggest that XCD evolved in humans to regulate X-linked genes in pre-implantation embryos and PGCs. Furthermore, we found a unique mechanism of X-chromosome regulation in human primordial oocytes. Therefore, future studies of human germline development must consider the sexually dimorphic X-chromosome dosage compensation mechanisms in the prenatal germline.",
+No,20201214,meqtl,33216750,Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles.,PLoS Genet,"Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.",
+No,20201214,methods,33205092,Patterns of Reliability: Assessing the Reproducibility and Integrity of DNA Methylation Measurement.,Patterns (N Y),"DNA methylation plays an important role in both normal human development and risk of disease. The most utilized method of assessing DNA methylation uses BeadChips, generating an epigenome-wide ""snapshot"" of >450,000 observations (probe measurements) per assay. However, the reliability of each of these measurements is not equal, and little consideration is paid to consequences for research. We correlated repeat measurements of the same DNA samples using the Illumina HumanMethylation450K and the Infinium MethylationEPIC BeadChips in 350 blood DNA samples. Probes that were reliably measured were more heritable and showed consistent associations with environmental exposures, gene expression, and greater cross-tissue concordance. Unreliable probes were less replicable and generated an unknown volume of false negatives. This serves as a lesson for working with DNA methylation data, but the lessons are equally applicable to working with other data: as we advance toward generating increasingly greater volumes of data, failure to document reliability risks harming reproducibility.© 2020 The Authors.",
+No,20201214,methods,33230324,Simultaneous profiling of chromatin accessibility and methylation on human cell lines with nanopore sequencing.,Nat Methods,"Probing epigenetic features on DNA has tremendous potential to advance our understanding of the phased epigenome. In this study, we use nanopore sequencing to evaluate CpG methylation and chromatin accessibility simultaneously on long strands of DNA by applying GpC methyltransferase to exogenously label open chromatin. We performed nanopore sequencing of nucleosome occupancy and methylome (nanoNOMe) on four human cell lines (GM12878, MCF-10A, MCF-7 and MDA-MB-231). The single-molecule resolution allows footprinting of protein and nucleosome binding, and determination of the combinatorial promoter epigenetic signature on individual molecules. Long-read sequencing makes it possible to robustly assign reads to haplotypes, allowing us to generate a fully phased human epigenome, consisting of chromosome-level allele-specific profiles of CpG methylation and chromatin accessibility. We further apply this to a breast cancer model to evaluate differential methylation and accessibility between cancerous and noncancerous cells.",
+No,20201214,prediction,33256852,Whole blood DNA methylation aging markers predict colorectal cancer survival: a prospective cohort study.,Clin Epigenetics,"Blood DNA methylation-based aging algorithms predict mortality in the general population. We investigated the prognostic value of five established DNA methylation aging algorithms for patients with colorectal cancer (CRC).AgeAccelHorvath, AgeAccelHannum, DNAmMRscore, AgeAccelPheno and AgeAccelGrim were constructed using whole blood epi-genomic data from 2206 CRC patients. After a median follow-up of 6.2 years, 1079 deaths were documented, including 596 from CRC. Associations of the aging algorithms with survival outcomes were evaluated using the Cox regression and survival curves. Harrell's C-statistics were computed to investigate predictive performance.Adjusted hazard ratios (95% confidence intervals) of all-cause mortality for patients in the third compared to the first tertile were 1.66 (1.32, 2.09) for the DNAmMRscore, 1.35 (1.14, 1.59) for AgeAccelPheno and 1.65 (1.37, 2.00) for AgeAccelGrim, even after adjustment for age, sex and stage. AgeAccelHorvath and AgeAccelHannum were not associated with all-cause or CRC-specific mortality. In stage-specific analyses, associations were much stronger for patients with early or intermediate stage cancers (stages I, II and III) than for patients with metastatic (stage IV) cancers. Associations were weaker and less often statistically significant for CRC-specific mortality. Adding DNAmMRscore, AgeAccelPheno or AgeAccelGrim to models including age, sex and tumor stage improved predictive performance moderately.DNAmMRscore, AgeAccelPheno and AgeAccelGrim could serve as non-invasive CRC prognostic biomarkers independent of other commonly used markers. Further research should aim for tailoring and refining such algorithms for CRC patients and to explore their value for enhanced prediction of treatment success and treatment decisions.",
+No,20201214,prediction,33213499,A pitfall for machine learning methods aiming to predict across cell types.,Genome Biol,"Machine learning models that predict genomic activity are most useful when they make accurate predictions across cell types. Here, we show that when the training and test sets contain the same genomic loci, the resulting model may falsely appear to perform well by effectively memorizing the average activity associated with each locus across the training cell types. We demonstrate this phenomenon in the context of predicting gene expression and chromatin domain boundaries, and we suggest methods to diagnose and avoid the pitfall. We anticipate that, as more data becomes available, future projects will increasingly risk suffering from this issue.",
+No,20201214,reference,33268789,A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation.,Nat Commun,"DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers.",
+No,20201214,wgbs,33228774,Comparison of methylation capture sequencing and Infinium MethylationEPIC array in peripheral blood mononuclear cells.,Epigenetics Chromatin,"Epigenome-wide association studies (EWAS) have been widely applied to identify methylation CpG sites associated with human disease. To date, the Infinium MethylationEPIC array (EPIC) is commonly used for high-throughput DNA methylation profiling. However, the EPIC array covers only 30% of the human methylome. Methylation Capture bisulfite sequencing (MC-seq) captures target regions of methylome and has advantages of extensive coverage in the methylome at an affordable price.Epigenome-wide DNA methylation in four peripheral blood mononuclear cell samples was profiled by using SureSelectXT Methyl-Seq for MC-seq and EPIC platforms separately. CpG site-based reproducibility of MC-seq was assessed with DNA sample inputs ranging in quantity of high (> 1000 ng), medium (300-1000 ng), and low (150 ng-300 ng). To compare the performance of MC-seq and the EPIC arrays, we conducted a Pearson correlation and methylation value difference at each CpG site that was detected by both MC-seq and EPIC. We compared the percentage and counts in each CpG island and gene annotation between MC-seq and the EPIC array.After quality control, an average of 3,708,550 CpG sites per sample were detected by MC-seq with DNA quantity > 1000 ng. Reproducibility of DNA methylation in MC-seq-detected CpG sites was high among samples with high, medium, and low DNA inputs (r > 0.96). The EPIC array captured an average of 846,464 CpG sites per sample. Compared with the EPIC array, MC-seq detected more CpGs in coding regions and CpG islands. Among the 472,540 CpG sites captured by both platforms, methylation of a majority of CpG sites was highly correlated in the same sample (r: 0.98-0.99). However, methylation for a small proportion of CpGs (N = 235) differed significantly between the two platforms, with differences in beta values of greater than 0.5.Our results show that MC-seq is an efficient and reliable platform for methylome profiling with a broader coverage of the methylome than the array-based platform. Although methylation measurements in majority of CpGs are highly correlated, a number of CpG sites show large discrepancy between the two platforms, which warrants further investigation and needs cautious interpretation.",
+No,20201214,cancer,33288854,Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression.,Commun Biol,"Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. In the current study we examine whether tumour DNA methylation (DNAme) profiling combined with genomic data is able to identify cell of origin and to reveal pathways involved in PanNET progression. We analyse genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confirm cell identity, we investigate ARX and PDX1 expression. Based on epigenetic similarities, PanNETs cluster in α-like, β-like and intermediate tumours. The epigenetic similarity to α-cells progressively decreases in the intermediate tumours, which present unclear differentiation. Specific transcription factor methylation and expression vary in the respective α/β-tumour groups. Depending on DNAme similarity to α/β-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.",
+No,20210111,dnam age,33377907,Racial Disparities in Epigenetic Aging of the Right vs Left Colon.,J Natl Cancer Inst,"There are well-documented racial differences in age-of-onset and laterality of colorectal cancer. Epigenetic age acceleration is postulated to be an underlying factor. However, comparative studies of side-specific colonic tissue epigenetic aging are lacking. Here, we performed DNA methylation analysis of matched right and left biopsies of normal colon from 128 individuals. Among African Americans (n = 88), the right colon showed accelerated epigenetic aging as compared to individual-matched left colon (1.51 years; 95% CI = 0.62 to 2.40 years; two-sided P = .001). In contrast, among European Americans (n = 40), the right colon shows remarkable age deceleration (1.93 years; 95% CI = 0.65 to 3.21 years; two-sided P = .004). Further, epigenome-wide analysis of DNA methylation identifies a unique pattern of hypermethylation in African American right colon. Our study is the first to report such race and side-specific differences in epigenetic aging of normal colon, providing novel insight into the observed younger age-of-onset and relative preponderance of right-side colon neoplasia in African Americans.© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
+No,20210111,dnamage,33384442,Targeted methods for epigenetic age predictions in mice.,Sci Rep,"Age-associated DNA methylation reflects aspect of biological aging-therefore epigenetic clocks for mice can elucidate how the aging process in this model organism is affected by specific treatments or genetic background. Initially, age-predictors for mice were trained for genome-wide DNA methylation profiles and we have recently described a targeted assay based on pyrosequencing of DNA methylation at only three age-associated genomic regions. Here, we established alternative approaches using droplet digital PCR (ddPCR) and barcoded bisulfite amplicon sequencing (BBA-seq). At individual CG dinucleotides (CpGs) the correlation of DNA methylation with chronological age was slightly higher for pyrosequencing and ddPCR as compared to BBA-seq. On the other hand, BBA-seq revealed that neighboring CpGs tend to be stochastically modified at murine age-associated regions. Furthermore, the binary sequel of methylated and non-methylated CpGs in individual reads can be used for single-read predictions, which may reflect heterogeneity in epigenetic aging. In comparison to C57BL/6 mice the single-read age-predictions using BBA-seq were also accelerated in the shorter-lived DBA/2 mice, and in C57BL/6 mice with a lifespan quantitative trait locus of DBA/2 mice. Taken together, we describe alternative targeted methods for epigenetic age predictions that provide new perspectives for aging-intervention studies in mice.",
+No,20210111,cell types,33407091,Cell-specific characterization of the placental methylome.,BMC Genomics,"DNA methylation (DNAm) profiling has emerged as a powerful tool for characterizing the placental methylome. However, previous studies have focused primarily on whole placental tissue, which is a mixture of epigenetically distinct cell populations. Here, we present the first methylome-wide analysis of first trimester (n = 9) and term (n = 19) human placental samples of four cell populations: trophoblasts, Hofbauer cells, endothelial cells, and stromal cells, using the Illumina EPIC methylation array, which quantifies DNAm at > 850,000 CpGs.The most distinct DNAm profiles were those of placental trophoblasts, which are central to many pregnancy-essential functions, and Hofbauer cells, which are a rare fetal-derived macrophage population. Cell-specific DNAm occurs at functionally-relevant genes, including genes associated with placental development and preeclampsia. Known placental-specific methylation marks, such as those associated with genomic imprinting, repetitive element hypomethylation, and placental partially methylated domains, were found to be more pronounced in trophoblasts and often absent in Hofbauer cells. Lastly, we characterize the cell composition and cell-specific DNAm dynamics across gestation.Our results provide a comprehensive analysis of DNAm in human placental cell types from first trimester and term pregnancies. This data will serve as a useful DNAm reference for future placental studies, and we provide access to this data via download from GEO (GSE159526), through interactive exploration from the web browser ( https://robinsonlab.shinyapps.io/Placental_Methylome_Browser/ ), and through the R package planet, which allows estimation of cell composition directly from placental DNAm data.",
+Yes,20210111,ewas,33317634,High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations.,Clin Epigenetics,"Children of aged fathers are at a higher risk of developing mental disorders. Alterations in sperm DNA methylation have been implicated as a potential cause. However, age-dependent modifications of the germ cells' epigenome remain poorly understood. Our objective was to assess the DNA methylation profile of human spermatozoa during aging.We used a high throughput, customized methylC-capture sequencing (MCC-seq) approach to characterize the dynamic DNA methylation in spermatozoa from 94 fertile and infertile men, who were categorized as young, 48 men between 18-38 years or old 46 men between 46-71 years. We identified more than 150,000 age-related CpG sites that are significantly differentially methylated among 2.65 million CpG sites covered. We conducted machine learning using our dataset to predict the methylation age of subjects; the age prediction accuracy based on our assay provided a more accurate prediction than that using the 450 K chip approach. In addition, we found that there are more hypermethylated (62%) than hypomethylated (38%) CpG sites in sperm of aged men, corresponding to 798 of total differential methylated regions (DMRs), of which 483 are hypermethylated regions (HyperDMR), and 315 hypomethylated regions (HypoDMR). Moreover, the distribution of age-related hyper- and hypomethylated CpGs in sperm is not random; the CpG sites that were hypermethylated with advanced age were frequently located in the distal region to genes, whereas hypomethylated sites were near to gene transcription start sites (TSS). We identified a high density of age-associated CpG changes in chromosomes 4 and 16, particularly HyperDMRs with localized clusters, the chr4 DMR cluster overlaps PGC1α locus, a protein involved in metabolic aging and the chr16 DMR cluster overlaps RBFOX1 locus, a gene implicated in neurodevelopmental disease. Gene ontology analysis revealed that the most affected genes by age were associated with development, neuron projection, differentiation and recognition, and behaviour, suggesting a potential link to the higher risk of neurodevelopmental disorders in children of aged fathers.We identified thousands of age-related and sperm-specific epigenetic alterations. These findings provide novel insight in understanding human sperm DNA methylation dynamics during paternal aging, and the subsequently affected genes potentially related to diseases in offspring.",
+Yes,20210111,ewas,33319642,Epigenome-wide association study and network analysis for IgA Nephropathy from CD19<sup>+</sup> B-cell in Chinese Population.,Epigenetics,"IgA nephropathy (IgAN) is the most common primary glomerular disease in China and worldwide. The proliferation of B cells is known to be associated with both risk and prognosis of IgAN, but the epigenetic mechanism underlying this association is unknown. In this study we carried out the first Epigenome-wide Association Study (EWAS) by using the latest Infinium Methylation EPIC BeadChip on 184 B cell-specific samples (92 case/control pairs) for Chinese IgAN population. After rigorous data normalization and residual batch effect correction, linear mixed effect model was used to detect methylation CpG sites associated with IgAN adjusting for age, gender and smoking. False discovery rate (FDR) less than 10% was used to account for multiple testing. Weighted gene co-methylation networks were generated to identify gene modules highly correlated with IgAN. A permutation test was performed to account for the potential effect of overfitting. After adjusting clinical covariates and potential technical batch effects, three CpGs corresponding toPCDH17, TERT, WDR82genes and three in the intergenic regions passed the genome-wide significant threshold. Methylation network analysis identified an additional IgAN associated gene module, containing 72 significant CpGs includingGALNT6, IQSEC1, CDC16 and SYS1, involved in the pathway related to tubular atrophy/interstitial fibrosis of IgAN. These results suggested important DNA methylation and gene targets in CD19+ B cells for the pathogenesis of IgAN.",
+Yes,20210111,ewas,33324494,Prenatal lead exposure and cord blood DNA methylation in PROGRESS: an epigenome-wide association study.,Environ Epigenet,"The effects of prenatal lead exposure on child development include impaired growth and cognitive function. DNA methylation might be involved in the underlying mechanisms and previous epigenome-wide association studies reported associations between lead exposure during pregnancy and cord blood methylation levels. However, it is unclear during which developmental stage lead exposure is most harmful. Cord blood methylation levels were assayed in 420 children from a Mexican pre-birth cohort using the Illumina Infinium MethylationEPIC microarray. Lead concentrations were measured in umbilical cord blood as well as in blood samples from the mothers collected at 2nd and 3rd trimester and delivery using inductively coupled plasma-mass spectrometry. In addition, maternal bone lead levels were measured in tibia and patella using X-ray fluorescence. Comprehensive quality control and preprocessing of microarray data was followed by an unbiased restriction to methylation sites with substantial variance. Methylation levels at 202 111 cytosine-phosphate-guanine sites were regressed on each exposure adjusting for child sex, leukocyte composition, batch variables, gestational age, birthweight-for-gestational-age, maternal age, maternal education and mode of delivery. We find no association between prenatal lead exposure and cord blood methylation. This null result is strengthened by a sensitivity analysis showing that in the same dataset known biomarkers for birthweight-for-gestational-age can be recovered and the fact that phenotypic associations with lead exposure have been described in the same cohort.© The Author(s) 2020. Published by Oxford University Press.",
+Yes,20210111,ewas,33331245,Maternal haemoglobin levels in pregnancy and child DNA methylation: a study in the Pregnancy And Childhood Epigenetics Consortium.,Epigenetics,"Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analysed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 child and 1,962 adolescent whole-blood samples derived from ten cohorts. DNA methylation was measured using Illumina Infinium Methylation450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.",
+Yes,20210111,ewas,33338541,Shared DNA methylation signatures in childhood allergy: the MeDALL study.,J Allergy Clin Immunol,"Differential DNA methylation associated with allergy might provide novel insights into shared or unique etiology of asthma, rhinitis and eczema.We sought to identify DNA methylation profiles associated with childhood allergy.Within the European Mechanisms of the Development of ALLergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation using a cross-sectional design. Allergy is defined as having symptoms from at least one allergic disease (asthma/rhinitis/eczema) and positive serum specific IgE to common aeroallergens. The discovery study included 219 cases and 417 controls at age 4 and 228 cases and 593 controls at age 8 from three birth cohorts, with replication analyses in 325 cases and 1,111 controls. We performed additional analyses on 21 replicated sites in 785 cases and 2,124 controls by allergic symptoms only from eight cohorts, three not previously included in analyses.We identified 80 differentially methylated CpG sites (CpGs) which showed 1-3% methylation difference in the discovery phase, of which 21, including five novel CpGs, passed genome-wide significance after meta-analysis. All 21 CpGs were also significantly differentially methylated with allergic symptoms, and shared between asthma, rhinitis and eczema. The 21 CpGs mapped to relevant genes, including ACOT7, LMAN3 and CLDN23. All 21 CpGs were differently methylated in asthma in isolated eosinophils, and ten were replicated in respiratory epithelium.Reduced whole blood DNA methylation at 21 CpGs was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis and eczema.Copyright © 2020. Published by Elsevier Inc.",
+Yes,20210111,ewas,33339956,Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males.,Mol Psychiatry,"Post-traumatic stress disorder (PTSD) is a heterogeneous condition evidenced by the absence of objective physiological measurements applicable to all who meet the criteria for the disorder as well as divergent responses to treatments. This study capitalized on biological diversity observed within the PTSD group observed following epigenome-wide analysis of a well-characterized Discovery cohort (N = 166) consisting of 83 male combat exposed veterans with PTSD, and 83 combat veterans without PTSD in order to identify patterns that might distinguish subtypes. Computational analysis of DNA methylation (DNAm) profiles identified two PTSD biotypes within the PTSD+ group, G1 and G2, associated with 34 clinical features that are associated with PTSD and PTSD comorbidities. The G2 biotype was associated with an increased PTSD risk and had higher polygenic risk scores and a greater methylation compared to the G1 biotype and healthy controls. The findings were validated at a 3-year follow-up (N = 59) of the same individuals as well as in two independent, veteran cohorts (N = 54 and N = 38), and an active duty cohort (N = 133). In some cases, for example Dopamine-PKA-CREB and GABA-PKC-CREB signaling pathways, the biotypes were oppositely dysregulated, suggesting that the biotypes were not simply a function of a dimensional relationship with symptom severity, but may represent distinct biological risk profiles underpinning PTSD. The identification of two novel distinct epigenetic biotypes for PTSD may have future utility in understanding biological and clinical heterogeneity in PTSD and potential applications in risk assessment for active duty military personnel under non-clinician-administered settings, and improvement of PTSD diagnostic markers.",
+Yes,20210111,ewas,33354722,Epigenome-wide association study of diet quality in the Women's Health Initiative and TwinsUK cohort.,Int J Epidemiol,"Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445 548 loci in the Women's Health Initiative (WHI) and the TwinsUK cohort.The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models that regressed methylation on AHEI-2010, adjusting for cell composition, chip number and location, study characteristics, principal components of genetic relatedness, age, smoking status, race/ethnicity and body mass index (BMI). Statistical significance was defined as a false discovery rate < 0.05. Significant sites were tested for replication in the TwinsUK cohort, with significant replication defined by P < 0.05 and a consistent direction.Diet quality was significantly associated with differential DNA methylation at 428 cytosine-phosphate-guanine (CpG) sites in the discovery cohort. A total of 24 CpG sites were consistent with replication in the TwinsUK cohort, more than would be expected by chance (P = 2.7x10-4), with one site replicated in both the blood and adipose tissue (cg16379999 located in the body of SEL1L).Diet quality was associated with methylation at 24 CpG sites, several of which have been associated with adiposity, inflammation and dysglycaemia. These findings may provide insight into pathways through which diet influences chronic disease.© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.",
+Yes,20210111,ewas,33356526,"Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study.",Environ Health Perspect,"Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype.We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators.Among 583 mother-infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate(FDR)<0.05and differentially methylated regions (DMRs) were identified using comb-p (Šidák-adjustedp<0.05). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin.Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations (�=0.28-0.76). Methylation at one DMP (cg18587484), annotated to the geneTJAP1, was associated with perfluorooctanoate (PFOA) atFDR< 0.05. Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth (RPTOR), lipid homeostasis (PON1,PON3,CIDEB,NR1H2), inflammation and immune activity (RASL11B,RNF39), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively (FDR< 0.1).DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. https://doi.org/10.1289/EHP6888.",
+Yes,20210111,ewas,33371772,DNA methylation signatures of adolescent victimization: analysis of a longitudinal monozygotic twin sample.,Epigenetics,"Accumulating evidence suggests that individuals exposed to victimization at key developmental stages may have different epigenetic fingerprints compared to those exposed to no/minimal stressful events, however results are inconclusive. This study aimed to strengthen causal inference regarding the impact of adolescent victimization on the epigenome by controlling for genetic variation, age, gender, and shared environmental exposures. We conducted longitudinal epigenome-wide association analyses (EWAS) on DNA methylation (DNAm) profiles of 118 monozygotic (MZ) twin pairs from the Environmental Risk study with and without severe adolescent victimization generated using buccal DNA collected at ages 5, 10 and 18, and the Illumina EPIC array. Additionally, we performed cross-sectional EWAS on age-18 blood and buccal DNA from the same individuals to elucidate tissue-specific signatures of severe adolescent victimization. Our analyses identified 20 suggestive differentially methylated positions (DMPs) (P< 5e-05), with altered DNAm trajectories between ages 10-18 associated with severe adolescent victimization (�Beta range = -5.5%-5.3%). Age-18 cross-sectional analyses revealed 72 blood (�Beta range = -2.2%-3.4%) and 42 buccal (�Beta range = -3.6%-4.6%) suggestive severe adolescent victimization-associated DMPs, with some evidence of convergent signals between these two tissue types. Downstream regional analysis identified significant differentially methylated regions (DMRs) inLGR6andANK3(ŠidákP = 5e-09 and 4.07e-06), and one upstream ofCCL27(ŠidákP = 2.80e-06) in age-18 blood and buccal EWAS, respectively. Our study represents the first longitudinal MZ twin analysis of DNAm and severe adolescent victimization, providing initial evidence for altered DNA methylomic signatures in individuals exposed to adolescent victimization.",
+Yes,20210111,ewas,33396735,Epigenome-Wide Association of Infant Feeding and Changes in DNA Methylation from Birth to 10 Years.,Nutrients,"Epigenetic factors have been suggested as mediators of early-life nutrition to future health. Prior studies focused on breastfeeding effects on DNA methylation (DNAm), ignoring other feeding modes. In this analysis of the Isle of Wight birth cohort, feeding modes were categorized as exclusive breastfeeding (EBF), exclusive formula feeding (EFF), and mixed feeding based on whether the respective feeding mode lasted for at least 3 months. In addition, in the past, infant feeding modes were assessed using DNAm at one time point in childhood, not changes of DNAm. In this paper, methylation differences (delta DNAm) were calculated by subtracting residual methylation values at birth from age 10 years (adjusting for cell types and season of blood collection at both ages). These deltas were estimated for all methylation sites where cytosine was followed by guanine (cytosine guanine dinucleotide (CpG) sites). Then, we performed an epigenome-wide association study contrasting EBF, EFF, and mixed feeding with delta DNAm that represents changes in methylation from birth to 10 years. A total of 87 CpGs (EBF: 27 CpGs, EFF: 48 CpGs, mixed: 12 CpGs) were identified using separate linear regression models adjusting for confounders and multiple testing. The sum of all changes in methylation from birth to age 10 years was significantly lower in the EFF group. Correspondingly, the number of CpGs with a methylation decline was 4.7% higher reflecting 13,683 CpGs. Lower methylation related to exclusive formula feeding and its adverse potential for the child's development needs future research to reduce adverse health effects.",
+Yes,20210111,ewas,33397400,Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles.,Genome Med,"The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer's disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses.We obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10-100 ≤ P ≤ 2.44 × 10-8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10-4 ≤ P ≤ 3.01 × 10-2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24.APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.",
+Yes,20210111,ewas,33400784,Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa.,J Infect Dis,"Tuberculosis (TB) is the most deadly infectious disease globally and highly prevalent in the developing world. For individuals infected with both Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV), the risk of active TB is 10% or more annually. Previously, we identified in a genome-wide association study (GWAS) a region on chromosome 5 associated with resistance to TB, which included epigenetic marks that could influence gene regulation. We hypothesized that HIV-infected individuals exposed to Mtb, who remain disease free, carry epigenetic changes that strongly protect them from active TB.We conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania and integrated data from our GWAS.We identified 3 regions of interest that included markers that were differentially methylated between TB cases and LTBI controls: chromosome 1 (RNF220, p=4x10 -5), chromosome 2 (between COPS8 and COL6A3, p=2.7x10 -5), and chromosome 5 (CEP72, p=1.3x10 -5). These methylation results co-localized with associated SNPs, methylation QTLs, and methylation x SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung.Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.",
+Yes,20210111,ewas,33406918,Epigenome-wide association study of maternal hemoglobin A1c in pregnancy and cord blood DNA methylation.,Epigenomics,"Background:Gestational hyperglycemia is associated with adverse perinatal outcomes and long-term offspring metabolic programming, likely through dysregulation of DNA methylation (DNAm).Materials & methods:We tested associations between maternal HbA1c and cord blood DNAm among 412 mother-child pairs in the genetics of glucose regulation in gestation and growth (Gen3G) and implemented Mendelian randomization to infer causality. We sought replication in an independent sample from Healthy Start.Results:Higher second trimester HbA1c levels were associated with lower DNAm at cg21645848 (p = 3.9 × 10-11) nearURGCP. Mendelian randomization and replication analyses showed same direction of effect between HbA1c and DNAm at cg21645848, but did not reach statistical significance.Conclusion:We found that higher maternal glycemia reflected by HbA1c is associated with cord blood DNAm atURGCP, a gene related with inflammatory pathways.",
+Yes,20210111,ewas,33407823,Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood.,Clin Epigenetics,"The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood.DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex.High and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases.The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.",
+No,20210111,global,33317014,Prenatal Multivitamin Use and <i>MTHFR</i> Genotype Are Associated with Newborn Cord Blood DNA Methylation.,Int J Environ Res Public Health,"Fetal development involves cellular differentiation and epigenetic changes-complex processes that are sensitive to environmental factors. Maternal nutrient levels during pregnancy affect development, and methylene tetrahydrofolate reductase (MTHFR) is important for processing the nutrient folate.We hypothesize that supplement intake before pregnancy and maternal genotype are associated with DNA methylation in newborns.In the pregnancy cohort, Early Autism Risk Longitudinal Investigation (EARLI), health history, and genotype information was obtained (n = 249 families). Cord blood DNA methylation (n = 130) was measured using the Illumina HumanMethylation450k array and global DNA methylation levels were computed over 455,698 sites. Supplement use preconception and during pregnancy were surveyed at visits during pregnancy. We evaluated associations between maternal preconception supplement intake and global DNA methylation or DNA methylation density distributions of newborn cord blood, stratified by the presence of a variant maternalMTHFRC677T allele.Maternal preconceptional multivitamin intake was associated with cord blood methylation, dependent on maternalMTHFRgenotype (interaction termp= 0.013). For mothers without theMTHFRvariant allele, multivitamin intake was associated with 0.96% (95% CI: 0.09, 1.83) higher global cord blood methylation (p= 0.04) and was also associated with the cumulative density distribution of methylation (p= 0.03). For mothers with at least one variant allele, multivitamin intake had a null -0.06% (95% CI: -0.45, 0.33) association with global cord blood DNA methylation, and was not associated with the cumulative density distribution (p= 0.37).We observed that cord blood DNA methylation was associated with maternal supplement exposure preconception and maternal genotype. Genetic context should be considered when assessing DNA methylation effects of modifiable risk factors around the time of pregnancy.",
+No,20210111,methods,33335112,Detecting methylation signatures in neurodegenerative disease by density-based clustering of applications with reducing noise.,Sci Rep,"There have been numerous genetic and epigenetic datasets generated for the study of complex disease including neurodegenerative disease. However, analysis of such data often suffers from detecting the outliers of the samples, which subsequently affects the extraction of the true biological signals involved in the disease. To address this critical issue, we developed a novel framework for identifying methylation signatures using consecutive adaptation of a well-known outlier detection algorithm, density based clustering of applications with reducing noise (DBSCAN) followed by hierarchical clustering. We applied the framework to two representative neurodegenerative diseases, Alzheimer's disease (AD) and Down syndrome (DS), using DNA methylation datasets from public sources (Gene Expression Omnibus, GEO accession ID: GSE74486). We first applied DBSCAN algorithm to eliminate outliers, and then used Limma statistical method to determine differentially methylated genes. Next, hierarchical clustering technique was applied to detect gene modules. Our analysis identified a methylation signature comprising 21 genes for AD and a methylation signature comprising 89 genes for DS, respectively. Our evaluation indicated that these two signatures could lead to high classification accuracy values (92% and 70%) for these two diseases. In summary, this framework will be useful to better detect outlier-free genetic and epigenetic signatures in various complex diseases and their developmental stages.",
+No,20210111,methods,33350870,Estimating cell-type-specific DNA methylation effects in heterogeneous cellular populations.,Epigenomics,Aim:To develop a method for estimating cell-specific effects in epigenomic association studies in the presence of cell type heterogeneity.Materials & methods:We utilized Monte Carlo Expectation-Maximization (MCEM) algorithm with Metropolis-Hastings sampler to reconstruct the 'missing' cell-specific methylations and to estimate their associations with phenotypes free of confounding by cell type proportions.Results:Simulations showed reliable performance of the method under various settings including when the cell type is rare. Application to a real dataset recapitulated the directly measured cell-specific methylation pattern in whole blood.Conclusion:This work provides a framework to identify important cell groups and account for cell type composition useful for studying the role of epigenetic changes in human traits and diseases.,
+No,20210111,variation,33402197,Equivalent DNA methylation variation between monozygotic co-twins and unrelated individuals reveals universal epigenetic inter-individual dissimilarity.,Genome Biol,"Although the genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. Particularly for young and healthy monozygotic twins, DNA methylation divergence, if any, may be restricted to stochastic processes occurring post-twinning during embryonic development and early life. However, to what extent such stochastic mechanisms can systematically provide a stable source of inter-individual epigenetic variation remains uncertain until now.We enriched for inter-individual stochastic variation by using an equivalence testing-based statistical approach on whole blood methylation microarray data from healthy adolescent monozygotic twins. As a result, we identified 333 CpGs displaying similarly large methylation variation between monozygotic co-twins and unrelated individuals. Although their methylation variation surpasses measurement error and is stable in a short timescale, susceptibility to aging is apparent in the long term. Additionally, 46% of these CpGs were replicated in adipose tissue. The identified sites are significantly enriched at the clustered protocadherin loci, known for stochastic methylation in developing neurons. We also confirmed an enrichment in monozygotic twin DNA methylation discordance at these loci in whole genome bisulfite sequencing data from blood and adipose tissue.We have isolated a component of stochastic methylation variation, distinct from genetic influence, measurement error, and epigenetic drift. Biomarkers enriched in this component may serve in the future as the basis for universal epigenetic fingerprinting, relevant for instance in the discrimination of monozygotic twin individuals in forensic applications, currently impossible with standard DNA profiling.",
+No,20210111,mitochondria,33385171,Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance.,Hum Genet,"Mitochondrial (MT) dysfunction is a hallmark of aging and has been associated with most aging-related diseases as well as immunological processes. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial DNA (mtDNA) abundance. In this study, mtDNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that the abundance of mtDNA was significantly elevated in women compared to men, was negatively correlated with advanced age, higher smoking exposure, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and lower mortality. In addition, several biochemistry markers in blood-related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with mtDNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with mtDNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of mtDNA abundance to be around 8%. To investigate the consequence of altered mtDNA abundance, we performed a phenome-wide association study and found that mtDNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating mtDNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease-relevant processes, particularly those related to immunity and established mitochondrial functions.",
+No,20210111,prediction,33337494,Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.,JAMA Netw Open,"Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies.To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB.This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019.Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites.The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation.Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways.This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.",
+No,20210111,prediction,33308293,Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm.,Mol Autism,"Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes.We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS.Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case-control status.The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited.Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.",
+No,20210111,prediction,33344728,A polyepigenetic glucocorticoid exposure score at birth and childhood mental and behavioral disorders.,Neurobiol Stress,"Maternal depression and anxiety during pregnancy may enhance fetal exposure to glucocorticoids (GCs) and harm neurodevelopment. We tested whether a novel cross-tissue polyepigenetic biomarker indicative ofin uteroexposure to GC is associated with mental and behavioral disorders and their severity in children, possibly mediating the associations between maternal prenatal depressive and anxiety symptoms and these child outcomes.Children (n = 814) from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study were followed-up from birth to age 7.1-10.7 years. A weighted polyepigenetic GC exposure score was calculated based on the methylation profile of 24 CpGs from umbilical cord blood. Child diagnosis of mental and behavioral disorder (n = 99) and its severity, defined as the number of days the child had received treatment (all 99 had received outpatient treatment and 8 had been additionally in inpatient treatment) for mental or behavioral disorder as the primary diagnosis, came from the Care Register for Health Care. Mothers (n = 408) reported on child total behavior problems at child's age of 2.3-5.8 years and their own depressive and anxiety symptoms during pregnancy (n = 583).The fetal polyepigenetic GC exposure score at birth was not associated with child hazard of mental and behavioral disorder (HR = 0.82, 95% CI 0.54; 1.24, p = 0.35) or total behavior problems (unstandardized beta = -0.10, 95% CI -0.31; 0.10, p = 0.33). However, for one standard deviation decrease in the polyepigenetic score, the child had spent 2.94 (95%CI 1.59; 5.45, p < 0.001) more days in inpatient or outpatient treatment with any mental and behavioral disorder as the primary diagnosis. Criteria for mediation tests were not met.These findings suggest that fetal polyepigenetic GC exposure score at birth was not associated with any mental or behavioral disorder diagnosis or mother-rated total behavior problems, but it may contribute to identifying children at birth who are at risk for more severe mental or behavioral disorders.© 2020 The Authors.",
+No,20210125,omics,33481009,Multi-omics analyses of cognitive traits and psychiatric disorders highlights brain-dependent mechanisms.,Hum Mol Genet,"Integrating findings from genome-wide association studies with molecular datasets can develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied the principles of Mendelian randomization (MR) to investigate whether brain-derived gene expression (n = 1194) may be responsible for mediating the effect of genetic variants on eight cognitive and psychological outcomes (attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, bipolar disorder, depression, intelligence, insomnia, neuroticism and schizophrenia). Transcriptome-wide analyses identified 83 genes associated with at least one outcome (PBonferroni < 6.72 × 10-6), with multiple-trait colocalization also implicating changes to brain-derived DNA methylation at nine of these loci. Comparing effects between outcomes identified evidence of enrichment which may reflect putative causal relationships, such as an inverse relationship between genetic liability towards schizophrenia risk and cognitive ability in later life. Repeating these analyses in whole blood (n = 31 684), we replicated 58.2% of brain-derived effects (based on P < 0.05). Finally, we undertook phenome-wide evaluations at associated loci to investigate pleiotropic effects with 700 complex traits. This highlighted pleiotropic loci such as FURIN (initially implicated in schizophrenia risk (P = 1.05 × 10-7)) which had evidence of an effect on 28 other outcomes, as well as genes which may have a more specific role in disease pathogenesis (e.g. SLC12A5 which only provided evidence of an effect on depression (P = 7.13 × 10-10)). Our results support the utility of whole blood as a valuable proxy for informing initial target identification but also suggest that gene discovery in a tissue-specific manner may be more informative. Finally, non-pleiotropic loci highlighted by our study may be of use for therapeutic translational endeavours.© The Author(s) 2021. Published by Oxford University Press.",
+Yes,20210125,ewas,33468710,DNA methylation perturbations may link altered development and aging in the lung.,Aging (Albany NY),"Fetal perturbations in DNA methylation during lung development may reveal insights into the enduring impacts on adult lung health and disease during aging that have not been explored altogether before. We studied the association between genome-wide DNA-methylation and post-conception age in fetal-lung (n=78, 42 exposed to in-utero-smoke (IUS)) tissue and chronological age in adult-lung tissue (n=160, 114 with Chronic Obstructive Pulmonary Disease) using multi-variate linear regression models with covariate adjustment and tested for effect modification by phenotypes. Overlapping age-associations were evaluated for functional and tissue-specific enrichment using the Genotype-Tissue-Expression (GTEx) project. We identified 244 age-associated differentially methylated positions and 878 regions overlapping between fetal and adult-lung tissues. Hyper-methylated CpGs (96%) were enriched in transcription factor activity (FDR adjusted P=2x10-33) and implicated in developmental processes including embryonic organ morphogenesis, neurogenesis and growth delay. Hypo-methylated CpGs (2%) were enriched in oxido-reductase activity and VEGFA-VEGFR2 Signaling. Twenty-one age-by-sex and eleven age-by-pack-years interactions were statistically significant (FDR<0.05) in adult-lung tissue. DNA methylation in transcription factors during development in fetal lung recapitulates in adult-lung tissue with aging. These findings reveal molecular mechanisms and pathways that may link disrupted development in early-life and age-associated lung diseases.",
+Yes,20210125,ewas,33450751,Epigenome-wide change and variation in DNA methylation in childhood: Trajectories from birth to late adolescence.,Hum Mol Genet,"DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for nonlinear change and inter-individual variation in nonlinear trajectories was somewhat less common (11% and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. By contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often nonlinear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.© The Author(s) 2021. Published by Oxford University Press.",
+Yes,20210125,ewas,33448462,"High blood pressure in pregnancy, DNA methylation, and later blood pressure in African American women enrolled in the InterGEN Study.",Birth,"Few studies have examined the effects of high blood pressure (BP) in pregnancy, preeclampsia, or eclampsia on later BP, and the epigenetics of this phenomenon is similarly poorly understood, especially among African Americans. The purpose of this study was to examine the association between high BP in pregnancy, epigenomics, and later BP in African American women in the InterGEN Study (n = 250).In cross-sectional analyses, regression and linear mixed-effects models were employed to examine the effects of high BP in pregnancy on: (a) epigenetic associations (DNA methylation) and (b) BP 3-5 years after birth. The 850K Illumina EPIC BeadChip was used for evaluating epigenome-wide DNA methylation. High BP in pregnancy, preeclampsia, or eclampsia was self-reported by women, and BP was measured 3-5 years after birth, per JNC-7 guidelines. DNA methylation and clinical BP were the main outcomes.Mean age of enrolled women was 31.2 years, 21.8% were smokers, 58% had some college or higher education, 46.6% reported an annual income <$15 000, and 13.6% reported high BP in pregnancy. After adjustment for obesity, smoking, and age, women with a history of high BP in pregnancy had significantly higher BP than those who did not report this complication (5.39 ± 2.4 mm Hg, P = .030). Epigenome-wide analysis revealed no significant sites after multiple testing correction.We observed a small, but clinically significant, increase in BP in women who reported high BP in pregnancy 3-5 years after that pregnancy. Future studies with larger sample sizes should examine epigenetic contributions to this finding.© 2020 Wiley Periodicals LLC.",
+Yes,20210125,ewas,33443234,DNA methylation is associated with airflow obstruction in patients living with HIV.,Thorax,"People living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.Using blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV1, FEV1/FVC ratio and FEV1decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.Airflow obstruction as defined by a FEV1/FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV1/FVC<lower limit of normal. These DMPs were enriched for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV1and FEV1/FVC, respectively. No positions were associated with FEV1decline.A large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
+Yes,20210125,omics,33436383,"Genetic variants shape rheumatoid arthritis-specific transcriptomic features in CD4<sup>+</sup> T cells through differential DNA methylation, explaining a substantial proportion of heritability.",Ann Rheum Dis,"CD4+T cells have been suggested as the most disease-relevant cell type in rheumatoid arthritis (RA) in which RA-risk non-coding variants exhibit allele-specific effects on regulation of RA-driving genes. This study aimed to understand RA-specific signatures in CD4+T cells using multi-omics data, interpreting inter-omics relationships in shaping the RA transcriptomic landscape.We profiled genome-wide variants, gene expression and DNA methylation in CD4+T cells from 82 patients with RA and 40 healthy controls using high-throughput technologies. We investigated differentially expressed genes (DEGs) and differential methylated regions (DMRs) in RA and localised quantitative trait loci (QTLs) for expression and methylation. We then integrated these based on individual-level correlations to inspect DEG-regulating sources and investigated the potential regulatory roles of RA-risk variants by a partitioned-heritability enrichment analysis with RA genome-wide association summary statistics.A large number of RA-specific DEGs were identified (n=2575), highlighting T cell differentiation and activation pathways. RA-specific DMRs, preferentially located in T cell regulatory regions, were correlated with the expression levels of 548 DEGs mostly in the same topologically associating domains. In addition, expressional variances in 771 and 83 DEGs were partially explained by expression QTLs for DEGs and methylation QTLs (meQTLs) for DEG-correlated DMRs, respectively. A large number of RA variants were moderately to strongly correlated with meQTLs. DEG-correlated DMRs, enriched with meQTLs, had strongly enriched heritability of RA.Our findings revealed that the methylomic changes, driven by RA heritability-explaining variants, shape the differential expression of a substantial fraction of DEGs in CD4+T cells in patients with RA, reinforcing the importance of a multidimensional approach in disease-relevant tissues.© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.",
+Yes,20210125,ewas,33436068,Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight.,Clin Epigenetics,"High early postnatal weight gain has been associated with childhood adiposity; however, the mechanism remains unknown. DNA methylation is a hypothesised mechanism linking early life exposures and subsequent disease. However, epigenetic changes associated with high early weight gain have not previously been investigated. Our aim was to investigate the associations between early weight gain, peripheral blood DNA methylation, and subsequent overweight/obese. Data from the UK Avon Longitudinal study of Parents and Children (ALSPAC) cohort were used to estimate associations between early postnatal weight gain and epigenome-wide DNA CpG site methylation (Illumina 450 K Methylation Beadchip) in blood in childhood (n = 125) and late adolescence (n = 96). High weight gain in the first year (a change in weight z-scores > 0.67), both unconditional (rapid weight gain) and conditional on birthweight (rapid thrive), was related to individual CpG site methylation and across regions using the meffil pipeline, with and without adjustment for cell type proportions, and with 5% false discovery rate correction. Variation in methylation at high weight gain-associated CpG sites was then examined with regard to body composition measures in childhood and adolescence. Replication of the differentially methylated CpG sites was sought using whole-blood DNA samples from 104 children from the UK Southampton Women's Survey.Rapid infant weight gain was associated with small (+ 1% change) increases in childhood methylation (age 7) for two distinct CpG sites (cg01379158 (NT5M) and cg11531579 (CHFR)). Childhood methylation at one of these CpGs (cg11531579) was also higher in those who experienced rapid weight gain and were subsequently overweight/obese in adolescence (age 17). Rapid weight gain was not associated with differential DNA methylation in adolescence. Childhood methylation at the cg11531579 site was also suggestively associated with rapid weight gain in the replication cohort.This study identified associations between rapid weight gain in infancy and small increases in childhood methylation at two CpG sites, one of which was replicated and was also associated with subsequent overweight/obese. It will be important to determine whether loci are markers of early rapid weight gain across different, larger populations. The mechanistic relevance of these differentially methylated sites requires further investigation.",
+No,20210125,reference,33434283,A comprehensive epigenome atlas reveals DNA methylation regulating skeletal muscle development.,Nucleic Acids Res,"DNA methylation is important for the epigenetic regulation of gene expression and plays a critical role in mammalian development. However, the dynamic regulation of genome-wide DNA methylation in skeletal muscle development remains largely unknown. Here, we generated the first single-base resolution DNA methylome and transcriptome maps of porcine skeletal muscle across 27 developmental stages. The overall methylation level decreased from the embryo to the adult, which was highly correlated with the downregulated expression of DNMT1 and an increase in partially methylated domains. Notably, we identified over 40 000 developmentally differentially methylated CpGs (dDMCs) that reconstitute the developmental trajectory of skeletal muscle and associate with muscle developmental genes and transcription factors (TFs). The dDMCs were significantly under-represented in promoter regulatory regions but strongly enriched as enhancer histone markers and in chromatin-accessible regions. Integrative analysis revealed the negative regulation of both promoter and gene body methylation in genes associated with muscle contraction and insulin signaling during skeletal muscle development. Mechanistically, DNA methylation affected the expression of muscle-related genes by modulating the accessibly of upstream myogenesis TF binding, indicating the involvement of the DNA methylation/SP1/IGF2BP3 axis in skeletal myogenesis. Our results highlight the function and regulation of dynamic DNA methylation in skeletal muscle development.© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",
+Yes,20210125,ewas,33431374,Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood DNA Methylation Which Associates With Body Composition in the Offspring.,Diabetes,"Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the TOP-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus controls (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus controls (FDR<5%) when using the Houseman reference-free method to correct for cell composition and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared to controls. Methylation at 17 sites, annotated to e.g.DISC1,GBX2,HERC2andHUWE1, partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR<5%). Moreover, 22 methylation sites were associated with offspring BMI z-scores during the first 3 years of life (p<0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring's lean mass and early growth.© 2021 by the American Diabetes Association.",
+Yes,20210125,ewas,33420481,DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.,Mol Psychiatry,"DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.",
+Yes,20210125,ewas,33414500,Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.,Mol Psychiatry,"Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.",
+Yes,20210125,ewas,33414392,A genome-wide methylation study reveals X chromosome and childhood trauma methylation alterations associated with borderline personality disorder.,Transl Psychiatry,"Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with (N = 49) and without (N = 47) childhood traumas and in a control group (N = 44). Results were confirmed in a replication cohort (N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome (PQBP1, ZNF41, RPL10, cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes (POU5F1, GGT6, TNFRSF13C and FAM113B), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.",
+Yes,20210125,ewas,33413638,DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures.,Clin Epigenetics,"The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10-10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.",
+No,20210125,dnam age,33442664,Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study.,JNCI Cancer Spectr,"We previously investigated the association between 5 ""first-generation"" measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging:PhenoAge,GrimAge, and predicted telomere length.We estimated rate ratios (RRs) for the association between these 3 age-adjusted measures and risk of colorectal (N = 813), gastric (N = 165), kidney (N = 139), lung (N = 327), mature B-cell (N = 423), prostate (N = 846), and urothelial (N = 404) cancer using conditional logistic regression models. We also assessed associations by time since blood draw and by cancer subtype, and we investigated potential nonlinearity.We observed relatively strong associations of age-adjustedPhenoAgewith risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers (RR per SD was approximately 1.2-1.3). Similar findings were obtained for age-adjustedGrimAge, but the association with lung cancer risk was much larger (RR per SD = 1.82, 95% confidence interval [CI] = 1.44 to 2.30), after adjustment for smoking status, pack-years, starting age, time since quitting, and other cancer risk factors. Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle, and anthropometric variables. For cancer overall, the comprehensively adjusted rate ratio per SD was 1.13 (95% CI = 1.07 to 1.19) forPhenoAgeand 1.12 (95% CI = 1.05 to 1.20) forGrimAgeand appeared larger within 5 years of blood draw (RR = 1.29, 95% CI = 1.15 to 1.44 and 1.19, 95% CI = 1.06 to 1.33, respectively).The methylation-based measuresPhenoAgeandGrimAgemay provide insights into the relationship between biological aging and cancer and be useful to predict cancer risk, particularly for lung cancer.© The Author(s) 2020. Published by Oxford University Press.",
+No,20210125,gene expression,33436844,Gene expression in blood reflects smoking exposure among cancer-free women in the Norwegian Women and Cancer (NOWAC) postgenome cohort.,Sci Rep,"Active smoking has been linked to modulated gene expression in blood. However, there is a need for a more thorough understanding of how quantitative measures of smoking exposure relate to differentially expressed genes (DEGs) in whole-blood among ever smokers. This study analysed microarray-based gene expression profiles from whole-blood samples according to smoking status and quantitative measures of smoking exposure among cancer-free women (n = 1708) in the Norwegian Women and Cancer postgenome cohort. When compared with never smokers and former smokers, current smokers had 911 and 1082 DEGs, respectively and their biological functions could indicate systemic impacts of smoking. LRRN3 was associated with smoking status with the lowest FDR-adjusted p-value. When never smokers and all former smokers were compared, no DEGs were observed, but LRRN3 was differentially expressed when never smokers were compared with former smokers who quit smoking ≤ 10 years ago. Further, LRRN3 was positively associated with smoking intensity, pack-years, and comprehensive smoking index score among current smokers; and negatively associated with time since cessation among former smokers. Consequently, LRRN3 expression in whole-blood is a molecular signal of smoking exposure that could supplant self-reported smoking data in further research targeting blood-based markers related to the health effects of smoking.",
+No,20210125,methods,33452255,Cellular Heterogeneity-Adjusted cLonal Methylation (CHALM) improves prediction of gene expression.,Nat Commun,"Promoter DNA methylation is a well-established mechanism of transcription repression, though its global correlation with gene expression is weak. This weak correlation can be attributed to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity-Adjusted cLonal Methylation (CHALM) as a methylation quantification method. CHALM improves understanding of the functional consequences of DNA methylation, including its correlations with gene expression and H3K4me3. When applied to different methylation datasets, the CHALM method enables detection of differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms.",
+No,20210125,gene expression,33436912,Longitudinal saliva omics responses to immune perturbation: a case study.,Sci Rep,"Saliva omics has immense potential for non-invasive diagnostics, including monitoring very young or elderly populations, or individuals in remote locations. In this study, multiple saliva omics from an individual were monitored over three periods (100 timepoints) involving: (1) hourly sampling over 24 h without intervention, (2) hourly sampling over 24 h including immune system activation using the standard 23-valent pneumococcal polysaccharide vaccine, (3) daily sampling for 33 days profiling the post-vaccination response. At each timepoint total saliva transcriptome and proteome, and small RNA from salivary extracellular vesicles were profiled, including mRNA, miRNA, piRNA and bacterial RNA. The two 24-h periods were used in a paired analysis to remove daily variation and reveal vaccination responses. Over 18,000 omics longitudinal series had statistically significant temporal trends compared to a healthy baseline. Various immune response and regulation pathways were activated following vaccination, including interferon and cytokine signaling, and MHC antigen presentation. Immune response timeframes were concordant with innate and adaptive immunity development, and coincided with vaccination and reported fever. Overall, mRNA results appeared more specific and sensitive (timewise) to vaccination compared to other omics. The results suggest saliva omics can be consistently assessed for non-invasive personalized monitoring and immune response diagnostics.",
+No,20210125,imprinting,33441584,Imprinting methylation predicts hippocampal volumes and hyperintensities and the change with age in later life.,Sci Rep,"Epigenetic imprinting is important for neurogenesis and brain function. Hippocampal volumes and brain hyperintensities in late life have been associated with early life circumstances. Epigenetic imprinting may underpin these associations. Methylation was measured at 982 sites in 13 imprinted locations in blood samples from a longitudinal cohort by bisulphite amplicon sequencing. Hippocampal volumes and hyperintensities were determined at age 64y and 72y using MRI. Hyperintensities were determined in white matter, grey matter and infratentorial regions. Permutation methods were used to adjust for multiple testing. At 64y, H19/IGF2 and NESPAS methylation predicted hippocampal volumes. PEG3 predicted hyperintensities in hippocampal grey matter, and white matter. GNASXL predicted grey matter hyperintensities. Changes with age were predicted for hippocampal volume (MEST1, KvDMR, L3MBTL, GNASXL), white matter (MEST1, PEG3) and hippocampal grey matter hyperintensities (MCTS2, GNASXL, NESPAS, L3MBTL, MCTS2, SNRPN, MEST1). Including childhood cognitive ability, years in education, or socioeconomic status as additional explanatory variables in regression analyses did not change the overall findings. Imprinting methylation in multiple genes predicts brain structures, and their change over time. These findings are potentially relevant to the development of novel tests of brain structure and function across the life-course, strategies to improve cognitive outcomes, and our understanding of early influences on brain development and function.",
+No,20210125,organoids,33436582,A logical network-based drug-screening platform for Alzheimer's disease representing pathological features of human brain organoids.,Nat Commun,"Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.",
+No,20210222,biomarker,33560371,A serum-based DNA methylation assay provides accurate detection of glioma.,Neuro Oncol,"The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a non-invasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with non-invasive approaches.Genome-wide DNA methylation profiling of tumor tissue and serum cell-free DNA of glioma patients.Here, we developed a non-invasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the ""glioma epigenetic liquid biopsy score"" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (e.g., progression, pseudoprogression or response to standard or experimental treatment).Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
+No,20210222,omics,33523105,"Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets.",JAMA Neurol,"Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD.To investigate what genes and genomic processes underlie the risk of sporadic PD.This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks.It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role.Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance.Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies.",
+No,20210222,dnam age,33558008,An integrative study of five biological clocks in somatic and mental health.,Elife,"Biological clocks have been developed at different molecular levels and were found to be more advanced in the presence of somatic illness and mental disorders. However, it is unclear whether different biological clocks reflect similar aging processes and determinants. In ~3000 subjects, we examined whether five biological clocks (telomere length, epigenetic, transcriptomic, proteomic, and metabolomic clocks) were interrelated and associated to somatic and mental health determinants. Correlations between biological aging indicators were small (allr< 0.2), indicating little overlap. The most consistent associations of advanced biological aging were found for male sex, higher body mass index (BMI), metabolic syndrome, smoking, and depression. As compared to the individual clocks, a composite index of all five clocks showed most pronounced associations with health determinants. The large effect sizes of the composite index and the low correlation between biological aging indicators suggest that one's biological age is best reflected by combining aging measures from multiple cellular levels.© 2021, Jansen et al.",
+No,20210222,epigenetics,33542217,An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine.,Nat Commun,"Epigenetic modifications of DNA play important roles in many biological processes. Identifying readers of these epigenetic marks is a critical step towards understanding the underlying mechanisms. Here, we present an all-to-all approach, dubbed digital affinity profiling via proximity ligation (DAPPL), to simultaneously profile human TF-DNA interactions using mixtures of random DNA libraries carrying different epigenetic modifications (i.e., 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine) on CpG dinucleotides. Many proteins that recognize consensus sequences carrying these modifications in symmetric and/or hemi-modified forms are identified. We further demonstrate that the modifications in different sequence contexts could either enhance or suppress TF binding activity. Moreover, many modifications can affect TF binding specificity. Furthermore, symmetric modifications show a stronger effect in either enhancing or suppressing TF-DNA interactions than hemi-modifications. Finally, in vivo evidence suggests that USF1 and USF2 might regulate transcription via hydroxymethylcytosine-binding activity in weak enhancers in human embryonic stem cells.",
+No,20210222,epigenetics,33505025,Systematic analysis of binding of transcription factors to noncoding variants.,Nature,"Many sequence variants have been linked to complex human traits and diseases1, but deciphering their biological functions remains challenging, as most of them reside in noncoding DNA. Here we have systematically assessed the binding of 270 human transcription factors to 95,886 noncoding variants in the human genome using an ultra-high-throughput multiplex protein-DNA binding assay, termed single-nucleotide polymorphism evaluation by systematic evolution of ligands by exponential enrichment (SNP-SELEX). The resulting 828 million measurements of transcription factor-DNA interactions enable estimation of the relative affinity of these transcription factors to each variant in vitro and evaluation of the current methods to predict the effects of noncoding variants on transcription factor binding. We show that the position weight matrices of most transcription factors lack sufficient predictive power, whereas the support vector machine combined with the gapped k-mer representation show much improved performance, when assessed on results from independent SNP-SELEX experiments involving a new set of 61,020 sequence variants. We report highly predictive models for 94 human transcription factors and demonstrate their utility in genome-wide association studies and understanding of the molecular pathways involved in diverse human traits and diseases.",
+No,20210222,cancer,33536596,An epigenetic tipping point in cancer comes under the microscope.,Nature,NA,
+No,20210222,reference,33536621,Regulatory genomic circuitry of human disease loci by integrative epigenomics.,Nature,"Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete1-3. Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits4, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits.",
+Yes,20210222,ewas,33566097,Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.,Genome Biol Evol,"High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.",
+Yes,20210222,ewas,33564054,Identification of epigenetic memory candidates associated with gestational age at birth through analysis of methylome and transcriptional data.,Sci Rep,"Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23-41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.",
+Yes,20210222,ewas,33554115,Cross-reactive probes on Illumina DNA methylation arrays: a large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies.,NAR Genom Bioinform,"Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of theC9orf72repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to theC9orf72locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS.© The Author(s) 2020. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
+Yes,20210222,ewas,33550919,Adiposity associated DNA methylation signatures in adolescents are related to leptin and perinatal factors.,Epigenetics,"Epigenetics links perinatal influences with later obesity. We identifed differentially methylated CpG (dmCpG) loci measured at 17 years associated with concurrent adiposity measures and examined whether these were associated with hsCRP, adipokines, and early life environmental factors. Genome-wide DNA methylation from 1192 Raine Study participants at 17 years, identified 29 dmCpGs (Bonferroni corrected p < 1.06E-07) associated with body mass index (BMI), 10 with waist circumference (WC) and 9 with subcutaneous fat thickness. DmCpGs within Ras Association (RalGDS/AF-6), Pleckstrin Homology Domains 1 (RAPH1), Musashi RNA-Binding Protein 2 (MSI2), and solute carrier family 25 member 10 (SLC25A10) are associated with both BMI and WC. Validation by pyrosequencing confirmed these associations and showed thatMSI2,SLC25A10, andRAPH1methylation was positively associated with serum leptin. These were  also associated with the early environment;MSI2methylation (β = 0.81, p = 0.0004) was associated with pregnancy maternal smoking,SLC25A10(CpG2 β = 0.12, p = 0.002) with pre- and early pregnancy BMI, andRAPH1(β = -1.49, p = 0.036) with gestational weight gain. Adjusting for perinatal factors, methylation of the dmCpGs withinMSI2, RAPH1,andSLC25A10independently predicted BMI, accounting for 24% of variance.MSI2methylation was additionally associated with BMI over time (17 years old β = 0.026, p = 0.0025; 20 years old β = 0.027, p = 0.0029) and between generations (mother β = 0.044, p = 7.5e-04). Overall findings suggest that DNA methylation inMSI2,RAPH1, andSLC25A10in blood may be robust markers, mediating through early life factors.",
+Yes,20210222,ewas,33547282,The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.,Nat Commun,"Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10-8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.",
+Yes,20210222,ewas,33542190,DNA methylation differences associated with social anxiety disorder and early life adversity.,Transl Psychiatry,"Social anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genes SLC43A2 and TNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within the SLC17A3 promoter region and the SIAH3 gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions within C2CD2L and MRPL28 showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.",
+Yes,20210222,ewas,33528912,Novel DNA methylation marker discovery by assumption-free genome-wide association analysis of cognitive function in twins.,Aging Cell,"Privileged by rapid increase in available epigenomic data, epigenome-wide association studies (EWAS) are to make a profound contribution to understand the molecular mechanism of DNA methylation in cognitive aging. Current statistical methods used in EWAS are dominated by models based on multiple assumptions, for example, linear relationship between molecular profiles and phenotype, normal distribution for the methylation data and phenotype. In this study, we applied an assumption-free method, the generalized correlation coefficient (GCC), and compare it to linear models, namely the linear mixed model and kinship model. We use DNA methylation associated with a cognitive score in 400 and 206 twins as discovery and replication samples respectively. DNA methylation associated with cognitive function using GCC, linear mixed model, and kinship model, identified 65 CpGs (p < 1e-04) from discovery sample displaying both nonlinear and linear correlations. Replication analysis successfully replicated 9 of these top CpGs. When combining results of GCC and linear models to cover diverse patterns of relationships, we identified genes like KLHDC4, PAPSS2, and MRPS18B as well as pathways including focal adhesion, axon guidance, and some neurological signaling. Genomic region-based analysis found 15 methylated regions harboring 11 genes, with three verified in gene expression analysis, also the 11 genes were related to top functional clusters including neurohypophyseal hormone and maternal aggressive behaviors. The GCC approach detects valuable methylation sites missed by traditional linear models. A combination of methylation markers from GCC and linear models enriched biological pathways sensible in neurological function that could implicate cognitive performance and cognitive aging.© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",
+Yes,20210222,ewas,33517419,Paternal body mass index and offspring DNA methylation: findings from the PACE consortium.,Int J Epidemiol,"Accumulating evidence links paternal adiposity in the periconceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans.In the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of coordinated epigenome-wide association studies (EWAS) of paternal prenatal body mass index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 data sets; total n = 4894) and in childhood (6 data sets; total n = 1982).We found little evidence of an association at either time point: at all CpGs, the false-discovery-rate-adjusted P-values were >0.05. In secondary sex-stratified analyses, we found just four CpGs for which there was robust evidence of an association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes.Our findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring-blood DNA methylation, even at imprinted regions.© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.",
+Yes,20210222,ewas,33515580,Prenatal lead exposure and cord blood DNA methylation in the Korean Exposome Study.,Environ Res,"Prenatal lead exposure has been reported to affect infant growth and nervous system development, as well as to influence DNA methylation. We conducted an epigenome-wide association study to identify associations between prenatal lead exposure and cord blood DNA methylation in Korean infants.Cord blood samples were assayed with the Illumina HumanMethylationEPIC BeadChip kits, and maternal blood lead levels during early and late pregnancy, as well as cord blood lead level, were measured. The association between CpG methylation and lead level was analyzed using the limma package, with adjusting for infant sex, maternal pre-pregnancy body mass index, and estimated leukocyte composition.Among 364 blood samples (182 males and 182 females), those for which maternal and cord blood lead concentrations during early and later pregnancy was known were used for analysis. Maternal lead concentration in blood during early pregnancy was significantly associated with the methylation status of specific positions. After data stratification by infant sex, we found that, in males, the level of maternal blood lead was associated with 18 CpG sites during early pregnancy, and with one CpG site near the NBAS gene, during late pregnancy. In female samples, there was no significant association between DNA methylation and lead concentrations.Prenatal lead exposure was associated with altered, gender-specific patterns of DNA methylation in Korean infants.Copyright © 2021 Elsevier Inc. All rights reserved.",
+Yes,20210222,ewas,33499918,Profile of copper-associated DNA methylation and its association with incident acute coronary syndrome.,Clin Epigenetics,"Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear.We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study.We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02-1.48; P = 0.03).We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.",
+Yes,20210222,ewas,33494854,"Epigenetic profiling of social communication trajectories and co-occurring mental health problems: a prospective, methylome-wide association study.",Dev Psychopathol,"While previous studies suggest that both genetic and environmental factors play an important role in the development of autism-related traits, little is known about potential biological mechanisms underlying these associations. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined prospective associations between DNA methylation (DNAm: nbirth = 804, nage 7 = 877) and trajectories of social communication deficits at age 8-17 years. Methylomic variation at three loci across the genome (false discovery rate = 0.048) differentiated children following high (n = 80) versus low (n = 724) trajectories of social communication deficits. This differential DNAm was specific to the neonatal period and not observed at 7 years of age. Associations between DNAm and trajectory membership remained robust after controlling for co-occurring mental health problems (i.e., hyperactivity/inattention, conduct problems). The three loci identified at birth were not replicated in the Generation R Study. However, to the best of our knowledge, ALSPAC is the only study to date that is prospective enough to examine DNAm in relation to longitudinal trajectories of social communication deficits from childhood to adolescence. Although the present findings might point to potentially novel sites that differentiate between a high versus low trajectory of social communication deficits, the results should be considered tentative until further replicated.",
+Yes,20210222,ewas,33484127,Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L.,J Clin Endocrinol Metab,"Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited.To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts.We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed.We identified 2 DMPs with epigenome-wide significant (P < 2.4E-7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E-10) and cg04173586 in DOT1L (P = 2.09E-16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH.This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
+Yes,20210222,ewas,33526782,Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.,Transl Psychiatry,"Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.",
+Yes,20210222,ewas,33466918,DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life.,Int J Mol Sci,"DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidakp≤ 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.",
+Yes,20210222,ewas,33542415,Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies.,Sci Rep,"Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.",
+Yes,20210222,ewas,33593402,Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects.,Clin Epigenetics,"Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers.A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA).Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results.This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.",
+No ,20210308,dnam age,33656257,BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy.,Aging Cell,"Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional, or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such as Caenorhabditis elegans and it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy. Here, we devised an approach that uses temporal scaling and binarization of C. elegans transcriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments, and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this binarized transcriptomic aging (BiT age) clock can also be applied to human age prediction with high accuracy. The BiT age clock could therefore find wide application in genetic, nutritional, environmental, and therapeutic interventions in the aging process.© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
+No ,20210308,methods,33623021,Single-cell multiomics sequencing reveals the functional regulatory landscape of early embryos.,Nat Commun,"Extensive epigenetic reprogramming occurs during preimplantation embryo development. However, it remains largely unclear how the drastic epigenetic reprogramming contributes to transcriptional regulatory network during this period. Here, we develop a single-cell multiomics sequencing technology (scNOMeRe-seq) that enables profiling of genome-wide chromatin accessibility, DNA methylation and RNA expression in the same individual cell. We apply this method to depict a single-cell multiomics map of mouse preimplantation development. We find that genome-wide DNA methylation remodeling facilitates the reconstruction of genetic lineages in early embryos. Further, we construct a zygotic genome activation (ZGA)-associated regulatory network and reveal coordination among multiple epigenetic layers, transcription factors and repeat elements that instruct proper ZGA. Cell fates associated cis-regulatory elements are activated stepwise in post-ZGA stages. Trophectoderm (TE)-specific transcription factors play dual roles in promoting the TE program while repressing the inner cell mass (ICM) program during the ICM/TE separation.",
+No ,20210308,prediction,33608029,Genome-wide cell-free DNA methylation analyses improve accuracy of non-invasive diagnostic imaging for early-stage breast cancer.,Mol Cancer,"Early detection is crucial to improve breast cancer (BC) patients' outcomes and survival. Mammogram and ultrasound adopting the Breast Imaging Reporting and Data System (BI-RADS) categorization are widely used for BC early detection, while suffering high false-positive rate leading to unnecessary biopsy, especially in BI-RADS category-4 patients. Plasma cell-free DNA (cfDNA) carrying on DNA methylation information has emerged as a non-invasive approach for cancer detection. Here we present a prospective multi-center study with whole-genome bisulfite sequencing data to address the clinical utility of cfDNA methylation markers from 203 female patients with breast lesions suspected for malignancy. The cfDNA is enriched with hypo-methylated genomic regions. A practical computational framework was devised to excavate optimal cfDNA-rich DNA methylation markers, which significantly improved the early diagnosis of BI-RADS category-4 patients (AUC from 0.78-0.79 to 0.93-0.94). As a proof-of-concept study, we performed the first blood-based whole-genome DNA methylation study for detecting early-stage breast cancer from benign tumors at single-base resolution, which suggests that combining the liquid biopsy with the traditional diagnostic imaging can improve the current clinical practice, by reducing the false-positive rate and avoiding unnecessary harms.",
+No ,20210308,dnam age,33606025,Epigenetic Age Acceleration and Cognitive Decline: A Twin Study.,J Gerontol A Biol Sci Med Sci,"Little is known about the role of DNA methylation (DNAm) epigenetic age acceleration in cognitive decline. Using a twin study design, we examined whether DNAm age acceleration is related to cognitive decline measured longitudinally in persons without a clinical diagnosis of dementia.We studied 266 paired male twins (133 pairs) with a mean age of 56 years at baseline. Of these, 114 paired twins returned for a follow-up after an average of 11.5 years. We obtained six indices of DNAm age acceleration based on epigenome-wide data from peripheral blood lymphocytes. At both baseline and follow-up, we administered a battery of cognitive measures and constructed two composite scores, one for executive function and one for memory function. We fitted multivariable mixed regression models to examine the association of DNAm age acceleration markers with cognitive function within pairs.In cross sectional analyses at baseline, there was no association between DNAm age acceleration and cognitive function scores. In longitudinal analyses, however, comparing twins within pairs, each additional year of age acceleration using the Horvath's method was associated with a 3% decline (95% CI, 1% to 5%) in the composite executive function score and a 2.5% decline (95% CI, 0.01% to 4.9%) in the memory function score. These results did not attenuate after adjusting for education and other risk factors.Middle-aged men who had older DNAm age relative to their brothers of the same demographic age, showed a faster rate of cognitive decline in the subsequent 11.5 years. These results point to the role of epigenetic modifications in cognitive aging.© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
+No ,20210308,epigenetics,33619309,Skewness of X-chromosome inactivation increases with age and varies across birth cohorts in elderly Danish women.,Sci Rep,"Mosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2-7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917-1923 and 1931-1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7-29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917-1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.",
+No,20210308,prediction,33632303,DNA methylation and cancer incidence: lymphatic-hematopoietic versus solid cancers in the Strong Heart Study.,Clin Epigenetics,"Epigenetic alterations may contribute to early detection of cancer. We evaluated the association of blood DNA methylation with lymphatic-hematopoietic cancers and, for comparison, with solid cancers. We also evaluated the predictive ability of DNA methylation for lymphatic-hematopoietic cancers.Blood DNA methylation was measured using the Illumina Infinium methylationEPIC array in 2324 Strong Heart Study participants (41.4% men, mean age 56 years). 788,368 CpG sites were available for differential DNA methylation analysis for lymphatic-hematopoietic, solid and overall cancers using elastic-net and Cox regression models. We conducted replication in an independent population: the Framingham Heart Study. We also analyzed differential variability and conducted bioinformatic analyses to assess for potential biological mechanisms.Over a follow-up of up to 28 years (mean 15), we identified 41 lymphatic-hematopoietic and 394 solid cancer cases. A total of 126 CpGs for lymphatic-hematopoietic cancers, 396 for solid cancers, and 414 for overall cancers were selected as predictors by the elastic-net model. For lymphatic-hematopoietic cancers, the predictive ability (C index) increased from 0.58 to 0.87 when adding these 126 CpGs to the risk factor model in the discovery set. The association was replicated with hazard ratios in the same direction in 28 CpGs in the Framingham Heart Study. When considering the association of variability, rather than mean differences, we found 432 differentially variable regions for lymphatic-hematopoietic cancers.This study suggests that differential methylation and differential variability in blood DNA methylation are associated with lymphatic-hematopoietic cancer risk. DNA methylation data may contribute to early detection of lymphatic-hematopoietic cancers.",
+Yes,20210308,ewas,33661023,Comparative epigenome-wide analysis highlights placenta-specific differentially methylated regions.,Epigenomics,Aim:The placenta undergoes DNA methylation (DNAm) programming that is unique compared with all other fetal tissues. We aim to decipher some of the physiologic roles of the placenta by comparing its DNAm profile with that of another fetal tissue.Materials & methods:We performed a comparative analysis of genome-wide DNAm of 444 placentas paired with cord blood samples collected at birth. Gene ontology term analyses were conducted on the resulting differentially methylated regions.Results:Genomic regions upstream of transcription start sites showing lower DNAm in the placenta were enriched with terms related to miRNA functions and genes encoding G protein-coupled receptors.Conclusion:These results highlight genomic regions that are differentially methylated in the placenta in contrast to fetal blood.,
+Yes,20210308,ewas,33646943,DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.,Elife,"We performed a systematic analysis of blood DNA methylation profiles from 4,483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1,048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.© 2021, Hannon et al.",
+Yes,20210308,ewas,33622391,DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts.,Clin Epigenetics,"Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones.We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%).This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.",
+No,20210329,cancer,33762478,Genome-wide association analysis reveals regulation of at-risk loci by DNA methylation in prostate cancer.,Asian J Androl,"Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations. Prostate cancer (PCa) is characterized by variable clinical manifestations and frequently unpredictable outcomes. We performed an expression quantitative trait loci (eQTL) analysis to identify the genomic regions that regulate gene expression in PCa and identified a relationship between DNA methylation and clinical information. Using multi-level information published in The Cancer Genome Atlas, we performed eQTL-based analyses on DNA methylation and gene expression. To better interpret these data, we correlated loci and clinical indexes to identify the important loci for both PCa development and progression. Our data demonstrated that although only a small proportion of genes are regulated via DNA methylation in PCa, these genes are enriched in important cancer-related groups. In addition, single nucleotide polymorphism analysis identified the locations of CpG sites and genes within at-risk loci, including the 19q13.2-q13.43 and 16q22.2-q23.1 loci. Further, an epigenetic association study of clinical indexes detected risk loci and pyrosequencing for site validation. Although DNA methylation-regulated genes across PCa samples are a small proportion, the associated genes play important roles in PCa carcinogenesis.",
+No,20210329,cancer,33666134,DNA-methylation for the detection and distinction of 19 human malignancies.,Epigenetics,"The contribution of DNA-methylation based gene silencing to carcinogenesis is well established. Increasingly, DNA-methylation is examined using genome-wide techniques, with recent public efforts yielding immense data sets of diverse malignancies representing the vast majority of human cancer related disease burden. Whereas mutation events may group preferentially or in high frequency with a given histology, mutations are poor classifiers of tumour type. Here we examine the hypothesis that cancer-specific DNA-methylation reflects the tissue of origin or carcinogenic risk factor, and these methylation abnormalities may be used to faithfully classify tumours according to histology. We present an analysis of 7427 tumours representing 19 human malignancies and 708 normal samples demonstrating that specific tumour changes in methylation can correctly determine site of origin and tumour histology with 86% overall accuracy. Examination of misclassified tumours reveals underlying shared biology as the source of misclassifications, including common cell of origin or risk factors.",
+No,20210329,cancer,33707228,DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia.,Genome Res,"Acute myeloid leukemia (AML) is a molecularly complex disease characterized by heterogeneous tumor genetic profiles and involving numerous pathogenic mechanisms and pathways. Integration of molecular data types across multiple patient cohorts may advance current genetic approaches for improved sub-classification and understanding of the biology of the disease. Here we analyzed genome-wide DNA methylation in 649 AML patients using Illumina arrays and identified a configuration of 13 subtypes (termed 'epitypes') using unbiased clustering. Integration of genetic data revealed that most epitypes were associated with a certain recurrent mutation (or combination) in a majority of patients, yet other epitypes were largely independent. Epitypes demonstrated developmental blockage at discrete stages of myeloid differentiation, revealing epitypes that retain arrested hematopoietic stem cell-like phenotypes. Detailed analyses of DNA methylation patterns identified unique patterns of aberrant hyper- and hypomethylation among epitypes, with variable involvement of transcription factors influencing promoter, enhancer, and repressed regions. Patients in epitypes with stem cell-like methylation features showed inferior overall survival along with upregulated stem cell gene expression signatures. We further identified a DNA methylation signature involving STAT motifs associated withFLT3-ITD mutations. Finally, DNA methylation signatures were stable at relapse for the large majority of patients, and rare epitype switching accompanied loss of the dominant epitype mutations and reversion to stem cell-like methylation patterns. These results demonstrate that DNA methylation-based classification integrates important molecular features of AML to reveal the diverse pathogenic and biological aspects of the disease.Published by Cold Spring Harbor Laboratory Press.",
+No,20210329,cell lines,33676569,Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines.,Clin Epigenetics,"Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents.We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta-values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epigenome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxygenases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes affecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlapping effects of each epigenetic factor on methylation of specific targets and the importance of such influences in tumor response to individual agents require further investigation.Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may affect response to therapeutic agents. Our findings suggest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly affect response to chemotherapy.",
+No,20210329,dnam age,33653394,Weight management intervention identifies association of decreased DNA methylation age with improved functional age measures in older adults with obesity.,Clin Epigenetics,"Assessing functional ability is an important component of understanding healthy aging. Objective measures of functional ability include grip strength, gait speed, sit-to-stand time, and 6-min walk distance. Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Peripheral blood DNA methylation was measured (pre/post) with the Illumina HumanMethylationEPIC array and the Hannum, Horvath, and PhenoAge DNA methylation age clocks were used. Linear regression models adjusted for chronological age and sex tested the relationship between DNA methylation age and grip strength, gait speed, sit-to-stand, and 6-min walk.Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively. Mean grip strength increased 3.2 kg. Decreased Hannum methylation age was significantly associated with increased grip strength (β = -0.30, p = 0.04), and increased gait speed (β = 0.02, p = 0.05), in adjusted models. Similarly, decreased methylation age using the PhenoAge clock was associated with significantly increased gait speed (β = 0.02, p = 0.04). A decrease in Horvath DNA methylation age and increase in physical functional ability did not demonstrate a significant association.The observed relationship between increased physical functional ability and decreased biological age using DNA methylation clocks demonstrate the potential utility of DNA methylation clocks to assess interventional approaches to improve health in older obese adults.National Institute on Aging (NIA), NCT03104192. Posted April 7, 2017, https://clinicaltrials.gov/ct2/show/NCT03104192.",
+No,20210329,dnam age,33726838,Epigenetic age acceleration is associated with cardiometabolic risk factors and clinical cardiovascular disease risk scores in African Americans.,Clin Epigenetics,"Cardiovascular disease (CVD) is the leading cause of mortality among US adults. African Americans have higher burden of CVD morbidity and mortality compared to any other racial group. Identifying biomarkers for clinical risk prediction of CVD offers an opportunity for precision prevention and earlier intervention.Using linear mixed models, we investigated the cross-sectional association between four measures of epigenetic age acceleration (intrinsic (IEAA), extrinsic (EEAA), PhenoAge (PhenoAA), and GrimAge (GrimAA)) and ten cardiometabolic markers of hypertension, insulin resistance, and dyslipidemia in 1,100 primarily hypertensive African Americans from sibships in the Genetic Epidemiology Network of Arteriopathy (GENOA). We then assessed the association between epigenetic age acceleration and time to self-reported incident CVD using frailty hazard models and investigated CVD risk prediction improvement compared to models with clinical risk scores (Framingham risk score (FRS) and the atherosclerotic cardiovascular disease (ASCVD) risk equation). After adjusting for sex and chronological age, increased epigenetic age acceleration was associated with higher systolic blood pressure (IEAA), higher pulse pressure (EEAA and GrimAA), higher fasting glucose (PhenoAA and GrimAA), higher fasting insulin (EEAA), lower low density cholesterol (GrimAA), and higher triglycerides (GrimAA). A five-year increase in GrimAA was associated with CVD incidence with a hazard ratio of 1.54 (95% CI 1.22-2.01) and remained significant after adjusting for CVD risk factors. The addition of GrimAA to risk score models improved model fit using likelihood ratio tests (P = 0.013 for FRS and P = 0.008 for ASCVD), but did not improve C statistics (P > 0.05). Net reclassification index (NRI) showed small but significant improvement in reassignment of risk categories with the addition of GrimAA to FRS (NRI: 0.055, 95% CI 0.040-0.071) and the ASCVD equation (NRI: 0.029, 95% CI 0.006-0.064).Epigenetic age acceleration measures are associated with traditional CVD risk factors in an African-American cohort with a high prevalence of hypertension. GrimAA was associated with CVD incidence and slightly improved prediction of CVD events over clinical risk scores.",
+No,20210329,dnam age,33712580,DNA methylation predicts age and provides insight into exceptional longevity of bats.,Nat Commun,"Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.",
+No,20210329,dnam age,33663610,Lifestyle weight-loss intervention may attenuate methylation aging: the CENTRAL MRI randomized controlled trial.,Clin Epigenetics,"DNA methylation age (mAge), a methylation biomarker for the aging process, might serve as a more accurate predictor of morbidity and aging status than chronological age. We evaluated the role of multiple factors, including fat deposition, cardiometabolic risk factors and lifestyle weight-loss intervention, on the deviation of mAge from chronological age (mAge deviation) or 18-month change in mAge (�mAge). In this sub-study of the CENTRAL magnetic resonance imaging weight-loss trial, we evaluated mAge by a validated 240-CpG-based prediction formula at baseline and after 18-month intervention of either low fat (LF) or mediterranean/low carbohydrate (MED/LC) diets.Among 120 CENTRAL participants with abdominal obesity or dyslipidemia, mAge (mean ± SD: 60.3 ± 7.5 years) was higher than the chronological age (48.6 ± 9.3 years) but strongly correlated (r = 0.93; p = 3.1 × 10-53). Participants in the lowest tertile of mAge deviation from their chronological age had significantly lower waist-circumference, visceral adipose tissue, intrahepatic fat (IHF) content, fasting-glucose and HOMA-IR, as compared with participants in the highest sex-specific residual tertile (p < 0.05 for all). IHF% remained associated with greater mAge deviation after further adjustments (β = 0.23; p = 0.02). After 18-month weight-loss lifestyle intervention, mAge remained significantly correlated with chronological age (r = 0.94, p = 1.5 × 10-55). mAging occurred, with no difference between lifestyle intervention groups (� = 0.9 ± 1.9 years in MED/LC vs. � = 1.3 ± 1.9 years in LF; p = 0.2); however, we observed a mAging attenuation in successful weight losers (> 5% weight loss) vs. weight-loss failures ( � = 0.6 years vs. � = 1.1 years; p = 0.04), and in participants who completed the trial with healthy liver fat content (< 5% IHF) vs. participants with fatty liver (� = 0.6 years vs. � = 1.8 years; p = 0.003). Overall, 18 months of weight-loss lifestyle intervention attenuated the mAging of the men, mainly the older, by 7.1 months than the expected (p < 0.05).Lifestyle weight-loss intervention may attenuate mAging. Deviation of mAge from chronological age might be related to body fat distribution and glycemic control and could indicate biological age, health status and the risk for premature cardiometabolic diseases.ClinicalTrials.gov NCT01530724. Registered 10 February 2012, https://clinicaltrials.gov/ct2/show/study/NCT01530724 .",
+No,20210329,dnam age,33749330,Epigenetic age associates with psychosocial stress and resilience in children of Latinx immigrants.,Epigenomics,"Aim:To investigate associations of psychosocial stressors and resilience factors with DNA methylation age in saliva of Latinx children of immigrants before and after the 2016 presidential election (2015-2018).Materials & methods:We compared psychosocial exposures with four distinct measures of epigenetic age assessed in saliva of children (6-13 years, n = 71 pre-election; n = 35 post-election). Exploratory genome-wide analyses were also conducted.Results:We found distinct associations across epigenetic clocks and time points: for example, greater maternal social status pre-election and fear of parent deportation post-election both associated with decreased Hannum Age (p ≤ 0.01).Conclusion:Though limited in size, our unique study design provides novel hypotheses regarding how the social environment may influence epigenetic aging and genome-wide methylation, potentially contributing to racial/ethnic health inequalities.",
+No,20210329,metastable epialleles,33680493,Rationale and design of the Baylor Infant Twin Study-A study assessing obesity-related risk factors from infancy.,Obes Sci Pract,"Early childhood (0-3 years) is a critical period for obesity prevention, when tendencies in eating behaviors and physical activity are established. Yet, little is understood about how the environment shapes children's genetic predisposition for these behaviors during this time. The Baylor Infant Twin Study (BITS) is a two phase study, initiated to study obesity risk factors from infancy. Data collection has been completed for Phase 1 in which three sub-studies pilot central measures for Phase 2. A novel infant temperament assessment, based on observations made by trained researchers was piloted inBehavior Observation Pilot Protocol(BOPP) study, a new device for measuring infant feeding parameters (the ""orometer"") in theBaylor Infant Orometer(BIO), and methods for analyzing DNA methylation in twins of unknown chorionicity inEpiTwin.EpiTwin was a cross-sectional study of neonatal twins, while up to three study visits occurred for the other studies, at 4- (BOPP, BIO), 6- (BOPP), and 12- (BOPP, BIO) of age. Measurements for BOPP and BIO included temperament observations, feeding observations, and body composition assessments while EpiTwin focused on collecting samples of hair, urine, nails, and blood for quantifying methylation levels at 10 metastable epialleles. Additional data collected include demographic information, zygosity, chorionicity, and questionnaire-based measures of infant behaviors.Recruitment for all three studies was completed in early 2020. EpiTwin recruited 80 twin pairs (50% monochorionic), 31 twin pairs completed the BOPP protocol, and 68 singleton infants participated in BIO.The psychometric properties of the data from all three studies are being analyzed currently. The resulting findings will inform the development of the full BITS protocol, with the goal of completing assessments at 4-, 6-, 12-, and 14-month of age for 400 twin pairs.© 2020 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.",
+No,20210329,methods,33707472,EMeth: An EM algorithm for cell type decomposition based on DNA methylation data.,Sci Rep,"We introduce a new computational method named EMeth to estimate cell type proportions using DNA methylation data. EMeth is a reference-based method that requires cell type-specific DNA methylation data from relevant cell types. EMeth improves on the existing reference-based methods by detecting the CpGs whose DNA methylation are inconsistent with the deconvolution model and reducing their contributions to cell type decomposition. Another novel feature of EMeth is that it allows a cell type with known proportions but unknown reference and estimates its methylation. This is motivated by the case of studying methylation in tumor cells while bulk tumor samples include tumor cells as well as other cell types such as infiltrating immune cells, and tumor cell proportion can be estimated by copy number data. We demonstrate that EMeth delivers more accurate estimates of cell type proportions than several other methods using simulated data and in silico mixtures. Applications in cancer studies show that the proportions of T regulatory cells estimated by DNA methylation have expected associations with mutation load and survival time, while the estimates from gene expression miss such associations.",
+No,20210329,methods,33722199,Correction for both common and rare cell types in blood is important to identify genes that correlate with age.,BMC Genomics,"Aging is a multifactorial process that affects multiple tissues and is characterized by changes in homeostasis over time, leading to increased morbidity. Whole blood gene expression signatures have been associated with aging and have been used to gain information on its biological mechanisms, which are still not fully understood. However, blood is composed of many cell types whose proportions in blood vary with age. As a result, previously observed associations between gene expression levels and aging might be driven by cell type composition rather than intracellular aging mechanisms. To overcome this, previous aging studies already accounted for major cell types, but the possibility that the reported associations are false positives driven by less prevalent cell subtypes remains.Here, we compared the regression model from our previous work to an extended model that corrects for 33 additional white blood cell subtypes. Both models were applied to whole blood gene expression data from 3165 individuals belonging to the general population (age range of 18-81 years). We evaluated that the new model is a better fit for the data and it identified fewer genes associated with aging (625, compared to the 2808 of the initial model; P ≤ 2.5⨯10-6). Moreover, 511 genes (~ 18% of the 2808 genes identified by the initial model) were found using both models, indicating that the other previously reported genes could be proxies for less abundant cell types. In particular, functional enrichment of the genes identified by the new model highlighted pathways and GO terms specifically associated with platelet activity.We conclude that gene expression analyses in blood strongly benefit from correction for both common and rare blood cell types, and recommend using blood-cell count estimates as standard covariates when studying whole blood gene expression.",
+No,20210329,methods,33752591,Nonlinear ridge regression improves cell-type-specific differential expression analysis.,BMC Bioinformatics,"Epigenome-wide association studies (EWAS) and differential gene expression analyses are generally performed on tissue samples, which consist of multiple cell types. Cell-type-specific effects of a trait, such as disease, on the omics expression are of interest but difficult or costly to measure experimentally. By measuring omics data for the bulk tissue, cell type composition of a sample can be inferred statistically. Subsequently, cell-type-specific effects are estimated by linear regression that includes terms representing the interaction between the cell type proportions and the trait. This approach involves two issues, scaling and multicollinearity.First, although cell composition is analyzed in linear scale, differential methylation/expression is analyzed suitably in the logit/log scale. To simultaneously analyze two scales, we applied nonlinear regression. Second, we show that the interaction terms are highly collinear, which is obstructive to ordinary regression. To cope with the multicollinearity, we applied ridge regularization. In simulated data, nonlinear ridge regression attained well-balanced sensitivity, specificity and precision. Marginal model attained the lowest precision and highest sensitivity and was the only algorithm to detect weak signal in real data.Nonlinear ridge regression performed cell-type-specific association test on bulk omics data with well-balanced performance. The omicwas package for R implements nonlinear ridge regression for cell-type-specific EWAS, differential gene expression and QTL analyses. The software is freely available from https://github.com/fumi-github/omicwas.",
+No,20210329,reference,33739972,Assessing the co-variability of DNA methylation across peripheral cells and tissues: Implications for the interpretation of findings in epigenetic epidemiology.,PLoS Genet,"Most epigenome-wide association studies (EWAS) quantify DNA methylation (DNAm) in peripheral tissues such as whole blood to identify positions in the genome where variation is statistically associated with a trait or exposure. As whole blood comprises a mix of cell types, it is unclear whether trait-associated DNAm variation is specific to an individual cellular population. We collected three peripheral tissues (whole blood, buccal epithelial and nasal epithelial cells) from thirty individuals. Whole blood samples were subsequently processed using fluorescence-activated cell sorting (FACS) to purify five constituent cell-types (monocytes, granulocytes, CD4+ T cells, CD8+ T cells, and B cells). DNAm was profiled in all eight sample-types from each individual using the Illumina EPIC array. We identified significant differences in both the level and variability of DNAm between different sample types, and DNAm data-derived estimates of age and smoking were found to differ dramatically across sample types from the same individual. We found that for the majority of loci variation in DNAm in individual blood cell types was only weakly predictive of variance in DNAm measured in whole blood, although the proportion of variance explained was greater than that explained by either buccal or nasal epithelial samples. Covariation across sample types was much higher for DNAm sites influenced by genetic factors. Overall, we observe that DNAm variation in whole blood is additively influenced by a combination of the major blood cell types. For a subset of sites, however, variable DNAm detected in whole blood can be attributed to variation in a single blood cell type providing potential mechanistic insight about EWAS findings. Our results suggest that associations between whole blood DNAm and traits or exposures reflect differences in multiple cell types and our data will facilitate the interpretation of findings in epigenetic epidemiology.",
+No,20210329,reference,33669975,Extensive Placental Methylation Profiling in Normal Pregnancies.,Int J Mol Sci,"The placental methylation pattern is crucial for the regulation of genes involved in trophoblast invasion and placental development, both key events for fetal growth. We investigated LINE-1 methylation and methylome profiling using a methylation EPIC array and the targeted methylation sequencing of 154 normal, full-term pregnancies, stratified by birth weight percentiles. LINE-1 methylation showed evidence of a more pronounced hypomethylation in small neonates compared with normal and large for gestational age. Genome-wide methylation, performed in two subsets of pregnancies, showed very similar methylation profiles among cord blood samples while placentae from different pregnancies appeared very variable. A unique methylation profile emerged in each placenta, which could represent the sum of adjustments that the placenta made during the pregnancy to preserve the epigenetic homeostasis of the fetus. Investigations into the 1000 most variable sites between cord blood and the placenta showed that promoters and gene bodies that are hypermethylated in the placenta are associated with blood-specific functions, whereas those that are hypomethylated belong mainly to pathways involved in cancer. These features support the functional analogies between a placenta and cancer. Our results, which provide a comprehensive analysis of DNA methylation profiling in the human placenta, suggest that its peculiar dynamicity can be relevant for understanding placental plasticity in response to the environment.",
+No,20210329,twas,33693414,The Human Blood Transcriptome in a Large Population Cohort and Its Relation to Aging and Health.,Front Big Data,"Background:The blood transcriptome is expected to provide a detailed picture of an organism's physiological state with potential outcomes for applications in medical diagnostics and molecular and epidemiological research. We here present the analysis of blood specimens of 3,388 adult individuals, together with phenotype characteristics such as disease history, medication status, lifestyle factors, and body mass index (BMI). The size and heterogeneity of this data challenges analytics in terms of dimension reduction, knowledge mining, feature extraction, and data integration.Methods:Self-organizing maps (SOM)-machine learning was applied to study transcriptional states on a population-wide scale. This method permits a detailed description and visualization of the molecular heterogeneity of transcriptomes and of their association with different phenotypic features.Results:The diversity of transcriptomes is described by personalized SOM-portraits, which specify the samples in terms of modules of co-expressed genes of different functional context. We identified two major blood transcriptome types where type 1 was found more in men, the elderly, and overweight people and it upregulated genes associated with inflammation and increased heme metabolism, while type 2 was predominantly found in women, younger, and normal weight participants and it was associated with activated immune responses, transcriptional, ribosomal, mitochondrial, and telomere-maintenance cell-functions. We find a striking overlap of signatures shared by multiple diseases, aging, and obesity driven by an underlying common pattern, which was associated with the immune response and the increase of inflammatory processes.Conclusions:Machine learning applications for large and heterogeneous omics data provide a holistic view on the diversity of the human blood transcriptome. It provides a tool for comparative analyses of transcriptional signatures and of associated phenotypes in population studies and medical applications.Copyright © 2020 Schmidt, Hopp, Arakelyan, Kirsten, Engel, Wirkner, Krohn, Burkhardt, Thiery, Loeffler, Loeffler-Wirth and Binder.",
+Yes,20210329,ewas,33752734,Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases.,Clin Epigenetics,"DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases.We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data.Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.",
+Yes,20210329,ewas,33751861,"Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children.",Pediatr Pulmonol,"Exposure to violence (ETV) or chronic stress may influence asthma through unclear mechanisms.Epigenome-wide association study (EWAS) of ETV or chronic stress measures and DNA methylation in nasal epithelium from 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed four measures of ETV and chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by p value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA).Three CpGs (in SNN, PTPRN2, and LINC01164) were associated with maternal perceived stress or gun violence (p = 1.28-3.36 × 10-7), but not with atopic asthma, in EVA-PR. In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence measures in EVA-PR, 12 CpGs (in STARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4, and ANAPC13) were associated with atopic asthma at FDR-p < .05.Pending confirmation in longitudinal studies, our findings suggest that nasal epithelial methylation markers associated with measures of ETV and chronic stress may be linked to atopic asthma in children and adolescents.© 2021 Wiley Periodicals LLC.",
+Yes,20210329,ewas,33748261,Epigenome-wide association study on diffusing capacity of the lung.,ERJ Open Res,"Epigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung.To identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (DLCO)).An epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) (asDLCO/VA), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the ""discovery panel"") and the Framingham Heart Study (FHS, the ""replication panel""). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression.We identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated withDLCO/VAand one (cg05575921) suggestively associated withDLCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression ofEXOC3in lung tissue is positively associated withDLCO/VAandDLCO.We report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation ofAHRRmight affect pulmonary gas exchange.Copyright ©ERS 2021.",
+Yes,20210329,ewas,33741061,Birthweight DNA methylation signatures in infant saliva.,Clin Epigenetics,"Low birthweight has been repeatedly associated with long-term adverse health outcomes and many non-communicable diseases. Our aim was to look-up cord blood birthweight-associated CpG sites identified by the PACE Consortium in infant saliva, and to explore saliva-specific DNA methylation signatures of birthweight.DNA methylation was assessed using Infinium HumanMethylation450K array in 135 saliva samples collected from children of the NINFEA birth cohort at an average age of 10.8 (range 7-17) months. The association analyses between birthweight and DNA methylation variations were carried out using robust linear regression models both in the exploratory EWAS analyses and in the look-up of the PACE findings in infant saliva.None of the cord blood birthweight-associated CpGs identified by the PACE Consortium was associated with birthweight when analysed in infant saliva. In saliva EWAS analyses, considering a false discovery rate p-values < 0.05, birthweight as continuous variable was associated with DNA methylation in 44 CpG sites; being born small for gestational age (SGA, lower 10thpercentile of birthweight for gestational age according to WHO reference charts) was associated with DNA methylation in 44 CpGs, with only one overlapping CpG between the two analyses. Despite no overlap with PACE results at the CpG level, two of the top saliva birthweight CpGs mapped at genes associated with birthweight with the same direction of the effect also in the PACE Consortium (MACROD1 and RPTOR).Our study provides an indication of the birthweight and SGA epigenetic salivary signatures in children around 10 months of age. DNA methylation signatures in cord blood may not be comparable with saliva DNA methylation signatures at about 10 months of age, suggesting that the birthweight epigenetic marks are likely time and tissue specific.",
+Yes,20210329,ewas,33729499,Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT study.,Int J Epidemiol,"It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development.We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer.The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P < 5 × 10-8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer.DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.",
+Yes,20210329,ewas,33667780,Epigenome-wide study of brain DNA methylation following acute opioid intoxication.,Drug Alcohol Depend,"Opioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of opioid abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. To clarify the association between opioid abuse and DNA methylation, we conducted an epigenome-wide analysis of DNA methylation in brain samples of individuals who died from acute opioid intoxication and group-matched controls.Tissue samples were extracted from the dorsolateral prefrontal cortex of 153 deceased individuals (Mage= 35.42; 62 % male; 77 % European ancestry). The study included 72 opioid samples, 53 psychiatric controls, and 28 normal controls. The epigenome-wide analysis was implemented using the Illumina MethylationEPIC BeadChip; analyses adjusted for sociodemographic characteristics, negative control principal components, ancestry principal components, cellular composition, and surrogate variables. Horvath's epigenetic age and Levine's PhenoAge were calculated, and gene set enrichment analyses were performed.Although no CpG sites survived false-discovery rate correction for multiple testing, 13 sites surpassed a relaxed significance threshold (p < 1.0 × 10-5). One of these sites was located within Netrin-1, a gene implicated in kappa opioid receptor activity. There was an association between opioid use and accelerated PhenoAge (b = 2.24, se = 1.11, p = .045). Gene set enrichment analyses revealed enrichment of differential methylation in GO and KEGG pathways broadly related to substance use.Netrin-1 may be associated with opioid overdose, and future research with larger samples across stages of opioid use will elucidate the complex genomics of opioid abuse.Copyright © 2021 Elsevier B.V. All rights reserved.",
+Yes,20210329,ewas,33663600,DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother-newborn pairs.,Clin Epigenetics,"Maternal smoking affects more than half a million pregnancies each year in the US and is known to result in fetal growth restriction as measured by lower birthweight and its associated long-term consequences. Maternal smoking also has been linked to altered fetal DNA methylation (DNAm). However, what remains largely unexplored is whether these DNAm alterations are merely markers of smoking exposure or if they also have implications for health outcomes. This study tested the hypothesis that fetal DNAm mediates the effect of maternal smoking on newborn birthweight.This study included mother-newborn pairs from a US predominantly urban, low-income multi-ethnic birth cohort. DNAm in cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip. After standard quality control and normalization procedures, an epigenome-wide association study (EWAS) of maternal smoking was performed using linear regression models, controlling for maternal age, education, race, parity, pre-pregnancy body mass index, alcohol consumption, gestational age, maternal pregestational/gestational diabetes, child sex, cord blood cell compositions and batch effects. To quantify the degree to which cord DNAm mediates the smoking-birthweight association, the VanderWeele-Vansteelandt approach for single mediator and structural equational model for multiple mediators were used, adjusting for pertinent covariates.The study included 954 mother-newborn pairs. Among mothers, 165 (17.3%) ever smoked before or during pregnancy. Newborns with smoking exposure had on average 258 g lower birthweight than newborns without exposure (P < 0.001). Using a false discovery rate (FDR) < 0.05 as the significance cutoff, the EWAS identified 38 differentially methylated CpG sites associated with maternal smoking. Of those, 17 CpG sites were mapped to previously reported genes: GFI1, AHRR, CYP1A1, and CNTNAP2; 8 of those, located in the first three genes, were Bonferroni significantly associated with newborn birthweight and mediated the smoking-birthweight association. The combined mediation effect of the three genes explained 67.8% of the smoking-birthweight association.Our study not only lends further support that maternal smoking alters fetal DNAm in a multiethnic population, but also suggests that fetal DNAm substantially mediates the maternal smoking-birthweight association. Our findings, if further validated, indicate that DNAm modification is likely an important pathway by which maternal smoking impairs fetal growth and, perhaps, even long-term health outcomes.",
+Yes,20210416,ewas,33845866,DNA methylation in cord blood in association with prenatal depressive symptoms.,Clin Epigenetics,"Prenatal symptoms of depression (PND) and anxiety affect up to every third pregnancy. Children of mothers with mental health problems are at higher risk of developmental problems, possibly through epigenetic mechanisms together with other factors such as genetic and environmental. We investigated DNA methylation in cord blood in relation to PND, taking into consideration a history of depression, co-morbidity with anxiety and selective serotonin reuptake inhibitors (SSRI) use, and stratified by sex of the child. Mothers (N = 373) prospectively filled out web-based questionnaires regarding mood symptoms and SSRI use throughout pregnancy. Cord blood was collected at birth and DNA methylation was measured using Illumina MethylationEPIC array at 850 000 CpG sites throughout the genome. Differentially methylated regions were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p-values < 0.05 were considered significant.No differential DNA methylation was associated with PND alone; however, differential DNA methylation was observed in children exposed to comorbid PND with anxiety symptoms compared with healthy controls in ABCF1 (log twofold change - 0.2), but not after stratification by sex of the child. DNA methylation in children exposed to PND without SSRI treatment and healthy controls both differed in comparison with SSRI exposed children at several sites and regions, among which hypomethylation was observed in CpGs in the promoter region of CRBN (log2 fold change - 0.57), involved in brain development, and hypermethylation in MDFIC (log2 fold change 0.45), associated with the glucocorticoid stress response.Although it is not possible to assess if these methylation differences are due to SSRI treatment itself or to more severe depression, our findings add on to existing knowledge that there might be different biological consequences for the child depending on whether maternal PND was treated with SSRIs or not.",
+No,20210416,epigenetics,33844406,The interplay between DNA and histone methylation: molecular mechanisms and disease implications.,EMBO Rep,"Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome-wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA- and histone-modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.© 2021 The Authors.",
+Yes,20210416,ewas,33838873,Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline.,Biol Psychiatry,"Cognitive trajectory varies widely and can distinguish people who develop dementia from people who remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. We sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human postmortem brain.We performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains simultaneously.We found an epigenome-wide association for differential methylation of sites in the CLDN5 locus and cognitive trajectory (p = 9.96 × 10-7) that was robust to adjustment for cell type proportions (p = 8.52 × 10-7). This association was primarily driven by association with declines in episodic (p = 4.65 × 10-6) and working (p = 2.54 × 10-7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs of amyloid-β and neurofibrillary tangle pathology.Differential methylation of CLDN5, a gene that encodes an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimer's disease pathologies. The association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer's disease.Copyright © 2021 Society of Biological Psychiatry. All rights reserved.",
+No,20210416,methods,33838111,Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing.,Cell,"A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff-a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing. We identify single guide RNAs (sgRNAs) capable of silencing the large majority of genes including those lacking canonical CpG islands (CGIs) and reveal a wide targeting window extending beyond annotated CGIs. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.Copyright © 2021 Elsevier Inc. All rights reserved.",
+Yes,20210416,ewas,33823916,Persistent variations of blood DNA methylation associated with treatment exposures and risk for cardiometabolic outcomes in long-term survivors of childhood cancer in the St. Jude Lifetime Cohort.,Genome Med,"It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions.We included 2052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA.By performing multiple treatment-specific EWAS, we identified 935 5'-cytosine-phosphate-guanine-3' (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p < 9 × 10-8). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (false discovery rate-adjusted p < 0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with a 32.9% mediation effect, and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA).In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.",
+Yes,20210416,ewas,33818294,Epigenome-wide analysis of long-term air pollution exposure and DNA methylation in monocytes: results from the Multi-Ethnic Study of Atherosclerosis.,Epigenetics,"Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals andcis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants' homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals andcis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or nearSDHAP3, ZFP57, HOXA5, andPRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5(p = 1.4×10-6) and NOX(p = 7.7×10-6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (nearTOMM20) had the smallest p-value (p = 5.6×10-8). NOXsignificantly associated with cg11756214 withinZNF347(p = 5.6×10-8). Several differentially methylated signals were also associated withcis-gene expression. The DMR located on chromosome 7 was associated with the expression ofHOXA5, HOXA9, andHOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression ofMRPL36andDEXI, respectively. The CpG cg05926640 was associated with expression ofARID4B, IRF2BP2, andTOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.",
+No,20210416,epigenetics,33808774,Identification of a Minimal 3-Transcript Signature to Differentiate Viral from Bacterial Infection from Best Genome-Wide Host RNA Biomarkers: A Multi-Cohort Analysis.,Int J Mol Sci,"The fight against the spread of antibiotic resistance is one of the most important challenges facing health systems worldwide. Given the limitations of current diagnostic methods, the development of fast and accurate tests for the diagnosis of viral and bacterial infections would improve patient management and treatment, as well as contribute to reducing antibiotic misuse in clinical settings. In this scenario, analysis of host transcriptomics constitutes a promising target to develop new diagnostic tests based on the host-specific response to infections. We carried out a multi-cohort meta-analysis of blood transcriptomic data available in public databases, including 11 different studies and 1209 samples from virus- (n= 695) and bacteria- (n= 514) infected patients. We applied a Parallel Regularized Regression Model Search (PReMS) on a set of previously reported genes that distinguished viral from bacterial infection to find a minimum gene expression bio-signature. This strategy allowed us to detect three genes, namelyBAFT,ISG15andDNMT1, that clearly differentiate groups of infection with high accuracy (training set: area under the curve (AUC) 0.86 (sensitivity: 0.81; specificity: 0.87); testing set: AUC 0.87 (sensitivity: 0.82; specificity: 0.86)).BAFTandISG15are involved in processes related to immune response, whileDNMT1is related to the preservation of methylation patterns, and its expression is modulated by pathogen infections. We successfully tested this three-transcript signature in the 11 independent studies, demonstrating its high performance under different scenarios. The main advantage of this three-gene signature is the low number of genes needed to differentiate both groups of patient categories.",
+Yes,20210416,ewas,33784941,"DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake.",Epigenetics,"Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at both the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human MethylationEPIC array we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women's Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p≤6.45x10-8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195g (95%CI: -241, -149g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin releasing hormone binding protein (CRHBP).. Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p=1.37x10-255), maternal smoking (7.71%, p=1.50x10-57) and maternal plasma folate levels during pregnancy (0.33%, p=0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and/or suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs.",
+Yes,20210416,ewas,33771206,Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.,Genome Biol,"People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.",
+No,20210416,ewas,33766110,Pre-adolescence DNA methylation is associated with BMI status change from pre- to post-adolescence.,Clin Epigenetics,"Previous studies have shown that DNA methylation (DNAm) is associated with body mass index (BMI). However, it is unknown whether DNAm at pre-adolescence is associated with BMI status transition from pre- to post-adolescence. In the Isle of Wight (IoW) birth cohort, genome-wide DNA methylation in whole blood was measured using Illumina Infinium Human450 and EPIC BeadChip arrays in n = 325 subjects, and pre- to post-adolescence BMI transition was classified into four groups: (1) normal to normal, (2) normal to overweight or obese, (3) overweight or obese to normal, and (4) persistent overweight or obese. We used recursive random forest to screen genome-wide Cytosine-phosphate-Guanine (CpG) sites with DNAm potentially associated with BMI transition for each gender, and the association of BMI status transition with DNAm at an earlier age was assessed via logistic regressions. To evaluate gender specificity, interactions between DNAm and gender were included in the model. Findings in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC).In total, 174 candidate CpGs were selected including CpGs from screening and CpGs previously associated correctionally with BMI in children and adults. Of these 174 CpGs, pre-adolescent DNAm of 38 CpGs in the IoW cohort was associated with BMI status transition, including 30 CpGs showing gender-specific associations. Thirteen CpGs showed consistent associations between the IoW cohort and the ALSPAC cohort (11 of which were gender-specific).Pre-adolescence DNAm is associated with the change in BMI status from pre- to post-adolescence and such associations are likely to be gender-specific.",
+No,20210416,y,33744870,Male-specific age estimation based on Y-chromosomal DNA methylation.,Aging (Albany NY),"Although DNA methylation variation of autosomal CpGs provides robust age predictive biomarkers, no male-specific age predictor exists based on Y-CpGs yet. Since sex chromosomes play an important role in aging, a Y-chromosome-based age predictor would allow studying male-specific aging effects and would also be useful in forensics. Here, we used blood-based DNA methylation microarray data of 1,057 males from six cohorts aged 15-87 and identified 75 Y-CpGs with an interquartile range of ≥0.1. Of these, 22 and six were significantly hyper- and hypomethylated with age (p(cor)<0.05, Bonferroni), respectively. Amongst several machine learning algorithms, a model based on support vector machines with radial kernel performed best in male-specific age prediction. We achieved a mean absolute deviation (MAD) between true and predicted age of 7.54 years (cor=0.81, validation) when using all 75 Y-CpGs, and a MAD of 8.46 years (cor=0.73, validation) based on the most predictive 19 Y-CpGs. The accuracies of both age predictors did not worsen with increased age, in contrast to autosomal CpG-based age predictors that are known to predict age with reduced accuracy in the elderly. Overall, we introduce the first-of-its-kind male-specific epigenetic age predictor for future applications in aging research and forensics.",
+No,20210416,omics,33836805,DNA methylation and gene expression integration in cardiovascular disease.,Clin Epigenetics,"The integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event.Four independent latent factors (9, 19, 21-only in women-and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination.Unsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.",
+No,20210416,epigenetics,33795684,Evolution of DNA methylation in the human brain.,Nat Commun,"DNA methylation is a critical regulatory mechanism implicated in development, learning, memory, and disease in the human brain. Here we have elucidated DNA methylation changes during recent human brain evolution. We demonstrate dynamic evolutionary trajectories of DNA methylation in cell-type and cytosine-context specific manner. Specifically, DNA methylation in non-CG context, namely CH methylation, has increased (hypermethylation) in neuronal gene bodies during human brain evolution, contributing to human-specific down-regulation of genes and co-expression modules. The effects of CH hypermethylation is particularly pronounced in early development and neuronal subtypes. In contrast, DNA methylation in CG context shows pronounced reduction (hypomethylation) in human brains, notably in cis-regulatory regions, leading to upregulation of downstream genes. We show that the majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and harbors strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage since the divergence from the chimpanzee lineage and carries significant genetic risk for schizophrenia. Therefore, recent epigenetic evolution of human cortex has shaped the cellular regulatory landscape and contributed to the increased vulnerability to neuropsychiatric diseases.",
+No,20210416,twas,33795786,Transcriptomic signals in blood prior to lung cancer focusing on time to diagnosis and metastasis.,Sci Rep,Recent studies have indicated that there are functional genomic signals that can be detected in blood years before cancer diagnosis. This study aimed to assess gene expression in prospective blood samples from the Norwegian Women and Cancer cohort focusing on time to lung cancer diagnosis and metastatic cancer using a nested case-control design. We employed several approaches to statistically analyze the data and the methods indicated that the case-control differences were subtle but most distinguishable in metastatic case-control pairs in the period 0-3 years prior to diagnosis. The genes of interest along with estimated blood cell populations could indicate disruption of immunological processes in blood. The genes identified from approaches focusing on alterations with time to diagnosis were distinct from those focusing on the case-control differences. Our results support that explorative analyses of prospective blood samples could indicate circulating signals of disease-related processes.,
+No,20210416,prediction,33785068,Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside.,Clin Epigenetics,"Despite impressive efforts invested in epigenetic research in the last 50 years, clinical applications are still lacking. Only a few university hospital centers currently use epigenetic biomarkers at the bedside. Moreover, the overall concept of precision medicine is not widely recognized in routine medical practice and the reductionist approach remains predominant in treating patients affected by major diseases such as cancer and cardiovascular diseases. By its' very nature, epigenetics is integrative of genetic networks. The study of epigenetic biomarkers has led to the identification of numerous drugs with an increasingly significant role in clinical therapy especially of cancer patients. Here, we provide an overview of clinical epigenetics within the context of network analysis. We illustrate achievements to date and discuss how we can move from traditional medicine into the era of network medicine (NM), where pathway-informed molecular diagnostics will allow treatment selection following the paradigm of precision medicine.",
+No,20210416,vntr,33824302,Variable number tandem repeats mediate the expression of proximal genes.,Nat Commun,"Variable number tandem repeats (VNTRs) account for significant genetic variation in many organisms. In humans, VNTRs have been implicated in both Mendelian and complex disorders, but are largely ignored by genomic pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks to genotype a VNTR in 18 seconds on 55X whole genome data, while maintaining high accuracy. We use adVNTR-NN to genotype 10,264 VNTRs in 652 GTEx individuals. Associating VNTR length with gene expression in 46 tissues, we identify 163 ""eVNTRs"". Of the 22 eVNTRs in blood where independent data is available, 21 (95%) are replicated in terms of significance and direction of association. 49% of the eVNTR loci show a strong and likely causal impact on the expression of genes and 80% have maximum effect size at least 0.3. The impacted genes are involved in diseases including Alzheimer's, obesity and familial cancers, highlighting the importance of VNTRs for understanding the genetic basis of complex diseases.",
+No,20210416,epigenetics,33828297,Genome-wide enhancer maps link risk variants to disease genes.,Nature,"Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.",
+No,20210416,cell-free dna,33752803,"Applications of genetic-epigenetic tissue mapping for plasma DNA in prenatal testing, transplantation and oncology.",Elife,"We developed genetic-epigenetic tissue mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung transplant recipients, we showed that, at 72 hr after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles, and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring, and cancer screening.",
+No,20210416,ewas,33785011,The impact of cesarean delivery on infant DNA methylation.,BMC Pregnancy Childbirth,"Mounting evidence suggests that cesarean delivery may have a long-lasting effect on infant health. But the underlying mechanisms remain unclear. This study aims to examine whether cesarean delivery on maternal request without any medical indications (CDMR) impacts DNA methylation status in the umbilical cord blood of the infant.A cross-sectional study was conducted in Shanghai, China. A total of 70 CDMR and 70 vaginal deliveries (VD) were recruited in 2012. The cord blood DNA methylation status was measured in 30 CDMR and 30 VD newborns using Illumina Infinium Human Methylation 450 K BeadChip. To validate the results, the cord blood DNA methylation status was measured in another 40 CDMR and 40 VD newborns using targeted bisulfite sequencing assay. A total of 497 CpG sites from 40 genes were included in the analysis.A total of 165 differentially methylated positions (DMPs) exhibited differences in DNA methylation by 10% or more between the CDMR and VD groups, many of which were related to the development of the immune system. Based on the targeted bisulfite sequencing assay, 16 genes (16/22, 72.7%) had higher methylation level in the CDMR group than the VD group. Among them, 5 genes were related to the immune system. After considering the estimation of cell type proportions, there was few significant differences in DNA methylation between CDMR and VD groups.The DMPs identified between CDMR and VD groups might be largely explained by the cell type proportions. Further studies are needed to examine DNA methylation in each cell type separately.",
+No,20210416,epigenetics,33758175,Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level.,Nat Commun,"To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.",
+No,20210416,prediction,33752746,DNA methylation biomarker for cumulative lead exposure is associated with Parkinson's disease.,Clin Epigenetics,"Lead, a known neurotoxicant, has previously received attention in Parkinson's disease (PD) research, but epidemiologic studies have been limited in sample size and findings are equivocal. We generated two methylation-based biomarkers for cumulative tibia and patella bone-measured lead exposure in 1528 PD patients and 1169 controls. PD status was associated with increased levels of the DNAm biomarker for tibia-lead levels. We estimated a meta-OR for PD of 1.89 per unit DNAm tibia-lead increase (95% CI 1.59, 2.24; p = 8.1E-13). The current study supports the notion that chronic and long-term lead exposure tracked via DNAm may contribute to PD pathogenesis.",
+No,20210416,epigenetics,33828295,"The structure, function and evolution of a complete human chromosome 8.",Nature,"The complete assembly of each human chromosome is essential for understanding human biology and evolution1,2. Here we use complementary long-read sequencing technologies to complete the linear assembly of human chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08-Mb centromeric α-satellite array, a 644-kb copy number polymorphism in the β-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order α-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confirm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the flanking sequence.",
+No,20210510,dnam age,33903745,Origins of human disease: the chrono-epigenetic perspective.,Nat Rev Genet,"Epigenetics has enriched human disease studies by adding new interpretations to disease features that cannot be explained by genetic and environmental factors. However, identifying causal mechanisms of epigenetic origin has been challenging. New opportunities have risen from recent findings in intra-individual and cyclical epigenetic variation, which includes circadian epigenetic oscillations. Cytosine modifications display deterministic temporal rhythms, which may drive ageing and complex disease. Temporality in the epigenome, or the 'chrono' dimension, may help the integration of epigenetic, environmental and genetic disease studies, and reconcile several disparities stemming from the arbitrarily delimited research fields. The ultimate goal of chrono-epigenetics is to predict disease risk, age of onset and disease dynamics from within individual-specific temporal dynamics of epigenomes.",
+No,20210510,dnam age,33911272,The central role of DNA damage in the ageing process.,Nature,"Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level-for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.",
+No,20210510,dnam age,33926514,Characteristics of epigenetic aging across gestational and perinatal tissues.,Clin Epigenetics,"Epigenetic clocks have been used to indicate differences in biological states between individuals of same chronological age. However, so far, only few studies have examined epigenetic aging in newborns-especially regarding different gestational or perinatal tissues. In this study, we investigated which birth- and pregnancy-related variables are most important in predicting gestational epigenetic age acceleration or deceleration (i.e., the deviation between gestational epigenetic age estimated from the DNA methylome and chronological gestational age) in chorionic villus, placenta and cord blood tissues from two independent study cohorts (ITU, n = 639 and PREDO, n = 966). We further characterized the correspondence of epigenetic age deviations between these tissues.Among the most predictive factors of epigenetic age deviations in single tissues were child sex, birth length, maternal smoking during pregnancy, maternal mental disorders until childbirth, delivery mode and parity. However, the specific factors related to epigenetic age deviation and the direction of association differed across tissues. In individuals with samples available from more than one tissue, relative epigenetic age deviations were not correlated across tissues.Gestational epigenetic age acceleration or deceleration was not related to more favorable or unfavorable factors in one direction in the investigated tissues, and the relative epigenetic age differed between tissues of the same person. This indicates that epigenetic age deviations associate with distinct, tissue specific, factors during the gestational and perinatal period. Our findings suggest that the epigenetic age of the newborn should be seen as a characteristic of a specific tissue, and less as a general characteristic of the child itself.",
+No,20210510,dnam age,33870444,Ageing affects subtelomeric DNA methylation in blood cells from a large European population enrolled in the MARK-AGE study.,Geroscience,"Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated.",
+No,20210510,dnam age,33821798,High social status males experience accelerated epigenetic aging in wild baboons.,Elife,"Aging, for virtually all life, is inescapable. However, within populations, biological aging rates vary. Understanding sources of variation in this process is central to understanding the biodemography of natural populations. We constructed a DNA methylation-based age predictor for an intensively studied wild baboon population in Kenya. Consistent with findings in humans, the resulting 'epigenetic clock' closely tracks chronological age, but individuals are predicted to be somewhat older or younger than their known ages. Surprisingly, these deviations are not explained by the strongest predictors of lifespan in this population, early adversity and social integration. Instead, they are best predicted by male dominance rank: high-ranking males are predicted to be older than their true ages, and epigenetic age tracks changes in rank over time. Our results argue that achieving high rank for male baboons - the best predictor of reproductive success - imposes costs consistent with a 'live fast, die young' life-history strategy.© 2021, Anderson et al.",
+No,20210510,dnam age,33875015,An EPIC predictor of gestational age and its application to newborns conceived by assisted reproductive technologies.,Clin Epigenetics,"Gestational age is a useful proxy for assessing developmental maturity, but correct estimation of gestational age is difficult using clinical measures. DNA methylation at birth has proven to be an accurate predictor of gestational age. Previous predictors of epigenetic gestational age were based on DNA methylation data from the Illumina HumanMethylation 27 K or 450 K array, which have subsequently been replaced by the Illumina MethylationEPIC 850 K array (EPIC). Our aims here were to build an epigenetic gestational age clock specific for the EPIC array and to evaluate its precision and accuracy using the embryo transfer date of newborns from the largest EPIC-derived dataset to date on assisted reproductive technologies (ART).We built an epigenetic gestational age clock using Lasso regression trained on 755 randomly selected non-ART newborns from the Norwegian Study of Assisted Reproductive Technologies (START)-a substudy of the Norwegian Mother, Father, and Child Cohort Study (MoBa). For the ART-conceived newborns, the START dataset had detailed information on the embryo transfer date and the specific ART procedure used for conception. The predicted gestational age was compared to clinically estimated gestational age in 200 non-ART and 838 ART newborns using MM-type robust regression. The performance of the clock was compared to previously published gestational age clocks in an independent replication sample of 148 newborns from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restrictions (PREDO) study-a prospective pregnancy cohort of Finnish women.Our new epigenetic gestational age clock showed higher precision and accuracy in predicting gestational age than previous gestational age clocks (R2 = 0.724, median absolute deviation (MAD) = 3.14 days). Restricting the analysis to CpGs shared between 450 K and EPIC did not reduce the precision of the clock. Furthermore, validating the clock on ART newborns with known embryo transfer date confirmed that DNA methylation is an accurate predictor of gestational age (R2 = 0.767, MAD = 3.7 days).We present the first EPIC-based predictor of gestational age and demonstrate its robustness and precision in ART and non-ART newborns. As more datasets are being generated on the EPIC platform, this clock will be valuable in studies using gestational age to assess neonatal development.",
+No,20210510,epigenetics,33956822,Comparative analysis reveals distinctive epigenetic features of the human cerebellum.,PLoS Genet,"Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution.",
+No,20210510,ewas,33870089,DNA Methylation at Birth is Associated with Childhood Serum Immunoglobulin E Levels.,Epigenet Insights,"Immunoglobulin E (IgE) is known to play an important role in allergic diseases. Epigenetic traits acquired due to modification of deoxyribonucleic acid (DNA) methylation (DNAm) in early life may have phenotypic consequences through their role in transcriptional regulation with relevance to the developmental origins of diseases including allergy. However, epigenome-scale studies on the longitudinal association of cord blood DNAm with IgE over time are lacking. Our study aimed to examine the association of DNAm at birth with childhood serum IgE levels during early life. Genome-scale DNAm and total serum IgE measured at birth, 5, 8, and 11 years of children in the Taiwan Maternal and Infant Cohort Study were included in the study in the discovery stage. Linear mixed models were implemented to assess the association between cord blood DNAm at ~310K 5'-cytosine-phosphate-guanine-3' (CpG) sites with repeated IgE measurements, adjusting for cord blood IgE. Identified statistically significant CpGs (at a false discovery rate, FDR, of 0.05) were further tested in an independent replication cohort, the Isle of Wight (IoW) birth cohort. We mapped replicated CpGs to genes and conducted gene ontology analysis using ToppFun to identify significantly enriched pathways and biological processes of the genes. Cord blood DNAm of 273 CpG sites were significantly (FDR = 0.05) associated with IgE levels longitudinally. Among the identified CpGs available in both cohorts (184 CpGs), 92 CpGs (50%) were replicated in the IoW in terms of consistency in direction of associations between DNA methylation and IgE levels later in life, and 16 of the 92 CpGs showed statistically significant associations (P < .05). Gene ontology analysis identified 4 pathways (FDR = 0.05). The identified 16 CpG sites had the potential to serve as epigenetic markers associated with later IgE production, beneficial to allergic disease prevention and intervention.© The Author(s) 2021.",x
+No,20210510,ewas,33940396,Blood lead levels in Peruvian adults are associated with proximity to mining and DNA methylation.,Environ Int,"Inorganic lead (Pb) is common in the environment, and is toxic to neurological, renal, and cardiovascular systems. Pb exposure influences the epigenome with documented effects on DNA methylation (DNAm). We assessed the impact of low levels of Pb exposure on DNAm among non-miner individuals from two locations in Peru: Lima, the capital, and Cerro de Pasco, a highland mining town, to study the effects of Pb exposure on physiological outcomes and DNAm.Pb levels were measured in whole blood (n = 305). Blood leukocyte DNAm was determined for 90 DNA samples using the Illumina MethylationEPIC chip. An epigenome-wide association study was performed to assess the relationship between Pb and DNAm.Individuals from Cerro de Pasco had higher Pb than individuals from Lima (p-value = 2.00E-16). Males had higher Pb than females (p-value = 2.36E-04). Pb was positively associated with hemoglobin (p-value = 8.60E-04). In Cerro de Pasco, blood Pb decreased with the distance from the mine (p-value = 0.04), and association with soil Pb was approaching significance (p-value = 0.08). We identified differentially methylated positions (DMPs) associated with genes SOX18, ZMIZ1, and KDM1A linked to neurological function. We also found 45 differentially methylated regions (DMRs), seven of which were associated with genes involved in metal ion binding and nine to neurological function and development.Our results demonstrate that even low levels of Pb can have a significant impact on the body including changes to DNAm. We report associations between Pb and hemoglobin, Pb and distance from mining, and between blood and soil Pb. We also report associations between loci- and region-specific DNAm and Pb.Copyright © 2021. Published by Elsevier Ltd.",
+Yes,20210510,ewas,33939316,DNA methylome analysis identifies BMI-related epigenetic changes associated with non-small cell lung cancer susceptibility.,Cancer Med,"Body mass index (BMI) has been reported to be inversely associated with incident risk of non-small cell lung cancer (NSCLC). However, the underlying mechanism is still unclear. This study aimed to investigate the role of DNA methylation in the relationship between BMI and NSCLC.We carried out a genome-wide DNA methylation study of BMI in peripheral blood among 2266 Chinese participants by using Illumina Methylation arrays. For the BMI-related DNA methylation changes, their associations with NSCLC risk were further analyzed and their mediation effects on BMI-NSCLC association were also evaluated.The methylation levels of four CpGs (cg12593793, cg17061862, cg11024682, and cg06500161, annotated to LMNA, ZNF143, SREBF1, and ABCG1, respectively) were found to be significantly associated with BMI. Methylation levels of cg12593793, cg11024682, and cg06500161 were observed to be inversely associated with NSCLC risk [OR (95%CI) =0.22 (0.16, 0.31), 0.39 (0.30, 0.50), and 0.66 (0.53, 0.82), respectively]. Additionally, cg11024682 in SREBF1 and cg06500161 in ABCG1 mediated 45.3% and 19.5% of the association between BMI and decreased NSCLC risk, respectively.In this study, we identified four DNA methylation sites associated with BMI in the Chinese populations at the genome-wide significant level. We also found that the BMI-related methylations of SREBF1 and ABCG1 could mediate about a quintile-to-half of the effect of BMI on reduced NSCLC risk, which adds a potential mechanism underlying this association.© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",
+Yes,20210510,ewas,33931109,Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.,Genome Med,"DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.",
+Yes,20210510,ewas,33902726,Sex-specific DNA methylation differences in Alzheimer's disease pathology.,Acta Neuropathol Commun,"Sex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer's disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation differences in AD neuropathology, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort, we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with the AD Braak stage in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated genes in AD neuropathology, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation differences were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Our study implicated multiple new loci and biological processes that affected AD neuropathology in a sex-specific manner.",
+Yes,20210510,ewas,33890633,DNA methylation patterns within whole blood of adolescents born from assisted reproductive technology are not different from adolescents born from natural conception.,Hum Reprod,"Do the epigenome-wide DNA methylation profiles of adolescents born from ART differ from the epigenome of naturally conceived counterparts?No significant differences in the DNA methylation profiles of adolescents born from ART [IVF or ICSI] were observed when compared to their naturally conceived, similar aged counterparts.Short-term and longer-term studies have investigated the general health outcomes of children born from IVF treatment, albeit without common agreement as to the cause and underlying mechanisms of these adverse health findings. Growing evidence suggests that the reported adverse health outcomes in IVF-born offspring might have underlying epigenetic mechanisms.The Growing Up Healthy Study (GUHS) is a prospective study that recruited 303 adolescents and young adults, conceived through ART, to compare various long-term health outcomes and DNA methylation profiles with similar aged counterparts from Generation 2 from the Raine Study. GUHS assessments were conducted between 2013 and 2017. The effect of ART on DNA methylation levels of 231 adolescents mean age 15.96 ± 1.59 years (52.8% male) was compared to 1188 naturally conceived counterparts, 17.25 ± 0.58 years (50.9% male) from the Raine Study.DNA methylation profiles from a subset of 231 adolescents (13-19.9 years) from the GUHS, generated using the Infinium Methylation Epic Bead Chip (EPIC) array were compared to 1188 profiles from the Raine Study previously measured using the Illumina 450K array. We conducted epigenome-wide association approach (EWAS) and tested for an association between the cohorts applying Firth's bias reduced logistic regression against the outcome of ART versus naturally conceived offspring. Additionally, within the GUHS cohort, we investigated differences in methylation status in fresh versus frozen embryo transfers, cause of infertility as well as IVF versus ICSI conceived offspring. Following the EWAS analysis we investigated nominally significant probes using Gene Set Enrichment Analysis (GSEA) to identify enriched biological pathways. Finally, within GUHS we compared four estimates (Horvath, Hanuum, PhenoAge [Levine], and skin Horvath) of epigenetic age and their correlation with chronological age.Between the two cohorts, we did not identify any DNA methylation probes that reached a Bonferroni corrected P-value < 1.24E-0.7. When comparing IVF versus ICSI conceived adolescents within the GUHS cohort, after adjustment for participant age, sex, maternal smoking, multiple births, and batch effect, three methylation probes (cg15016734, cg26744878 and cg20233073) reached a Bonferroni correction of 6.31E-08. After correcting for cell count heterogeneity, two of the aforementioned probes remained significant and an additional two probes (cg 0331628 and cg 20235051) were identified. A general trend towards hypomethylation in the ICSI offspring was observed. All four measures of epigenetic age were highly correlated with chronological age and showed no evidence of accelerated epigenetic aging within their whole blood.The small sample size coupled with the use of whole blood, where epigenetic differences may occur in other tissue. This was corrected by the utilized statistical method that accounts for imbalanced sample size between groups and adjusting for cell count heterogeneity. Only a small portion of the methylome was analysed and rare individual differences may be missed.Our findings provide further reassurance that the effects of the ART manipulations occurring during early embryogenesis, existing in the neonatal period are indeed of a transient nature and do not persist into adolescence. However, we have not excluded that alternative epigenetic mechanisms may be at play.This project was supported by NHMRC project Grant no. 1042269 and R.J.H. received funding support from Ferring Pharmaceuticals Pty Ltd. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from Merck Sharp & Dohme Corp.- Australia, Merck-Serono Australia Pty Ltd and Ferring Pharmaceuticals Pty Ltd. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. The remaining authors have no conflicts of interest.© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
+Yes,20210510,ewas,33890479,DNA methylation as the link between migration and the major noncommunicable diseases: the RODAM study.,Epigenomics,"Aim:We assessed epigenome-wide DNA methylation (DNAm) differences between migrant and non-migrant Ghanaians.Materials & methods:We used the Illumina Infinium®HumanMethylation450 BeadChip to profile DNAm of 712 Ghanaians in whole blood. We used linear models to detect differentially methylated positions (DMPs) associated with migration. We performed multiple post hoc analyses to validate our findings.Results:We identified 13 DMPs associated with migration (delta-beta values: 0.2-4.5%). Seven DMPs inCPLX2,EIF4E3,MEF2D,TLX3,ST8SIA1,ANGandCHRM3were independent of extrinsic genomic influences in public databases. Two DMPs inNLRC5were associated with duration of stay in Europe among migrants. All DMPs were biologically linked to migration-related factors.Conclusion:Our findings provide the first insights into DNAm differences between migrants and non-migrants.",
+Yes,20210510,ewas,33883019,Epigenome-wide association study of level and change in cognitive abilities from midlife through late life.,Clin Epigenetics,"Epigenetic mechanisms are important in aging and may be involved in late-life changes in cognitive abilities. We conducted an epigenome-wide association study of leukocyte DNA methylation in relation to level and change in cognitive abilities, from midlife through late life in 535 Swedish twins.Methylation levels were measured with the Infinium Human Methylation 450 K or Infinium MethylationEPIC array, and all sites passing quality control on both arrays were selected for analysis (n = 250,816). Empirical Bayes estimates of individual intercept (age 65), linear, and quadratic change were obtained from latent growth curve models of cognitive traits and used as outcomes in linear regression models. Significant sites (p < 2.4 × 10-7) were followed up in between-within twin pair models adjusting for familial confounding and full-growth modeling. We identified six significant associations between DNA methylation and level of cognitive abilities at age 65: cg18064256 (PPP1R13L) with processing speed and spatial ability; cg04549090 (NRXN3) with spatial ability; cg09988380 (POGZ), cg25651129 (-), and cg08011941 (ENTPD8) with working memory. The genes are involved in neuroinflammation, neuropsychiatric disorders, and ATP metabolism. Within-pair associations were approximately half that of between-pair associations across all sites. In full-growth curve models, associations between DNA methylation and cognitive level at age 65 were of small effect sizes, and associations between DNA methylation and longitudinal change in cognitive abilities of very small effect sizes.Leukocyte DNA methylation was associated with level, but not change in cognitive abilities. The associations were substantially attenuated in within-pair analyses, indicating they are influenced in part by genetic factors.",
+Yes,20210510,ewas,33883000,DNA methylation biomarkers of myocardial infarction and cardiovascular disease.,Clin Epigenetics,"The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identified biomarkers is still limited. We aimed to identify differentially methylated loci associated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers.We designed a case-control, two-stage, epigenome-wide association study on AMI (ndiscovery = 391, nvalidation = 204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. We performed a fixed-effects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n ~ 1800 and n ~ 2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infinium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic influence and therefore the results were not conclusive.We have identified 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.",
+Yes,20210510,ewas,33872906,Effect of prenatal exposure to phthalates on epigenome-wide DNA methylations in cord blood and implications for fetal growth: The Hokkaido Study on Environment and Children's Health.,Sci Total Environ,"Prenatal exposure to phthalates negatively affects the offspring's health. In particular, epigenetic alterations, such as DNA methylation, may connect phthalate exposure with health outcomes. Here, we evaluated the association of di-2-ethylhexyl phthalate (DEHP) exposure in utero with cord blood epigenome-wide DNA methylation in 203 mother-child pairs enrolled in the Hokkaido Study on Environment and Children's Health, using the Illumina HumanMethylation450 BeadChip. Epigenome-wide association analysis demonstrated the predominant positive associations between the levels of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), in maternal blood and DNA methylation levels in cord blood. The genes annotated to the CpGs positively associated with MEHP levels were enriched for pathways related to metabolism, the endocrine system, and signal transduction. Among them, methylation levels of CpGs involved in metabolism were inversely associated with the offspring's ponderal index (PI). Further, clustering and mediation analyses suggested that multiple increased methylation changes may jointly mediate the association of DEHP exposure in utero with the offspring's PI at birth. Although further studies are required to assess the impact of these changes, this study suggests that differential DNA methylation may link phthalate exposure in utero to fetal growth and further imply that DNA methylation has predictive value for the offspring's obesity.Copyright © 2021. Published by Elsevier B.V.",
+Yes,20210510,ewas,33867313,Epigenome-wide association study of COVID-19 severity with respiratory failure.,EBioMedicine,"Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities.Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients.The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease.We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2.The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.",
+Yes,20210510,ewas,33862401,Residential surrounding greenness and DNA methylation: An epigenome-wide association study.,Environ Int,"DNA methylation is a potential biological mechanism through which residential greenness affects health, but little is known about its association with greenness and whether the association could be modified by genetic background. We aimed to evaluate the association between surrounding greenness and genome-wide DNA methylation and potential gene-greenness interaction effects on DNA methylation.We measured blood-derived DNA methylation using the HumanMethylation450 BeadChip array (Illumina) for 479 Australian women, including 66 monozygotic, 66 dizygotic twin pairs, and 215 sisters of these twins. Surrounding greenness was represented by Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI) within 300, 500, 1000 or 2000 m surrounding participants' home addresses. For each cytosine-guanine dinucleotide (CpG), the associations between its methylation level and NDVI or EVI were evaluated by generalized estimating equations, after adjusting for age, education, marital status, area-level socioeconomic status, smoking behavior, cell-type proportions, and familial clustering. We used comb-p and DMRcate to identify significant differentially methylated regions (DMRs). For each significant CpG, we evaluated the interaction effects of greenness and single-nucleotide polymorphisms (SNPs) within ±1 Mb window on its methylation level.We found associations between surrounding greenness and blood DNA methylation for one CpG (cg04720477, mapped to the promoter region of CNP gene) with false discovery rate [FDR] < 0.05, and for another 9 CpGs with 0.05 ≤ FDR < 0.10. For two of these CpGs, we found 33 SNPs significantly (FDR < 0.05) modified the greenness-methylation association. There were 35 significant DMRs related to surrounding greenness that were identified by both comb-p (Sidak p-value < 0.01) and DMRcate (FDR < 0.01). Those CpGs and DMRs were mapped to genes related to many human diseases, such as mental health disorders and neoplasms as well as nutritional and metabolic diseases.Surrounding greenness was associated with blood DNA methylation of many loci across human genome, and this association could be modified by genetic variations.Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.",
+No,20210510,dnam age,33926538,"Associations of circulating folate, vitamin B12 and homocysteine concentrations in early pregnancy and cord blood with epigenetic gestational age: the Generation R Study.",Clin Epigenetics,"Circulating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration.Up to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin's training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin's method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight's training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(- 0.16 weeks, 95% CI - 0.30, - 0.02) and (- 0.15 weeks, 95% CI - 0.29, - 0.01), respectively] by Knight's method.We found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.",
+No,20210510,meqtls,33931130,Genetic impacts on DNA methylation: research findings and future perspectives.,Genome Biol,"Multiple recent studies highlight that genetic variants can have strong impacts on a significant proportion of the human DNA methylome. Methylation quantitative trait loci, or meQTLs, allow for the exploration of biological mechanisms that underlie complex human phenotypes, with potential insights for human disease onset and progression. In this review, we summarize recent milestones in characterizing the human genetic basis of DNA methylation variation over the last decade, including heritability findings and genome-wide identification of meQTLs. We also discuss challenges in this field and future areas of research geared to generate insights into molecular processes underlying human complex traits.",
+No,20210510,methods,33926513,Estimands in epigenome-wide association studies.,Clin Epigenetics,"In DNA methylation analyses like epigenome-wide association studies, effects in differentially methylated CpG sites are assessed. Two kinds of outcomes can be used for statistical analysis: Beta-values and M-values. M-values follow a normal distribution and help to detect differentially methylated CpG sites. As biological effect measures, differences of M-values are more or less meaningless. Beta-values are of more interest since they can be interpreted directly as differences in percentage of DNA methylation at a given CpG site, but they have poor statistical properties. Different frameworks are proposed for reporting estimands in DNA methylation analysis, relying on Beta-values, M-values, or both.We present and discuss four possible approaches of achieving estimands in DNA methylation analysis. In addition, we present the usage of M-values or Beta-values in the context of bioinformatical pipelines, which often demand a predefined outcome. We show the dependencies between the differences in M-values to differences in Beta-values in two data simulations: a analysis with and without confounder effect. Without present confounder effects, M-values can be used for the statistical analysis and Beta-values statistics for the reporting. If confounder effects exist, we demonstrate the deviations and correct the effects by the intercept method. Finally, we demonstrate the theoretical problem on two large human genome-wide DNA methylation datasets to verify the results.The usage of M-values in the analysis of DNA methylation data will produce effect estimates, which cannot be biologically interpreted. The parallel usage of Beta-value statistics ignores possible confounder effects and can therefore not be recommended. Hence, if the differences in Beta-values are the focus of the study, the intercept method is recommendable. Hyper- or hypomethylated CpG sites must then be carefully evaluated. If an exploratory analysis of possible CpG sites is the aim of the study, M-values can be used for inference.",x
+No,20210510,review,33895575,Air pollution and DNA methylation in adults: A systematic review and meta-analysis of observational studies.,Environ Pollut,"This systematic review and meta-analysis aimed to investigate the association between air pollution and DNA methylation in adults from published observational studies. PubMed, Web of Science and Embase databases were systematically searched for available studies on the association between air pollution and DNA methylation published up to March 9, 2021. Three DNA methylation approaches were considered: global methylation, candidate-gene, and epigenome-wide association studies (EWAS). Meta-analysis was used to summarize the combined estimates for the association between air pollutants and global DNA methylation levels. Heterogeneity was assessed with the Cochran Q test and quantified with the I2statistic. In total, 38 articles were included in this study: 16 using global methylation, 18 using candidate genes, and 11 using EWAS, with 7 studies using more than one approach. Meta-analysis revealed an imprecise but inverse association between exposure to PM2.5and global DNA methylation (for each 10-μg/m3PM2.5, combined estimate: 0.39; 95% confidence interval: 0.97 - 0.19). The candidate-gene results were consistent for the ERCC3 and SOX2 genes, suggesting hypermethylation in ERCC3 associated with benzene and that in SOX2 associated with PM2.5exposure. EWAS identified 201 CpG sites and 148 differentially methylated regions that showed differential methylation associated with air pollution. Among the 307 genes investigated in 11 EWAS, a locus in nucleoredoxin gene was found to be positively associated with PM2.5in two studies. Current meta-analysis indicates that PM2.5is imprecisely and inversely associated with DNA methylation. The candidate-gene results consistently suggest hypermethylation in ERCC3 associated with benzene exposure and that in SOX2 associated with PM2.5exposure. The Kyoto Encyclopedia of Genes and Genomes (KEGG) network analyses revealed that these genes were associated with African trypanosomiasis, Malaria, Antifolate resistance, Graft-versus-host disease, and so on. More evidence is needed to clarify the association between air pollution and DNA methylation.Copyright © 2021 Elsevier Ltd. All rights reserved.",x
+Yes,20210510,variance,33937763,Human methylome variation across Infinium 450K data on the Gene Expression Omnibus.,NAR Genom Bioinform,"While DNA methylation (DNAm) is the most-studied epigenetic mark, few recent studies probe the breadth of publicly available DNAm array samples. We collectively analyzed 35 360 Illumina Infinium HumanMethylation450K DNAm array samples published on the Gene Expression Omnibus. We learned a controlled vocabulary of sample labels by applying regular expressions to metadata and used existing models to predict various sample properties including epigenetic age. We found approximately two-thirds of samples were from blood, one-quarter were from brain and one-third were from cancer patients. About 19% of samples failed at least one of Illumina's 17 prescribed quality assessments; signal distributions across samples suggest modifying manufacturer-recommended thresholds for failure would make these assessments more informative. We further analyzed DNAm variances in seven tissues (adipose, nasal, blood, brain, buccal, sperm and liver) and characterized specific probes distinguishing them. Finally, we compiled DNAm array data and metadata, including our learned and predicted sample labels, into database files accessible via the recountmethylation R/Bioconductor companion package. Its vignettes walk the user through some analyses contained in this paper.© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
+No,20210607,aging,33813140,Clinical biomarkers and associations with healthspan and lifespan: Evidence from observational and genetic data,EBioMedicine,"Background: Biomarker-disease relationships are extensively investigated. However, associations between common clinical biomarkers and healthspan, the disease-free lifespan, are largely unknown. We aimed to explore the predictive values of ten biomarkers on healthspan and lifespan, and to identify putative causal mechanisms.
 
 Methods: Using data from 12,098 Swedish individuals aged 47-94 years, we examined both serum concentrations and genetically predicted levels of ten glycemic, lipid-, inflammatory, and hematological biomarkers. During a follow-up period of up to 16 years, 3681 incident cases of any chronic disease (i.e., end of healthspan) and 2674 deaths (i.e., end of lifespan) were documented. Cox regression models were applied to estimate the associations of a one standard deviation increase in biomarkers with healthspan and lifespan.
 
 Findings: Seven out of ten serum biomarkers were significantly associated with risks of any chronic disease and death; elevated glycemic biomarkers and high-density lipoprotein-related biomarkers showed the strongest detrimental (hazard ratio [HR] 1·29 [95% CI 1·24-1·34]) and protective effects (HR 0·92 [95% CI 0·89-0·96]), respectively. Genetic predisposition to elevated fasting blood glucose (FBG) was associated with increased risks of any chronic disease (HR 1·05 [95% CI 1·02-1·09]); genetically determined higher C-reactive protein correlated with lower death risks (HR 0·91 [95% CI 0·87-0·95]). Notably, the genetically proxied FBG-healthspan association was largely explained by serum FBG concentration.
 
 Interpretation: Circulating concentrations of glycemic, lipid-, and inflammatory biomarkers are predictive of healthspan and lifespan. Glucose control is a putative causal mechanism and a potential intervention target for healthspan maintenance.",
-,No,20210607,aging,33982659,Sex differences in biological aging with a focus on human studies.,Elife,"Aging is a complex biological process characterized by hallmark features accumulating over the life course, shaping the individual's aging trajectory and subsequent disease risks. There is substantial individual variability in the aging process between men and women. In general, women live longer than men, consistent with lower biological ages as assessed by molecular biomarkers, but there is a paradox. Women are frailer and have worse health at the end of life, while men still perform better in physical function examinations. Moreover, many age-related diseases show sex-specific patterns. In this review, we aim to summarize the current knowledge on sexual dimorphism in human studies, with support from animal research, on biological aging and illnesses. We also attempt to place it in the context of the theories of aging, as well as discuss the explanations for the sex differences, for example, the sex-chromosome linked mechanisms and hormonally driven differences.© 2021, Hägg and Jylhävä.",
-,No,20210607,dnam age,34001218,Blood and skeletal muscle ageing determined by epigenetic clocks and their associations with physical activity and functioning.,Clin Epigenetics,"The aim of this study was to investigate the correspondence of different biological ageing estimates (i.e. epigenetic age) in blood and muscle tissue and their associations with physical activity (PA), physical function and body composition. Two independent cohorts (N = 139 and N = 47) were included, whose age span covered adulthood (23-69 years). Whole blood and m. vastus lateralis samples were collected, and DNA methylation was analysed. Four different DNA methylation age (DNAmAge) estimates were calculated using genome-wide methylation data and publicly available online tools. A novel muscle-specific methylation age was estimated using the R-package 'MEAT'. PA was measured with questionnaires and accelerometers. Several tests were conducted to estimate cardiorespiratory fitness and muscle strength. Body composition was estimated by dual-energy X-ray absorptiometry. DNAmAge estimates from blood and muscle were highly correlated with chronological age, but different age acceleration estimates were weakly associated with each other. The monozygotic twin within-pair similarity of ageing pace was higher in blood (r = 0.617-0.824) than in muscle (r = 0.523-0.585). Associations of age acceleration estimates with PA, physical function and body composition were weak in both tissues and mostly explained by smoking and sex. The muscle-specific epigenetic clock MEAT was developed to predict chronological age, which may explain why it did not associate with functional phenotypes. The Horvath's clock and GrimAge were weakly associated with PA and related phenotypes, suggesting that higher PA would be linked to accelerated biological ageing in muscle. This may, however, be more reflective of the low capacity of epigenetic clock algorithms to measure functional muscle ageing than of actual age acceleration. Based on our results, the investigated epigenetic clocks have rather low value in estimating muscle ageing with respect to the physiological adaptations that typically occur due to ageing or PA. Thus, further development of methods is needed to gain insight into muscle tissue-specific ageing and the underlying biological pathways.",
-,No,20210607,epigenetics,34050148,Impact of DNA methylation on 3D genome structure.,Nat Commun,"Determining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases in Saccharomyces cerevisiae and analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5' end of the gene increasing gradually toward the 3' end, with concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites respectively, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.",
-,Yes,20210607,ewas,34034806,Blood DNA methylation and COVID-19 outcomes.,Clin Epigenetics,"There are no prior reports that compare differentially methylated regions of DNA in blood samples from COVID-19 patients to samples collected before the SARS-CoV-2 pandemic using a shared epigenotyping platform. We performed a genome-wide analysis of circulating blood DNA CpG methylation using the Infinium Human MethylationEPIC BeadChip on 124 blood samples from hospitalized COVID-19-positive and COVID-19-negative patients and compared these data with previously reported data from 39 healthy individuals collected before the pandemic. Prospective outcome measures such as COVID-19-GRAM risk-score and mortality were combined with methylation data.Global mean methylation levels did not differ between COVID-19 patients and healthy pre-pandemic controls. About 75% of acute illness-associated differentially methylated regions were located near gene promoter regions and were hypo-methylated in comparison with healthy pre-pandemic controls. Gene ontology analyses revealed terms associated with the immune response to viral infections and leukocyte activation; and disease ontology analyses revealed a predominance of autoimmune disorders. Among COVID-19-positive patients, worse outcomes were associated with a prevailing hyper-methylated status. Recursive feature elimination identified 77 differentially methylated positions predictive of COVID-19 severity measured by the GRAM-risk score.Our data contribute to the awareness that DNA methylation may influence the expression of genes that regulate COVID-19 progression and represent a targetable process in that setting.",
-,Yes,20210607,ewas,34008478,Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood.,Epigenetics,"DNA methylation markers have been associated with lung cancer risk and may identify aetiologically relevant genomic regions, or alternatively, be markers of disease risk factors or biological processes associated with disease development.In a nested case-control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 participants (208 cases; 222 controls) in the 1989 CLUE II cohort. We compared DNA methylation levels with case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years-based smoking methylation score. Stratification analyses were conducted over time from blood draw to diagnosis, histology, and smoking status.We identified 16 single CpG sites and 40 DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes including H19, HOXA3/HOXA4, RUNX3, BRICD5, PLXNB2, and RP13. For the single CpG sites, the strongest association was noted for cg09736286 in the DIABLO gene (OR [for 1 SD] = 2.99, 95% CI: 1.95-4.59, P-value = 4.81 × 10-7). We found that CpG sites in the HOXA3/HOXA4 region were hypermethylated in cases compared to controls.The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing potential biomarkers for lung cancer risk stratification. Future studies will need to examine whether these regions are causally related to lung cancer.",
-,Yes,20210607,ewas,33993705,Genome-wide associations between alcohol consumption and blood DNA methylation: evidence from twin study.,Epigenomics,"Aim:Alcohol intake alters DNA methylation profiles and methylation might mediate the association between alcohol and disease, but limited number of positive CpG sites repeatedly replicated.Materials & methods:In total, 57 monozygotic (MZ) twin pairs discordant for alcohol drinking from the Chinese National Twin Registry and 158 MZ and dizygotic twin pairs in the Swedish Adoption/Twin Study of Aging were evaluated. DNA methylation was detected using the Infinium HumanMethylation450 BeadChip.Results:Among candidate CpG sites, cg07326074 was significantly correlated with drinking after adjusting for covariates in MZ twins in both datasets but not in the entire sample or dizygotic twins.Conclusion:The hypermethylation of cg07326074, located in the tumor-promoting geneC16orf59, was associated with alcohol consumption.",
-,Yes,20210607,ewas,33990564,Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.,Nat Commun,"Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1Ă—10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0Ă—10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.",
-,Yes,20210607,ewas,33980183,Genome-wide analysis of DNA methylation and risk of cardiovascular disease in a Chinese population.,BMC Cardiovasc Disord,"Systemic studies of association of genome-wide DNA methylated sites with cardiovascular disease (CVD) in prospective cohorts are lacking. Our aim was to identify DNA methylation sites associated with the risk of CVD and further investigate their potential predictive value in CVD development for high-risk subjects.We performed an epigenome-wide association study (EWAS) to identify CpGs related to CVD development in a Chinese population.We adopted a nested case-control design based on data from China PEACE Million Persons Project. A total of 83 cases who developed CVD events during follow-up and 83 controls who were matched with cases by age, sex, BMI, ethnicity, medications treatment and behavior risk factors were included in the discovery stage. Genome-wide DNA methylation from whole blood was detected using Infinium Human Methylation EPIC Beadchip (850 K). For significant CpGs [FDR(false discovery rate) < 0.005], we further validated in an independent cohort including 38 cases and 38 controls.In discovery set, we identified 8 significant CpGs (FDR < 0.005) associated with the risk of CVD after adjustment for cell components, demographic and cardiac risk factors and the first 5 principal components. Two of these identified CpGs (cg06901278 and cg09306458 in UACA) were replicated in another independent set (p < 0.05). Enrichment analysis in 787 individual genes from 1036 CpGs in discovery set revealed a significant enrichment for anatomical structure homeostasis as well as regulation of vesicle-mediated transport. Receiver operating characteristic (ROC) analysis showed that the model combined 8 CVD-related CpGs with baseline characteristics showed much better predictive effect for CVD occurrence compared with the model with baseline characteristics only [AUC (area under the curve) = 0.967, 95% CI (0.942 - 0.991); AUC = 0.621, 95% CI (0.536 - 0.706); p = 9.716E-15].Our study identified the novel CpGs associated with CVD development and revealed their additional predictive power in the risk of CVD for high-risk subjects.",
-,Yes,20210607,ewas,33964519,Differential DNA Methylation is associated with Hippocampal Abnormalities in Pediatric Posttraumatic Stress Disorder.,Biol Psychiatry Cogn Neurosci Neuroimaging,"Recent findings in neuroimaging and epigenetics offer important insights into brain structures and biological pathways of altered gene expression associated with posttraumatic stress disorder (PTSD). However, it is unknown to what extent epigenetic mechanisms are associated with PTSD and its neurobiology in youth.In this study we combined a methylome-wide association study and structural neuroimaging measures in a Dutch cohort of youth with PTSD (ages 8-18 years). We aimed to replicate findings in a similar independent American cohort.We found significant methylome-wide associations for pediatric PTSD (FDR p <0.05) compared to non-PTSD control groups (traumatized and non-traumatized youth). Methylation differences on 9 genes were replicated, including genes related to glucocorticoid functioning. In both cohorts, methylation on OLFM3 gene was further associated with anterior hippocampal volume.These findings point to molecular pathways involved in inflammation, stress response, and neuroplasticity as potential contributors to neural abnormalities and provide potentially unique biomarkers and treatment targets for pediatric PTSD.Copyright © 2021. Published by Elsevier Inc.",
-,Yes,20210607,ewas,34044884,A cross-cohort analysis of autosomal DNA methylation sex differences in the term placenta.,Biol Sex Differ,"Human placental DNA methylation (DNAme) data is a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation. Here, we present an analysis of sex differences in autosomal DNAme in the uncomplicated term placenta (n = 343) using the Illumina 450K array.At a false discovery rate < 0.05 and a mean sex difference in DNAme beta value of > 0.10, we identified 162 autosomal CpG sites that were differentially methylated by sex and replicated in an independent cohort of samples (n = 293). Several of these differentially methylated CpG sites were part of larger correlated regions of sex differential DNAme. Although global DNAme levels did not differ by sex, the majority of significantly differentially methylated CpGs were more highly methylated in male placentae, the opposite of what is seen in differential methylation analyses of somatic tissues. Patterns of autosomal DNAme at these 162 CpGs were significantly associated with maternal age (in males) and newborn birthweight standard deviation (in females).Our results provide a comprehensive analysis of sex differences in autosomal DNAme in the term human placenta. We report a list of high-confidence autosomal sex-associated differentially methylated CpGs and identify several key features of these loci that suggest their relevance to sex differences observed in normative and complicated pregnancies.",
-,Yes,20210607,ewas,33867313,Epigenome-wide association study of COVID-19 severity with respiratory failure.,EBioMedicine,"Background: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities.
+No,20210607,aging,33982659,Sex differences in biological aging with a focus on human studies.,Elife,"Aging is a complex biological process characterized by hallmark features accumulating over the life course, shaping the individual's aging trajectory and subsequent disease risks. There is substantial individual variability in the aging process between men and women. In general, women live longer than men, consistent with lower biological ages as assessed by molecular biomarkers, but there is a paradox. Women are frailer and have worse health at the end of life, while men still perform better in physical function examinations. Moreover, many age-related diseases show sex-specific patterns. In this review, we aim to summarize the current knowledge on sexual dimorphism in human studies, with support from animal research, on biological aging and illnesses. We also attempt to place it in the context of the theories of aging, as well as discuss the explanations for the sex differences, for example, the sex-chromosome linked mechanisms and hormonally driven differences.© 2021, Hägg and Jylhävä.",
+No,20210607,dnam age,34001218,Blood and skeletal muscle ageing determined by epigenetic clocks and their associations with physical activity and functioning.,Clin Epigenetics,"The aim of this study was to investigate the correspondence of different biological ageing estimates (i.e. epigenetic age) in blood and muscle tissue and their associations with physical activity (PA), physical function and body composition. Two independent cohorts (N = 139 and N = 47) were included, whose age span covered adulthood (23-69 years). Whole blood and m. vastus lateralis samples were collected, and DNA methylation was analysed. Four different DNA methylation age (DNAmAge) estimates were calculated using genome-wide methylation data and publicly available online tools. A novel muscle-specific methylation age was estimated using the R-package 'MEAT'. PA was measured with questionnaires and accelerometers. Several tests were conducted to estimate cardiorespiratory fitness and muscle strength. Body composition was estimated by dual-energy X-ray absorptiometry. DNAmAge estimates from blood and muscle were highly correlated with chronological age, but different age acceleration estimates were weakly associated with each other. The monozygotic twin within-pair similarity of ageing pace was higher in blood (r = 0.617-0.824) than in muscle (r = 0.523-0.585). Associations of age acceleration estimates with PA, physical function and body composition were weak in both tissues and mostly explained by smoking and sex. The muscle-specific epigenetic clock MEAT was developed to predict chronological age, which may explain why it did not associate with functional phenotypes. The Horvath's clock and GrimAge were weakly associated with PA and related phenotypes, suggesting that higher PA would be linked to accelerated biological ageing in muscle. This may, however, be more reflective of the low capacity of epigenetic clock algorithms to measure functional muscle ageing than of actual age acceleration. Based on our results, the investigated epigenetic clocks have rather low value in estimating muscle ageing with respect to the physiological adaptations that typically occur due to ageing or PA. Thus, further development of methods is needed to gain insight into muscle tissue-specific ageing and the underlying biological pathways.",
+No,20210607,epigenetics,34050148,Impact of DNA methylation on 3D genome structure.,Nat Commun,"Determining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases in Saccharomyces cerevisiae and analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5' end of the gene increasing gradually toward the 3' end, with concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites respectively, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.",
+Yes,20210607,ewas,34034806,Blood DNA methylation and COVID-19 outcomes.,Clin Epigenetics,"There are no prior reports that compare differentially methylated regions of DNA in blood samples from COVID-19 patients to samples collected before the SARS-CoV-2 pandemic using a shared epigenotyping platform. We performed a genome-wide analysis of circulating blood DNA CpG methylation using the Infinium Human MethylationEPIC BeadChip on 124 blood samples from hospitalized COVID-19-positive and COVID-19-negative patients and compared these data with previously reported data from 39 healthy individuals collected before the pandemic. Prospective outcome measures such as COVID-19-GRAM risk-score and mortality were combined with methylation data.Global mean methylation levels did not differ between COVID-19 patients and healthy pre-pandemic controls. About 75% of acute illness-associated differentially methylated regions were located near gene promoter regions and were hypo-methylated in comparison with healthy pre-pandemic controls. Gene ontology analyses revealed terms associated with the immune response to viral infections and leukocyte activation; and disease ontology analyses revealed a predominance of autoimmune disorders. Among COVID-19-positive patients, worse outcomes were associated with a prevailing hyper-methylated status. Recursive feature elimination identified 77 differentially methylated positions predictive of COVID-19 severity measured by the GRAM-risk score.Our data contribute to the awareness that DNA methylation may influence the expression of genes that regulate COVID-19 progression and represent a targetable process in that setting.",
+Yes,20210607,ewas,34008478,Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood.,Epigenetics,"DNA methylation markers have been associated with lung cancer risk and may identify aetiologically relevant genomic regions, or alternatively, be markers of disease risk factors or biological processes associated with disease development.In a nested case-control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 participants (208 cases; 222 controls) in the 1989 CLUE II cohort. We compared DNA methylation levels with case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years-based smoking methylation score. Stratification analyses were conducted over time from blood draw to diagnosis, histology, and smoking status.We identified 16 single CpG sites and 40 DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes including H19, HOXA3/HOXA4, RUNX3, BRICD5, PLXNB2, and RP13. For the single CpG sites, the strongest association was noted for cg09736286 in the DIABLO gene (OR [for 1 SD] = 2.99, 95% CI: 1.95-4.59, P-value = 4.81 × 10-7). We found that CpG sites in the HOXA3/HOXA4 region were hypermethylated in cases compared to controls.The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing potential biomarkers for lung cancer risk stratification. Future studies will need to examine whether these regions are causally related to lung cancer.",
+Yes,20210607,ewas,33993705,Genome-wide associations between alcohol consumption and blood DNA methylation: evidence from twin study.,Epigenomics,"Aim:Alcohol intake alters DNA methylation profiles and methylation might mediate the association between alcohol and disease, but limited number of positive CpG sites repeatedly replicated.Materials & methods:In total, 57 monozygotic (MZ) twin pairs discordant for alcohol drinking from the Chinese National Twin Registry and 158 MZ and dizygotic twin pairs in the Swedish Adoption/Twin Study of Aging were evaluated. DNA methylation was detected using the Infinium HumanMethylation450 BeadChip.Results:Among candidate CpG sites, cg07326074 was significantly correlated with drinking after adjusting for covariates in MZ twins in both datasets but not in the entire sample or dizygotic twins.Conclusion:The hypermethylation of cg07326074, located in the tumor-promoting geneC16orf59, was associated with alcohol consumption.",
+Yes,20210607,ewas,33990564,Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.,Nat Commun,"Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1Ă—10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0Ă—10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.",
+Yes,20210607,ewas,33980183,Genome-wide analysis of DNA methylation and risk of cardiovascular disease in a Chinese population.,BMC Cardiovasc Disord,"Systemic studies of association of genome-wide DNA methylated sites with cardiovascular disease (CVD) in prospective cohorts are lacking. Our aim was to identify DNA methylation sites associated with the risk of CVD and further investigate their potential predictive value in CVD development for high-risk subjects.We performed an epigenome-wide association study (EWAS) to identify CpGs related to CVD development in a Chinese population.We adopted a nested case-control design based on data from China PEACE Million Persons Project. A total of 83 cases who developed CVD events during follow-up and 83 controls who were matched with cases by age, sex, BMI, ethnicity, medications treatment and behavior risk factors were included in the discovery stage. Genome-wide DNA methylation from whole blood was detected using Infinium Human Methylation EPIC Beadchip (850 K). For significant CpGs [FDR(false discovery rate) < 0.005], we further validated in an independent cohort including 38 cases and 38 controls.In discovery set, we identified 8 significant CpGs (FDR < 0.005) associated with the risk of CVD after adjustment for cell components, demographic and cardiac risk factors and the first 5 principal components. Two of these identified CpGs (cg06901278 and cg09306458 in UACA) were replicated in another independent set (p < 0.05). Enrichment analysis in 787 individual genes from 1036 CpGs in discovery set revealed a significant enrichment for anatomical structure homeostasis as well as regulation of vesicle-mediated transport. Receiver operating characteristic (ROC) analysis showed that the model combined 8 CVD-related CpGs with baseline characteristics showed much better predictive effect for CVD occurrence compared with the model with baseline characteristics only [AUC (area under the curve) = 0.967, 95% CI (0.942 - 0.991); AUC = 0.621, 95% CI (0.536 - 0.706); p = 9.716E-15].Our study identified the novel CpGs associated with CVD development and revealed their additional predictive power in the risk of CVD for high-risk subjects.",
+Yes,20210607,ewas,33964519,Differential DNA Methylation is associated with Hippocampal Abnormalities in Pediatric Posttraumatic Stress Disorder.,Biol Psychiatry Cogn Neurosci Neuroimaging,"Recent findings in neuroimaging and epigenetics offer important insights into brain structures and biological pathways of altered gene expression associated with posttraumatic stress disorder (PTSD). However, it is unknown to what extent epigenetic mechanisms are associated with PTSD and its neurobiology in youth.In this study we combined a methylome-wide association study and structural neuroimaging measures in a Dutch cohort of youth with PTSD (ages 8-18 years). We aimed to replicate findings in a similar independent American cohort.We found significant methylome-wide associations for pediatric PTSD (FDR p <0.05) compared to non-PTSD control groups (traumatized and non-traumatized youth). Methylation differences on 9 genes were replicated, including genes related to glucocorticoid functioning. In both cohorts, methylation on OLFM3 gene was further associated with anterior hippocampal volume.These findings point to molecular pathways involved in inflammation, stress response, and neuroplasticity as potential contributors to neural abnormalities and provide potentially unique biomarkers and treatment targets for pediatric PTSD.Copyright © 2021. Published by Elsevier Inc.",
+Yes,20210607,ewas,34044884,A cross-cohort analysis of autosomal DNA methylation sex differences in the term placenta.,Biol Sex Differ,"Human placental DNA methylation (DNAme) data is a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation. Here, we present an analysis of sex differences in autosomal DNAme in the uncomplicated term placenta (n = 343) using the Illumina 450K array.At a false discovery rate < 0.05 and a mean sex difference in DNAme beta value of > 0.10, we identified 162 autosomal CpG sites that were differentially methylated by sex and replicated in an independent cohort of samples (n = 293). Several of these differentially methylated CpG sites were part of larger correlated regions of sex differential DNAme. Although global DNAme levels did not differ by sex, the majority of significantly differentially methylated CpGs were more highly methylated in male placentae, the opposite of what is seen in differential methylation analyses of somatic tissues. Patterns of autosomal DNAme at these 162 CpGs were significantly associated with maternal age (in males) and newborn birthweight standard deviation (in females).Our results provide a comprehensive analysis of sex differences in autosomal DNAme in the term human placenta. We report a list of high-confidence autosomal sex-associated differentially methylated CpGs and identify several key features of these loci that suggest their relevance to sex differences observed in normative and complicated pregnancies.",
+Yes,20210607,ewas,33867313,Epigenome-wide association study of COVID-19 severity with respiratory failure.,EBioMedicine,"Background: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities.
 
 Methods: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ? 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients.
 
 Findings: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease.
 
 Interpretation: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2.",
-,No,20210607,methods,33957961,Tejaas: reverse regression increases power for detecting trans-eQTLs.,Genome Biol,"Trans-acting expression quantitative trait loci (trans-eQTLs) account for ≥70% expression heritability and could therefore facilitate uncovering mechanisms underlying the origination of complex diseases. Identifying trans-eQTLs is challenging because of small effect sizes, tissue specificity, and a severe multiple-testing burden. Tejaas predicts trans-eQTLs by performing L2-regularized ""reverse"" multiple regression of each SNP on all genes, aggregating evidence from many small trans-effects while being unaffected by the strong expression correlations. Combined with a novel unsupervised k-nearest neighbor method to remove confounders, Tejaas predicts 18851 unique trans-eQTLs across 49 tissues from GTEx. They are enriched in open chromatin, enhancers, and other regulatory regions. Many overlap with disease-associated SNPs, pointing to tissue-specific transcriptional regulation mechanisms.",
-,No,20210607,methods,34020542,Interpretation of deep learning in genomics and epigenomics.,Brief Bioinform,"Machine learning methods have been widely applied to big data analysis in genomics and epigenomics research. Although accuracy and efficiency are common goals in many modeling tasks, model interpretability is especially important to these studies towards understanding the underlying molecular and cellular mechanisms. Deep neural networks (DNNs) have recently gained popularity in various types of genomic and epigenomic studies due to their capabilities in utilizing large-scale high-throughput bioinformatics data and achieving high accuracy in predictions and classifications. However, DNNs are often challenged by their potential to explain the predictions due to their black-box nature. In this review, we present current development in the model interpretation of DNNs, focusing on their applications in genomics and epigenomics. We first describe state-of-the-art DNN interpretation methods in representative machine learning fields. We then summarize the DNN interpretation methods in recent studies on genomics and epigenomics, focusing on current data- and computing-intensive topics such as sequence motif identification, genetic variations, gene expression, chromatin interactions and non-coding RNAs. We also present the biological discoveries that resulted from these interpretation methods. We finally discuss the advantages and limitations of current interpretation approaches in the context of genomic and epigenomic studies. Contact:xiaoman@mail.ucf.edu, haihu@cs.ucf.edu.© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,No,20210607,methods,33975646,On the optimistic performance evaluation of newly introduced bioinformatic methods.,Genome Biol,"Most research articles presenting new data analysis methods claim that ""the new method performs better than existing methods,"" but the veracity of such statements is questionable. Our manuscript discusses and illustrates consequences of the optimistic bias occurring during the evaluation of novel data analysis methods, that is, all biases resulting from, for example, selection of datasets or competing methods, better ability to fix bugs in a preferred method, and selective reporting of method variants. We quantitatively investigate this bias using an example from epigenetic analysis: normalization methods for data generated by the Illumina HumanMethylation450K BeadChip microarray.",
-,Yes,20210607,omics,33958779,Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.,Nat Genet,"The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.",
-,No,20210607,pwas,34045743,Human plasma proteomic profiles indicative of cardiorespiratory fitness.,Nat Metab,"Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans.",
-,No,20210607,pwas,34016094,Metabolic syndrome and the plasma proteome: from association to causation.,Cardiovasc Diabetol,"The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering.Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization.Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71-0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = - 0.12, Wald-p = 3.63e-13), apolipoprotein B (APOB) (Wald-Ratio = - 0.09, Wald-p = 2.54e-04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e-04).Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.",
-,No,20210607,pwas,33969320,"Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions.",Cell Rep Med,"Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.© 2021 The Authors.",
-,No,20210607,single cell,34012112,Interpreting type 1 diabetes risk with genetics and single-cell epigenomics.,Nature,"Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding1. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types2. Here we combined two approaches: a genome-wide association study of type 1 diabetes (T1D) using 520,580 samples, and the identification of candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cells using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) of 131,554 nuclei. Risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression. At the CFTR locus, the T1D risk variant rs7795896 mapped to a ductal-specific cCRE that regulated CFTR; the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in the pathogenesis of T1D and highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease.",
-,No,20210607,single cell,34024118,Single-Cell Epigenomics and Functional Fine-Mapping of Atherosclerosis GWAS Loci,Circ Res,"Rationale: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD). Many of these loci are enriched in cis-regulatory elements (CREs) but not linked to cardiometabolic risk factors nor to candidate causal genes, complicating their functional interpretation. Objective: Single nucleus chromatin accessibility profiling of the human atherosclerotic lesions was used to investigate cell type-specific patterns of CREs, to understand transcription factors establishing cell identity and to interpret CAD-relevant, non-coding genetic variation. Methods and Results: We used single nucleus ATAC-seq to generate DNA accessibility maps in > 7,000 cells derived from human atherosclerotic lesions. We identified five major lesional cell types including endothelial cells, smooth muscle cells, monocyte/macrophages, NK/T-cells and B-cells and further investigated subtype characteristics of macrophages and smooth muscle cells transitioning into fibromyocytes. We demonstrated that CAD associated genetic variants are particularly enriched in endothelial and smooth muscle cell-specific open chromatin. Using single cell co-accessibility and cis-eQTL information, we prioritized putative target genes and candidate regulatory elements for ~30% of all known CAD loci. Finally, we performed genome-wide experimental fine-mapping of the CAD GWAS variants using epigenetic QTL analysis in primary human aortic endothelial cells and STARR-Seq massively parallel reporter assay in smooth muscle cells. This analysis identified potential causal SNP(s) and the associated target gene for over 30 CAD loci. We present several examples where the chromatin accessibility and gene expression could be assigned to one cell type predicting the cell type of action for CAD loci. Conclusions: These findings highlight the potential of applying snATAC-seq to human tissues in revealing relative contributions of distinct cell types to diseases and in identifying genes likely to be influenced by non-coding GWAS variants.",
-,No,20210628,dnam age,34162876,Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus.,Nat Commun,"The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.",
-,No,20210628,dnam age,34120642,Does the epigenetic clock GrimAge predict mortality independent of genetic influences: an 18 year follow-up study in older female twin pairs.,Clin Epigenetics,"Epigenetic clocks are based on DNA methylation (DNAm). It has been suggested that these clocks are useable markers of biological aging and premature mortality. Because genetic factors explain variations in both epigenetic aging and mortality, this association could also be explained by shared genetic factors. We investigated the influence of genetic and lifestyle factors (smoking, alcohol consumption, physical activity, chronic diseases, body mass index) and education on the association of accelerated epigenetic aging with mortality using a longitudinal twin design. Utilizing a publicly available online tool, we calculated the epigenetic age using two epigenetic clocks, Horvath DNAmAge and DNAm GrimAge, in 413 Finnish twin sisters, aged 63-76 years, at the beginning of the 18-year mortality follow-up. Epigenetic age acceleration was calculated as the residuals from a linear regression model of epigenetic age estimated on chronological age (AAHorvath, AAGrimAge, respectively). Cox proportional hazard models were conducted for individuals and twin pairs.The results of the individual-based analyses showed an increased mortality hazard ratio (HR) of 1.31 (CI95: 1.13-1.53) per one standard deviation (SD) increase in AAGrimAge. The results indicated no significant associations of AAHorvathwith mortality. Pairwise mortality analyses showed an HR of 1.50 (CI95: 1.02-2.20) per 1 SD increase in AAGrimAge. However, after adjusting for smoking, the HR attenuated substantially and was statistically non-significant (1.29; CI95: 0.84-1.99). Similarly, in multivariable adjusted models the HR (1.42-1.49) was non-significant. In AAHorvath, the non-significant HRs were lower among monozygotic pairs in comparison to dizygotic pairs, while in AAGrimAgethere were no systematic differences by zygosity. Further, the pairwise analysis in quartiles showed that the increased within pair difference in AAGrimAgewas associated with a higher all-cause mortality risk.In conclusion, the findings suggest that DNAm GrimAge is a strong predictor of mortality independent of genetic influences. Smoking, which is known to alter DNAm levels and is built into the DNAm GrimAge algorithm, attenuated the association between epigenetic aging and mortality risk.",
-,No,20210628,dnam age,34078457,DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function.,Clin Epigenetics,"The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E-06). The ""first-generation"" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria.DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.",
-,No,20210628,dnam age,34035236,Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit.,Nat Commun,"We investigated the dynamic properties of the organism state fluctuations along individual aging trajectories in a large longitudinal database of CBC measurements from a consumer diagnostics laboratory. To simplify the analysis, we used a log-linear mortality estimate from the CBC variables as a single quantitative measure of the aging process, henceforth referred to as dynamic organism state indicator (DOSI). We observed, that the age-dependent population DOSI distribution broadening could be explained by a progressive loss of physiological resilience measured by the DOSI auto-correlation time. Extrapolation of this trend suggested that DOSI recovery time and variance would simultaneously diverge at a critical point of 120 - 150 years of age corresponding to a complete loss of resilience. The observation was immediately confirmed by the independent analysis of correlation properties of intraday physical activity levels fluctuations collected by wearable devices. We conclude that the criticality resulting in the end of life is an intrinsic biological property of an organism that is independent of stress factors and signifies a fundamental or absolute limit of human lifespan.",
-,No,20210628,ewas,34112938,Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors.,Sci Rep,"Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p < 0.05) OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. These results suggest opportunities for better treatment strategies for NETs based on molecular features.",
-,No,20210628,methods,34103055,Gene set enrichment analysis for genome-wide DNA methylation data.,Genome Biol,"DNA methylation is one of the most commonly studied epigenetic marks, due to its role in disease and development. Illumina methylation arrays have been extensively used to measure methylation across the human genome. Methylation array analysis has primarily focused on preprocessing, normalization, and identification of differentially methylated CpGs and regions. GOmeth and GOregion are new methods for performing unbiased gene set testing following differential methylation analysis. Benchmarking analyses demonstrate GOmeth outperforms other approaches, and GOregion is the first method for gene set testing of differentially methylated regions. Both methods are publicly available in the missMethyl Bioconductor R package.",
-,No,20210628,methods,34155396,The triumphs and limitations of computational methods for scRNA-seq.,Nat Methods,"The rapid progress of protocols for sequencing single-cell transcriptomes over the past decade has been accompanied by equally impressive advances in the computational methods for analysis of such data. As capacity and accuracy of the experimental techniques grew, the emerging algorithm developments revealed increasingly complex facets of the underlying biology, from cell type composition to gene regulation to developmental dynamics. At the same time, rapid growth has forced continuous reevaluation of the underlying statistical models, experimental aims, and sheer volumes of data processing that are handled by these computational tools. Here, I review key computational steps of single-cell RNA sequencing (scRNA-seq) analysis, examine assumptions made by different approaches, and highlight successes, remaining ambiguities, and limitations that are important to keep in mind as scRNA-seq becomes a mainstream technique for studying biology.",
-,No,20210628,mtdna,34099068,Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences.,Hum Genomics,"Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718).We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 Ă— 10-8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 Ă— 10-8), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 Ă— 10-21) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition.These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.",
-,No,20210628,prediction,34149812,Multi-Omics Marker Analysis Enables Early Prediction of Breast Tumor Progression.,Front Genet,"Ductal carcinomain situ(DCIS) is a preinvasive form of breast cancer with a highly variable potential of becoming invasive and affecting mortality of the patients. Due to the lack of accurate markers of disease progression, many women with detected DCIS are currently overtreated. To distinguish those DCIS cases who are likely to require therapy from those who should be left untreated, there is a need for robust and predictive biomarkers extracted from molecular or genetic profiles. We developed a supervised machine learning approach that implements multi-omics feature selection and model regularization for the identification of biomarker combinations that could be used to distinguish low-risk DCIS lesions from those with a higher likelihood of progression. To investigate the genetic heterogeneity of disease progression, we applied this approach to 40 pure DCIS and 259 invasive breast cancer (IBC) samples profiled with genome-wide transcriptomics, DNA methylation, and DNA copy number variation. Feature selection using the multi-omics Lasso-regularized algorithm identified both known genes involved in breast cancer development, as well as novel markers for early detection. Even though the gene expression-based model features led to the highest classification accuracy alone, methylation data provided a complementary source of features and improved especially the sensitivity of correctly classifying DCIS cases. We also identified a number of repeatedly misclassified DCIS cases when using either the expression or methylation markers. A small panel of 10 gene markers was able to distinguish DCIS and IBC cases with high accuracy in nested cross-validation (AU-ROC = 0.99). The marker panel was not specific to any of the established breast cancer subtypes, suggesting that the 10-gene signature may provide a subtype-agnostic and cost-effective approach for breast cancer detection and patient stratification. We further confirmed high accuracy of the 10-gene signature in an external validation cohort (AU-ROC = 0.95), profiled using distinct transcriptomic assay, hence demonstrating robustness of the risk signature.Copyright © 2021 Xu, Lien, Bergholtz, Fleischer, Djerroudi, Vincent-Salomon, Sørlie and Aittokallio.",
-,No,20210628,twas,34158615,Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing.,Neuropsychopharmacology,"Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20-30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.",
-,No ,20210628,methods,34130352,Inverse probability weighting is an effective method to address selection bias during the analysis of high dimensional data.,Genet Epidemiol,"Omics studies frequently use samples collected during cohort studies. Conditioning on sample availability can cause selection bias if sample availability is nonrandom. Inverse probability weighting (IPW) is purported to reduce this bias. We evaluated IPW in an epigenome-wide analysis testing the association between DNA methylation (261,435 probes) and age in healthy adolescent subjects (n = 114). We simulated age and sex to be correlated with sample selection and then evaluated four conditions: complete population/no selection bias (all subjects), naïve selection bias (no adjustment), and IPW selection bias (selection bias with IPW adjustment). Assuming the complete population condition represented the ""truth,"" we compared each condition to the complete population condition. Bias or difference in associations between age and methylation was reduced in the IPW condition versus the naïve condition. However, genomic inflation and type 1 error were higher in the IPW condition relative to the naïve condition. Postadjustment using bacon, type 1 error and inflation were similar across all conditions. Power was higher under the IPW condition compared with the naïve condition before and after inflation adjustment. IPW methods can reduce bias in genome-wide analyses. Genomic inflation is a potential concern that can be minimized using methods that adjust for inflation.© 2021 Wiley Periodicals LLC.",
-,Yes,20210628,ewas,34155504,Genetic and in-utero environmental contributions to DNA methylation variation in placenta.,Hum Mol Genet,"Genetic and prenatal environmental factors shape fetal development and cardiometabolic health in later life. A key target of genetic and prenatal environmental factors is the epigenome of the placenta, an organ that is implicated in fetal growth and diseases in later life. This study had two aims: 1) to identify and functionally characterize placental variably methylated regions (VMRs), which are regions in the epigenome with high interindividual methylation variability; 2) to investigate the contributions of fetal genetic loci and 12 prenatal environmental factors (maternal psychosocial-, cardiometabolic-, demographic-, and obstetric- related) on methylation at each VMR. Akaike's information criterion was used to select the best model out of four models (prenatal environment only, genotype only, additive effect of genotype and prenatal environment [G + E], and their interaction effect [GxE]). We identified 5850 VMRs in placenta. Methylation at 70% of VMRs was best explained by GxE followed by genotype only (17.7%), and G + E (12.3%). Prenatal environment alone best explained only 0.03% of VMRs. We observed that 95.4% of GxE models and 93.9% of G + E models included maternal age, parity, delivery mode, maternal depression, or gestational weight gain. VMR methylation sites and their regulatory genetic variants were enriched (P < 0.05) for genomic regions that have known links with regulatory functions and complex traits. This study provided a genome-wide catalog of VMRs in placenta and highlighted that variation in placental DNA methylation at loci with regulatory and trait relevance is best elucidated by integrating genetic and prenatal environmental factors, and rarely by environmental factors alone.Published by Oxford University Press 2021.",
-,Yes,20210628,ewas,34116986,Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome.,Diabetes Care,"Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure.We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring.We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10-2) CpG at the cg22790973 probe (TFCP2)associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within theUBE3Cgene and cg17065901 inFAM13A,both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within theDLGAP2gene, known to be involved in insulin resistance during pregnancy.Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.© 2021 by the American Diabetes Association.",
-,Yes,20210628,ewas,34086604,Different epigenetic signatures of newborn telomere length and telomere attrition rate in early life.,Aging,"Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIRONAGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging.",
-,Yes,20210628,ewas,34095363,Childhood adversity correlates with stable changes in DNA methylation trajectories in children and converges with epigenetic signatures of prenatal stress.,Neurobiol Stress,"Childhood maltreatment (CM) is an established major risk factor for a number of negative health outcomes later in life. While epigenetic mechanisms, such as DNA methylation (DNAm), have been proposed as a means of embedding this environmental risk factor, little is known about its timing and trajectory, especially in very young children. It is also not clear whether additional environmental adversities, often experienced by these children, converge on similar DNAm changes. Here, we calculated a cumulative adversity score, which additionally to CM includes socioeconomic status (SES), other life events, parental psychopathology and epigenetic biomarkers of prenatal smoking and alcohol consumption. We investigated the effects of CM alone as well as the adversity score on longitudinal DNAm trajectories in the Berlin Longitudinal Child Study. This is a cohort of 173 children aged 3-5 years at baseline of whom 86 were exposed to CM. These children were followed-up for 2 years with extensive psychometric and biological assessments as well as saliva collection at 5 time points providing genome-wide DNAm levels. Overall, only a few DNAm patterns were stable over this timeframe, but less than 10 DNAm regions showed significant changes. At baseline, neither CM nor the adversity score associated with DNAm changes. However, in 6 differentially methylated regions (DMRs), CM and the adversity score significantly moderated DNAm trajectories over time. A number of these DMRs have previously been associated with adverse prenatal exposures. In our study, children exposed to CM also presented with epigenetic signatures indicative of increased prenatal exposure to tobacco and alcohol, as compared to non-CM exposed children. These epigenetic signatures of prenatal exposure strongly correlate with DNAm regions associated with CM and the adversity score. Finally, weighted correlation network analysis revealed a module of CpGs exclusively associated with CM. While our study identifies DNAm loci specifically associated with CM, especially within long non-coding RNAs, the majority of associations were found with the adversity score with convergent association with indicators of adverse prenatal exposures. This study highlights the importance of mapping not only of the epigenome but also the exposome and extending the observational timeframe to well before birth.© 2021 The Authors.",
-,Yes,20210628,ewas,34116608,Association of mammographic density with blood DNA methylation.,Epigenetics,"Background:Altered DNA methylation may be an intermediate phenotype between breast cancer risk factors and disease. Mammographic density is a strong risk factor for breast cancer. However, no studies to date have identified an epigenetic signature of mammographic density. We performed an epigenome-wide association study of mammographic density.Methods:White blood cell DNA methylation was measured for 385 postmenopausal women using the Illumina Infinium MethylationEPIC BeadChip array. Differential methylation was assessed using genome-wide, probe-level, and regional analyses. We implemented a resampling-based approach to improve the stability of our findings.Results:On average, women with elevated mammographic density exhibited DNA hypermethylation within CpG islands and gene promoters compared to women with lower mammographic density. We identified 250 CpG sites for which DNA methylation was significantly associated with mammographic density. The top sites were located within genes associated with cancer, includingHDLBP, TGFB2, CCT4, andPAX8, and were more likely to be located in regulatory regions of the genome. We also identified differential DNA methylation in 37 regions, including within the promoters ofPAX8andPF4, a gene involved in the regulation of angiogenesis. Overall, our results paint a picture of epigenetic dysregulation associated with mammographic density.Conclusion:Mammographic density is associated with differential DNA methylation throughout the genome, including within genes associated with cancer. Our results suggest the potential involvement of several genes in the biological mechanisms behind differences in breast density between women. Further studies are warranted to explore these potential mechanisms and potential links to breast cancer risk.",
-,Yes,20210628,ewas,34101077,Pre-diagnostic DNA methylation patterns differ according to mammographic breast density amongst women who subsequently develop breast cancer: a case-only study in the EPIC-Florence cohort.,Breast Cancer Res Treat,"Mammographic breast density (MBD) is a marker of increased breast cancer (BC) risk, yet much remains to be clarified about the underlying mechanisms. We investigated whether DNA methylation patterns differ between high- vs. low-MBD women who developed BC during an 8.9-year median follow-up in the Florence section of the European Prospective Investigation into Cancer and Nutrition.We analysed 96 pairs of women with BC arising on high- vs. low-MBD breasts (BI-RADS category III-IV vs. I). DNA methylation was determined on pre-diagnostic blood samples using the Illumina Infinium MethylationEPIC BeadChip assay. The statistical analysis was conducted by performing an epigenome-wide association study (EWAS), by searching differentially methylated regions (DMRs) in gene promoters (followed by functional enrichment and gene annotation analysis); and through a ""candidate pathways"" approach focusing on pre-defined inflammation-related pathways.In EWAS, no single CpG site was differentially methylated between high- and low-MBD women after correction for multiple testing. A total of 140 DMRs were identified, of which 131 were hyper- and 9 hypo-methylated amongst high-MBD women. These DMRs encompassed an annotation cluster of 35 genes coding for proteins implicated in transcription regulation and DNA binding. The ""apoptosis signalling"" was the only inflammation-related candidate pathway differentially methylated between high- and low-MBD women.Pre-diagnostic methylation patterns differ between high- vs. low-MBD women who subsequently develop BC, particularly, in genes involved in the regulation of DNA transcription and cell apoptosis. Our study provides novel clues about the mechanisms linking MBD and BC.",
-,Yes,20210628,ewas,34091768,Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.,Eur J Epidemiol,"Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.",
-,Yes,20210628,ewas,34117263,Genome-wide DNA methylation analysis on C-reactive protein among Ghanaians suggests molecular links to the emerging risk of cardiovascular diseases.,NPJ Genom Med,"Molecular mechanisms at the intersection of inflammation and cardiovascular diseases (CVD) among Africans are still unknown. We performed an epigenome-wide association study to identify loci associated with serum C-reactive protein (marker of inflammation) among Ghanaians and further assessed whether differentially methylated positions (DMPs) were linked to CVD in previous reports, or to estimated CVD risk in the same population. We used the Illumina Infinium® HumanMethylation450 BeadChip to obtain DNAm profiles of blood samples in 589 Ghanaians from the RODAM study (without acute infections, not taking anti-inflammatory medications, CRP levels < 40 mg/L). We then used linear models to identify DMPs associated with CRP concentrations. Post-hoc, we evaluated associations of identified DMPs with elevated CVD risk estimated via ASCVD risk score. We also performed subset analyses at CRP levels ≤10 mg/L and replication analyses on candidate probes. Finally, we assessed for biological relevance of our findings in public databases. We subsequently identified 14 novel DMPs associated with CRP. In post-hoc evaluations, we found that DMPs in PC, BTG4 and PADI1 showed trends of associations with estimated CVD risk, we identified a separate DMP in MORC2 that was associated with CRP levels ≤10 mg/L, and we successfully replicated 65 (24%) of previously reported DMPs. All DMPs with gene annotations (13) were biologically linked to inflammation or CVD traits. We have identified epigenetic loci that may play a role in the intersection between inflammation and CVD among Ghanaians. Further studies among other Africans are needed to confirm our findings.",
-,Yes,20210628,ewas,34112773,A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex.,Nat Commun,"Epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer's disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource ( www.epigenomicslab.com/ad-meta-analysis/ ).",
-,No,20210726,review,32151655,DNA methylation and brain structure and function across the life course: A systematic review,Neurosci Biobehav Rev,"MRI has enhanced our capacity to understand variations in brain structure and function conferred by the genome. We identified 60 studies that report associations between DNA methylation (DNAm) and human brain structure/function. Forty-three studies measured candidate loci DNAm; seventeen measured epigenome-wide DNAm. MRI features included region-of-interest and whole-brain structural, diffusion and functional imaging features. The studies report DNAm-MRI associations for: neurodevelopment and neurodevelopmental disorders; major depression and suicidality; alcohol use disorder; schizophrenia and psychosis; ageing, stroke, ataxia and neurodegeneration; post-traumatic stress disorder; and socio-emotional processing. Consistency between MRI features and differential DNAm is modest. Sources of bias: variable inclusion of comparator groups; different surrogate tissues used; variation in DNAm measurement methods; lack of control for genotype and cell-type composition; and variations in image processing. Knowledge of MRI features associated with differential DNAm may improve understanding of the role of DNAm in brain health and disease, but caution is required because conventions for linking DNAm and MRI data are not established, and clinical and methodological heterogeneity in existing literature is substantial.",
-,Yes,20210726,ewas,31811260,Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group,Mol Psychiatry,"DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.",
-,No,20210726,cell types,34254878,A comparison of epithelial cell content of oral samples estimated using cytology and DNA methylation.,Epigenetics,"Saliva and buccal samples are popular for epigenome wide association studies (EWAS) due to their ease of collection compared and their ability to sample a different cell lineage compared to blood. As these samples contain a mix of white blood cells and buccal epithelial cells that can vary within a population, this cellular heterogeneity may confound EWAS. This has been addressed by including cellular heterogeneity obtained through cytology at the time of collection or by using cellular deconvolution algorithms built on epigenetic data from specific cell types. However, to our knowledge, the two methods have not yet been compared. Here we show that the two methods are highly correlated in saliva and buccal samples (R = 0.84, P < 0.0001) by comparing data generated from cytological staining and Infinium MethylationEPIC arrays and the EpiDISH deconvolution algorithm from buccal and saliva samples collected from twenty adults. In addition, by using an expanded dataset from both sample types, we confirmed our previous finding that age has strong, non-linear negative correlation with epithelial cell proportion in both sample types. However, children and adults showed a large within-population variation in cellular heterogeneity. Our results validate the use of the EpiDISH algorithm in estimating the effect of cellular heterogeneity in EWAS and showed DNA methylation generally underestimates the epithelial cell content obtained from cytology.",
-,No,20210726,dnam age,34174924,Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.,Mol Brain,"Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.",
-,No,20210726,dnam age,34187551,Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.,Genome Biol,"Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.",
-,No,20210726,epigenetics,34234345,BANP opens chromatin and activates CpG-island-regulated genes.,Nature,"The majority of gene transcripts generated by RNA polymerase II in mammalian genomes initiate at CpG island (CGI) promoters1,2, yet our understanding of their regulation remains limited. This is in part due to the incomplete information that we have on transcription factors, their DNA-binding motifs and which genomic binding sites are functional in any given cell type3-5. In addition, there are orphan motifs without known binders, such as the CGCG element, which is associated with highly expressed genes across human tissues and enriched near the transcription start site of a subset of CGI promoters6-8. Here we combine single-molecule footprinting with interaction proteomics to identify BTG3-associated nuclear protein (BANP) as the transcription factor that binds this element in the mouse and human genome. We show that BANP is a strong CGI activator that controls essential metabolic genes in pluripotent stem and terminally differentiated neuronal cells. BANP binding is repelled by DNA methylation of its motif in vitro and in vivo, which epigenetically restricts most binding to CGIs and accounts for differential binding at aberrantly methylated CGI promoters in cancer cells. Upon binding to an unmethylated motif, BANP opens chromatin and phases nucleosomes. These findings establish BANP as a critical activator of a set of essential genes and suggest a model in which the activity of CGI promoters relies on methylation-sensitive transcription factors that are capable of chromatin opening.",
-,No,20210726,ewas,34215292,Ageing-associated changes in DNA methylation in X and Y chromosomes.,Epigenetics Chromatin,"Ageing displays clear sexual dimorphism, evident in both morbidity and mortality. Ageing is also associated with changes in DNA methylation, but very little focus has been on the sex chromosomes, potential biological contributors to the observed sexual dimorphism. Here, we sought to identify DNA methylation changes associated with ageing in the Y and X chromosomes, by utilizing datasets available in data repositories, comprising in total of 1240 males and 1191 females, aged 14-92 years.In total, we identified 46 age-associated CpG sites in the male Y, 1327 age-associated CpG sites in the male X, and 325 age-associated CpG sites in the female X. The X chromosomal age-associated CpGs showed significant overlap between females and males, with 122 CpGs identified as age-associated in both sexes. Age-associated X chromosomal CpGs in both sexes were enriched in CpG islands and depleted from gene bodies and showed no strong trend towards hypermethylation nor hypomethylation. In contrast, the Y chromosomal age-associated CpGs were enriched in gene bodies, and showed a clear trend towards hypermethylation with age.Significant overlap in X chromosomal age-associated CpGs identified in males and females and their shared features suggest that despite the uneven chromosomal dosage, differences in ageing-associated DNA methylation changes in the X chromosome are unlikely to be a major contributor of sex dimorphism in ageing. While age-associated CpGs showed good replication across datasets in the present study, only a limited set of previously reported age-associated CpGs were replicated. One contributor to the limited overlap are differences in the age range of individuals included in each data set. Further study is needed to identify biologically significant age-associated CpGs in the sex chromosomes.",
-,No,20210726,hydroxymethylation,34253716,Tissue-specific 5-hydroxymethylcytosine landscape of the human genome.,Nat Commun,"5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially-hydroxymethylated regions (tsDhMRs), which are deposited in regions that potentially regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription factors and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with single-nucleotide polymorphisms identified by genome-wide association studies and are linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific gene expression programs and functions.© 2021. The Author(s).",
-,No,20210726,methods,34256818,2dFDR: a new approach to confounder adjustment substantially increases detection power in omics association studies.,Genome Biol,"One challenge facing omics association studies is the loss of statistical power when adjusting for confounders and multiple testing. The traditional statistical procedure involves fitting a confounder-adjusted regression model for each omics feature, followed by multiple testing correction. Here we show that the traditional procedure is not optimal and present a new approach, 2dFDR, a two-dimensional false discovery rate control procedure, for powerful confounder adjustment in multiple testing. Through extensive evaluation, we demonstrate that 2dFDR is more powerful than the traditional procedure, and in the presence of strong confounding and weak signals, the power improvement could be more than 100%.© 2021. The Author(s).",
-,No,20210726,omics,34282340,Single-cell analysis enters the multiomics age.,Nature,NA,
-,No,20210726,prediction,34204621,DNA Methylation-Based Estimates of Circulating Leukocyte Composition for Predicting Colorectal Cancer Survival: A Prospective Cohort Study.,Cancers (Basel),"Leukocytes are involved in the progression of colorectal cancer (CRC). The proportion of six major leukocyte subtypes can be estimated using epigenome-wide DNA methylation (DNAm) data from stored blood samples. Whether the composition of circulating leukocytes can be used as a prognostic factor is unclear. DNAm-based leukocyte proportions were obtained from a prospective cohort of 2206 CRC patients. Multivariate Cox regression models and survival curves were applied to assess associations between leukocyte composition and survival outcomes. A higher proportion of lymphocytes, including CD4+ T cells, CD8+ T cells, B cells, and NK cells, was associated with better survival, while a higher proportion of neutrophils was associated with poorer survival. CD4+ T cells outperformed other leukocytes in estimating the patients' prognosis. Comparing the highest quantile to the lowest quantile of CD4+ T cells, hazard ratios (95% confidence intervals) of all-cause and CRC-specific mortality were 0.59 (0.48, 0.72) and 0.59 (0.45, 0.77), respectively. Furthermore, the association of CD4+ T cells and prognosis was stronger among patients with early or intermediate CRC or patients with colon cancer. In conclusion, the composition of circulating leukocytes estimated from DNAm, particularly the proportions of CD4+ T cells, could be used as promising independent predictors of CRC survival.",
-,No,20210726,prediction,34247653,DNA methylation under the major depression pathway predicts pediatric quality of life four-month post-pediatric mild traumatic brain injury.,Clin Epigenetics,"Major depression has been recognized as the most commonly diagnosed psychiatric complication of mild traumatic brain injury (mTBI). Moreover, major depression is associated with poor outcomes following mTBI; however, the underlying biological mechanisms of this are largely unknown. Recently, genomic and epigenetic factors have been increasingly implicated in the recovery following TBI.This study leveraged DNA methylation within the major depression pathway, along with demographic and behavior measures (features used in the clinical model) to predict post-concussive symptom burden and quality of life four-month post-injury in a cohort of 110 pediatric mTBI patients and 87 age-matched healthy controls. The results demonstrated that including DNA methylation markers in the major depression pathway improved the prediction accuracy for quality of life but not persistent post-concussive symptom burden. Specifically, the prediction accuracy (i.e., the correlation between the predicted value and observed value) of quality of life was improved from 0.59 (p = 1.20 × 10-3) (clinical model) to 0.71 (p = 3.89 × 10-5); the identified cytosine-phosphate-guanine sites were mainly in the open sea regions and the mapped genes were related to TBI in several molecular studies. Moreover, depression symptoms were a strong predictor (with large weights) for both post-concussive symptom burden and pediatric quality of life.This study emphasized that both molecular and behavioral manifestations of depression symptoms played a prominent role in predicting the recovery process following pediatric mTBI, suggesting the urgent need to further study TBI-caused depression symptoms for better recovery outcome.© 2021. The Author(s).",
-,Yes,20210726,ewas,34167563,The epigenetic etiology of cardiovascular disease in a longitudinal Swedish twin study.,Clin Epigenetics,"Studies on DNA methylation have the potential to discover mechanisms of cardiovascular disease (CVD) risk. However, the role of DNA methylation in CVD etiology remains unclear.We performed an epigenome-wide association study (EWAS) on CVD in a longitudinal sample of Swedish twins (535 individuals). We selected CpGs reaching the Bonferroni-corrected significance level (2 [Formula: see text] 10-7) or the top-ranked 20 CpGs with the lowest P values if they did not reach this significance level in EWAS analysis associated with non-stroke CVD, overall stroke, and ischemic stroke, respectively. We further applied a bivariate autoregressive latent trajectory model with structured residuals (ALT-SR) to evaluate the cross-lagged effect between DNA methylation of these CpGs and cardiometabolic traits (blood lipids, blood pressure, and body mass index). Furthermore, mediation analysis was performed to evaluate whether the cross-lagged effects had causal impacts on CVD. In the EWAS models, none of the CpGs we selected reached the Bonferroni-corrected significance level. The ALT-SR model showed that DNA methylation levels were more likely to predict the subsequent level of cardiometabolic traits rather than the other way around (numbers of significant cross-lagged paths of methylation → trait/trait → methylation were 84/4, 45/6, 66/1 for the identified three CpG sets, respectively). Finally, we demonstrated significant indirect effects from DNA methylation on CVD mediated by cardiometabolic traits.We present evidence for a directional association from DNA methylation on cardiometabolic traits and CVD, rather than the opposite, highlighting the role of epigenetics in CVD development.",
-,Yes,20210726,ewas,34170065,Neonatal DNA methylation and childhood low prosocial behavior: An epigenome-wide association meta-analysis.,Am J Med Genet B Neuropsychiatr Genet,"Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of ""chronic-low"" versus ""typical"" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous ""low prosocial"" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.© 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.",
-,Yes,20210726,ewas,34174944,Detecting cord blood cell type-specific epigenetic associations with gestational diabetes mellitus and early childhood growth.,Clin Epigenetics,"Epigenome-wide association studies (EWAS) have provided opportunities to understand the role of epigenetic mechanisms in development and pathophysiology of many chronic diseases. However, an important limitation of conventional EWAS is that profiles of epigenetic variability are often obtained in samples of mixed cell types. Here, we aim to assess whether changes in cord blood DNA methylation (DNAm) associated with gestational diabetes mellitus (GDM) exposure and early childhood growth markers occur in a cell type-specific manner.We analyzed 275 cord blood samples collected at delivery from a prospective pre-birth cohort with genome-wide DNAm profiled by the Illumina MethylationEPIC array. We estimated proportions of seven common cell types in each sample using a cord blood-specific DNAm reference panel. Leveraging a recently developed approach named CellDMC, we performed cell type-specific EWAS to identify CpG loci significantly associated with GDM, or 3-year-old body mass index (BMI) z-score. A total of 1410 CpG loci displayed significant cell type-specific differences in methylation level between 23 GDM cases and 252 controls with a false discovery rate < 0.05. Gene Ontology enrichment analysis indicated that LDL transportation emerged from CpG specifically identified from B-cells DNAm analyses and the mitogen-activated protein kinase pathway emerged from CpG specifically identified from natural killer cells DNAm analyses. In addition, we identified four and six loci associated with 3-year-old BMI z-score that were specific to CD8+ T-cells and monocytes, respectively. By performing genome-wide permutation tests, we validated that most of our detected signals had low false positive rates.Compared to conventional EWAS adjusting for the effects of cell type heterogeneity, the proposed approach based on cell type-specific EWAS could provide additional biologically meaningful associations between CpG methylation, prenatal maternal GDM or 3-year-old BMI. With careful validation, these findings may provide new insights into the pathogenesis, programming, and consequences of related childhood metabolic dysregulation. Therefore, we propose that cell type-specific analyses are worth cautious explorations.",
-,Yes,20210726,ewas,34183656,A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.,Nat Commun,"Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.",
-,Yes,20210726,ewas,34214161,DNA Methylation Changes Associated with Type 2 Diabetes and Diabetic Kidney Disease in an East Asian Population.,J Clin Endocrinol Metab,"There is a growing body of evidence that epigenetic changes including DNA methylation influence the risk of type 2 diabetes (T2D) and its microvascular complications. We conducted a methylome-wide association study (MWAS) to identify differentially methylated sites (DMSs) of T2D and diabetic kidney disease (DKD) in a Korean population.We performed an MWAS in 232 participants with T2D and 197 non-diabetic controls with Illumina EPIC bead chip using peripheral blood leukocytes. T2D group was subdivided into 87 DKD cases and 80 non-DKD controls. Additional 819 individuals from two population-based cohorts were used to investigate the association of identified DMSs with quantitative metabolic phenotypes. Mendelian randomization (MR) approach was applied to evaluate the causal effect of metabolic phenotypes on identified DMSs.We identified eight DMSs (each at BMP8A, NBPF20, STX18, ZNF365, CPT1A, and TRIM37, and two at TXNIP) which were significantly associated with the risk of T2D (P < 9.0×10 -8), including three that were previously known (DMSs in TXNIP and CPT1A). We also identified three DMSs (in COMMD1, TMOD1, and FHOD1) associated with DKD. With our limited sample size, we were not able to observe a significant overlap between DMSs of T2D and DKD. DMSs in TXNIP and CTP1A were associated with fasting glucose and HbA1c. In MR analysis, fasting glucose was causally associated with DMS in CPT1A.In an East Asian population, we identified eight DMSs, including five novel CpG loci, associated with T2D and three DMSs associated with DKD at methylome-wide statistical significance.© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
-,Yes,20210726,ewas,34265559,"Exposure to polycyclic aromatic hydrocarbons, DNA methylation and heart rate variability among non-current smokers.",Environ Pollut,"Polycyclic aromatic hydrocarbons (PAHs) exposure is associated with heart rate variability (HRV) reduction, a widely used marker of cardiovascular autonomic dysfunction. The role of DNA methylation in the relationship between PAHs exposure and decreased HRV is largely unknown. This study aims to explore epigenome-wide DNA methylation changes associated with PAHs exposure and further evaluate their associations with HRV alternations among non-current smokers. We measured 10 mono-hydroxylated PAHs (OH-PAHs) in urine and DNA methylation levels in blood leukocytes among participants from three panels of Chinese non-current smokers (152 in WHZH, 99 in SY, and 53 in COW). We conducted linear regression analyses between DNA methylation and OH-PAHs metabolites with adjustment for age, gender, body mass index, drinking, blood cell counts, and surrogate variables in each panel separately, and combined the results by using inverse-variance weighted fixed-effect meta-analysis to obtain estimates of effect size. The median value of total OH-PAHs ranged from 0.92 × 10-2in SY panel (62.6% men) to 13.82 × 10-2 μmol/mmol creatinine in COW panel (43.4% men). The results showed that methylation levels of cg18223625 (COL20A1) and cg07805771 (SLC16A1) were significantly or marginally significantly associated with urinary 2-hydroxynaphthalene [β(SE) = 0.431(0.074) and 0.354(0.068), FDR = 0.016 and 0.056, respectively], while methylation level of cg09235308 (PLEC1) was positively associated with urinary total OH-PAHs [β(SE) = 0.478(0.079), FDR = 0.004]. Hypermethylations of cg18223625, cg07805771, and cg09235308 were inversely associated with HRV indices among the WHZH and COW non-current smokers. However, we did not observe significant epigenome-wide associations for the other 9 urinary OH-PAHs. These findings provide new evidence that PAHs exposure is linked to differential DNA methylation, which may help better understand the influences of PAHs exposure on HRV alternations.Copyright © 2021 Elsevier Ltd. All rights reserved.",
-,No,20210920,epigenetics,34489442,The concurrence of DNA methylation and demethylation is associated with transcription regulation.,Nat Commun,"The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40~60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.© 2021. The Author(s).",
-,No,20210920,longitudinal ewas,34454584,Longitudinal analysis of individual cfDNA methylome patterns in metastatic prostate cancer.,Clin Epigenetics,"Disease progression and therapeutic resistance are hallmarks of advanced stage prostate cancer (PCa), which remains a major cause of cancer-related mortality around the world. Longitudinal studies, coupled with the use of liquid biopsies, offer a potentially new and minimally invasive platform to study the dynamics of tumour progression. Our aim was to investigate the dynamics of personal DNA methylomic profiles of metastatic PCa (mPCa) patients, during disease progression and therapy administration.Forty-eight plasma samples from 9 mPCa patients were collected, longitudinally, over 13-21 months. After circulating cell-free DNA (cfDNA) isolation, DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The top 5% most variable probes across time, within each individual, were utilised to study dynamic methylation patterns during disease progression and therapeutic response. Statistical testing was carried out to identify differentially methylated genes (DMGs) in cfDNA, which were subsequently validated in two independent mPCa (cfDNA and FFPE tissue) cohorts. Individual cfDNA global methylation patterns were temporally stable throughout the disease course. However, a proportion of CpG sites presented a dynamic temporal pattern that was consistent with clinical events, including different therapies, and were prominently associated with genes linked to immune response pathways. Additionally, study of the tumour fraction of cfDNA identified > 2000 DMGs with dynamic methylation patterns.Longitudinal assessment of cfDNA methylation in mPCa patients unveiled dynamic patterns associated with disease progression and therapy administration, thus highlighting the potential of using liquid biopsies to study PCa evolution at a methylomic level.© 2021. The Author(s).",
-,No,20210920,methods,34496950,An effective processing pipeline for harmonizing DNA methylation data from Illumina's 450K and EPIC platforms for epidemiological studies.,BMC Res Notes,"Illumina BeadChip arrays are commonly used to generate DNA methylation data for large epidemiological studies. Updates in technology over time create challenges for data harmonization within and between studies, many of which obtained data from the older 450K and newer EPIC platforms. The pre-processing pipeline for DNA methylation is not trivial, and influences the downstream analyses. Incorporating different platforms adds a new level of technical variability that has not yet been taken into account by recommended pipelines. Our study evaluated the performance of various tools on different versions of platform data harmonization at each step of pre-processing pipeline, including quality control (QC), normalization, batch effect adjustment, and genomic inflation. We illustrate our novel approach using 450K and EPIC data from the Diabetes Autoimmunity Study in the Young (DAISY) prospective cohort.We found normalization and probe filtering had the biggest effect on data harmonization. Employing a meta-analysis was an effective and easily executable method for accounting for platform variability. Correcting for genomic inflation also helped with harmonization. We present guidelines for studies seeking to harmonize data from the 450K and EPIC platforms, which includes the use of technical replicates for evaluating numerous pre-processing steps, and employing a meta-analysis.© 2021. The Author(s).",
-,No,20210920,mqtl,34493871,Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.,Nat Genet,"Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20210920,single-cell,34417589,Multi-omics integration in the age of million single-cell data.,Nat Rev Nephrol,"An explosion in single-cell technologies has revealed a previously underappreciated heterogeneity of cell types and novel cell-state associations with sex, disease, development and other processes. Starting with transcriptome analyses, single-cell techniques have extended to multi-omics approaches and now enable the simultaneous measurement of data modalities and spatial cellular context. Data are now available for millions of cells, for whole-genome measurements and for multiple modalities. Although analyses of such multimodal datasets have the potential to provide new insights into biological processes that cannot be inferred with a single mode of assay, the integration of very large, complex, multimodal data into biological models and mechanisms represents a considerable challenge. An understanding of the principles of data integration and visualization methods is required to determine what methods are best applied to a particular single-cell dataset. Each class of method has advantages and pitfalls in terms of its ability to achieve various biological goals, including cell-type classification, regulatory network modelling and biological process inference. In choosing a data integration strategy, consideration must be given to whether the multi-omics data are matched (that is, measured on the same cell) or unmatched (that is, measured on different cells) and, more importantly, the overall modelling and visualization goals of the integrated analysis.© 2021. Springer Nature Limited.",
-,No,20210920,somatic mutations,34433965,A body map of somatic mutagenesis in morphologically normal human tissues.,Nature,"Somatic mutations that accumulate in normal tissues are associated with ageing and disease1,2. Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual.© 2021. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20210920,somatic mutations,34433962,The mutational landscape of human somatic and germline cells.,Nature,"Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.© 2021. Crown.",
-,No,20210920,prediction,34400642,Circulating cell-free DNA-based methylation patterns for breast cancer diagnosis.,NPJ Breast Cancer,"Mammography is used to detect breast cancer (BC), but its sensitivity is limited, especially for dense breasts. Circulating cell-free DNA (cfDNA) methylation tests is expected to compensate for the deficiency of mammography. We derived a specific panel of markers based on computational analysis of the DNA methylation profiles from The Cancer Genome Atlas (TCGA). Through training (n = 160) and validation set (n = 69), we developed a diagnostic prediction model with 26 markers, which yielded a sensitivity of 89.37% and a specificity of 100% for differentiating malignant disease from normal lesions [AUROC = 0.9816 (95% CI: 96.09-100%), and AUPRC = 0.9704 (95% CI: 94.54-99.46%)]. A simplified 4-marker model including cg23035715, cg16304215, cg20072171, and cg21501525 had a similar diagnostic power [AUROC = 0.9796 (95% CI: 95.56-100%), and AUPRC = 0.9220 (95% CI: 91.02-94.37%)]. We found that a single cfDNA methylation marker, cg23035715, has a high diagnostic power [AUROC = 0.9395 (95% CI: 89.72-99.27%), and AUPRC = 0.9111 (95% CI: 88.45-93.76%)], with a sensitivity of 84.90% and a specificity of 93.88%. In an independent testing dataset (n = 104), the obtained diagnostic prediction model discriminated BC patients from normal controls with high accuracy [AUROC = 0.9449 (95% CI: 90.07-98.91%), and AUPRC = 0.8640 (95% CI: 82.82-89.98%)]. We compared the diagnostic power of cfDNA methylation and mammography. Our model yielded a sensitivity of 94.79% (95% CI: 78.72-97.87%) and a specificity of 98.70% (95% CI: 86.36-100%) for differentiating malignant disease from normal lesions [AUROC = 0.9815 (95% CI: 96.75-99.55%), and AUPRC = 0.9800 (95% CI: 96.6-99.4%)], with better diagnostic power and had better diagnostic power than that of using mammography [AUROC = 0.9315 (95% CI: 89.95-96.34%), and AUPRC = 0.9490 (95% CI: 91.7-98.1%)]. In addition, hypermethylation profiling provided insights into lymph node metastasis stratifications (p < 0.05). In conclusion, we developed and tested a cfDNA methylation model for BC diagnosis with better performance than mammography.© 2021. The Author(s).",
-,No,20210920,prediction,34518533,"DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.",Nat Commun,"DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.© 2021. The Author(s).",
-,No,20210920,ewas,34401410,Placental DNA methylation marks are associated with maternal depressive symptoms during early pregnancy.,Neurobiol Stress,"Maternal depressive symptoms during pregnancy are a significant risk factor for adverse developmental and health outcomes of the offspring. The molecular mechanisms mediating the long-term effects of this exposure are not well understood. Previous studies have found association between prenatal exposure to maternal psychological distress and placental DNA methylation of candidate genes, which can influence placental barrier function and development of the fetus. Our objective in this study was to determine epigenome wide association of maternal depressive symptoms in early pregnancy with the placental DNA methylation. For this purpose we examined DNA methylomes of 92 placental samples by using reduced representation bisulfite sequencing. The placental samples were collected after deliveries of 39 girls and 59 boys, whose mothers had Edinburgh Postnatal Depression Score ranging from 0 to 19 at gestational week 14. According to our results maternal depressive symptoms are associated with DNA methylation of 2833 CpG sites, which are particularly over-represented in genic enhancers. The genes overlapping or nearest to these sites are functionally enriched for development of neurons and show expression enrichment in several regions of developing brain. The genomic regions harboring the DNA methylation marks are enriched for single nucleotide polymorphisms associated with mental disease trait class. Potential cellular signaling cascades mediating the effects include inflammatory and hormonal pathways. As a conclusion our results suggest that maternal depressive symptoms during early pregnancy are associated with DNA methylation marks in placenta in genes, which are important for the development and long-term health of the brain. Whether similar marks can be detected in exposed children remains to be elucidated in further studies.© 2021 The Authors.",
-,No,20210920,methods,34461822,A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis.,BMC Genomics,"There exist few, if any, practical guidelines for predictive and falsifiable multi-omic data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules.We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omic integration of 20 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor-associated genes from several independent cohorts. Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS genes. The multi-omic case study using MS data revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module were differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10- 47) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS.We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omic approaches for complex diseases.© 2021. The Author(s).",
-,No,20210920,methods,34461811,Novel DNA methylation loci and genes showing pleiotropic association with Alzheimer's dementia: a network Mendelian randomization analysis.,Epigenetics,"Previous genome-wide association studies (GWAS) have identified potential genetic variants involved in the risk of Alzheimer's dementia, but their underlying biological interpretation remains largely unclear. In addition, the effects of DNA methylation and gene expression on Alzheimer's dementia are not well understood. A network summary data-based Mendelian randomization (SMR) analysis was performed integrating cis- DNA methylation quantitative trait loci (mQTL) /cis- gene expression QTL (eQTL) data in the brain and blood, as well as GWAS summarized data for Alzheimer's dementia to evaluate the pleiotropic associations of DNA methylation and gene expression with Alzheimer's dementia and to explore the complex mechanisms underpinning Alzheimer's dementia. After correction for multiple testing (false discovery rate [FDR]P< 0.05) and filtering using the heterogeneity in dependent instruments (HEIDI) test (PHEIDI>0.01), we identified dozens of DNA methylation sites and genes showing pleiotropic associations with Alzheimer's dementia. We found 22 and 16 potentially causal pathways of Alzheimer's dementia (i.e., SNP→DNA methylation→Gene expression→Alzheimer's dementia) in the brain and blood, respectively. Approximately two-thirds of the identified DNA methylation sites had an influence on gene expression and the expression of almost all the identified genes was regulated by DNA methylation. Our network SMR analysis provided evidence supporting the pleiotropic association of some novel DNA methylation sites and genes with Alzheimer's dementia and revealed possible causal pathways underlying the pathogenesis of Alzheimer's dementia. Our findings shed light on the role of DNA methylation in gene expression and in the development of Alzheimer's dementia.",
-,Yes,20210920,ewas,34523531,Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort.,Environ Pollut,"In utero exposure to environmental chemicals, such as synthetic phenols, may alter DNA methylation in different tissues, including placenta - a critical organ for fetal development. We studied associations between prenatal urinary biomarker concentrations of synthetic phenols and placental DNA methylation. Our study involved 202 mother-son pairs from the French EDEN cohort. Nine phenols were measured in spot urine samples collected between 22 and 29 gestational weeks. We performed DNA methylation analysis of the fetal side of placental tissues using the IlluminaHM450 BeadChips. We evaluated methylation changes of individual CpGs in an adjusted epigenome-wide association study (EWAS) and identified differentially methylated regions (DMRs). We performed mediation analysis to test whether placental tissue heterogeneity mediated the association between urinary phenol concentrations and DNA methylation. We identified 46 significant DMRs (≥5 CpGs) associated with triclosan (37 DMRs), 2,4-dichlorophenol (3), benzophenone-3 (3), methyl- (2) and propylparaben (1). All but 2 DMRs were positively associated with phenol concentrations. Out of the 46 identified DMRs, 7 (6 for triclosan) encompassed imprinted genes (APC, FOXG1, GNAS, GNASAS, MIR886, PEG10, SGCE), which represented a significant enrichment. Other identified DMRs encompassed genes encoding proteins responsible for cell signaling, transmembrane transport, cell adhesion, inflammatory, apoptotic and immunological response, genes encoding transcription factors, histones, tumor suppressors, genes involved in tumorigenesis and several cancer risk biomarkers. Mediation analysis suggested that placental cell heterogeneity may partly explain these associations. This is the first study describing the genome-wide modifications of placental DNA methylation associated with pregnancy exposure to synthetic phenols or their precursors. Our results suggest that cell heterogeneity might mediate the effects of triclosan exposure on placental DNA methylation. Additionally, the enrichment of imprinted genes within the DMRs suggests mechanisms by which certain exposures, mainly to triclosan, could affect fetal development.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",
-,Yes,20210920,ewas,34516295,Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study.,Environ Health Perspect,"Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides.We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients.The Agricultural Lung Health Study is a case-control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina's EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009-2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users.Using family-wise error rate (p<9Ă—10-8) or false-discovery rate (FDR<0.05), we identified 162 differentially methylated CpGs across 8 of 9 currently marketed active ingredients (acetochlor, atrazine, dicamba, glyphosate, malathion, metolachlor, mesotrione, and picloram) and one banned organochlorine (heptachlor). Differentially methylated CpGs were unique to each active ingredient, and a dose-response relationship with lifetime days of use was observed for most. Significant CpGs were enriched for transcription motifs and 28% of CpGs were associated with whole bloodcis-gene expression, supporting functional effects of findings. We corroborated a previously reported association between dichlorodiphenyltrichloroethane (banned in the United States in 1972) and epigenetic age acceleration.We identified differential methylation for several active ingredients in male farmers of European ancestry. These may serve as biomarkers of chronic exposure and could inform mechanisms of long-term health outcomes from pesticide exposure. https://doi.org/10.1289/EHP8928.",
-,Yes,20210920,ewas,34515027,Epigenome-wide analysis of DNA methylation and coronary heart disease: a nested case-control study.,Elife,"Background:Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population.Methods:We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10-year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module.Results:After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR <0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47% decrease to a 118% increase. Mediation analyses revealed 28.5% of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region ofANKS1Agene (P for mediation effect = 0.036). Methylation level at the promoter region ofSNX30was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7% (P = 0.003) via systolic blood pressure and 6.4% (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD.Conclusions:We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and BP-related pathways to CHD risk.Funding:This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key and Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).© 2021, Si et al.",
-,Yes,20210920,ewas,34507616,Prenatal risk factors and neonatal DNA methylation in very preterm infants.,Clin Epigenetics,"Prenatal risk factors are related to poor health and developmental outcomes for infants, potentially via epigenetic mechanisms. We tested associations between person-centered prenatal risk profiles, cumulative prenatal risk models, and epigenome-wide DNA methylation (DNAm) in very preterm neonates.We studied 542 infants from a multi-center study of infants born < 30 weeks postmenstrual age. We assessed 24 prenatal risk factors via maternal report and medical record review. Latent class analysis was used to define prenatal risk profiles. DNAm was quantified from neonatal buccal cells using the Illumina MethylationEPIC Beadarray.We identified three latent profiles of women: a group with few risk factors (61%) and groups with elevated physical (26%) and psychological (13%) risk factors. Neonates born to women in higher risk subgroups had differential DNAm at 2 CpG sites. Higher cumulative prenatal risk was associated with methylation at 15 CpG sites, 12 of which were located in genes previously linked to physical and mental health and neurodevelopment.We observed associations between prenatal risk factors and DNAm in very preterm infants using both person-centered and cumulative risk approaches. Epigenetics offers a potential biological indicator of prenatal risk exposure.© 2021. The Author(s).",
-,Yes,20210920,ewas,34482817,DNA methylation changes in African American women with a history of preterm birth from the InterGEN study.,BMC Genom Data,"Preterm birth (< 37 weeks' gestation) is a common outcome of pregnancy that has been associated with increased risk of cardiovascular disease for women later in life. Little is known about the physiologic mechanisms underlying this risk. To date, no studies have evaluated if differences in DNA methylation (DNAm) among women who experience preterm birth are short-term or if they persist and are associated with subsequent cardiovascular sequelae or other health disorders. The purpose of this study was to examine long-term epigenetic effects of preterm birth in African American mothers (n = 182) from the InterGEN Study (2014-2019). In this study, we determine if differences in DNAm exist between women who reported a preterm birth in the last 3-5 years compared to those who had full-term births by using two different approaches: epigenome-wide association study (EWAS) and genome-wide co-methylation analyses.Though no significant CpG sites were identified using the EWAS approach, we did identify significant modules of co-methylation associated with preterm birth. Co-methylation analyses showed correlations with preterm birth in gene ontology and KEGG pathways. Functional annotation analysis revealed enrichment for pathways related to central nervous system and sensory perception. No association was observed between DNAm age and preterm birth, though larger samples are needed to confirm this further.We identified differentially methylated gene networks associated with preterm birth in African American women 3-5 years after birth, including pathways related to neurogenesis and sensory processing. More research is needed to understand better these associations and replicate them in an independent cohort. Further study should be done in this area to elucidate mechanisms linking preterm birth and later epigenomic changes that may contribute to the development of health disorders and maternal mood and well-being.© 2021. The Author(s).",
-,Yes,20210920,ewas,34473906,Infant RSV immunoprophylaxis changes nasal epithelial DNA methylation at 6 years of age.,Pediatr Pulmonol,"Respiratory syncytial virus (RSV) infection has been associated with childhood wheeze and asthma, and potential mechanisms include persistent epigenetic effects.In the randomized, placebo-controlled MAKI trial, 429 preterm infants randomly received RSV immunoprophylaxis with palivizumab or placebo during their first RSV season. Children were followed until age 6 for asthma evaluation. DNA methylation in cells obtained by nasal brushes at age 6 was measured by Illumina MethylationEPIC array.RSV immunoprophylaxis in infancy had a significant impact on global methylation patterns in nasal cells at age 6. The first principal component (PC) related to the immunoprophylaxis intervention was enriched for the pathway ""detection of chemical stimulus involved in sensory perception of smell"" and ""T cell differentiation."" Subsequent analysis of these PCs indicated an effect of RSV immunoprophylaxis on cell type composition of nasal brushed cells. Three CpG sites, cg18040241, cg08243963, and cg19555973 which are annotated to genes GLB1L2, SC5D, and BPIFB1, were differentially methylated at genome-wide significance, but were not associated with asthma.The study provides the first proof of concept that RSV immunoprophylaxis during infancy has long-term effects on nasal epigenetic signatures at age 6, relating to host sensory perception, epidermal growth factor receptor signaling, and adaptive immune responses.© 2021 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.",
-,Yes,20210920,ewas,34461807,Association between dietary patterns reflecting one-carbon metabolism nutrients intake before pregnancy and placental DNA methylation.,Epigenetics,"The preconception period represents an important window for foetal and epigenetic programming. Some micronutrients (B vitamins, choline, betaine, methionine) implicated in one-carbon metabolism (OCM) are essential for major epigenetic processes that take place in early pregnancy. However, few studies have evaluated the implication of the micronutrients in placental DNA methylation. We investigated whether intake of OCM nutrients in the year before pregnancy was associated with placental DNA methylation in the EDEN mother-child cohort. Maternal dietary intake was assessed with a food-frequency questionnaire. Three dietary patterns, 'varied and balanced diet,' 'vegetarian tendency,' and 'bread and starchy food,' were used to characterize maternal OCM dietary intake. The Illumina Infinium HumanMethylation450 BeadChip was used to measure placental DNA methylation of 573 women included in the analyses. We evaluated the association of dietary patterns with global DNA methylation. Then, we conducted an agnostic epigenome-wide association study (EWAS) and investigated differentially methylated regions (DMRs) associated with each dietary pattern. We found no significant association between the three dietary patterns and global DNA methylation or individual CpG sites. DMR analyses highlighted associations between the 'varied and balanced' or 'vegetarian tendency' pattern and DMRs located at genes previously implicated in functions essential for embryonic development, such as neurodevelopment. The 'bread and starchy food' pattern was associated with regions related to genes whose functions involve various metabolic and cell synthesis-related processes. In mainly well-nourished French women without major deficiencies, OCM intake before pregnancy was not associated with major variation in DNA methylation.",
-,Yes,20210920,ewas,34427971,Age patterns of intra-pair DNA methylation discordance in twins: Sex difference in epigenomic instability and implication on survival.,Aging Cell,"Aging is a biological process linked to specific patterns and changes in the epigenome. We hypothesize that age-related variation in the DNA methylome could reflect cumulative environmental modulation to the epigenome which could impact epigenomic instability and survival differentially by sex. To test the hypothesis, we performed sex-stratified epigenome-wide association studies on age-related intra-pair DNA methylation discordance in 492 twins aged 56-80 years. We identified 3084 CpGs showing increased methylation variability with age (FDR < 0.05, 7 CpGs with p < 1e-07) in male twins but no significant site found in female twins. The results were replicated in an independent cohort of 292 twins aged 30-74 years with 37% of the discovery CpGs successfully replicated in male twins. Functional annotation showed that genes linked to the identified CpGs were significantly enriched in signaling pathways, neurological functions, extracellular matrix assembly, and cancer. We further explored the implication of discovery CpGs on individual survival in an old cohort of 224 twins (220 deceased). In total, 264 CpGs displayed significant association with risk of death in male twins. In female twins, 175 of the male discovery CpGs also showed non-random correlation with mortality. Intra-pair comparison showed that majority of the discovery CpGs have higher methylation in the longer-lived twins suggesting that loss of DNA methylation during aging contributes to increased risk of death which is more pronounced in male twins. In conclusion, age-related epigenomic instability in the DNA methylome is more evident in males than in females and could impact individual survival and contribute to sex difference in human lifespan.© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
-,Yes,20210920,ewas,34425644,Methylation biomarkers of polybrominated diphenyl ethers (PBDEs) and association with breast cancer risk at the time of menopause.,Environ Int,"Exposure to polybrominated diphenyl ethers (PBDEs) may influence risk of developing post-menopausal breast cancer. Although mechanisms are poorly understood, epigenetic regulation of gene expression may play a role.To identify DNA methylation (DNAm) changes associated with PBDE serum levels and test the association of these biomarkers with breast cancer risk.We studied 397 healthy women (controls) and 133 women diagnosed with breast cancer (cases) between ages 40 and 58 years who participated in the California Teachers Study. PBDE levels were measured in blood. Infinium Human Methylation EPIC Bead Chips were used to measure DNAm. Using multivariable linear regression models, differentially methylated CpG sites (DMSs) and regions (DMRs) associated with serum PBDE levels were identified using controls. For top-ranked DMSs and DMRs, targeted next-generation bisulfite sequencing was used to measure DNAm for 133 invasive breast cancer cases and 301 age-matched controls. Conditional logistic regression was used to evaluate associations between DMSs and DMRs and breast cancer risk.We identified 15 DMSs and 10 DMRs statistically significantly associated with PBDE levels (FDR < 0.05). Methylation changes in a DMS at BMP8B and DMRs at TP53 and A2M-AS1 were statistically significantly (FDR < 0.05) associated with breast cancer risk.We show for the first time that serum PBDE levels are associated with differential methylation and that PBDE-associated DNAm changes in blood are associated with breast cancer risk.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",
-,Yes,20210920,ewas,34415308,Epigenome-wide association study of mitochondrial genome copy number.,Hum Mol Genet,"We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10-7), with a 0.7 to 3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes (PRDM16, NR1H3, XRCC3, POLK, and PDSS2), which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, p = 4 x 10-8) and positively associated with the NR1H3 expression level (effect size = 0.43, p = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor, and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,Yes,20210920,ewas,34429407,Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth.,Nat Commun,"Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.© 2021. The Author(s).",
-,No,20211004,epigenetics,34551299,DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity.,Cell Rep,"DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation.Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.",
-,No,20211004,epigenetics,34526716,UTX condensation underlies its tumour-suppressive activity,Nature,"UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers1. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.",
-,No,20211004,epigenetics,34526684,Protein condensates provide a platform for controlling chromatin.,Nature,,
-,Yes,20211004,ewas,34585950,Impact of depression and stress on placental DNA methylation in ethnically diverse pregnant women.,Epigenomics,"Aim:To investigate the association between placental genome-wide methylation at birth and antenatal depression and stress during pregnancy.Methods:We examined the association between placental genome-wide DNA methylation (n = 301) and maternal depression and stress assessed at six gestation periods during pregnancy. Correlation between DNA methylation at the significantly associated CpGs and expression of nearby genes in the placenta was tested.Results:Depression and stress were associated with methylation of 16 CpGs and two CpGs, respectively, at a 5% false discovery rate. Methylation levels at two of the CpGs associated with depression were significantly associated with expression ofADAM23andCTDP1, genes implicated in neurodevelopment and neuropsychiatric diseases.Conclusion:Placental epigenetic changes linked to antenatal depression suggest potential fetal brain programming. Clinical trial registration number: NCT00912132 (ClinicalTrials.gov).",
-,Yes,20211004,ewas,34583751,Investigating the DNA methylation profile of e-cigarette use.,Clin Epigenetics,"Little evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use.Among 117 smokers, 117 non-smokers and 116 non-smoking vapers, we evaluated associations between e-cigarette use and epigenome-wide methylation from saliva. DNA methylation at 7 cytosine-phosphate-guanine sites (CpGs) was associated with e-cigarette use at p < 1 × 10-5and none at p < 5.91 × 10-8. 13 CpGs were associated with smoking at p < 1 × 10-5and one at p < 5.91 × 10-8. CpGs associated with e-cigarette use were largely distinct from those associated with smoking. There was strong enrichment of known smoking-related CpGs in the smokers but not the vapers. We also tested associations between e-cigarette use and methylation scores known to predict smoking and biological ageing. Methylation scores for smoking and biological ageing were similar between vapers and non-smokers. Higher levels of all smoking scores and a biological ageing score (GrimAge) were observed in smokers. A methylation score for e-cigarette use showed poor prediction internally (AUC 0.55, 0.41-0.69) and externally (AUC 0.57, 0.36-0.74) compared with a smoking score (AUCs 0.80) and was less able to discriminate lung squamous cell carcinoma from adjacent normal tissue (AUC 0.64, 0.52-0.76 versus AUC 0.73, 0.61-0.85).The DNA methylation profile for e-cigarette use is largely distinct from that of cigarette smoking, did not replicate in independent samples, and was unable to discriminate lung cancer from normal tissue. The extent to which methylation related to long-term e-cigarette use translates into chronic effects requires further investigation.© 2021. The Author(s).",
-,Yes,20211004,ewas,34569420,"Associations between infant sex and DNA methylation across umbilical cord blood, artery, and placenta samples.",Epigenetics,"DNA methylation (DNAm) is vulnerable to dysregulation by environmental exposures during epigenetic reprogramming that occurs in embryogenesis. Sexual dimorphism in environmentally induced DNAm dysregulation has been identified and therefore it is important to understand sex-specific DNAm patterns. DNAm at several autosomal sites has been consistently associated with sex in cord blood and placental fetal tissues. However, there is limited research comparing sex-specific DNAm across tissues, particularly differentially methylated regions (DMRs). This study leverages DNAm data measured using the Illumina HumanMethylation450 BeadChip in cord blood (N = 179), placenta (N = 229), and umbilical artery samples (N = 229) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort to identify autosomal DMRs and differentially methylated positions (DMPs). A replication analyses was conducted in an independent cohort (GEO Accession GSE129841). We identified 183, 257, and 419 DMRs and 2119, 2281, and 3405 DMPs (pBonferroni< 0.05) in cord blood, placenta, and artery samples, respectively. Thirty-nine DMRs overlapped in all three tissues, overlapping with genes involved in spermatogenesis (NKAPL, PIWIL2, AURKC) and X-inactivation (LRIF1). In replication analysis, 85% of DMRs overlapped with those identified in PRISM. Overall DMRs and DMPs had higher methylation levels among females in cord blood and artery samples, but higher methylation levels among males in placenta samples. Further research is necessary to understand biological mechanisms that contribute to differences in sex-specific DNAm signatures across tissues, as well as to determine if sexual dimorphism in the epigenome impacts response to environmental stressors.",
-,Yes,20211004,ewas,34561420,SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study.,Transl Psychiatry,"Conduct disorder (CD), a psychiatric disorder characterized by a repetitive pattern of antisocial behaviors, results from a complex interplay between genetic and environmental factors. The clinical presentation of CD varies both according to the individual's sex and level of callous-unemotional (CU) traits, but it remains unclear how genetic and environmental factors interact at the molecular level to produce these differences. Emerging evidence in males implicates methylation of genes associated with socio-affective processes. Here, we combined an epigenome-wide association study with structural neuroimaging in 51 females with CD and 59 typically developing (TD) females to examine DNA methylation in relation to CD, CU traits, and gray matter volume (GMV). We demonstrate an inverse pattern of correlation between CU traits and methylation of a chromosome 1 region in CD females (positive) as compared to TD females (negative). The identified region spans exon 1 of the SLC25A24 gene, central to energy metabolism due to its role in mitochondrial function. Increased SLC25A24 methylation was also related to lower GMV in multiple brain regions in the overall cohort. These included the superior frontal gyrus, prefrontal cortex, and supramarginal gyrus, secondary visual cortex and ventral posterior cingulate cortex, which are regions that have previously been implicated in CD and CU traits. While our findings are preliminary and need to be replicated in larger samples, they provide novel evidence that CU traits in females are associated with methylation levels in a fundamentally different way in CD and TD, which in turn may relate to observable variations in GMV across the brain.© 2021. The Author(s).",
-,Yes,20211004,ewas,34556110,Epigenome-wide association study detects a novel loci associated with central obesity in healthy subjects.,BMC Med Genomics,"Central obesity is a condition that poses a significant risk to global health and requires the employment of novel scientific methods for exploration. The objective of this study is to use DNA methylation analysis to detect DNA methylation loci linked to obesity phenotypes, i.e. waist circumference and waist-to-hip ratio adjusted for BMI.Two-hundred and ten healthy European participants from the STANISLAS Family Study (SFS), comprising 73 nuclear families, were comprehensively assessed for methylation status using Illumina Infinium HumanMethylation450 BeadChip. An epigenome-wide association study was performed, which identified a CpG site cg16170243 located on chromosome 18q21.2 significantly associated with waist circumference, after adjusting for BMI (β = 2.32, SE = 0.41, Padj = 0.048). Cg16170243 corresponds to a 50 bp-length human methylation oligoprobe located within the AC090241.2 gene that overlaps ST8SIA5 gene. No significant association was observed with waist-to-hip ratio adjusted for BMI (Padj > 0.05).A novel association between DNA methylation and WC was identified, which is demonstrating that epigenetic mechanisms may have a significant impact on waist circumference ratio in healthy individuals. Further studies are warranted to address the causal effects of this association.© 2021. The Author(s).",
-,Yes,20211004,ewas,34541665,A methylation study implicates the rewiring of brain neural circuits during puberty in the emergence of sex differences in depression symptoms.,J Child Psychol Psychiatry,"Women are 1.5-3 times more likely to suffer from depression than men. This sex bias first emerges during puberty and then persists across the reproductive years. As the cause remains largely elusive, we performed a methylation-wide association study (MWAS) to generate novel hypotheses.We assayed nearly all 28 million possible methylation sites in blood in 595 blood samples from 487 participants aged 9-17. MWASs were performed to identify methylation sites associated with increasing sex differences in depression symptoms as a function of pubertal stage. Epigenetic deconvolution was applied to perform analyses on a cell-type specific level.In monocytes, a substantial number of significant associations were detected after controlling the FDR at 0.05. These results could not be explained by plasma testosterone/estradiol or current/lifetime trauma. Our top results in monocytes were significantly enriched (ratio of 2.48) for genes in the top of a large genome-wide association study (GWAS) meta-analysis of depression and neurodevelopment-related Gene Ontology (GO) terms that remained significant after correcting for multiple testing. Focusing on our most robust findings (70 genes overlapping with the GWAS meta-analysis and the significant GO terms), we find genes coding for members of each of the major classes of axon guidance molecules (netrins, slits, semaphorins, ephrins, and cell adhesion molecules). Many of these genes were previously implicated in rodent studies of brain development and depression-like phenotypes, as well as human methylation, gene expression and GWAS studies.Our study suggests that the emergence of sex differences in depression may be related to the differential rewiring of brain circuits between boys and girls during puberty.© 2021 Association for Child and Adolescent Mental Health.",
-,Yes,20211004,ewas,34539625,Genome-Wide DNA Methylation Profile in Whole Blood of Patients With Chronic Spontaneous Urticaria.,Front Immunol,"Chronic spontaneous urticaria (CSU) is a common autoimmune skin disease. Little is known about the role of epigenetics in the pathogenesis of CSU. This study aimed to investigate genome-wide DNA methylation profile in whole blood of patients with CSU.Genome-wide DNA methylation levels in whole blood samples of 95 Chinese Han ethnicity adult CSU patients and 95 ethnicity-, age- and sex-matched healthy controls were analyzed using Illumina 850K methylation chip. The differentially methylated genes (DMGs) were screened out and then functionally annotated by the gene ontology and the Kyoto encyclopedia of genes and genomes databases.A total of 439 differentially methylated positions (DMPs) (p< 0.01 and |Δβ| ≥ 0.06) were identified with 380 hypomethylated and 59 hypermethylated. The average global DNA methylation levels of the 439 DMPs in the CSU patients were significantly lower than those in the healthy controls (p< 0.001). The distribution of the 439 DMPs was wide on chromosome 1 to 22 and chromosome X. Chromosome 6 embodied the largest number of DMPs (n= 51) and their annotated genes were predominantly related to autoimmunity. The 304 annotated DMGs were mainly enriched in autoimmune disease- and immune-related pathways. A total of 41 DMPs annotated to 28 DMGs were identified whenp< 0.01 and |Δβ| ≥ 0.1. Of the 28 DMGs, HLA-DPB2, HLA-DRB1, PPP2R5C, and LTF were associated with autoimmunity. CSU cases with elevated total IgE, positive anti-thyroid peroxidase IgG autoantibodies, positive anti-thyroglobulin IgG autoantibodies, angioedema, UASday > 4, or recurrent CSU showed phenotype-specific DMPs as compared with cases with normal total IgE, negative anti-thyroid peroxidase IgG autoantibodies, negative anti-thyroglobulin IgG autoantibodies, no angioedema, UASday ≤ 4, or non-recurrent CSU respectively.This study shows a distinct genome-wide DNA methylation profile in Chinese Han ethnicity adult CSU patients and indicates a role of epigenetics in the pathogenesis of CSU. The predominant enrichment of the CSU-associated DMGs in immunological pathways provides supportive evidence for the immunopathogenesis of CSU. Future research on the CSU-associated DMPs and DMGs will help discover potential therapeutic targets for CSU.Copyright © 2021 Qi, Zhang, Yang, Tang and Xiao.",
-,Yes,20211004,ewas,34529553,Prenatal exposure to endocrine disrupting chemicals is associated with altered DNA methylation in cord blood.,Epigenetics,"Prenatal exposure to endocrine disrupting chemicals can interfere with development, and has been associated with social-cognitive functioning and adverse health outcomes later in life. Exposure-associated changes of DNA methylation (DNAm) patterns have been suggested as a possible mediator of this relationship. This study investigated whether prenatal low-dose exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) is associated with altered DNAm patterns across the genome in a Western urban-industrial population. In 142 mother-infant pairs from the Duisburg Birth Cohort Study, PCBs and PCDD/Fs levels were quantified from maternal blood during late pregnancy and associated with DNAm levels in cord blood using the Illumina EPIC beadchip. The epigenome-wide association studies (EWAS) identified 32 significantly differentially methylated positions (DMPs) and eight differentially methylated regions (DMRs) associated with six congeners of PCB and PCDD in females or males (FDRs < 0.05). DMPs and DMRs mapped to genes involved in neurodevelopment, gene regulation, and immune functioning. Weighted gene correlation network analysis (WGCNA) showed 31 co-methylated modules (FDRs < 0.05) associated with one congener of PCDF levels in females. Results of both analytical strategies indicate that prenatal exposure to PCBs and PCDD/Fs is associated with altered DNAm of genes involved in neurodevelopment, gene expression and immune functioning. DNAm and gene expression levels of several of these genes were previously associated with EDC exposure in rodent models. Follow-up studies will clarify whether these epigenetic changes might contribute to the origin for adverse mental and health outcomes.",
-,Yes,20211004,ewas,34584077,Identical twins carry a persistent epigenetic signature of early genome programming.,Nat Commun,"Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.© 2021. The Author(s).",
-,No,20211004,ewas,34531495,DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers.,Sci Rep,"The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM, RIPOR2, AFAP1 and MOCOS. In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation-the key agent in trauma focused treatments-and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma.Trial registration: Addressing Heightened Levels of Aggression in Traumatized Offenders With Psychotherapeutic Means (ClinicalTrials.gov Identifier: NCT02992561, 14/12/2016).© 2021. The Author(s).",
-,No,20211004,methods,34548083,Revisiting genetic artifacts on DNA methylation microarrays exposes novel biological implications.,Genome Biol,"Illumina DNA methylation microarrays enable epigenome-wide analysis vastly used for the discovery of novel DNA methylation variation in health and disease. However, the microarrays' probe design cannot fully consider the vast human genetic diversity, leading to genetic artifacts. Distinguishing genuine from artifactual genetic influence is of particular relevance in the study of DNA methylation heritability and methylation quantitative trait loci. But despite its importance, current strategies to account for genetic artifacts are lagging due to a limited mechanistic understanding on how such artifacts operate.To address this, we develop and benchmark UMtools, an R-package containing novel methods for the quantification and qualification of genetic artifacts based on fluorescence intensity signals. With our approach, we model and validate known SNPs/indels on a genetically controlled dataset of monozygotic twins, and we estimate minor allele frequency from DNA methylation data and empirically detect variants not included in dbSNP. Moreover, we identify examples where genetic artifacts interact with each other or with imprinting, X-inactivation, or tissue-specific regulation. Finally, we propose a novel strategy based on co-methylation that can discern between genetic artifacts and genuine genomic influence.We provide an atlas to navigate through the huge diversity of genetic artifacts encountered on DNA methylation microarrays. Overall, our study sets the ground for a paradigm shift in the study of the genetic component of epigenetic variation in DNA methylation microarrays.© 2021. The Author(s).",
-,No,20211004,methods,34556866,"Reproducible, scalable, and shareable analysis pipelines with bioinformatics workflow managers.",Nat Methods,"The rapid growth of high-throughput technologies has transformed biomedical research. With the increasing amount and complexity of data, scalability and reproducibility have become essential not just for experiments, but also for computational analysis. However, transforming data into information involves running a large number of tools, optimizing parameters, and integrating dynamically changing reference data. Workflow managers were developed in response to such challenges. They simplify pipeline development, optimize resource usage, handle software installation and versions, and run on different compute platforms, enabling workflow portability and sharing. In this Perspective, we highlight key features of workflow managers, compare commonly used approaches for bioinformatics workflows, and provide a guide for computational and noncomputational users. We outline community-curated pipeline initiatives that enable novice and experienced users to perform complex, best-practice analyses without having to manually assemble workflows. In sum, we illustrate how workflow managers contribute to making computational analysis in biomedical research shareable, scalable, and reproducible.© 2021. Springer Nature America, Inc.",
-,No,20211004,methods,34527193,Application of long-read sequencing to the detection of structural variants in human cancer genomes.,Comput Struct Biotechnol J,"In recent years, the so-called long-read sequencing technology has had a substantial impact on various aspects of genome sciences. Here, we introduce recent studies of cancerous structural variants (SVs) using long-read sequencing technologies, namely Pacific Biosciences (PacBio) sequencers, Oxford Nanopore Technologies (ONT) sequencers, and linked-read methods. By taking advantage of long-read lengths, these technologies have enabled the precise detection of SVs, including long insertions by transposable elements, such as LINE-1. In addition to SV detection, the epigenome status (including DNA methylation and haplotype information) surrounding SV loci has also been unveiled by long-read sequencing technologies, to identify the effects of SVs. Among the various research fields in which long-read sequencing has been applied, cancer genomics has shown the most remarkable advances. In fact, many studies are beginning to shed light on the detection of SVs and the elucidation of their complex structures in various types of cancer. In the particular case of cancers, we summarize the technical limitations of the application of this technology to the analysis of clinical samples. We will introduce recent achievements from this viewpoint. However, a similar approach will be started for other applications in the near future. Therefore, by complementing the current short-read sequencing analysis, long-read sequencing should reveal the complex nature of human genomes in their healthy and disease states, which will open a new opportunity for a better understanding of disease development and for a novel strategy for drug development.© 2021 The Authors.",
-,No,20211004,prediction,34556700,Identification of early and intermediate biomarkers for ARDS mortality by multi-omic approaches.,Sci Rep,"The lack of successful clinical trials in acute respiratory distress syndrome (ARDS) has highlighted the unmet need for biomarkers predicting ARDS mortality and for novel therapeutics to reduce ARDS mortality. We utilized a systems biology multi-""omics"" approach to identify predictive biomarkers for ARDS mortality. Integrating analyses were designed to differentiate ARDS non-survivors and survivors (568 subjects, 27% overall 28-day mortality) using datasets derived from multiple 'omics' studies in a multi-institution ARDS cohort (54% European descent, 40% African descent). 'Omics' data was available for each subject and included genome-wide association studies (GWAS, n = 297), RNA sequencing (n = 93), DNA methylation data (n = 61), and selective proteomic network analysis (n = 240). Integration of available ""omic"" data identified a 9-gene set (TNPO1, NUP214, HDAC1, HNRNPA1, GATAD2A, FOSB, DDX17, PHF20, CREBBP) that differentiated ARDS survivors/non-survivors, results that were validated utilizing a longitudinal transcription dataset. Pathway analysis identified TP53-, HDAC1-, TGF-β-, and IL-6-signaling pathways to be associated with ARDS mortality. Predictive biomarker discovery identified transcription levels of the 9-gene set (AUC-0.83) and Day 7 angiopoietin 2 protein levels as potential candidate predictors of ARDS mortality (AUC-0.70). These results underscore the value of utilizing integrated ""multi-omics"" approaches in underpowered datasets from racially diverse ARDS subjects.© 2021. The Author(s).",
-,No,20211004,prediction,34526487,DNA methylation of the glucocorticoid receptor gene predicts substance use in adolescence: longitudinal data from over 1000 young individuals.,Transl Psychiatry,"Early life stress has been linked to increased methylation of the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene, which codes for the glucocorticoid receptor. Moreover, early life stress has been associated with substance use initiation at a younger age, a risk factor for developing substance use disorders. However, no studies to date have investigated whether NR3C1 methylation can predict substance use in young individuals. This study included adolescents 13-14 years of age that reported no history of substance use at baseline, (N = 1041; males = 46%). Participants contributed saliva DNA samples and were followed in middle adolescence as part of KUPOL, a prospective cohort study of 7th-grade students in Sweden. Outcome variables were self-reports of (i) recent use, (ii) lifetime use, and (iii) use duration of (a) alcohol, (b) tobacco products, (c) cannabis, or (d) any substance. Outcomes were measured annually for three consecutive years. The predictor variable was DNA methylation at the exon 1 F locus of NR3C1. Risk and rate ratios were calculated as measures of association, with or without adjustment for internalizing symptoms and parental psychiatric disorders. For a subset of individuals (N = 320), there were also morning and afternoon salivary cortisol measurements available that were analyzed in relation to NR3C1 methylation levels. Baseline NR3C1 hypermethylation associated with future self-reports of recent use and use duration of any substance, before and after adjustment for potential confounders. The overall estimates were attenuated when considering lifetime use. Sex-stratified analyses revealed the strongest association for cigarette use in males. Cortisol analyses revealed associations between NR3C1 methylation and morning cortisol levels. Findings from this study suggest that saliva NR3C1 hypermethylation can predict substance use in middle adolescence. Additional longitudinal studies are warranted to confirm these findings.© 2021. The Author(s).",
-,No,20211004,methods,34019650,Long-read whole-genome methylation patterning using enzymatic base conversion and nanopore sequencing,Nucleic Acids Res,"Long-read whole-genome sequencing analysis of DNA methylation would provide useful information on the chromosomal context of gene expression regulation. Here we describe the development of a method that improves the read length generated by using the bisulfite-sequencing-based approach. In this method, we combined recently developed enzymatic base conversion, where an unmethylated cytosine (C) should be converted to thymine (T), with nanopore sequencing. After methylation-sensitive base conversion, the sequencing library was constructed using long-range polymerase chain reaction. This type of analysis is possible using a minimum of 1 ng genomic DNA, and an N50 read length of 3.4–7.6 kb is achieved. To analyze the produced data, which contained a substantial number of base mismatches due to sequence conversion and an inaccurate base read of the nanopore sequencing, a new analytical pipeline was constructed. To demonstrate the performance of long-read methylation sequencing, breast cancer cell lines and clinical specimens were subjected to analysis, which revealed the chromosomal methylation context of key cancer-related genes, allele-specific methylated genes, and repetitive or deletion regions. This method should convert the intractable specimens for which the amount of available genomic DNA is limited to the tractable targets.",
-,Yes,20211018,ewas,34633450,Dichotomy in the Impact of Elevated Maternal Glucose Levels on Neonatal Epigenome.,J Clin Endocrinol Metab,"Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child.We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation.This study included 830 mother-offspring dyads from the GUSTO cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (FPG) and 2h plasma glucose (2hPG) post-75g oral glucose challenge (OGTT) with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately.Maternal age, pre-pregnancy BMI and blood pressure measures were associated with both FPG and 2hPG; while Chinese ethnicity (p=1.9×10 -4), maternal height (p=1.1×10 -4), pregnancy weight gain (p=2.2×10 -3), pre-pregnancy alcohol consumption (p=4.6×10 -4), and tobacco exposure (p=1.9×10 -3) showed significantly opposite associations between the two glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the two glucose measures also reflected differences in gene ontologies and had different associations with offspring birthweight.Our findings suggest that two traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.",
-,No,20211018,ewas,34628353,Genome-wide analysis of DNA methylation in 106 schizophrenia family trios in Han Chinese.,EBioMedicine,"Schizophrenia (SCZ) is a severe psychiatric disorder that affects approximately 0.75% of the global population. Both genetic and environmental factors contribute to development of SCZ. SCZ tends to run in family while both genetic and environmental factor contribute to its etiology. Much evidence suggested that alterations in DNA methylations occurred in SCZ patients.To investigate potential inheritable pattern of DNA methylation in SCZ family, we performed a genome-wide analysis of DNA methylation of peripheral blood samples from 106 Chinese SCZ family trios. Genome-wide DNA methylations were quantified by Agilent 1 × 244 k Human Methylation Microarray.In this study, we proposed a loci inheritance frequency model that allows characterization of differential methylated regions as SCZ biomarkers. Based on this model, 112 hypermethylated and 125 hypomethylated regions were identified. Additionally, 121 hypermethylated and 139 hypomethylated genes were annotated. The results of functional enrichment analysis indicated that multiple differentially methylated genes (DMGs) involved in Notch/HH/Wnt signaling, MAPK signaling, GPCR signaling, immune response signaling. Notably, a number of hypomethylated genes were significantly enriched in cerebral cortex and functionally enriched in nervous system development.Our findings not only validated previously discovered risk genes of SCZ but also identified novel candidate DMGs in SCZ. These results may further the understanding of altered DNA methylations in SCZ.Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.",
-,Yes,20211018,ewas,34600028,Differential regulation of the DNA methylome in adults born during the Great Chinese Famine in 1959-1961.,Genomics,"Extensive epidemiological studies have established the association between exposure to early-life adversity and health status and diseases in adults. Epigenetic regulation is considered as a key mediator for this phenomenon but analysis on humans is sparse. The Great Chinese Famine lasting from 1958 to 1961 is a natural string of disasters offering a precious opportunity for elucidating the underlying epigenetic mechanism of the long-term effect of early adversity.Using a high-throughput array platform for DNA methylome profiling, we conducted a case-control epigenome-wide association study on early-life exposure to Chinese famine in 79 adults born during 1959-1961 and compared to 105 unexposed subjects born 1963-1964.The single CpG site analysis of whole epigenome revealed a predominant pattern of decreased DNA methylation levels associated with fetal exposure to famine. Four CpG sites were detected with p < 1e-06 (linked to EHMT1, CNR1, UBXN7 and ESM1 genes), 16 CpGs detected with 1e-06 < p < 1e-05 and 157 CpGs with 1e-05 < p < 1e-04, with a predominant pattern of hypomethylation. Functional annotation to genes and their enriched biological pathways mainly involved neurodevelopment, neuropsychological disorders and metabolism. Multiple sites analysis detected two top-rank differentially methylated regions harboring RNF39 on chromosome 6 and PTPRN2 on chromosome 7, both showing epigenetic association with stress-related conditions.Early-life exposure to famine could mediate DNA methylation regulations that persist into adulthood with broad impacts in the activities of genes and biological pathways. Results from this study provide new clues to the epigenetic embedding of early-life adversity and its impacts on adult health.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
-,Yes,20211018,ewas,34596421,Associations between an integrated component of maternal glycemic regulation in pregnancy and cord blood DNA methylation.,Epigenomics,"Background:Previous studies suggest that fetal programming to hyperglycemia in pregnancy is due to modulation of DNA methylation (DNAm), but they have been limited in their maternal glycemic characterization.Methods:In the Gen3G study, we used a principal component analysis to integrate multiple glucose and insulin values measured during the second trimester oral glucose tolerance test. We investigated associations between principal components and cord blood DNAm levels in an epigenome-wide analysis among 430 mother-child pairs.Results:The first principal component was robustly associated with lower DNAm at cg26974062 (TXNIP; p = 9.9 × 10-9) in cord blood.TXNIPis a well-known DNAm marker for type 2 diabetes in adults.Conclusion:We hypothesize that abnormal glucose metabolism in pregnancy may program dysregulation ofTXNIPacross the life course.",
-,No,20211018,prediction,34534207,Hierarchy and control of ageing-related methylation networks.,PLoS Comput Biol,"DNA methylation provides one of the most widely studied biomarkers of ageing. Since the methylation of CpG dinucleotides function as switches in cellular mechanisms, it is plausible to assume that by proper adjustment of these switches age may be tuned. Though, adjusting hundreds of CpG methylation levels coherently may never be feasible and changing just a few positions may lead to biologically unstable state. A prominent example of methylation-based age estimators is provided by Horvath's clock, based on 353 CpG dinucleotides, showing a high correlation (not necessarily causation) with chronological age across multiple tissue types. On this small subset of CpG dinucleotides we demonstrate how the adjustment of one methylation level leads to a cascade of changes at other sites. Among the studied subset, we locate the most important CpGs (and related genes) that may have a large influence on the rest of the sub-system. According to our analysis, the structure of this network is way more hierarchical compared to what one would expect based on ensembles of uncorrelated connections. Therefore, only a handful of CpGs is enough to modify the system towards a desired state. When propagation of the change over the network is taken into account, the resulting modification in the predicted age can be significantly larger compared to the effect of isolated CpG perturbations. By adjusting the most influential single CpG site and following the propagation of methylation level changes we can reach up to 5.74 years in virtual age reduction, significantly larger than without taking into account of the network control. Extending our approach to the whole methylation network may identify key nodes that have controller role in the ageing process.",
-,No,20211018,genetics,34594039,A cross-population atlas of genetic associations for 220 human phenotypes.,Nat Genet,"Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20211018,single-cell,34616061,DNA methylation atlas of the mouse brain at single-cell resolution.,Nature,"Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing1,2to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data3enabled prediction of high-confidence enhancer-gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments4. By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum.© 2021. The Author(s).",
-,No,20211018,prediction,34587932,"Combined effects of cigarette smoking, DNA methyltransferase 3B genetic polymorphism, and DNA damage on lung cancer.",BMC Cancer,"Smoking increases DNA methylation and DNA damage, and DNA damage acts as a vital cause of tumor development. The DNA methyltransferase 3B (DNMT3B) enhances promoter activity and methylation of tumor suppressor genes. Tea polyphenols may inhibit DNMT activity. We designed a case-control study to evaluate the combined effects of smoking, green tea consumption, DNMT3B - 149 polymorphism, and DNA damage on lung cancer occurrence.Questionnaires were administered to obtain demographic characteristics, life styles, and family histories of lung cancer from 190 primary lung cancer cases and 380 healthy controls. Genotypes and cellular DNA damage were determined by polymerase chain reaction and comet assay, respectively.The mean DNA tail moment for lung cancer cases was significantly higher than that for healthy controls. Compared to nonsmokers carrying the DNMT3B - 149 CT genotype, smokers carrying the TT genotype had a greater lung cancer risk (odds ratio [OR]: 2.83, 95% confidence interval [CI]: 1.62-4.93). DNA damage levels were divided by the tertile of the healthy controls' values. Compared to nonsmokers with low DNA damage, smokers with moderate DNA damage (OR: 2.37, 95% CI: 1.54-3.63) and smokers with high DNA damage (OR: 3.97, 95% CI: 2.63-5.98) had elevated lung cancer risks. Interaction between smoking and DNA damage significantly affected lung cancer risk.Our study suggested that the DNMT3B - 149 TT genotype, which has higher promoter activity, can increase the lung cancer risk elicited by smoking, and DNA damage may further promote smoking related lung cancer development.© 2021. The Author(s).",
-,No,20211018,methods,34579788,"Deep learning in cancer diagnosis, prognosis and treatment selection.",Genome Med,"Deep learning is a subdiscipline of artificial intelligence that uses a machine learning technique called artificial neural networks to extract patterns and make predictions from large data sets. The increasing adoption of deep learning across healthcare domains together with the availability of highly characterised cancer datasets has accelerated research into the utility of deep learning in the analysis of the complex biology of cancer. While early results are promising, this is a rapidly evolving field with new knowledge emerging in both cancer biology and deep learning. In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools. We provide specific examples of how deep learning may be applied in cancer diagnosis, prognosis and treatment management. We also assess the current limitations and challenges for the application of deep learning in precision oncology, including the lack of phenotypically rich data and the need for more explainable deep learning models. Finally, we conclude with a discussion of how current obstacles can be overcome to enable future clinical utilisation of deep learning.© 2021. The Author(s).",
-,No,20211018,methods,34617014,"Deep learning identifies erroneous microarray-based, gene-level conclusions in literature.",NAR Genom Bioinform,"More than 110 000 publications have used microarrays to decipher phenotype-associated genes, clinical biomarkers and gene functions. Microarrays rely on digital assaying the fluorescence signals of arrays. In this study, we retrospectively constructed raw images for 37 724 published microarray data, and developed deep learning algorithms to automatically detect systematic defects. We report that an alarming amount of 26.73% of the microarray-based studies are affected by serious imaging defects. By literature mining, we found that publications associated with these affected microarrays have reported disproportionately more biological discoveries on the genes in the contaminated areas compared to other genes. 28.82% of the gene-level conclusions reported in these publications were based on measurements falling into the contaminated area, indicating severe, systematic problems caused by such contaminations. We provided the identified published, problematic datasets, affected genes and the imputed arrays as well as software tools for scanning such contamination that will become essential to future studies to scrutinize and critically analyze microarray data.© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
-,No,20211018,epigenetics,34593797,Chromatin accessibility associates with protein-RNA correlation in human cancer.,Nat Commun,"Although alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease.© 2021. The Author(s).",
-,No,20211018,methods,34415323,Multi-omics Data Integration by Generative Adversarial Network,Bioinformatics,,
-,No,20211018,methods,36277076,A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking,Nat Aging,"Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies, and clinical trials of aging interventions.
+No,20210607,methods,33957961,Tejaas: reverse regression increases power for detecting trans-eQTLs.,Genome Biol,"Trans-acting expression quantitative trait loci (trans-eQTLs) account for ≥70% expression heritability and could therefore facilitate uncovering mechanisms underlying the origination of complex diseases. Identifying trans-eQTLs is challenging because of small effect sizes, tissue specificity, and a severe multiple-testing burden. Tejaas predicts trans-eQTLs by performing L2-regularized ""reverse"" multiple regression of each SNP on all genes, aggregating evidence from many small trans-effects while being unaffected by the strong expression correlations. Combined with a novel unsupervised k-nearest neighbor method to remove confounders, Tejaas predicts 18851 unique trans-eQTLs across 49 tissues from GTEx. They are enriched in open chromatin, enhancers, and other regulatory regions. Many overlap with disease-associated SNPs, pointing to tissue-specific transcriptional regulation mechanisms.",
+No,20210607,methods,34020542,Interpretation of deep learning in genomics and epigenomics.,Brief Bioinform,"Machine learning methods have been widely applied to big data analysis in genomics and epigenomics research. Although accuracy and efficiency are common goals in many modeling tasks, model interpretability is especially important to these studies towards understanding the underlying molecular and cellular mechanisms. Deep neural networks (DNNs) have recently gained popularity in various types of genomic and epigenomic studies due to their capabilities in utilizing large-scale high-throughput bioinformatics data and achieving high accuracy in predictions and classifications. However, DNNs are often challenged by their potential to explain the predictions due to their black-box nature. In this review, we present current development in the model interpretation of DNNs, focusing on their applications in genomics and epigenomics. We first describe state-of-the-art DNN interpretation methods in representative machine learning fields. We then summarize the DNN interpretation methods in recent studies on genomics and epigenomics, focusing on current data- and computing-intensive topics such as sequence motif identification, genetic variations, gene expression, chromatin interactions and non-coding RNAs. We also present the biological discoveries that resulted from these interpretation methods. We finally discuss the advantages and limitations of current interpretation approaches in the context of genomic and epigenomic studies. Contact:xiaoman@mail.ucf.edu, haihu@cs.ucf.edu.© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+No,20210607,methods,33975646,On the optimistic performance evaluation of newly introduced bioinformatic methods.,Genome Biol,"Most research articles presenting new data analysis methods claim that ""the new method performs better than existing methods,"" but the veracity of such statements is questionable. Our manuscript discusses and illustrates consequences of the optimistic bias occurring during the evaluation of novel data analysis methods, that is, all biases resulting from, for example, selection of datasets or competing methods, better ability to fix bugs in a preferred method, and selective reporting of method variants. We quantitatively investigate this bias using an example from epigenetic analysis: normalization methods for data generated by the Illumina HumanMethylation450K BeadChip microarray.",
+Yes,20210607,omics,33958779,Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.,Nat Genet,"The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.",
+No,20210607,pwas,34045743,Human plasma proteomic profiles indicative of cardiorespiratory fitness.,Nat Metab,"Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans.",
+No,20210607,pwas,34016094,Metabolic syndrome and the plasma proteome: from association to causation.,Cardiovasc Diabetol,"The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering.Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization.Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71-0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = - 0.12, Wald-p = 3.63e-13), apolipoprotein B (APOB) (Wald-Ratio = - 0.09, Wald-p = 2.54e-04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e-04).Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.",
+No,20210607,pwas,33969320,"Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions.",Cell Rep Med,"Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.© 2021 The Authors.",
+No,20210607,single cell,34012112,Interpreting type 1 diabetes risk with genetics and single-cell epigenomics.,Nature,"Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding1. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types2. Here we combined two approaches: a genome-wide association study of type 1 diabetes (T1D) using 520,580 samples, and the identification of candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cells using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) of 131,554 nuclei. Risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression. At the CFTR locus, the T1D risk variant rs7795896 mapped to a ductal-specific cCRE that regulated CFTR; the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in the pathogenesis of T1D and highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease.",
+No,20210607,single cell,34024118,Single-Cell Epigenomics and Functional Fine-Mapping of Atherosclerosis GWAS Loci,Circ Res,"Rationale: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD). Many of these loci are enriched in cis-regulatory elements (CREs) but not linked to cardiometabolic risk factors nor to candidate causal genes, complicating their functional interpretation. Objective: Single nucleus chromatin accessibility profiling of the human atherosclerotic lesions was used to investigate cell type-specific patterns of CREs, to understand transcription factors establishing cell identity and to interpret CAD-relevant, non-coding genetic variation. Methods and Results: We used single nucleus ATAC-seq to generate DNA accessibility maps in > 7,000 cells derived from human atherosclerotic lesions. We identified five major lesional cell types including endothelial cells, smooth muscle cells, monocyte/macrophages, NK/T-cells and B-cells and further investigated subtype characteristics of macrophages and smooth muscle cells transitioning into fibromyocytes. We demonstrated that CAD associated genetic variants are particularly enriched in endothelial and smooth muscle cell-specific open chromatin. Using single cell co-accessibility and cis-eQTL information, we prioritized putative target genes and candidate regulatory elements for ~30% of all known CAD loci. Finally, we performed genome-wide experimental fine-mapping of the CAD GWAS variants using epigenetic QTL analysis in primary human aortic endothelial cells and STARR-Seq massively parallel reporter assay in smooth muscle cells. This analysis identified potential causal SNP(s) and the associated target gene for over 30 CAD loci. We present several examples where the chromatin accessibility and gene expression could be assigned to one cell type predicting the cell type of action for CAD loci. Conclusions: These findings highlight the potential of applying snATAC-seq to human tissues in revealing relative contributions of distinct cell types to diseases and in identifying genes likely to be influenced by non-coding GWAS variants.",
+No,20210628,dnam age,34162876,Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus.,Nat Commun,"The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.",
+No,20210628,dnam age,34120642,Does the epigenetic clock GrimAge predict mortality independent of genetic influences: an 18 year follow-up study in older female twin pairs.,Clin Epigenetics,"Epigenetic clocks are based on DNA methylation (DNAm). It has been suggested that these clocks are useable markers of biological aging and premature mortality. Because genetic factors explain variations in both epigenetic aging and mortality, this association could also be explained by shared genetic factors. We investigated the influence of genetic and lifestyle factors (smoking, alcohol consumption, physical activity, chronic diseases, body mass index) and education on the association of accelerated epigenetic aging with mortality using a longitudinal twin design. Utilizing a publicly available online tool, we calculated the epigenetic age using two epigenetic clocks, Horvath DNAmAge and DNAm GrimAge, in 413 Finnish twin sisters, aged 63-76 years, at the beginning of the 18-year mortality follow-up. Epigenetic age acceleration was calculated as the residuals from a linear regression model of epigenetic age estimated on chronological age (AAHorvath, AAGrimAge, respectively). Cox proportional hazard models were conducted for individuals and twin pairs.The results of the individual-based analyses showed an increased mortality hazard ratio (HR) of 1.31 (CI95: 1.13-1.53) per one standard deviation (SD) increase in AAGrimAge. The results indicated no significant associations of AAHorvathwith mortality. Pairwise mortality analyses showed an HR of 1.50 (CI95: 1.02-2.20) per 1 SD increase in AAGrimAge. However, after adjusting for smoking, the HR attenuated substantially and was statistically non-significant (1.29; CI95: 0.84-1.99). Similarly, in multivariable adjusted models the HR (1.42-1.49) was non-significant. In AAHorvath, the non-significant HRs were lower among monozygotic pairs in comparison to dizygotic pairs, while in AAGrimAgethere were no systematic differences by zygosity. Further, the pairwise analysis in quartiles showed that the increased within pair difference in AAGrimAgewas associated with a higher all-cause mortality risk.In conclusion, the findings suggest that DNAm GrimAge is a strong predictor of mortality independent of genetic influences. Smoking, which is known to alter DNAm levels and is built into the DNAm GrimAge algorithm, attenuated the association between epigenetic aging and mortality risk.",
+No,20210628,dnam age,34078457,DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function.,Clin Epigenetics,"The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E-06). The ""first-generation"" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria.DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.",
+No,20210628,dnam age,34035236,Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit.,Nat Commun,"We investigated the dynamic properties of the organism state fluctuations along individual aging trajectories in a large longitudinal database of CBC measurements from a consumer diagnostics laboratory. To simplify the analysis, we used a log-linear mortality estimate from the CBC variables as a single quantitative measure of the aging process, henceforth referred to as dynamic organism state indicator (DOSI). We observed, that the age-dependent population DOSI distribution broadening could be explained by a progressive loss of physiological resilience measured by the DOSI auto-correlation time. Extrapolation of this trend suggested that DOSI recovery time and variance would simultaneously diverge at a critical point of 120 - 150 years of age corresponding to a complete loss of resilience. The observation was immediately confirmed by the independent analysis of correlation properties of intraday physical activity levels fluctuations collected by wearable devices. We conclude that the criticality resulting in the end of life is an intrinsic biological property of an organism that is independent of stress factors and signifies a fundamental or absolute limit of human lifespan.",
+No,20210628,ewas,34112938,Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors.,Sci Rep,"Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p < 0.05) OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. These results suggest opportunities for better treatment strategies for NETs based on molecular features.",
+No,20210628,methods,34103055,Gene set enrichment analysis for genome-wide DNA methylation data.,Genome Biol,"DNA methylation is one of the most commonly studied epigenetic marks, due to its role in disease and development. Illumina methylation arrays have been extensively used to measure methylation across the human genome. Methylation array analysis has primarily focused on preprocessing, normalization, and identification of differentially methylated CpGs and regions. GOmeth and GOregion are new methods for performing unbiased gene set testing following differential methylation analysis. Benchmarking analyses demonstrate GOmeth outperforms other approaches, and GOregion is the first method for gene set testing of differentially methylated regions. Both methods are publicly available in the missMethyl Bioconductor R package.",
+No,20210628,methods,34155396,The triumphs and limitations of computational methods for scRNA-seq.,Nat Methods,"The rapid progress of protocols for sequencing single-cell transcriptomes over the past decade has been accompanied by equally impressive advances in the computational methods for analysis of such data. As capacity and accuracy of the experimental techniques grew, the emerging algorithm developments revealed increasingly complex facets of the underlying biology, from cell type composition to gene regulation to developmental dynamics. At the same time, rapid growth has forced continuous reevaluation of the underlying statistical models, experimental aims, and sheer volumes of data processing that are handled by these computational tools. Here, I review key computational steps of single-cell RNA sequencing (scRNA-seq) analysis, examine assumptions made by different approaches, and highlight successes, remaining ambiguities, and limitations that are important to keep in mind as scRNA-seq becomes a mainstream technique for studying biology.",
+No,20210628,mtdna,34099068,Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences.,Hum Genomics,"Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718).We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 Ă— 10-8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 Ă— 10-8), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 Ă— 10-21) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition.These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.",
+No,20210628,prediction,34149812,Multi-Omics Marker Analysis Enables Early Prediction of Breast Tumor Progression.,Front Genet,"Ductal carcinomain situ(DCIS) is a preinvasive form of breast cancer with a highly variable potential of becoming invasive and affecting mortality of the patients. Due to the lack of accurate markers of disease progression, many women with detected DCIS are currently overtreated. To distinguish those DCIS cases who are likely to require therapy from those who should be left untreated, there is a need for robust and predictive biomarkers extracted from molecular or genetic profiles. We developed a supervised machine learning approach that implements multi-omics feature selection and model regularization for the identification of biomarker combinations that could be used to distinguish low-risk DCIS lesions from those with a higher likelihood of progression. To investigate the genetic heterogeneity of disease progression, we applied this approach to 40 pure DCIS and 259 invasive breast cancer (IBC) samples profiled with genome-wide transcriptomics, DNA methylation, and DNA copy number variation. Feature selection using the multi-omics Lasso-regularized algorithm identified both known genes involved in breast cancer development, as well as novel markers for early detection. Even though the gene expression-based model features led to the highest classification accuracy alone, methylation data provided a complementary source of features and improved especially the sensitivity of correctly classifying DCIS cases. We also identified a number of repeatedly misclassified DCIS cases when using either the expression or methylation markers. A small panel of 10 gene markers was able to distinguish DCIS and IBC cases with high accuracy in nested cross-validation (AU-ROC = 0.99). The marker panel was not specific to any of the established breast cancer subtypes, suggesting that the 10-gene signature may provide a subtype-agnostic and cost-effective approach for breast cancer detection and patient stratification. We further confirmed high accuracy of the 10-gene signature in an external validation cohort (AU-ROC = 0.95), profiled using distinct transcriptomic assay, hence demonstrating robustness of the risk signature.Copyright © 2021 Xu, Lien, Bergholtz, Fleischer, Djerroudi, Vincent-Salomon, Sørlie and Aittokallio.",
+No,20210628,twas,34158615,Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing.,Neuropsychopharmacology,"Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20-30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.",
+No ,20210628,methods,34130352,Inverse probability weighting is an effective method to address selection bias during the analysis of high dimensional data.,Genet Epidemiol,"Omics studies frequently use samples collected during cohort studies. Conditioning on sample availability can cause selection bias if sample availability is nonrandom. Inverse probability weighting (IPW) is purported to reduce this bias. We evaluated IPW in an epigenome-wide analysis testing the association between DNA methylation (261,435 probes) and age in healthy adolescent subjects (n = 114). We simulated age and sex to be correlated with sample selection and then evaluated four conditions: complete population/no selection bias (all subjects), naïve selection bias (no adjustment), and IPW selection bias (selection bias with IPW adjustment). Assuming the complete population condition represented the ""truth,"" we compared each condition to the complete population condition. Bias or difference in associations between age and methylation was reduced in the IPW condition versus the naïve condition. However, genomic inflation and type 1 error were higher in the IPW condition relative to the naïve condition. Postadjustment using bacon, type 1 error and inflation were similar across all conditions. Power was higher under the IPW condition compared with the naïve condition before and after inflation adjustment. IPW methods can reduce bias in genome-wide analyses. Genomic inflation is a potential concern that can be minimized using methods that adjust for inflation.© 2021 Wiley Periodicals LLC.",
+Yes,20210628,ewas,34155504,Genetic and in-utero environmental contributions to DNA methylation variation in placenta.,Hum Mol Genet,"Genetic and prenatal environmental factors shape fetal development and cardiometabolic health in later life. A key target of genetic and prenatal environmental factors is the epigenome of the placenta, an organ that is implicated in fetal growth and diseases in later life. This study had two aims: 1) to identify and functionally characterize placental variably methylated regions (VMRs), which are regions in the epigenome with high interindividual methylation variability; 2) to investigate the contributions of fetal genetic loci and 12 prenatal environmental factors (maternal psychosocial-, cardiometabolic-, demographic-, and obstetric- related) on methylation at each VMR. Akaike's information criterion was used to select the best model out of four models (prenatal environment only, genotype only, additive effect of genotype and prenatal environment [G + E], and their interaction effect [GxE]). We identified 5850 VMRs in placenta. Methylation at 70% of VMRs was best explained by GxE followed by genotype only (17.7%), and G + E (12.3%). Prenatal environment alone best explained only 0.03% of VMRs. We observed that 95.4% of GxE models and 93.9% of G + E models included maternal age, parity, delivery mode, maternal depression, or gestational weight gain. VMR methylation sites and their regulatory genetic variants were enriched (P < 0.05) for genomic regions that have known links with regulatory functions and complex traits. This study provided a genome-wide catalog of VMRs in placenta and highlighted that variation in placental DNA methylation at loci with regulatory and trait relevance is best elucidated by integrating genetic and prenatal environmental factors, and rarely by environmental factors alone.Published by Oxford University Press 2021.",
+Yes,20210628,ewas,34116986,Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome.,Diabetes Care,"Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure.We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring.We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10-2) CpG at the cg22790973 probe (TFCP2)associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within theUBE3Cgene and cg17065901 inFAM13A,both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within theDLGAP2gene, known to be involved in insulin resistance during pregnancy.Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.© 2021 by the American Diabetes Association.",
+Yes,20210628,ewas,34086604,Different epigenetic signatures of newborn telomere length and telomere attrition rate in early life.,Aging,"Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIRONAGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging.",
+Yes,20210628,ewas,34095363,Childhood adversity correlates with stable changes in DNA methylation trajectories in children and converges with epigenetic signatures of prenatal stress.,Neurobiol Stress,"Childhood maltreatment (CM) is an established major risk factor for a number of negative health outcomes later in life. While epigenetic mechanisms, such as DNA methylation (DNAm), have been proposed as a means of embedding this environmental risk factor, little is known about its timing and trajectory, especially in very young children. It is also not clear whether additional environmental adversities, often experienced by these children, converge on similar DNAm changes. Here, we calculated a cumulative adversity score, which additionally to CM includes socioeconomic status (SES), other life events, parental psychopathology and epigenetic biomarkers of prenatal smoking and alcohol consumption. We investigated the effects of CM alone as well as the adversity score on longitudinal DNAm trajectories in the Berlin Longitudinal Child Study. This is a cohort of 173 children aged 3-5 years at baseline of whom 86 were exposed to CM. These children were followed-up for 2 years with extensive psychometric and biological assessments as well as saliva collection at 5 time points providing genome-wide DNAm levels. Overall, only a few DNAm patterns were stable over this timeframe, but less than 10 DNAm regions showed significant changes. At baseline, neither CM nor the adversity score associated with DNAm changes. However, in 6 differentially methylated regions (DMRs), CM and the adversity score significantly moderated DNAm trajectories over time. A number of these DMRs have previously been associated with adverse prenatal exposures. In our study, children exposed to CM also presented with epigenetic signatures indicative of increased prenatal exposure to tobacco and alcohol, as compared to non-CM exposed children. These epigenetic signatures of prenatal exposure strongly correlate with DNAm regions associated with CM and the adversity score. Finally, weighted correlation network analysis revealed a module of CpGs exclusively associated with CM. While our study identifies DNAm loci specifically associated with CM, especially within long non-coding RNAs, the majority of associations were found with the adversity score with convergent association with indicators of adverse prenatal exposures. This study highlights the importance of mapping not only of the epigenome but also the exposome and extending the observational timeframe to well before birth.© 2021 The Authors.",
+Yes,20210628,ewas,34116608,Association of mammographic density with blood DNA methylation.,Epigenetics,"Background:Altered DNA methylation may be an intermediate phenotype between breast cancer risk factors and disease. Mammographic density is a strong risk factor for breast cancer. However, no studies to date have identified an epigenetic signature of mammographic density. We performed an epigenome-wide association study of mammographic density.Methods:White blood cell DNA methylation was measured for 385 postmenopausal women using the Illumina Infinium MethylationEPIC BeadChip array. Differential methylation was assessed using genome-wide, probe-level, and regional analyses. We implemented a resampling-based approach to improve the stability of our findings.Results:On average, women with elevated mammographic density exhibited DNA hypermethylation within CpG islands and gene promoters compared to women with lower mammographic density. We identified 250 CpG sites for which DNA methylation was significantly associated with mammographic density. The top sites were located within genes associated with cancer, includingHDLBP, TGFB2, CCT4, andPAX8, and were more likely to be located in regulatory regions of the genome. We also identified differential DNA methylation in 37 regions, including within the promoters ofPAX8andPF4, a gene involved in the regulation of angiogenesis. Overall, our results paint a picture of epigenetic dysregulation associated with mammographic density.Conclusion:Mammographic density is associated with differential DNA methylation throughout the genome, including within genes associated with cancer. Our results suggest the potential involvement of several genes in the biological mechanisms behind differences in breast density between women. Further studies are warranted to explore these potential mechanisms and potential links to breast cancer risk.",
+Yes,20210628,ewas,34101077,Pre-diagnostic DNA methylation patterns differ according to mammographic breast density amongst women who subsequently develop breast cancer: a case-only study in the EPIC-Florence cohort.,Breast Cancer Res Treat,"Mammographic breast density (MBD) is a marker of increased breast cancer (BC) risk, yet much remains to be clarified about the underlying mechanisms. We investigated whether DNA methylation patterns differ between high- vs. low-MBD women who developed BC during an 8.9-year median follow-up in the Florence section of the European Prospective Investigation into Cancer and Nutrition.We analysed 96 pairs of women with BC arising on high- vs. low-MBD breasts (BI-RADS category III-IV vs. I). DNA methylation was determined on pre-diagnostic blood samples using the Illumina Infinium MethylationEPIC BeadChip assay. The statistical analysis was conducted by performing an epigenome-wide association study (EWAS), by searching differentially methylated regions (DMRs) in gene promoters (followed by functional enrichment and gene annotation analysis); and through a ""candidate pathways"" approach focusing on pre-defined inflammation-related pathways.In EWAS, no single CpG site was differentially methylated between high- and low-MBD women after correction for multiple testing. A total of 140 DMRs were identified, of which 131 were hyper- and 9 hypo-methylated amongst high-MBD women. These DMRs encompassed an annotation cluster of 35 genes coding for proteins implicated in transcription regulation and DNA binding. The ""apoptosis signalling"" was the only inflammation-related candidate pathway differentially methylated between high- and low-MBD women.Pre-diagnostic methylation patterns differ between high- vs. low-MBD women who subsequently develop BC, particularly, in genes involved in the regulation of DNA transcription and cell apoptosis. Our study provides novel clues about the mechanisms linking MBD and BC.",
+Yes,20210628,ewas,34091768,Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.,Eur J Epidemiol,"Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.",
+Yes,20210628,ewas,34117263,Genome-wide DNA methylation analysis on C-reactive protein among Ghanaians suggests molecular links to the emerging risk of cardiovascular diseases.,NPJ Genom Med,"Molecular mechanisms at the intersection of inflammation and cardiovascular diseases (CVD) among Africans are still unknown. We performed an epigenome-wide association study to identify loci associated with serum C-reactive protein (marker of inflammation) among Ghanaians and further assessed whether differentially methylated positions (DMPs) were linked to CVD in previous reports, or to estimated CVD risk in the same population. We used the Illumina Infinium® HumanMethylation450 BeadChip to obtain DNAm profiles of blood samples in 589 Ghanaians from the RODAM study (without acute infections, not taking anti-inflammatory medications, CRP levels < 40 mg/L). We then used linear models to identify DMPs associated with CRP concentrations. Post-hoc, we evaluated associations of identified DMPs with elevated CVD risk estimated via ASCVD risk score. We also performed subset analyses at CRP levels ≤10 mg/L and replication analyses on candidate probes. Finally, we assessed for biological relevance of our findings in public databases. We subsequently identified 14 novel DMPs associated with CRP. In post-hoc evaluations, we found that DMPs in PC, BTG4 and PADI1 showed trends of associations with estimated CVD risk, we identified a separate DMP in MORC2 that was associated with CRP levels ≤10 mg/L, and we successfully replicated 65 (24%) of previously reported DMPs. All DMPs with gene annotations (13) were biologically linked to inflammation or CVD traits. We have identified epigenetic loci that may play a role in the intersection between inflammation and CVD among Ghanaians. Further studies among other Africans are needed to confirm our findings.",
+Yes,20210628,ewas,34112773,A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex.,Nat Commun,"Epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer's disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource ( www.epigenomicslab.com/ad-meta-analysis/ ).",
+No,20210726,review,32151655,DNA methylation and brain structure and function across the life course: A systematic review,Neurosci Biobehav Rev,"MRI has enhanced our capacity to understand variations in brain structure and function conferred by the genome. We identified 60 studies that report associations between DNA methylation (DNAm) and human brain structure/function. Forty-three studies measured candidate loci DNAm; seventeen measured epigenome-wide DNAm. MRI features included region-of-interest and whole-brain structural, diffusion and functional imaging features. The studies report DNAm-MRI associations for: neurodevelopment and neurodevelopmental disorders; major depression and suicidality; alcohol use disorder; schizophrenia and psychosis; ageing, stroke, ataxia and neurodegeneration; post-traumatic stress disorder; and socio-emotional processing. Consistency between MRI features and differential DNAm is modest. Sources of bias: variable inclusion of comparator groups; different surrogate tissues used; variation in DNAm measurement methods; lack of control for genotype and cell-type composition; and variations in image processing. Knowledge of MRI features associated with differential DNAm may improve understanding of the role of DNAm in brain health and disease, but caution is required because conventions for linking DNAm and MRI data are not established, and clinical and methodological heterogeneity in existing literature is substantial.",
+Yes,20210726,ewas,31811260,Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group,Mol Psychiatry,"DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.",
+No,20210726,cell types,34254878,A comparison of epithelial cell content of oral samples estimated using cytology and DNA methylation.,Epigenetics,"Saliva and buccal samples are popular for epigenome wide association studies (EWAS) due to their ease of collection compared and their ability to sample a different cell lineage compared to blood. As these samples contain a mix of white blood cells and buccal epithelial cells that can vary within a population, this cellular heterogeneity may confound EWAS. This has been addressed by including cellular heterogeneity obtained through cytology at the time of collection or by using cellular deconvolution algorithms built on epigenetic data from specific cell types. However, to our knowledge, the two methods have not yet been compared. Here we show that the two methods are highly correlated in saliva and buccal samples (R = 0.84, P < 0.0001) by comparing data generated from cytological staining and Infinium MethylationEPIC arrays and the EpiDISH deconvolution algorithm from buccal and saliva samples collected from twenty adults. In addition, by using an expanded dataset from both sample types, we confirmed our previous finding that age has strong, non-linear negative correlation with epithelial cell proportion in both sample types. However, children and adults showed a large within-population variation in cellular heterogeneity. Our results validate the use of the EpiDISH algorithm in estimating the effect of cellular heterogeneity in EWAS and showed DNA methylation generally underestimates the epithelial cell content obtained from cytology.",
+No,20210726,dnam age,34174924,Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.,Mol Brain,"Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.",
+No,20210726,dnam age,34187551,Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.,Genome Biol,"Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.",
+No,20210726,epigenetics,34234345,BANP opens chromatin and activates CpG-island-regulated genes.,Nature,"The majority of gene transcripts generated by RNA polymerase II in mammalian genomes initiate at CpG island (CGI) promoters1,2, yet our understanding of their regulation remains limited. This is in part due to the incomplete information that we have on transcription factors, their DNA-binding motifs and which genomic binding sites are functional in any given cell type3-5. In addition, there are orphan motifs without known binders, such as the CGCG element, which is associated with highly expressed genes across human tissues and enriched near the transcription start site of a subset of CGI promoters6-8. Here we combine single-molecule footprinting with interaction proteomics to identify BTG3-associated nuclear protein (BANP) as the transcription factor that binds this element in the mouse and human genome. We show that BANP is a strong CGI activator that controls essential metabolic genes in pluripotent stem and terminally differentiated neuronal cells. BANP binding is repelled by DNA methylation of its motif in vitro and in vivo, which epigenetically restricts most binding to CGIs and accounts for differential binding at aberrantly methylated CGI promoters in cancer cells. Upon binding to an unmethylated motif, BANP opens chromatin and phases nucleosomes. These findings establish BANP as a critical activator of a set of essential genes and suggest a model in which the activity of CGI promoters relies on methylation-sensitive transcription factors that are capable of chromatin opening.",
+No,20210726,ewas,34215292,Ageing-associated changes in DNA methylation in X and Y chromosomes.,Epigenetics Chromatin,"Ageing displays clear sexual dimorphism, evident in both morbidity and mortality. Ageing is also associated with changes in DNA methylation, but very little focus has been on the sex chromosomes, potential biological contributors to the observed sexual dimorphism. Here, we sought to identify DNA methylation changes associated with ageing in the Y and X chromosomes, by utilizing datasets available in data repositories, comprising in total of 1240 males and 1191 females, aged 14-92 years.In total, we identified 46 age-associated CpG sites in the male Y, 1327 age-associated CpG sites in the male X, and 325 age-associated CpG sites in the female X. The X chromosomal age-associated CpGs showed significant overlap between females and males, with 122 CpGs identified as age-associated in both sexes. Age-associated X chromosomal CpGs in both sexes were enriched in CpG islands and depleted from gene bodies and showed no strong trend towards hypermethylation nor hypomethylation. In contrast, the Y chromosomal age-associated CpGs were enriched in gene bodies, and showed a clear trend towards hypermethylation with age.Significant overlap in X chromosomal age-associated CpGs identified in males and females and their shared features suggest that despite the uneven chromosomal dosage, differences in ageing-associated DNA methylation changes in the X chromosome are unlikely to be a major contributor of sex dimorphism in ageing. While age-associated CpGs showed good replication across datasets in the present study, only a limited set of previously reported age-associated CpGs were replicated. One contributor to the limited overlap are differences in the age range of individuals included in each data set. Further study is needed to identify biologically significant age-associated CpGs in the sex chromosomes.",
+No,20210726,hydroxymethylation,34253716,Tissue-specific 5-hydroxymethylcytosine landscape of the human genome.,Nat Commun,"5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially-hydroxymethylated regions (tsDhMRs), which are deposited in regions that potentially regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription factors and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with single-nucleotide polymorphisms identified by genome-wide association studies and are linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific gene expression programs and functions.© 2021. The Author(s).",
+No,20210726,methods,34256818,2dFDR: a new approach to confounder adjustment substantially increases detection power in omics association studies.,Genome Biol,"One challenge facing omics association studies is the loss of statistical power when adjusting for confounders and multiple testing. The traditional statistical procedure involves fitting a confounder-adjusted regression model for each omics feature, followed by multiple testing correction. Here we show that the traditional procedure is not optimal and present a new approach, 2dFDR, a two-dimensional false discovery rate control procedure, for powerful confounder adjustment in multiple testing. Through extensive evaluation, we demonstrate that 2dFDR is more powerful than the traditional procedure, and in the presence of strong confounding and weak signals, the power improvement could be more than 100%.© 2021. The Author(s).",
+No,20210726,omics,34282340,Single-cell analysis enters the multiomics age.,Nature,NA,
+No,20210726,prediction,34204621,DNA Methylation-Based Estimates of Circulating Leukocyte Composition for Predicting Colorectal Cancer Survival: A Prospective Cohort Study.,Cancers (Basel),"Leukocytes are involved in the progression of colorectal cancer (CRC). The proportion of six major leukocyte subtypes can be estimated using epigenome-wide DNA methylation (DNAm) data from stored blood samples. Whether the composition of circulating leukocytes can be used as a prognostic factor is unclear. DNAm-based leukocyte proportions were obtained from a prospective cohort of 2206 CRC patients. Multivariate Cox regression models and survival curves were applied to assess associations between leukocyte composition and survival outcomes. A higher proportion of lymphocytes, including CD4+ T cells, CD8+ T cells, B cells, and NK cells, was associated with better survival, while a higher proportion of neutrophils was associated with poorer survival. CD4+ T cells outperformed other leukocytes in estimating the patients' prognosis. Comparing the highest quantile to the lowest quantile of CD4+ T cells, hazard ratios (95% confidence intervals) of all-cause and CRC-specific mortality were 0.59 (0.48, 0.72) and 0.59 (0.45, 0.77), respectively. Furthermore, the association of CD4+ T cells and prognosis was stronger among patients with early or intermediate CRC or patients with colon cancer. In conclusion, the composition of circulating leukocytes estimated from DNAm, particularly the proportions of CD4+ T cells, could be used as promising independent predictors of CRC survival.",
+No,20210726,prediction,34247653,DNA methylation under the major depression pathway predicts pediatric quality of life four-month post-pediatric mild traumatic brain injury.,Clin Epigenetics,"Major depression has been recognized as the most commonly diagnosed psychiatric complication of mild traumatic brain injury (mTBI). Moreover, major depression is associated with poor outcomes following mTBI; however, the underlying biological mechanisms of this are largely unknown. Recently, genomic and epigenetic factors have been increasingly implicated in the recovery following TBI.This study leveraged DNA methylation within the major depression pathway, along with demographic and behavior measures (features used in the clinical model) to predict post-concussive symptom burden and quality of life four-month post-injury in a cohort of 110 pediatric mTBI patients and 87 age-matched healthy controls. The results demonstrated that including DNA methylation markers in the major depression pathway improved the prediction accuracy for quality of life but not persistent post-concussive symptom burden. Specifically, the prediction accuracy (i.e., the correlation between the predicted value and observed value) of quality of life was improved from 0.59 (p = 1.20 × 10-3) (clinical model) to 0.71 (p = 3.89 × 10-5); the identified cytosine-phosphate-guanine sites were mainly in the open sea regions and the mapped genes were related to TBI in several molecular studies. Moreover, depression symptoms were a strong predictor (with large weights) for both post-concussive symptom burden and pediatric quality of life.This study emphasized that both molecular and behavioral manifestations of depression symptoms played a prominent role in predicting the recovery process following pediatric mTBI, suggesting the urgent need to further study TBI-caused depression symptoms for better recovery outcome.© 2021. The Author(s).",
+Yes,20210726,ewas,34167563,The epigenetic etiology of cardiovascular disease in a longitudinal Swedish twin study.,Clin Epigenetics,"Studies on DNA methylation have the potential to discover mechanisms of cardiovascular disease (CVD) risk. However, the role of DNA methylation in CVD etiology remains unclear.We performed an epigenome-wide association study (EWAS) on CVD in a longitudinal sample of Swedish twins (535 individuals). We selected CpGs reaching the Bonferroni-corrected significance level (2 [Formula: see text] 10-7) or the top-ranked 20 CpGs with the lowest P values if they did not reach this significance level in EWAS analysis associated with non-stroke CVD, overall stroke, and ischemic stroke, respectively. We further applied a bivariate autoregressive latent trajectory model with structured residuals (ALT-SR) to evaluate the cross-lagged effect between DNA methylation of these CpGs and cardiometabolic traits (blood lipids, blood pressure, and body mass index). Furthermore, mediation analysis was performed to evaluate whether the cross-lagged effects had causal impacts on CVD. In the EWAS models, none of the CpGs we selected reached the Bonferroni-corrected significance level. The ALT-SR model showed that DNA methylation levels were more likely to predict the subsequent level of cardiometabolic traits rather than the other way around (numbers of significant cross-lagged paths of methylation → trait/trait → methylation were 84/4, 45/6, 66/1 for the identified three CpG sets, respectively). Finally, we demonstrated significant indirect effects from DNA methylation on CVD mediated by cardiometabolic traits.We present evidence for a directional association from DNA methylation on cardiometabolic traits and CVD, rather than the opposite, highlighting the role of epigenetics in CVD development.",
+Yes,20210726,ewas,34170065,Neonatal DNA methylation and childhood low prosocial behavior: An epigenome-wide association meta-analysis.,Am J Med Genet B Neuropsychiatr Genet,"Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of ""chronic-low"" versus ""typical"" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous ""low prosocial"" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.© 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.",
+Yes,20210726,ewas,34174944,Detecting cord blood cell type-specific epigenetic associations with gestational diabetes mellitus and early childhood growth.,Clin Epigenetics,"Epigenome-wide association studies (EWAS) have provided opportunities to understand the role of epigenetic mechanisms in development and pathophysiology of many chronic diseases. However, an important limitation of conventional EWAS is that profiles of epigenetic variability are often obtained in samples of mixed cell types. Here, we aim to assess whether changes in cord blood DNA methylation (DNAm) associated with gestational diabetes mellitus (GDM) exposure and early childhood growth markers occur in a cell type-specific manner.We analyzed 275 cord blood samples collected at delivery from a prospective pre-birth cohort with genome-wide DNAm profiled by the Illumina MethylationEPIC array. We estimated proportions of seven common cell types in each sample using a cord blood-specific DNAm reference panel. Leveraging a recently developed approach named CellDMC, we performed cell type-specific EWAS to identify CpG loci significantly associated with GDM, or 3-year-old body mass index (BMI) z-score. A total of 1410 CpG loci displayed significant cell type-specific differences in methylation level between 23 GDM cases and 252 controls with a false discovery rate < 0.05. Gene Ontology enrichment analysis indicated that LDL transportation emerged from CpG specifically identified from B-cells DNAm analyses and the mitogen-activated protein kinase pathway emerged from CpG specifically identified from natural killer cells DNAm analyses. In addition, we identified four and six loci associated with 3-year-old BMI z-score that were specific to CD8+ T-cells and monocytes, respectively. By performing genome-wide permutation tests, we validated that most of our detected signals had low false positive rates.Compared to conventional EWAS adjusting for the effects of cell type heterogeneity, the proposed approach based on cell type-specific EWAS could provide additional biologically meaningful associations between CpG methylation, prenatal maternal GDM or 3-year-old BMI. With careful validation, these findings may provide new insights into the pathogenesis, programming, and consequences of related childhood metabolic dysregulation. Therefore, we propose that cell type-specific analyses are worth cautious explorations.",
+Yes,20210726,ewas,34183656,A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.,Nat Commun,"Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.",
+Yes,20210726,ewas,34214161,DNA Methylation Changes Associated with Type 2 Diabetes and Diabetic Kidney Disease in an East Asian Population.,J Clin Endocrinol Metab,"There is a growing body of evidence that epigenetic changes including DNA methylation influence the risk of type 2 diabetes (T2D) and its microvascular complications. We conducted a methylome-wide association study (MWAS) to identify differentially methylated sites (DMSs) of T2D and diabetic kidney disease (DKD) in a Korean population.We performed an MWAS in 232 participants with T2D and 197 non-diabetic controls with Illumina EPIC bead chip using peripheral blood leukocytes. T2D group was subdivided into 87 DKD cases and 80 non-DKD controls. Additional 819 individuals from two population-based cohorts were used to investigate the association of identified DMSs with quantitative metabolic phenotypes. Mendelian randomization (MR) approach was applied to evaluate the causal effect of metabolic phenotypes on identified DMSs.We identified eight DMSs (each at BMP8A, NBPF20, STX18, ZNF365, CPT1A, and TRIM37, and two at TXNIP) which were significantly associated with the risk of T2D (P < 9.0×10 -8), including three that were previously known (DMSs in TXNIP and CPT1A). We also identified three DMSs (in COMMD1, TMOD1, and FHOD1) associated with DKD. With our limited sample size, we were not able to observe a significant overlap between DMSs of T2D and DKD. DMSs in TXNIP and CTP1A were associated with fasting glucose and HbA1c. In MR analysis, fasting glucose was causally associated with DMS in CPT1A.In an East Asian population, we identified eight DMSs, including five novel CpG loci, associated with T2D and three DMSs associated with DKD at methylome-wide statistical significance.© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
+Yes,20210726,ewas,34265559,"Exposure to polycyclic aromatic hydrocarbons, DNA methylation and heart rate variability among non-current smokers.",Environ Pollut,"Polycyclic aromatic hydrocarbons (PAHs) exposure is associated with heart rate variability (HRV) reduction, a widely used marker of cardiovascular autonomic dysfunction. The role of DNA methylation in the relationship between PAHs exposure and decreased HRV is largely unknown. This study aims to explore epigenome-wide DNA methylation changes associated with PAHs exposure and further evaluate their associations with HRV alternations among non-current smokers. We measured 10 mono-hydroxylated PAHs (OH-PAHs) in urine and DNA methylation levels in blood leukocytes among participants from three panels of Chinese non-current smokers (152 in WHZH, 99 in SY, and 53 in COW). We conducted linear regression analyses between DNA methylation and OH-PAHs metabolites with adjustment for age, gender, body mass index, drinking, blood cell counts, and surrogate variables in each panel separately, and combined the results by using inverse-variance weighted fixed-effect meta-analysis to obtain estimates of effect size. The median value of total OH-PAHs ranged from 0.92 × 10-2in SY panel (62.6% men) to 13.82 × 10-2 μmol/mmol creatinine in COW panel (43.4% men). The results showed that methylation levels of cg18223625 (COL20A1) and cg07805771 (SLC16A1) were significantly or marginally significantly associated with urinary 2-hydroxynaphthalene [β(SE) = 0.431(0.074) and 0.354(0.068), FDR = 0.016 and 0.056, respectively], while methylation level of cg09235308 (PLEC1) was positively associated with urinary total OH-PAHs [β(SE) = 0.478(0.079), FDR = 0.004]. Hypermethylations of cg18223625, cg07805771, and cg09235308 were inversely associated with HRV indices among the WHZH and COW non-current smokers. However, we did not observe significant epigenome-wide associations for the other 9 urinary OH-PAHs. These findings provide new evidence that PAHs exposure is linked to differential DNA methylation, which may help better understand the influences of PAHs exposure on HRV alternations.Copyright © 2021 Elsevier Ltd. All rights reserved.",
+No,20210920,epigenetics,34489442,The concurrence of DNA methylation and demethylation is associated with transcription regulation.,Nat Commun,"The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40~60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.© 2021. The Author(s).",
+No,20210920,longitudinal ewas,34454584,Longitudinal analysis of individual cfDNA methylome patterns in metastatic prostate cancer.,Clin Epigenetics,"Disease progression and therapeutic resistance are hallmarks of advanced stage prostate cancer (PCa), which remains a major cause of cancer-related mortality around the world. Longitudinal studies, coupled with the use of liquid biopsies, offer a potentially new and minimally invasive platform to study the dynamics of tumour progression. Our aim was to investigate the dynamics of personal DNA methylomic profiles of metastatic PCa (mPCa) patients, during disease progression and therapy administration.Forty-eight plasma samples from 9 mPCa patients were collected, longitudinally, over 13-21 months. After circulating cell-free DNA (cfDNA) isolation, DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The top 5% most variable probes across time, within each individual, were utilised to study dynamic methylation patterns during disease progression and therapeutic response. Statistical testing was carried out to identify differentially methylated genes (DMGs) in cfDNA, which were subsequently validated in two independent mPCa (cfDNA and FFPE tissue) cohorts. Individual cfDNA global methylation patterns were temporally stable throughout the disease course. However, a proportion of CpG sites presented a dynamic temporal pattern that was consistent with clinical events, including different therapies, and were prominently associated with genes linked to immune response pathways. Additionally, study of the tumour fraction of cfDNA identified > 2000 DMGs with dynamic methylation patterns.Longitudinal assessment of cfDNA methylation in mPCa patients unveiled dynamic patterns associated with disease progression and therapy administration, thus highlighting the potential of using liquid biopsies to study PCa evolution at a methylomic level.© 2021. The Author(s).",
+No,20210920,methods,34496950,An effective processing pipeline for harmonizing DNA methylation data from Illumina's 450K and EPIC platforms for epidemiological studies.,BMC Res Notes,"Illumina BeadChip arrays are commonly used to generate DNA methylation data for large epidemiological studies. Updates in technology over time create challenges for data harmonization within and between studies, many of which obtained data from the older 450K and newer EPIC platforms. The pre-processing pipeline for DNA methylation is not trivial, and influences the downstream analyses. Incorporating different platforms adds a new level of technical variability that has not yet been taken into account by recommended pipelines. Our study evaluated the performance of various tools on different versions of platform data harmonization at each step of pre-processing pipeline, including quality control (QC), normalization, batch effect adjustment, and genomic inflation. We illustrate our novel approach using 450K and EPIC data from the Diabetes Autoimmunity Study in the Young (DAISY) prospective cohort.We found normalization and probe filtering had the biggest effect on data harmonization. Employing a meta-analysis was an effective and easily executable method for accounting for platform variability. Correcting for genomic inflation also helped with harmonization. We present guidelines for studies seeking to harmonize data from the 450K and EPIC platforms, which includes the use of technical replicates for evaluating numerous pre-processing steps, and employing a meta-analysis.© 2021. The Author(s).",
+No,20210920,mqtl,34493871,Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.,Nat Genet,"Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20210920,single-cell,34417589,Multi-omics integration in the age of million single-cell data.,Nat Rev Nephrol,"An explosion in single-cell technologies has revealed a previously underappreciated heterogeneity of cell types and novel cell-state associations with sex, disease, development and other processes. Starting with transcriptome analyses, single-cell techniques have extended to multi-omics approaches and now enable the simultaneous measurement of data modalities and spatial cellular context. Data are now available for millions of cells, for whole-genome measurements and for multiple modalities. Although analyses of such multimodal datasets have the potential to provide new insights into biological processes that cannot be inferred with a single mode of assay, the integration of very large, complex, multimodal data into biological models and mechanisms represents a considerable challenge. An understanding of the principles of data integration and visualization methods is required to determine what methods are best applied to a particular single-cell dataset. Each class of method has advantages and pitfalls in terms of its ability to achieve various biological goals, including cell-type classification, regulatory network modelling and biological process inference. In choosing a data integration strategy, consideration must be given to whether the multi-omics data are matched (that is, measured on the same cell) or unmatched (that is, measured on different cells) and, more importantly, the overall modelling and visualization goals of the integrated analysis.© 2021. Springer Nature Limited.",
+No,20210920,somatic mutations,34433965,A body map of somatic mutagenesis in morphologically normal human tissues.,Nature,"Somatic mutations that accumulate in normal tissues are associated with ageing and disease1,2. Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual.© 2021. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20210920,somatic mutations,34433962,The mutational landscape of human somatic and germline cells.,Nature,"Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.© 2021. Crown.",
+No,20210920,prediction,34400642,Circulating cell-free DNA-based methylation patterns for breast cancer diagnosis.,NPJ Breast Cancer,"Mammography is used to detect breast cancer (BC), but its sensitivity is limited, especially for dense breasts. Circulating cell-free DNA (cfDNA) methylation tests is expected to compensate for the deficiency of mammography. We derived a specific panel of markers based on computational analysis of the DNA methylation profiles from The Cancer Genome Atlas (TCGA). Through training (n = 160) and validation set (n = 69), we developed a diagnostic prediction model with 26 markers, which yielded a sensitivity of 89.37% and a specificity of 100% for differentiating malignant disease from normal lesions [AUROC = 0.9816 (95% CI: 96.09-100%), and AUPRC = 0.9704 (95% CI: 94.54-99.46%)]. A simplified 4-marker model including cg23035715, cg16304215, cg20072171, and cg21501525 had a similar diagnostic power [AUROC = 0.9796 (95% CI: 95.56-100%), and AUPRC = 0.9220 (95% CI: 91.02-94.37%)]. We found that a single cfDNA methylation marker, cg23035715, has a high diagnostic power [AUROC = 0.9395 (95% CI: 89.72-99.27%), and AUPRC = 0.9111 (95% CI: 88.45-93.76%)], with a sensitivity of 84.90% and a specificity of 93.88%. In an independent testing dataset (n = 104), the obtained diagnostic prediction model discriminated BC patients from normal controls with high accuracy [AUROC = 0.9449 (95% CI: 90.07-98.91%), and AUPRC = 0.8640 (95% CI: 82.82-89.98%)]. We compared the diagnostic power of cfDNA methylation and mammography. Our model yielded a sensitivity of 94.79% (95% CI: 78.72-97.87%) and a specificity of 98.70% (95% CI: 86.36-100%) for differentiating malignant disease from normal lesions [AUROC = 0.9815 (95% CI: 96.75-99.55%), and AUPRC = 0.9800 (95% CI: 96.6-99.4%)], with better diagnostic power and had better diagnostic power than that of using mammography [AUROC = 0.9315 (95% CI: 89.95-96.34%), and AUPRC = 0.9490 (95% CI: 91.7-98.1%)]. In addition, hypermethylation profiling provided insights into lymph node metastasis stratifications (p < 0.05). In conclusion, we developed and tested a cfDNA methylation model for BC diagnosis with better performance than mammography.© 2021. The Author(s).",
+No,20210920,prediction,34518533,"DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.",Nat Commun,"DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.© 2021. The Author(s).",
+No,20210920,ewas,34401410,Placental DNA methylation marks are associated with maternal depressive symptoms during early pregnancy.,Neurobiol Stress,"Maternal depressive symptoms during pregnancy are a significant risk factor for adverse developmental and health outcomes of the offspring. The molecular mechanisms mediating the long-term effects of this exposure are not well understood. Previous studies have found association between prenatal exposure to maternal psychological distress and placental DNA methylation of candidate genes, which can influence placental barrier function and development of the fetus. Our objective in this study was to determine epigenome wide association of maternal depressive symptoms in early pregnancy with the placental DNA methylation. For this purpose we examined DNA methylomes of 92 placental samples by using reduced representation bisulfite sequencing. The placental samples were collected after deliveries of 39 girls and 59 boys, whose mothers had Edinburgh Postnatal Depression Score ranging from 0 to 19 at gestational week 14. According to our results maternal depressive symptoms are associated with DNA methylation of 2833 CpG sites, which are particularly over-represented in genic enhancers. The genes overlapping or nearest to these sites are functionally enriched for development of neurons and show expression enrichment in several regions of developing brain. The genomic regions harboring the DNA methylation marks are enriched for single nucleotide polymorphisms associated with mental disease trait class. Potential cellular signaling cascades mediating the effects include inflammatory and hormonal pathways. As a conclusion our results suggest that maternal depressive symptoms during early pregnancy are associated with DNA methylation marks in placenta in genes, which are important for the development and long-term health of the brain. Whether similar marks can be detected in exposed children remains to be elucidated in further studies.© 2021 The Authors.",
+No,20210920,methods,34461822,A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis.,BMC Genomics,"There exist few, if any, practical guidelines for predictive and falsifiable multi-omic data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules.We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omic integration of 20 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor-associated genes from several independent cohorts. Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS genes. The multi-omic case study using MS data revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module were differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10- 47) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS.We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omic approaches for complex diseases.© 2021. The Author(s).",
+No,20210920,methods,34461811,Novel DNA methylation loci and genes showing pleiotropic association with Alzheimer's dementia: a network Mendelian randomization analysis.,Epigenetics,"Previous genome-wide association studies (GWAS) have identified potential genetic variants involved in the risk of Alzheimer's dementia, but their underlying biological interpretation remains largely unclear. In addition, the effects of DNA methylation and gene expression on Alzheimer's dementia are not well understood. A network summary data-based Mendelian randomization (SMR) analysis was performed integrating cis- DNA methylation quantitative trait loci (mQTL) /cis- gene expression QTL (eQTL) data in the brain and blood, as well as GWAS summarized data for Alzheimer's dementia to evaluate the pleiotropic associations of DNA methylation and gene expression with Alzheimer's dementia and to explore the complex mechanisms underpinning Alzheimer's dementia. After correction for multiple testing (false discovery rate [FDR]P< 0.05) and filtering using the heterogeneity in dependent instruments (HEIDI) test (PHEIDI>0.01), we identified dozens of DNA methylation sites and genes showing pleiotropic associations with Alzheimer's dementia. We found 22 and 16 potentially causal pathways of Alzheimer's dementia (i.e., SNP→DNA methylation→Gene expression→Alzheimer's dementia) in the brain and blood, respectively. Approximately two-thirds of the identified DNA methylation sites had an influence on gene expression and the expression of almost all the identified genes was regulated by DNA methylation. Our network SMR analysis provided evidence supporting the pleiotropic association of some novel DNA methylation sites and genes with Alzheimer's dementia and revealed possible causal pathways underlying the pathogenesis of Alzheimer's dementia. Our findings shed light on the role of DNA methylation in gene expression and in the development of Alzheimer's dementia.",
+Yes,20210920,ewas,34523531,Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort.,Environ Pollut,"In utero exposure to environmental chemicals, such as synthetic phenols, may alter DNA methylation in different tissues, including placenta - a critical organ for fetal development. We studied associations between prenatal urinary biomarker concentrations of synthetic phenols and placental DNA methylation. Our study involved 202 mother-son pairs from the French EDEN cohort. Nine phenols were measured in spot urine samples collected between 22 and 29 gestational weeks. We performed DNA methylation analysis of the fetal side of placental tissues using the IlluminaHM450 BeadChips. We evaluated methylation changes of individual CpGs in an adjusted epigenome-wide association study (EWAS) and identified differentially methylated regions (DMRs). We performed mediation analysis to test whether placental tissue heterogeneity mediated the association between urinary phenol concentrations and DNA methylation. We identified 46 significant DMRs (≥5 CpGs) associated with triclosan (37 DMRs), 2,4-dichlorophenol (3), benzophenone-3 (3), methyl- (2) and propylparaben (1). All but 2 DMRs were positively associated with phenol concentrations. Out of the 46 identified DMRs, 7 (6 for triclosan) encompassed imprinted genes (APC, FOXG1, GNAS, GNASAS, MIR886, PEG10, SGCE), which represented a significant enrichment. Other identified DMRs encompassed genes encoding proteins responsible for cell signaling, transmembrane transport, cell adhesion, inflammatory, apoptotic and immunological response, genes encoding transcription factors, histones, tumor suppressors, genes involved in tumorigenesis and several cancer risk biomarkers. Mediation analysis suggested that placental cell heterogeneity may partly explain these associations. This is the first study describing the genome-wide modifications of placental DNA methylation associated with pregnancy exposure to synthetic phenols or their precursors. Our results suggest that cell heterogeneity might mediate the effects of triclosan exposure on placental DNA methylation. Additionally, the enrichment of imprinted genes within the DMRs suggests mechanisms by which certain exposures, mainly to triclosan, could affect fetal development.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",
+Yes,20210920,ewas,34516295,Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study.,Environ Health Perspect,"Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides.We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients.The Agricultural Lung Health Study is a case-control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina's EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009-2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users.Using family-wise error rate (p<9Ă—10-8) or false-discovery rate (FDR<0.05), we identified 162 differentially methylated CpGs across 8 of 9 currently marketed active ingredients (acetochlor, atrazine, dicamba, glyphosate, malathion, metolachlor, mesotrione, and picloram) and one banned organochlorine (heptachlor). Differentially methylated CpGs were unique to each active ingredient, and a dose-response relationship with lifetime days of use was observed for most. Significant CpGs were enriched for transcription motifs and 28% of CpGs were associated with whole bloodcis-gene expression, supporting functional effects of findings. We corroborated a previously reported association between dichlorodiphenyltrichloroethane (banned in the United States in 1972) and epigenetic age acceleration.We identified differential methylation for several active ingredients in male farmers of European ancestry. These may serve as biomarkers of chronic exposure and could inform mechanisms of long-term health outcomes from pesticide exposure. https://doi.org/10.1289/EHP8928.",
+Yes,20210920,ewas,34515027,Epigenome-wide analysis of DNA methylation and coronary heart disease: a nested case-control study.,Elife,"Background:Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population.Methods:We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10-year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module.Results:After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR <0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47% decrease to a 118% increase. Mediation analyses revealed 28.5% of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region ofANKS1Agene (P for mediation effect = 0.036). Methylation level at the promoter region ofSNX30was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7% (P = 0.003) via systolic blood pressure and 6.4% (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD.Conclusions:We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and BP-related pathways to CHD risk.Funding:This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key and Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).© 2021, Si et al.",
+Yes,20210920,ewas,34507616,Prenatal risk factors and neonatal DNA methylation in very preterm infants.,Clin Epigenetics,"Prenatal risk factors are related to poor health and developmental outcomes for infants, potentially via epigenetic mechanisms. We tested associations between person-centered prenatal risk profiles, cumulative prenatal risk models, and epigenome-wide DNA methylation (DNAm) in very preterm neonates.We studied 542 infants from a multi-center study of infants born < 30 weeks postmenstrual age. We assessed 24 prenatal risk factors via maternal report and medical record review. Latent class analysis was used to define prenatal risk profiles. DNAm was quantified from neonatal buccal cells using the Illumina MethylationEPIC Beadarray.We identified three latent profiles of women: a group with few risk factors (61%) and groups with elevated physical (26%) and psychological (13%) risk factors. Neonates born to women in higher risk subgroups had differential DNAm at 2 CpG sites. Higher cumulative prenatal risk was associated with methylation at 15 CpG sites, 12 of which were located in genes previously linked to physical and mental health and neurodevelopment.We observed associations between prenatal risk factors and DNAm in very preterm infants using both person-centered and cumulative risk approaches. Epigenetics offers a potential biological indicator of prenatal risk exposure.© 2021. The Author(s).",
+Yes,20210920,ewas,34482817,DNA methylation changes in African American women with a history of preterm birth from the InterGEN study.,BMC Genom Data,"Preterm birth (< 37 weeks' gestation) is a common outcome of pregnancy that has been associated with increased risk of cardiovascular disease for women later in life. Little is known about the physiologic mechanisms underlying this risk. To date, no studies have evaluated if differences in DNA methylation (DNAm) among women who experience preterm birth are short-term or if they persist and are associated with subsequent cardiovascular sequelae or other health disorders. The purpose of this study was to examine long-term epigenetic effects of preterm birth in African American mothers (n = 182) from the InterGEN Study (2014-2019). In this study, we determine if differences in DNAm exist between women who reported a preterm birth in the last 3-5 years compared to those who had full-term births by using two different approaches: epigenome-wide association study (EWAS) and genome-wide co-methylation analyses.Though no significant CpG sites were identified using the EWAS approach, we did identify significant modules of co-methylation associated with preterm birth. Co-methylation analyses showed correlations with preterm birth in gene ontology and KEGG pathways. Functional annotation analysis revealed enrichment for pathways related to central nervous system and sensory perception. No association was observed between DNAm age and preterm birth, though larger samples are needed to confirm this further.We identified differentially methylated gene networks associated with preterm birth in African American women 3-5 years after birth, including pathways related to neurogenesis and sensory processing. More research is needed to understand better these associations and replicate them in an independent cohort. Further study should be done in this area to elucidate mechanisms linking preterm birth and later epigenomic changes that may contribute to the development of health disorders and maternal mood and well-being.© 2021. The Author(s).",
+Yes,20210920,ewas,34473906,Infant RSV immunoprophylaxis changes nasal epithelial DNA methylation at 6 years of age.,Pediatr Pulmonol,"Respiratory syncytial virus (RSV) infection has been associated with childhood wheeze and asthma, and potential mechanisms include persistent epigenetic effects.In the randomized, placebo-controlled MAKI trial, 429 preterm infants randomly received RSV immunoprophylaxis with palivizumab or placebo during their first RSV season. Children were followed until age 6 for asthma evaluation. DNA methylation in cells obtained by nasal brushes at age 6 was measured by Illumina MethylationEPIC array.RSV immunoprophylaxis in infancy had a significant impact on global methylation patterns in nasal cells at age 6. The first principal component (PC) related to the immunoprophylaxis intervention was enriched for the pathway ""detection of chemical stimulus involved in sensory perception of smell"" and ""T cell differentiation."" Subsequent analysis of these PCs indicated an effect of RSV immunoprophylaxis on cell type composition of nasal brushed cells. Three CpG sites, cg18040241, cg08243963, and cg19555973 which are annotated to genes GLB1L2, SC5D, and BPIFB1, were differentially methylated at genome-wide significance, but were not associated with asthma.The study provides the first proof of concept that RSV immunoprophylaxis during infancy has long-term effects on nasal epigenetic signatures at age 6, relating to host sensory perception, epidermal growth factor receptor signaling, and adaptive immune responses.© 2021 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.",
+Yes,20210920,ewas,34461807,Association between dietary patterns reflecting one-carbon metabolism nutrients intake before pregnancy and placental DNA methylation.,Epigenetics,"The preconception period represents an important window for foetal and epigenetic programming. Some micronutrients (B vitamins, choline, betaine, methionine) implicated in one-carbon metabolism (OCM) are essential for major epigenetic processes that take place in early pregnancy. However, few studies have evaluated the implication of the micronutrients in placental DNA methylation. We investigated whether intake of OCM nutrients in the year before pregnancy was associated with placental DNA methylation in the EDEN mother-child cohort. Maternal dietary intake was assessed with a food-frequency questionnaire. Three dietary patterns, 'varied and balanced diet,' 'vegetarian tendency,' and 'bread and starchy food,' were used to characterize maternal OCM dietary intake. The Illumina Infinium HumanMethylation450 BeadChip was used to measure placental DNA methylation of 573 women included in the analyses. We evaluated the association of dietary patterns with global DNA methylation. Then, we conducted an agnostic epigenome-wide association study (EWAS) and investigated differentially methylated regions (DMRs) associated with each dietary pattern. We found no significant association between the three dietary patterns and global DNA methylation or individual CpG sites. DMR analyses highlighted associations between the 'varied and balanced' or 'vegetarian tendency' pattern and DMRs located at genes previously implicated in functions essential for embryonic development, such as neurodevelopment. The 'bread and starchy food' pattern was associated with regions related to genes whose functions involve various metabolic and cell synthesis-related processes. In mainly well-nourished French women without major deficiencies, OCM intake before pregnancy was not associated with major variation in DNA methylation.",
+Yes,20210920,ewas,34427971,Age patterns of intra-pair DNA methylation discordance in twins: Sex difference in epigenomic instability and implication on survival.,Aging Cell,"Aging is a biological process linked to specific patterns and changes in the epigenome. We hypothesize that age-related variation in the DNA methylome could reflect cumulative environmental modulation to the epigenome which could impact epigenomic instability and survival differentially by sex. To test the hypothesis, we performed sex-stratified epigenome-wide association studies on age-related intra-pair DNA methylation discordance in 492 twins aged 56-80 years. We identified 3084 CpGs showing increased methylation variability with age (FDR < 0.05, 7 CpGs with p < 1e-07) in male twins but no significant site found in female twins. The results were replicated in an independent cohort of 292 twins aged 30-74 years with 37% of the discovery CpGs successfully replicated in male twins. Functional annotation showed that genes linked to the identified CpGs were significantly enriched in signaling pathways, neurological functions, extracellular matrix assembly, and cancer. We further explored the implication of discovery CpGs on individual survival in an old cohort of 224 twins (220 deceased). In total, 264 CpGs displayed significant association with risk of death in male twins. In female twins, 175 of the male discovery CpGs also showed non-random correlation with mortality. Intra-pair comparison showed that majority of the discovery CpGs have higher methylation in the longer-lived twins suggesting that loss of DNA methylation during aging contributes to increased risk of death which is more pronounced in male twins. In conclusion, age-related epigenomic instability in the DNA methylome is more evident in males than in females and could impact individual survival and contribute to sex difference in human lifespan.© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
+Yes,20210920,ewas,34425644,Methylation biomarkers of polybrominated diphenyl ethers (PBDEs) and association with breast cancer risk at the time of menopause.,Environ Int,"Exposure to polybrominated diphenyl ethers (PBDEs) may influence risk of developing post-menopausal breast cancer. Although mechanisms are poorly understood, epigenetic regulation of gene expression may play a role.To identify DNA methylation (DNAm) changes associated with PBDE serum levels and test the association of these biomarkers with breast cancer risk.We studied 397 healthy women (controls) and 133 women diagnosed with breast cancer (cases) between ages 40 and 58 years who participated in the California Teachers Study. PBDE levels were measured in blood. Infinium Human Methylation EPIC Bead Chips were used to measure DNAm. Using multivariable linear regression models, differentially methylated CpG sites (DMSs) and regions (DMRs) associated with serum PBDE levels were identified using controls. For top-ranked DMSs and DMRs, targeted next-generation bisulfite sequencing was used to measure DNAm for 133 invasive breast cancer cases and 301 age-matched controls. Conditional logistic regression was used to evaluate associations between DMSs and DMRs and breast cancer risk.We identified 15 DMSs and 10 DMRs statistically significantly associated with PBDE levels (FDR < 0.05). Methylation changes in a DMS at BMP8B and DMRs at TP53 and A2M-AS1 were statistically significantly (FDR < 0.05) associated with breast cancer risk.We show for the first time that serum PBDE levels are associated with differential methylation and that PBDE-associated DNAm changes in blood are associated with breast cancer risk.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",
+Yes,20210920,ewas,34415308,Epigenome-wide association study of mitochondrial genome copy number.,Hum Mol Genet,"We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10-7), with a 0.7 to 3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes (PRDM16, NR1H3, XRCC3, POLK, and PDSS2), which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, p = 4 x 10-8) and positively associated with the NR1H3 expression level (effect size = 0.43, p = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor, and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+Yes,20210920,ewas,34429407,Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth.,Nat Commun,"Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.© 2021. The Author(s).",
+No,20211004,epigenetics,34551299,DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity.,Cell Rep,"DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation.Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.",
+No,20211004,epigenetics,34526716,UTX condensation underlies its tumour-suppressive activity,Nature,"UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers1. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.",
+No,20211004,epigenetics,34526684,Protein condensates provide a platform for controlling chromatin.,Nature,,
+Yes,20211004,ewas,34585950,Impact of depression and stress on placental DNA methylation in ethnically diverse pregnant women.,Epigenomics,"Aim:To investigate the association between placental genome-wide methylation at birth and antenatal depression and stress during pregnancy.Methods:We examined the association between placental genome-wide DNA methylation (n = 301) and maternal depression and stress assessed at six gestation periods during pregnancy. Correlation between DNA methylation at the significantly associated CpGs and expression of nearby genes in the placenta was tested.Results:Depression and stress were associated with methylation of 16 CpGs and two CpGs, respectively, at a 5% false discovery rate. Methylation levels at two of the CpGs associated with depression were significantly associated with expression ofADAM23andCTDP1, genes implicated in neurodevelopment and neuropsychiatric diseases.Conclusion:Placental epigenetic changes linked to antenatal depression suggest potential fetal brain programming. Clinical trial registration number: NCT00912132 (ClinicalTrials.gov).",
+Yes,20211004,ewas,34583751,Investigating the DNA methylation profile of e-cigarette use.,Clin Epigenetics,"Little evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use.Among 117 smokers, 117 non-smokers and 116 non-smoking vapers, we evaluated associations between e-cigarette use and epigenome-wide methylation from saliva. DNA methylation at 7 cytosine-phosphate-guanine sites (CpGs) was associated with e-cigarette use at p < 1 × 10-5and none at p < 5.91 × 10-8. 13 CpGs were associated with smoking at p < 1 × 10-5and one at p < 5.91 × 10-8. CpGs associated with e-cigarette use were largely distinct from those associated with smoking. There was strong enrichment of known smoking-related CpGs in the smokers but not the vapers. We also tested associations between e-cigarette use and methylation scores known to predict smoking and biological ageing. Methylation scores for smoking and biological ageing were similar between vapers and non-smokers. Higher levels of all smoking scores and a biological ageing score (GrimAge) were observed in smokers. A methylation score for e-cigarette use showed poor prediction internally (AUC 0.55, 0.41-0.69) and externally (AUC 0.57, 0.36-0.74) compared with a smoking score (AUCs 0.80) and was less able to discriminate lung squamous cell carcinoma from adjacent normal tissue (AUC 0.64, 0.52-0.76 versus AUC 0.73, 0.61-0.85).The DNA methylation profile for e-cigarette use is largely distinct from that of cigarette smoking, did not replicate in independent samples, and was unable to discriminate lung cancer from normal tissue. The extent to which methylation related to long-term e-cigarette use translates into chronic effects requires further investigation.© 2021. The Author(s).",
+Yes,20211004,ewas,34569420,"Associations between infant sex and DNA methylation across umbilical cord blood, artery, and placenta samples.",Epigenetics,"DNA methylation (DNAm) is vulnerable to dysregulation by environmental exposures during epigenetic reprogramming that occurs in embryogenesis. Sexual dimorphism in environmentally induced DNAm dysregulation has been identified and therefore it is important to understand sex-specific DNAm patterns. DNAm at several autosomal sites has been consistently associated with sex in cord blood and placental fetal tissues. However, there is limited research comparing sex-specific DNAm across tissues, particularly differentially methylated regions (DMRs). This study leverages DNAm data measured using the Illumina HumanMethylation450 BeadChip in cord blood (N = 179), placenta (N = 229), and umbilical artery samples (N = 229) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort to identify autosomal DMRs and differentially methylated positions (DMPs). A replication analyses was conducted in an independent cohort (GEO Accession GSE129841). We identified 183, 257, and 419 DMRs and 2119, 2281, and 3405 DMPs (pBonferroni< 0.05) in cord blood, placenta, and artery samples, respectively. Thirty-nine DMRs overlapped in all three tissues, overlapping with genes involved in spermatogenesis (NKAPL, PIWIL2, AURKC) and X-inactivation (LRIF1). In replication analysis, 85% of DMRs overlapped with those identified in PRISM. Overall DMRs and DMPs had higher methylation levels among females in cord blood and artery samples, but higher methylation levels among males in placenta samples. Further research is necessary to understand biological mechanisms that contribute to differences in sex-specific DNAm signatures across tissues, as well as to determine if sexual dimorphism in the epigenome impacts response to environmental stressors.",
+Yes,20211004,ewas,34561420,SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study.,Transl Psychiatry,"Conduct disorder (CD), a psychiatric disorder characterized by a repetitive pattern of antisocial behaviors, results from a complex interplay between genetic and environmental factors. The clinical presentation of CD varies both according to the individual's sex and level of callous-unemotional (CU) traits, but it remains unclear how genetic and environmental factors interact at the molecular level to produce these differences. Emerging evidence in males implicates methylation of genes associated with socio-affective processes. Here, we combined an epigenome-wide association study with structural neuroimaging in 51 females with CD and 59 typically developing (TD) females to examine DNA methylation in relation to CD, CU traits, and gray matter volume (GMV). We demonstrate an inverse pattern of correlation between CU traits and methylation of a chromosome 1 region in CD females (positive) as compared to TD females (negative). The identified region spans exon 1 of the SLC25A24 gene, central to energy metabolism due to its role in mitochondrial function. Increased SLC25A24 methylation was also related to lower GMV in multiple brain regions in the overall cohort. These included the superior frontal gyrus, prefrontal cortex, and supramarginal gyrus, secondary visual cortex and ventral posterior cingulate cortex, which are regions that have previously been implicated in CD and CU traits. While our findings are preliminary and need to be replicated in larger samples, they provide novel evidence that CU traits in females are associated with methylation levels in a fundamentally different way in CD and TD, which in turn may relate to observable variations in GMV across the brain.© 2021. The Author(s).",
+Yes,20211004,ewas,34556110,Epigenome-wide association study detects a novel loci associated with central obesity in healthy subjects.,BMC Med Genomics,"Central obesity is a condition that poses a significant risk to global health and requires the employment of novel scientific methods for exploration. The objective of this study is to use DNA methylation analysis to detect DNA methylation loci linked to obesity phenotypes, i.e. waist circumference and waist-to-hip ratio adjusted for BMI.Two-hundred and ten healthy European participants from the STANISLAS Family Study (SFS), comprising 73 nuclear families, were comprehensively assessed for methylation status using Illumina Infinium HumanMethylation450 BeadChip. An epigenome-wide association study was performed, which identified a CpG site cg16170243 located on chromosome 18q21.2 significantly associated with waist circumference, after adjusting for BMI (β = 2.32, SE = 0.41, Padj = 0.048). Cg16170243 corresponds to a 50 bp-length human methylation oligoprobe located within the AC090241.2 gene that overlaps ST8SIA5 gene. No significant association was observed with waist-to-hip ratio adjusted for BMI (Padj > 0.05).A novel association between DNA methylation and WC was identified, which is demonstrating that epigenetic mechanisms may have a significant impact on waist circumference ratio in healthy individuals. Further studies are warranted to address the causal effects of this association.© 2021. The Author(s).",
+Yes,20211004,ewas,34541665,A methylation study implicates the rewiring of brain neural circuits during puberty in the emergence of sex differences in depression symptoms.,J Child Psychol Psychiatry,"Women are 1.5-3 times more likely to suffer from depression than men. This sex bias first emerges during puberty and then persists across the reproductive years. As the cause remains largely elusive, we performed a methylation-wide association study (MWAS) to generate novel hypotheses.We assayed nearly all 28 million possible methylation sites in blood in 595 blood samples from 487 participants aged 9-17. MWASs were performed to identify methylation sites associated with increasing sex differences in depression symptoms as a function of pubertal stage. Epigenetic deconvolution was applied to perform analyses on a cell-type specific level.In monocytes, a substantial number of significant associations were detected after controlling the FDR at 0.05. These results could not be explained by plasma testosterone/estradiol or current/lifetime trauma. Our top results in monocytes were significantly enriched (ratio of 2.48) for genes in the top of a large genome-wide association study (GWAS) meta-analysis of depression and neurodevelopment-related Gene Ontology (GO) terms that remained significant after correcting for multiple testing. Focusing on our most robust findings (70 genes overlapping with the GWAS meta-analysis and the significant GO terms), we find genes coding for members of each of the major classes of axon guidance molecules (netrins, slits, semaphorins, ephrins, and cell adhesion molecules). Many of these genes were previously implicated in rodent studies of brain development and depression-like phenotypes, as well as human methylation, gene expression and GWAS studies.Our study suggests that the emergence of sex differences in depression may be related to the differential rewiring of brain circuits between boys and girls during puberty.© 2021 Association for Child and Adolescent Mental Health.",
+Yes,20211004,ewas,34539625,Genome-Wide DNA Methylation Profile in Whole Blood of Patients With Chronic Spontaneous Urticaria.,Front Immunol,"Chronic spontaneous urticaria (CSU) is a common autoimmune skin disease. Little is known about the role of epigenetics in the pathogenesis of CSU. This study aimed to investigate genome-wide DNA methylation profile in whole blood of patients with CSU.Genome-wide DNA methylation levels in whole blood samples of 95 Chinese Han ethnicity adult CSU patients and 95 ethnicity-, age- and sex-matched healthy controls were analyzed using Illumina 850K methylation chip. The differentially methylated genes (DMGs) were screened out and then functionally annotated by the gene ontology and the Kyoto encyclopedia of genes and genomes databases.A total of 439 differentially methylated positions (DMPs) (p< 0.01 and |Δβ| ≥ 0.06) were identified with 380 hypomethylated and 59 hypermethylated. The average global DNA methylation levels of the 439 DMPs in the CSU patients were significantly lower than those in the healthy controls (p< 0.001). The distribution of the 439 DMPs was wide on chromosome 1 to 22 and chromosome X. Chromosome 6 embodied the largest number of DMPs (n= 51) and their annotated genes were predominantly related to autoimmunity. The 304 annotated DMGs were mainly enriched in autoimmune disease- and immune-related pathways. A total of 41 DMPs annotated to 28 DMGs were identified whenp< 0.01 and |Δβ| ≥ 0.1. Of the 28 DMGs, HLA-DPB2, HLA-DRB1, PPP2R5C, and LTF were associated with autoimmunity. CSU cases with elevated total IgE, positive anti-thyroid peroxidase IgG autoantibodies, positive anti-thyroglobulin IgG autoantibodies, angioedema, UASday > 4, or recurrent CSU showed phenotype-specific DMPs as compared with cases with normal total IgE, negative anti-thyroid peroxidase IgG autoantibodies, negative anti-thyroglobulin IgG autoantibodies, no angioedema, UASday ≤ 4, or non-recurrent CSU respectively.This study shows a distinct genome-wide DNA methylation profile in Chinese Han ethnicity adult CSU patients and indicates a role of epigenetics in the pathogenesis of CSU. The predominant enrichment of the CSU-associated DMGs in immunological pathways provides supportive evidence for the immunopathogenesis of CSU. Future research on the CSU-associated DMPs and DMGs will help discover potential therapeutic targets for CSU.Copyright © 2021 Qi, Zhang, Yang, Tang and Xiao.",
+Yes,20211004,ewas,34529553,Prenatal exposure to endocrine disrupting chemicals is associated with altered DNA methylation in cord blood.,Epigenetics,"Prenatal exposure to endocrine disrupting chemicals can interfere with development, and has been associated with social-cognitive functioning and adverse health outcomes later in life. Exposure-associated changes of DNA methylation (DNAm) patterns have been suggested as a possible mediator of this relationship. This study investigated whether prenatal low-dose exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) is associated with altered DNAm patterns across the genome in a Western urban-industrial population. In 142 mother-infant pairs from the Duisburg Birth Cohort Study, PCBs and PCDD/Fs levels were quantified from maternal blood during late pregnancy and associated with DNAm levels in cord blood using the Illumina EPIC beadchip. The epigenome-wide association studies (EWAS) identified 32 significantly differentially methylated positions (DMPs) and eight differentially methylated regions (DMRs) associated with six congeners of PCB and PCDD in females or males (FDRs < 0.05). DMPs and DMRs mapped to genes involved in neurodevelopment, gene regulation, and immune functioning. Weighted gene correlation network analysis (WGCNA) showed 31 co-methylated modules (FDRs < 0.05) associated with one congener of PCDF levels in females. Results of both analytical strategies indicate that prenatal exposure to PCBs and PCDD/Fs is associated with altered DNAm of genes involved in neurodevelopment, gene expression and immune functioning. DNAm and gene expression levels of several of these genes were previously associated with EDC exposure in rodent models. Follow-up studies will clarify whether these epigenetic changes might contribute to the origin for adverse mental and health outcomes.",
+Yes,20211004,ewas,34584077,Identical twins carry a persistent epigenetic signature of early genome programming.,Nat Commun,"Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.© 2021. The Author(s).",
+No,20211004,ewas,34531495,DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers.,Sci Rep,"The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM, RIPOR2, AFAP1 and MOCOS. In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation-the key agent in trauma focused treatments-and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma.Trial registration: Addressing Heightened Levels of Aggression in Traumatized Offenders With Psychotherapeutic Means (ClinicalTrials.gov Identifier: NCT02992561, 14/12/2016).© 2021. The Author(s).",
+No,20211004,methods,34548083,Revisiting genetic artifacts on DNA methylation microarrays exposes novel biological implications.,Genome Biol,"Illumina DNA methylation microarrays enable epigenome-wide analysis vastly used for the discovery of novel DNA methylation variation in health and disease. However, the microarrays' probe design cannot fully consider the vast human genetic diversity, leading to genetic artifacts. Distinguishing genuine from artifactual genetic influence is of particular relevance in the study of DNA methylation heritability and methylation quantitative trait loci. But despite its importance, current strategies to account for genetic artifacts are lagging due to a limited mechanistic understanding on how such artifacts operate.To address this, we develop and benchmark UMtools, an R-package containing novel methods for the quantification and qualification of genetic artifacts based on fluorescence intensity signals. With our approach, we model and validate known SNPs/indels on a genetically controlled dataset of monozygotic twins, and we estimate minor allele frequency from DNA methylation data and empirically detect variants not included in dbSNP. Moreover, we identify examples where genetic artifacts interact with each other or with imprinting, X-inactivation, or tissue-specific regulation. Finally, we propose a novel strategy based on co-methylation that can discern between genetic artifacts and genuine genomic influence.We provide an atlas to navigate through the huge diversity of genetic artifacts encountered on DNA methylation microarrays. Overall, our study sets the ground for a paradigm shift in the study of the genetic component of epigenetic variation in DNA methylation microarrays.© 2021. The Author(s).",
+No,20211004,methods,34556866,"Reproducible, scalable, and shareable analysis pipelines with bioinformatics workflow managers.",Nat Methods,"The rapid growth of high-throughput technologies has transformed biomedical research. With the increasing amount and complexity of data, scalability and reproducibility have become essential not just for experiments, but also for computational analysis. However, transforming data into information involves running a large number of tools, optimizing parameters, and integrating dynamically changing reference data. Workflow managers were developed in response to such challenges. They simplify pipeline development, optimize resource usage, handle software installation and versions, and run on different compute platforms, enabling workflow portability and sharing. In this Perspective, we highlight key features of workflow managers, compare commonly used approaches for bioinformatics workflows, and provide a guide for computational and noncomputational users. We outline community-curated pipeline initiatives that enable novice and experienced users to perform complex, best-practice analyses without having to manually assemble workflows. In sum, we illustrate how workflow managers contribute to making computational analysis in biomedical research shareable, scalable, and reproducible.© 2021. Springer Nature America, Inc.",
+No,20211004,methods,34527193,Application of long-read sequencing to the detection of structural variants in human cancer genomes.,Comput Struct Biotechnol J,"In recent years, the so-called long-read sequencing technology has had a substantial impact on various aspects of genome sciences. Here, we introduce recent studies of cancerous structural variants (SVs) using long-read sequencing technologies, namely Pacific Biosciences (PacBio) sequencers, Oxford Nanopore Technologies (ONT) sequencers, and linked-read methods. By taking advantage of long-read lengths, these technologies have enabled the precise detection of SVs, including long insertions by transposable elements, such as LINE-1. In addition to SV detection, the epigenome status (including DNA methylation and haplotype information) surrounding SV loci has also been unveiled by long-read sequencing technologies, to identify the effects of SVs. Among the various research fields in which long-read sequencing has been applied, cancer genomics has shown the most remarkable advances. In fact, many studies are beginning to shed light on the detection of SVs and the elucidation of their complex structures in various types of cancer. In the particular case of cancers, we summarize the technical limitations of the application of this technology to the analysis of clinical samples. We will introduce recent achievements from this viewpoint. However, a similar approach will be started for other applications in the near future. Therefore, by complementing the current short-read sequencing analysis, long-read sequencing should reveal the complex nature of human genomes in their healthy and disease states, which will open a new opportunity for a better understanding of disease development and for a novel strategy for drug development.© 2021 The Authors.",
+No,20211004,prediction,34556700,Identification of early and intermediate biomarkers for ARDS mortality by multi-omic approaches.,Sci Rep,"The lack of successful clinical trials in acute respiratory distress syndrome (ARDS) has highlighted the unmet need for biomarkers predicting ARDS mortality and for novel therapeutics to reduce ARDS mortality. We utilized a systems biology multi-""omics"" approach to identify predictive biomarkers for ARDS mortality. Integrating analyses were designed to differentiate ARDS non-survivors and survivors (568 subjects, 27% overall 28-day mortality) using datasets derived from multiple 'omics' studies in a multi-institution ARDS cohort (54% European descent, 40% African descent). 'Omics' data was available for each subject and included genome-wide association studies (GWAS, n = 297), RNA sequencing (n = 93), DNA methylation data (n = 61), and selective proteomic network analysis (n = 240). Integration of available ""omic"" data identified a 9-gene set (TNPO1, NUP214, HDAC1, HNRNPA1, GATAD2A, FOSB, DDX17, PHF20, CREBBP) that differentiated ARDS survivors/non-survivors, results that were validated utilizing a longitudinal transcription dataset. Pathway analysis identified TP53-, HDAC1-, TGF-β-, and IL-6-signaling pathways to be associated with ARDS mortality. Predictive biomarker discovery identified transcription levels of the 9-gene set (AUC-0.83) and Day 7 angiopoietin 2 protein levels as potential candidate predictors of ARDS mortality (AUC-0.70). These results underscore the value of utilizing integrated ""multi-omics"" approaches in underpowered datasets from racially diverse ARDS subjects.© 2021. The Author(s).",
+No,20211004,prediction,34526487,DNA methylation of the glucocorticoid receptor gene predicts substance use in adolescence: longitudinal data from over 1000 young individuals.,Transl Psychiatry,"Early life stress has been linked to increased methylation of the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene, which codes for the glucocorticoid receptor. Moreover, early life stress has been associated with substance use initiation at a younger age, a risk factor for developing substance use disorders. However, no studies to date have investigated whether NR3C1 methylation can predict substance use in young individuals. This study included adolescents 13-14 years of age that reported no history of substance use at baseline, (N = 1041; males = 46%). Participants contributed saliva DNA samples and were followed in middle adolescence as part of KUPOL, a prospective cohort study of 7th-grade students in Sweden. Outcome variables were self-reports of (i) recent use, (ii) lifetime use, and (iii) use duration of (a) alcohol, (b) tobacco products, (c) cannabis, or (d) any substance. Outcomes were measured annually for three consecutive years. The predictor variable was DNA methylation at the exon 1 F locus of NR3C1. Risk and rate ratios were calculated as measures of association, with or without adjustment for internalizing symptoms and parental psychiatric disorders. For a subset of individuals (N = 320), there were also morning and afternoon salivary cortisol measurements available that were analyzed in relation to NR3C1 methylation levels. Baseline NR3C1 hypermethylation associated with future self-reports of recent use and use duration of any substance, before and after adjustment for potential confounders. The overall estimates were attenuated when considering lifetime use. Sex-stratified analyses revealed the strongest association for cigarette use in males. Cortisol analyses revealed associations between NR3C1 methylation and morning cortisol levels. Findings from this study suggest that saliva NR3C1 hypermethylation can predict substance use in middle adolescence. Additional longitudinal studies are warranted to confirm these findings.© 2021. The Author(s).",
+No,20211004,methods,34019650,Long-read whole-genome methylation patterning using enzymatic base conversion and nanopore sequencing,Nucleic Acids Res,"Long-read whole-genome sequencing analysis of DNA methylation would provide useful information on the chromosomal context of gene expression regulation. Here we describe the development of a method that improves the read length generated by using the bisulfite-sequencing-based approach. In this method, we combined recently developed enzymatic base conversion, where an unmethylated cytosine (C) should be converted to thymine (T), with nanopore sequencing. After methylation-sensitive base conversion, the sequencing library was constructed using long-range polymerase chain reaction. This type of analysis is possible using a minimum of 1 ng genomic DNA, and an N50 read length of 3.4–7.6 kb is achieved. To analyze the produced data, which contained a substantial number of base mismatches due to sequence conversion and an inaccurate base read of the nanopore sequencing, a new analytical pipeline was constructed. To demonstrate the performance of long-read methylation sequencing, breast cancer cell lines and clinical specimens were subjected to analysis, which revealed the chromosomal methylation context of key cancer-related genes, allele-specific methylated genes, and repetitive or deletion regions. This method should convert the intractable specimens for which the amount of available genomic DNA is limited to the tractable targets.",
+Yes,20211018,ewas,34633450,Dichotomy in the Impact of Elevated Maternal Glucose Levels on Neonatal Epigenome.,J Clin Endocrinol Metab,"Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child.We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation.This study included 830 mother-offspring dyads from the GUSTO cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (FPG) and 2h plasma glucose (2hPG) post-75g oral glucose challenge (OGTT) with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately.Maternal age, pre-pregnancy BMI and blood pressure measures were associated with both FPG and 2hPG; while Chinese ethnicity (p=1.9×10 -4), maternal height (p=1.1×10 -4), pregnancy weight gain (p=2.2×10 -3), pre-pregnancy alcohol consumption (p=4.6×10 -4), and tobacco exposure (p=1.9×10 -3) showed significantly opposite associations between the two glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the two glucose measures also reflected differences in gene ontologies and had different associations with offspring birthweight.Our findings suggest that two traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.",
+No,20211018,ewas,34628353,Genome-wide analysis of DNA methylation in 106 schizophrenia family trios in Han Chinese.,EBioMedicine,"Schizophrenia (SCZ) is a severe psychiatric disorder that affects approximately 0.75% of the global population. Both genetic and environmental factors contribute to development of SCZ. SCZ tends to run in family while both genetic and environmental factor contribute to its etiology. Much evidence suggested that alterations in DNA methylations occurred in SCZ patients.To investigate potential inheritable pattern of DNA methylation in SCZ family, we performed a genome-wide analysis of DNA methylation of peripheral blood samples from 106 Chinese SCZ family trios. Genome-wide DNA methylations were quantified by Agilent 1 × 244 k Human Methylation Microarray.In this study, we proposed a loci inheritance frequency model that allows characterization of differential methylated regions as SCZ biomarkers. Based on this model, 112 hypermethylated and 125 hypomethylated regions were identified. Additionally, 121 hypermethylated and 139 hypomethylated genes were annotated. The results of functional enrichment analysis indicated that multiple differentially methylated genes (DMGs) involved in Notch/HH/Wnt signaling, MAPK signaling, GPCR signaling, immune response signaling. Notably, a number of hypomethylated genes were significantly enriched in cerebral cortex and functionally enriched in nervous system development.Our findings not only validated previously discovered risk genes of SCZ but also identified novel candidate DMGs in SCZ. These results may further the understanding of altered DNA methylations in SCZ.Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.",
+Yes,20211018,ewas,34600028,Differential regulation of the DNA methylome in adults born during the Great Chinese Famine in 1959-1961.,Genomics,"Extensive epidemiological studies have established the association between exposure to early-life adversity and health status and diseases in adults. Epigenetic regulation is considered as a key mediator for this phenomenon but analysis on humans is sparse. The Great Chinese Famine lasting from 1958 to 1961 is a natural string of disasters offering a precious opportunity for elucidating the underlying epigenetic mechanism of the long-term effect of early adversity.Using a high-throughput array platform for DNA methylome profiling, we conducted a case-control epigenome-wide association study on early-life exposure to Chinese famine in 79 adults born during 1959-1961 and compared to 105 unexposed subjects born 1963-1964.The single CpG site analysis of whole epigenome revealed a predominant pattern of decreased DNA methylation levels associated with fetal exposure to famine. Four CpG sites were detected with p < 1e-06 (linked to EHMT1, CNR1, UBXN7 and ESM1 genes), 16 CpGs detected with 1e-06 < p < 1e-05 and 157 CpGs with 1e-05 < p < 1e-04, with a predominant pattern of hypomethylation. Functional annotation to genes and their enriched biological pathways mainly involved neurodevelopment, neuropsychological disorders and metabolism. Multiple sites analysis detected two top-rank differentially methylated regions harboring RNF39 on chromosome 6 and PTPRN2 on chromosome 7, both showing epigenetic association with stress-related conditions.Early-life exposure to famine could mediate DNA methylation regulations that persist into adulthood with broad impacts in the activities of genes and biological pathways. Results from this study provide new clues to the epigenetic embedding of early-life adversity and its impacts on adult health.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
+Yes,20211018,ewas,34596421,Associations between an integrated component of maternal glycemic regulation in pregnancy and cord blood DNA methylation.,Epigenomics,"Background:Previous studies suggest that fetal programming to hyperglycemia in pregnancy is due to modulation of DNA methylation (DNAm), but they have been limited in their maternal glycemic characterization.Methods:In the Gen3G study, we used a principal component analysis to integrate multiple glucose and insulin values measured during the second trimester oral glucose tolerance test. We investigated associations between principal components and cord blood DNAm levels in an epigenome-wide analysis among 430 mother-child pairs.Results:The first principal component was robustly associated with lower DNAm at cg26974062 (TXNIP; p = 9.9 × 10-9) in cord blood.TXNIPis a well-known DNAm marker for type 2 diabetes in adults.Conclusion:We hypothesize that abnormal glucose metabolism in pregnancy may program dysregulation ofTXNIPacross the life course.",
+No,20211018,prediction,34534207,Hierarchy and control of ageing-related methylation networks.,PLoS Comput Biol,"DNA methylation provides one of the most widely studied biomarkers of ageing. Since the methylation of CpG dinucleotides function as switches in cellular mechanisms, it is plausible to assume that by proper adjustment of these switches age may be tuned. Though, adjusting hundreds of CpG methylation levels coherently may never be feasible and changing just a few positions may lead to biologically unstable state. A prominent example of methylation-based age estimators is provided by Horvath's clock, based on 353 CpG dinucleotides, showing a high correlation (not necessarily causation) with chronological age across multiple tissue types. On this small subset of CpG dinucleotides we demonstrate how the adjustment of one methylation level leads to a cascade of changes at other sites. Among the studied subset, we locate the most important CpGs (and related genes) that may have a large influence on the rest of the sub-system. According to our analysis, the structure of this network is way more hierarchical compared to what one would expect based on ensembles of uncorrelated connections. Therefore, only a handful of CpGs is enough to modify the system towards a desired state. When propagation of the change over the network is taken into account, the resulting modification in the predicted age can be significantly larger compared to the effect of isolated CpG perturbations. By adjusting the most influential single CpG site and following the propagation of methylation level changes we can reach up to 5.74 years in virtual age reduction, significantly larger than without taking into account of the network control. Extending our approach to the whole methylation network may identify key nodes that have controller role in the ageing process.",
+No,20211018,genetics,34594039,A cross-population atlas of genetic associations for 220 human phenotypes.,Nat Genet,"Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20211018,single-cell,34616061,DNA methylation atlas of the mouse brain at single-cell resolution.,Nature,"Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing1,2to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data3enabled prediction of high-confidence enhancer-gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments4. By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum.© 2021. The Author(s).",
+No,20211018,prediction,34587932,"Combined effects of cigarette smoking, DNA methyltransferase 3B genetic polymorphism, and DNA damage on lung cancer.",BMC Cancer,"Smoking increases DNA methylation and DNA damage, and DNA damage acts as a vital cause of tumor development. The DNA methyltransferase 3B (DNMT3B) enhances promoter activity and methylation of tumor suppressor genes. Tea polyphenols may inhibit DNMT activity. We designed a case-control study to evaluate the combined effects of smoking, green tea consumption, DNMT3B - 149 polymorphism, and DNA damage on lung cancer occurrence.Questionnaires were administered to obtain demographic characteristics, life styles, and family histories of lung cancer from 190 primary lung cancer cases and 380 healthy controls. Genotypes and cellular DNA damage were determined by polymerase chain reaction and comet assay, respectively.The mean DNA tail moment for lung cancer cases was significantly higher than that for healthy controls. Compared to nonsmokers carrying the DNMT3B - 149 CT genotype, smokers carrying the TT genotype had a greater lung cancer risk (odds ratio [OR]: 2.83, 95% confidence interval [CI]: 1.62-4.93). DNA damage levels were divided by the tertile of the healthy controls' values. Compared to nonsmokers with low DNA damage, smokers with moderate DNA damage (OR: 2.37, 95% CI: 1.54-3.63) and smokers with high DNA damage (OR: 3.97, 95% CI: 2.63-5.98) had elevated lung cancer risks. Interaction between smoking and DNA damage significantly affected lung cancer risk.Our study suggested that the DNMT3B - 149 TT genotype, which has higher promoter activity, can increase the lung cancer risk elicited by smoking, and DNA damage may further promote smoking related lung cancer development.© 2021. The Author(s).",
+No,20211018,methods,34579788,"Deep learning in cancer diagnosis, prognosis and treatment selection.",Genome Med,"Deep learning is a subdiscipline of artificial intelligence that uses a machine learning technique called artificial neural networks to extract patterns and make predictions from large data sets. The increasing adoption of deep learning across healthcare domains together with the availability of highly characterised cancer datasets has accelerated research into the utility of deep learning in the analysis of the complex biology of cancer. While early results are promising, this is a rapidly evolving field with new knowledge emerging in both cancer biology and deep learning. In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools. We provide specific examples of how deep learning may be applied in cancer diagnosis, prognosis and treatment management. We also assess the current limitations and challenges for the application of deep learning in precision oncology, including the lack of phenotypically rich data and the need for more explainable deep learning models. Finally, we conclude with a discussion of how current obstacles can be overcome to enable future clinical utilisation of deep learning.© 2021. The Author(s).",
+No,20211018,methods,34617014,"Deep learning identifies erroneous microarray-based, gene-level conclusions in literature.",NAR Genom Bioinform,"More than 110 000 publications have used microarrays to decipher phenotype-associated genes, clinical biomarkers and gene functions. Microarrays rely on digital assaying the fluorescence signals of arrays. In this study, we retrospectively constructed raw images for 37 724 published microarray data, and developed deep learning algorithms to automatically detect systematic defects. We report that an alarming amount of 26.73% of the microarray-based studies are affected by serious imaging defects. By literature mining, we found that publications associated with these affected microarrays have reported disproportionately more biological discoveries on the genes in the contaminated areas compared to other genes. 28.82% of the gene-level conclusions reported in these publications were based on measurements falling into the contaminated area, indicating severe, systematic problems caused by such contaminations. We provided the identified published, problematic datasets, affected genes and the imputed arrays as well as software tools for scanning such contamination that will become essential to future studies to scrutinize and critically analyze microarray data.© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
+No,20211018,epigenetics,34593797,Chromatin accessibility associates with protein-RNA correlation in human cancer.,Nat Commun,"Although alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease.© 2021. The Author(s).",
+No,20211018,methods,34415323,Multi-omics Data Integration by Generative Adversarial Network,Bioinformatics,,
+No,20211018,methods,36277076,A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking,Nat Aging,"Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies, and clinical trials of aging interventions.
 ",
-,No,20211101,epigenetics,34691960,Evolutionary transition between invertebrates and vertebrates via methylation reprogramming in embryogenesis.,Natl Sci Rev,"Major evolutionary transitions are enigmas, and the most notable enigma is between invertebrates and vertebrates, with numerous spectacular innovations. To search for the molecular connections involved, we asked whether global epigenetic changes may offer a clue by surveying the inheritance and reprogramming of parental DNA methylation across metazoans. We focused on gametes and early embryos, where the methylomes are known to evolve divergently between fish and mammals. Here, we find that methylome reprogramming during embryogenesis occurs neither in pre-bilaterians such as cnidarians nor in protostomes such as insects, but clearly presents in deuterostomes such as echinoderms and invertebrate chordates, and then becomes more evident in vertebrates. Functional association analysis suggests that DNA methylation reprogramming is associated with development, reproduction and adaptive immunity for vertebrates, but not for invertebrates. Interestingly, the single HOX cluster of invertebrates maintains unmethylated status in all stages examined. In contrast, the multiple HOX clusters show dramatic dynamics of DNA methylation during vertebrate embryogenesis. Notably, the methylation dynamics of HOX clusters are associated with their spatiotemporal expression in mammals. Our study reveals that DNA methylation reprogramming has evolved dramatically during animal evolution, especially after the evolutionary transitions from invertebrates to vertebrates, and then to mammals.© The Author(s) 2019. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.",
-,Yes,20211101,ewas,34696705,An investigation into DNA methylation patterns associated with risk preference in older individuals.,Epigenetics,"Risk preference is a complex trait governed by psycho-social, environmental and genetic determinants. We aimed to examine how an individual's risk preference associates with their epigenetic profile.Risk preferences were ascertained by asking participants of the Northern Ireland COhort for the Longitudinal study of Ageing to make a series of choices between two hypothetical income scenarios. From these, four risk preference categories were derived, ranging from risk-averse to risk-seeking. Illumina's Infinium High Density Methylation Assay was used to evaluate the status of 862,927 CpGs.Risk preference and DNA methylation data were obtained for 1,656 individuals. The distribution of single site DNA methylation levels between risk-averse and risk-seeking individuals was assessed whilst adjusting for covariates including age, sex and peripheral white cell counts. In this discovery cohort, 55 CpG sites were identified with significantly different levels of methylation (p≤x10-5) between risk-averse and risk-seeking individuals when adjusting for the maximum number of covariates. No CpGs were significantly differentially methylated in any of the risk preference groups at an epigenome-wide association level (p<9x10-8) following covariate adjustment.Protein-coding genesNWD1andLRP1were among the genes in which top-ranked dmCpGs were located for all analyses conducted. Mutations in these genes have previously been linked to neurological conditions.Epigenetic modifications have not previously been linked to risk-aversion using a population cohort but may represent important biomarkers of accumulated, complex determinants of this trait. Several striking results from this study support further analysis of DNA methylation as an important link between measurable biomarkers and health behaviours.",
-,Yes,20211101,ewas,34689037,Residential greenness-related DNA methylation changes.,Environ Int,"Residential greenness has been associated with health benefits, but its biological mechanism is largely unknown. Investigation of greenness-related DNA methylation profiles can contribute to mechanistic understanding of the health benefits of residential greenness.To identify DNA methylation profiles associated with greenness in the immediate surroundings of the residence.We analyzed genome-wide DNA methylation in 1938 blood samples (982 participants) from the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). We estimated residential greenness based on normalized difference vegetation index at 30 × 30 m cell (green30) and 500 m buffer (green500) around the residential address. We conducted epigenome-wide association study (EWAS) to identify differentially methylated CpGs and regions, and enrichment tests by comparing to the CpGs that previous EWAS identified as associated with allergy, physical activity, and allostatic load-relevant biomarkers.We identified no genome-wide significant CpGs, but 163 and 56 differentially methylated regions for green30 and green500, respectively. Green30-related DNA methylation profiles showed enrichments in allergy, physical activity, and allostatic load, while green500-related methylation was enriched in allergy and allostatic load.Residential greenness may have health impacts through allergic sensitization, stress coping, or behavioral changes. Exposure to more proximal greenness may be more health-relevant.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",
-,Yes,20211101,ewas,34670603,Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: an EWAS in multi-ethnic Asian individuals.,Clin Epigenetics,"The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations.We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined.EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR < 0.05 in 409 Asian samples. We replicated 110 BMI-associated CpGs previously reported in Europeans and identified six novel BMI-associated CpGs and two novel WC-associated CpGs. We observed high consistency in association direction of effect compared to studies in other populations. Causal relationship analyses indicated that BMI was more likely to be the cause of DNA methylation alteration, rather than the consequence. The causal analyses using BMI-associated methylation risk score also suggested that higher levels of the inflammation marker IL-6 were likely the consequence of methylation change.Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.© 2021. The Author(s).",
-,Yes,20211101,ewas,34654479,Association of peripheral blood DNA methylation level with Alzheimer's disease progression.,Clin Epigenetics,"Identifying biomarkers associated with Alzheimer's disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.The rate of cognitive decline from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigitand mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. In addition, diagnosis conversion status was assessed using a dichotomized endpoint. Two CpG sites were significantly associated with the slope of mPACC in CN participants (P < 5.79 × 10-8[Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACCdigit, and cg09422696 annotated to RP11-661A12.5 was associated with the slope of CDR-SB. No significant CpG sites associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 19, 13, and 5 differentially methylated regions (DMRs) associated with the slopes of mPACCtrailsB, mPACCdigit, and CDR-SB, respectively, were identified by both comb-p and DMRcate algorithms; these included DMRs annotated to HOXA4. Furthermore, 5 and 19 DMRs were associated with conversion status in CN and MCI participants, respectively. The most significant DMR was annotated to the AD-associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak-corrected P = 7.74 × 10-24), which was associated with both the slope of CDR-SB and the MCI conversion status.Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in participants in the ADNI cohort. While we did not identify a single CpG site with sufficient clinical utility to be used by itself due to the observed effect size, a biosignature composed of DNA methylation changes may have utility as a prognostic biomarker for AD progression.© 2021. The Author(s).",
-,No,20211101,prediction,34678958,Prenatal Particulate Matter Exposure Is Associated with Saliva DNA Methylation at Age 15: Applying Cumulative DNA Methylation Scores as an Exposure Biomarker.,Toxics,"Exposure in utero to particulate matter (PM2.5 and PM10) is associated with maladaptive health outcomes. Although exposure to prenatal PM2.5 and PM10 has cord blood DNA methylation signatures at birth, signature persistence into childhood and saliva cross-tissue applicability has not been tested. In the Fragile Families and Child Wellbeing Study, a United States 20-city birth cohort, average residential PM2.5 and PM10 during the three months prior to birth was estimated using air quality monitors with inverse distance weighting. Saliva DNA methylation at ages 9 (n= 749) and 15 (n= 793) was measured using the Illumina HumanMethylation 450 k BeadArray. Cumulative DNA methylation scores for particulate matter were estimated by weighting participant DNA methylation at each site by independent meta-analysis effect estimates and standardizing the sums. Using a mixed-effects regression analysis, we tested the associations between cumulative DNA methylation scores at ages 9 and 15 and PM exposure during pregnancy, adjusted for child sex, age, race/ethnicity, maternal income-to-needs ratio, nonmartial birth status, and saliva cell-type proportions. Our study sample was 50.5% male, 56.3% non-Hispanic Black, and 19.8% Hispanic, with a median income-to-needs ratio of 1.4. Mean exposure levels for PM2.5 were 27.9 ÎĽg/m3/day (standard deviation: 7.0; 23.7% of observations exceeded safety standards) and for PM10 were 15.0 ÎĽg/m3/day (standard deviation: 3.1). An interquartile range increase in PM2.5 exposure (10.73 ÎĽg/m3/day) was associated with a -0.0287 standard deviation lower cumulative DNA methylation score for PM2.5 (95% CI: -0.0732, 0.0158,p= 0.20) across all participants. An interquartile range increase in PM10 exposure (3.20 ÎĽg/m3/day) was associated with a -0.1472 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.3038, 0.0095,p= 0.06) across all participants. The PM10 findings were driven by the age 15 subset where an interquartile range increase in PM10 exposure was associated with a -0.024 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.043, -0.005,p= 0.012). Findings were robust to adjustment for PM exposure at ages 1 and 3. In utero PM10-associated DNA methylation differences were identified at age 15 in saliva. Benchmarking the timing and cell-type generalizability is critical for epigenetic exposure biomarker assessment.",
-,Yes,20211101,ewas,34596434,Association of grandmaternal smoking during pregnancy with DNA methylation of grandchildren: the Isle of Wight study.,Epigenomics,"Background:To investigate the intergenerational effects of grandmaternal smoking during pregnancy (GMSDP) on the DNA methylation of grandchildren.Methods:Data from the Isle of Wight birth cohort with information regarding GMSDP and DNA methylation profiling at the birth of grandchildren (n = 161) were used. Differentially methylated CpG sites related to GMSDP were identified using testing-training screening, analysis of variance and multivariate analysis of covariance. The association between identified CpG sites and expression levels of neighboring genes was tested by linear regression.Results:Twenty-three CpG sites were differentially methylated in grandchildren because of GMSDP, and eight of these were associated with expression levels of 13 neighboring genes.Conclusion:GMSDP has an intergenerational effect on the DNA methylation profile of grandchildren independent of maternal smoking during pregnancy.",
-,No,20211101,methods,34709110,Comparison of EM-seq and PBAT methylome library methods for low-input DNA.,Epigenetics,"DNA methylation is the most studied epigenetic mark involved in regulation of gene expression. For low input samples, a limited number of methods for quantifying DNA methylation genome-wide has been evaluated. Here, we compared a series of input DNA amounts (1-10ng) from two methylome library preparation protocols, enzymatic methyl-seq (EM-seq) and post-bisulfite adaptor tagging (PBAT) adapted from single-cell PBAT. EM-seq takes advantage of enzymatic activity while PBAT relies on conventional bisulfite conversion for detection of DNA methylation. We found that both methods accurately quantified DNA methylation genome-wide. They produced expected distribution patterns around genomic features, high C-T transition efficiency at non-CpG sites and high correlation between input amounts. However, EM-seq performed better in regard to library and sequencing quality, i.e. EM-seq produced larger insert sizes, higher alignment rates and higher library complexity with lower duplication rate compared to PBAT. Moreover, EM-seq demonstrated higher CpG coverage, better CpG site overlap and higher consistency between input series. In summary, our data suggests that EM-seq overall performed better than PBAT in whole genome methylation quantification of low input samples.",
-,No,20211101,methods,34663425,DNA methylation-calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation.,Genome Biol,"Nanopore long-read sequencing technology greatly expands the capacity of long-range, single-molecule DNA-modification detection. A growing number of analytical tools have been developed to detect DNA methylation from nanopore sequencing reads. Here, we assess the performance of different methylation-calling tools to provide a systematic evaluation to guide researchers performing human epigenome-wide studies.We compare seven analytic tools for detecting DNA methylation from nanopore long-read sequencing data generated from human natural DNA at a whole-genome scale. We evaluate the per-read and per-site performance of CpG methylation prediction across different genomic contexts, CpG site coverage, and computational resources consumed by each tool. The seven tools exhibit different performances across the evaluation criteria. We show that the methylation prediction at regions with discordant DNA methylation patterns, intergenic regions, low CG density regions, and repetitive regions show room for improvement across all tools. Furthermore, we demonstrate that 5hmC levels at least partly contribute to the discrepancy between bisulfite and nanopore sequencing. Lastly, we provide an online DNA methylation database ( https://nanome.jax.org ) to display the DNA methylation levels detected by nanopore sequencing and bisulfite sequencing data across different genomic contexts.Our study is the first systematic benchmark of computational methods for detection of mammalian whole-genome DNA modifications in nanopore sequencing. We provide a broad foundation for cross-platform standardization and an evaluation of analytical tools designed for genome-scale modified base detection using nanopore sequencing.© 2021. The Author(s).",
-,No,20211101,methods,34651232,A robust mean and variance test with application to high-dimensional phenotypes.,Eur J Epidemiol,"Most studies of continuous health-related outcomes examine differences in mean levels (location) of the outcome by exposure. However, identifying effects on the variability (scale) of an outcome, and combining tests of mean and variability (location-and-scale), could provide additional insights into biological mechanisms. A joint test could improve power for studies of high-dimensional phenotypes, such as epigenome-wide association studies of DNA methylation at CpG sites. One possible cause of heterogeneity of variance is a variable interacting with exposure in its effect on outcome, so a joint test of mean and variability could help in the identification of effect modifiers. Here, we review a scale test, based on the Brown-Forsythe test, for analysing variability of a continuous outcome with respect to both categorical and continuous exposures, and develop a novel joint location-and-scale score (JLSsc) test. These tests were compared to alternatives in simulations and used to test associations of mean and variability of DNA methylation with gender and gestational age using data from the Accessible Resource for Integrated Epigenomics Studies (ARIES). In simulations, the Brown-Forsythe and JLSsc tests retained correct type I error rates when the outcome was not normally distributed in contrast to the other approaches tested which all had inflated type I error rates. These tests also identified > 7500 CpG sites for which either mean or variability in cord blood methylation differed according to gender or gestational age. The Brown-Forsythe test and JLSsc are robust tests that can be used to detect associations not solely driven by a mean effect.© 2021. The Author(s).",
-,No,20211101,methods,34663819,Incorporating functional priors improves polygenic prediction accuracy in UK Biobank and 23andMe data sets.,Nat Commun,"Polygenic risk prediction is a widely investigated topic because of its promising clinical applications. Genetic variants in functional regions of the genome are enriched for complex trait heritability. Here, we introduce a method for polygenic prediction, LDpred-funct, that leverages trait-specific functional priors to increase prediction accuracy. We fit priors using the recently developed baseline-LD model, including coding, conserved, regulatory, and LD-related annotations. We analytically estimate posterior mean causal effect sizes and then use cross-validation to regularize these estimates, improving prediction accuracy for sparse architectures. We applied LDpred-funct to predict 21 highly heritable traits in the UK Biobank (avg N = 373 K as training data). LDpred-funct attained a +4.6% relative improvement in average prediction accuracy (avg prediction R2= 0.144; highest R2= 0.413 for height) compared to SBayesR (the best method that does not incorporate functional information). For height, meta-analyzing training data from UK Biobank and 23andMe cohorts (N = 1107 K) increased prediction R2to 0.431. Our results show that incorporating functional priors improves polygenic prediction accuracy, consistent with the functional architecture of complex traits.© 2021. The Author(s).",
-,No,20211101,methods,34663458,Guidelines for pre-analytical conditions for assessing the methylation of circulating cell-free DNA.,Clin Epigenetics,"Methylation analysis of circulating cell-free DNA (cirDNA), as a liquid biopsy, has a significant potential to advance the detection, prognosis, and treatment of cancer, as well as many genetic disorders. The role of epigenetics in disease development has been reported in several hereditary disorders, and epigenetic modifications are regarded as one of the earliest and most significant genomic aberrations that arise during carcinogenesis. Liquid biopsy can be employed for the detection of these epigenetic biomarkers. It consists of isolation (pre-analytical) and detection (analytical) phases. The choice of pre-analytical variables comprising cirDNA extraction and bisulfite conversion methods can affect the identification of cirDNA methylation. Indeed, different techniques give a different return of cirDNA, which confirms the importance of pre-analytical procedures in clinical diagnostics. Although novel techniques have been developed for the simplification of methylation analysis, the process remains complex, as the steps of DNA extraction, bisulfite treatment, and methylation detection are each carried out separately. Recent studies have noted the absence of any standard method for the pre-analytical processing of methylated cirDNA. We have therefore conducted a comprehensive and systematic review of the important pre-analytical and analytical variables and the patient-related factors which form the basis of our guidelines for analyzing methylated cirDNA in liquid biopsy.© 2021. The Author(s).",
-,No,20211101,methods,34669035,Interpretable machine learning for genomics.,Hum Genet,"High-throughput technologies such as next-generation sequencing allow biologists to observe cell function with unprecedented resolution, but the resulting datasets are too large and complicated for humans to understand without the aid of advanced statistical methods. Machine learning (ML) algorithms, which are designed to automatically find patterns in data, are well suited to this task. Yet these models are often so complex as to be opaque, leaving researchers with few clues about underlying mechanisms. Interpretable machine learning (iML) is a burgeoning subdiscipline of computational statistics devoted to making the predictions of ML models more intelligible to end users. This article is a gentle and critical introduction to iML, with an emphasis on genomic applications. I define relevant concepts, motivate leading methodologies, and provide a simple typology of existing approaches. I survey recent examples of iML in genomics, demonstrating how such techniques are increasingly integrated into research workflows. I argue that iML solutions are required to realize the promise of precision medicine. However, several open challenges remain. I examine the limitations of current state-of-the-art tools and propose a number of directions for future research. While the horizon for iML in genomics is wide and bright, continued progress requires close collaboration across disciplines.© 2021. The Author(s).",
-,No,20211101,mirna,34667192,"Faecal miRNA profiles associated with age, sex, BMI, and lifestyle habits in healthy individuals.",Sci Rep,"For their stability and detectability faecal microRNAs represent promising molecules with potential clinical interest as non-invasive diagnostic and prognostic biomarkers. However, there is no evidence on how stool miRNA profiles change according to an individual's age, sex, and body mass index (BMI) or how lifestyle habits influence the expression levels of these molecules. We explored the relationship between the stool miRNA levels and common traits (sex, age, BMI, and menopausal status) or lifestyle habits (physical activity, smoking status, coffee, and alcohol consumption) as derived by a self-reported questionnaire, using small RNA-sequencing data of samples from 335 healthy subjects. We detected 151 differentially expressed miRNAs associated with one variable and 52 associated with at least two. Differences in miR-638 levels were associated with age, sex, BMI, and smoking status. The highest number of differentially expressed miRNAs was associated with BMI (n = 92) and smoking status (n = 84), with several miRNAs shared between them. Functional enrichment analyses revealed the involvement of the miRNA target genes in pathways coherent with the analysed variables. Our findings suggest that miRNA profiles in stool may reflect common traits and lifestyle habits and should be considered in relation to disease and association studies based on faecal miRNA expression.© 2021. The Author(s).",
-,No,20211101,tandem repeats,34650204,"Revisiting tandem repeats in psychiatric disorders from perspectives of genetics, physiology, and brain evolution.",Mol Psychiatry,"Genome-wide association studies (GWASs) have revealed substantial genetic components comprised of single nucleotide polymorphisms (SNPs) in the heritable risk of psychiatric disorders. However, genetic risk factors not covered by GWAS also play pivotal roles in these illnesses. Tandem repeats, which are likely functional but frequently overlooked by GWAS, may account for an important proportion in the ""missing heritability"" of psychiatric disorders. Despite difficulties in characterizing and quantifying tandem repeats in the genome, studies have been carried out in an attempt to describe impact of tandem repeats on gene regulation and human phenotypes. In this review, we have introduced recent research progress regarding the genomic distribution and regulatory mechanisms of tandem repeats. We have also summarized the current knowledge of the genetic architecture and biological underpinnings of psychiatric disorders brought by studies of tandem repeats. These findings suggest that tandem repeats, in candidate psychiatric risk genes or in different levels of linkage disequilibrium (LD) with psychiatric GWAS SNPs and haplotypes, may modulate biological phenotypes related to psychiatric disorders (e.g., cognitive function and brain physiology) through regulating alternative splicing, promoter activity, enhancer activity and so on. In addition, many tandem repeats undergo tight natural selection in the human lineage, and likely exert crucial roles in human brain evolution. Taken together, the putative roles of tandem repeats in the pathogenesis of psychiatric disorders is strongly implicated, and using examples from previous literatures, we wish to call for further attention to tandem repeats in the post-GWAS era of psychiatric disorders.© 2021. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20211129,dnam age,34747582,When Anger Remains Unspoken: Anger and Accelerated Epigenetic Aging Among Stress-Exposed Black Americans.,Psychosom Med,"Race-related lifetime stress exposure (LSE) including racial discrimination, trauma, and stressful life events have been shown to contribute to racial health disparities. However, little is known about associations between race-related stressors and premature biological aging that confer the risk of adverse health outcomes. Even less is known about the mechanisms through which race-related stressors may be associated with accelerated aging. Early evidence suggests psychological processes such as anger, and particularly the internalization of anger, may play a role.In a community sample of predominantly low-income Black adults (n = 219; age = 45.91 [12.33] years; 64% female), the present study examined the association of race-related LSE (as defined by exposure to racial discrimination, trauma, and stressful life events) and epigenetic age acceleration through anger expression.Internalized and externalized anger expression were each significantly associated with LSE and age acceleration. Although LSE was not directly associated with age acceleration (ΔR2 = 0.001, p = .64), we found that greater LSE was indirectly associated with age acceleration through increases in internalized, but not externalized, anger (indirect effect: β = 0.03, standard error = 0.02, 95% confidence interval = 0.003 to 0.08; total effect: β = 0.02, 95% confidence interval = -0.25 to 0.31).These results suggest race-related LSE may elicit the internalization of anger, which, along with the externalization of anger, may initiate detrimental epigenetic alterations that confer the risk of adverse health outcomes. These findings lay the groundwork for longitudinal studies of the association between race-related stress and racial health disparities.Copyright © 2021 by the American Psychosomatic Society.",
-,No,20211129,epigenetics,34795220,Epromoters function as a hub to recruit key transcription factors required for the inflammatory response.,Nat Commun,"Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results demonstrated that a subset of gene promoters, termed Epromoters, work as bona fide enhancers and regulate distal gene expression. Here, we hypothesized that Epromoters play a key role in the coordination of rapid gene induction during the inflammatory response. Using a high-throughput reporter assay we explored the function of Epromoters in response to type I interferon. We find that clusters of IFNa-induced genes are frequently associated with Epromoters and that these regulatory elements preferentially recruit the STAT1/2 and IRF transcription factors and distally regulate the activation of interferon-response genes. Consistently, we identified and validated the involvement of Epromoter-containing clusters in the regulation of LPS-stimulated macrophages. Our findings suggest that Epromoters function as a local hub recruiting the key TFs required for coordinated regulation of gene clusters during the inflammatory response.© 2021. The Author(s).",
-,No,20211129,epigenetics,34789882,Cell-type specialization is encoded by specific chromatin topologies.,Nature,"The three-dimensional (3D) structure of chromatin is intrinsically associated with gene regulation and cell function1-3. Methods based on chromatin conformation capture have mapped chromatin structures in neuronal systems such as in vitro differentiated neurons, neurons isolated through fluorescence-activated cell sorting from cortical tissues pooled from different animals and from dissociated whole hippocampi4-6. However, changes in chromatin organization captured by imaging, such as the relocation of Bdnf away from the nuclear periphery after activation7, are invisible with such approaches8. Here we developed immunoGAM, an extension of genome architecture mapping (GAM)2,9, to map 3D chromatin topology genome-wide in specific brain cell types, without tissue disruption, from single animals. GAM is a ligation-free technology that maps genome topology by sequencing the DNA content from thin (about 220 nm) nuclear cryosections. Chromatin interactions are identified from the increased probability of co-segregation of contacting loci across a collection of nuclear slices. ImmunoGAM expands the scope of GAM to enable the selection of specific cell types using low cell numbers (approximately 1,000 cells) within a complex tissue and avoids tissue dissociation2,10. We report cell-type specialized 3D chromatin structures at multiple genomic scales that relate to patterns of gene expression. We discover extensive 'melting' of long genes when they are highly expressed and/or have high chromatin accessibility. The contacts most specific of neuron subtypes contain genes associated with specialized processes, such as addiction and synaptic plasticity, which harbour putative binding sites for neuronal transcription factors within accessible chromatin regions. Moreover, sensory receptor genes are preferentially found in heterochromatic compartments in brain cells, which establish strong contacts across tens of megabases. Our results demonstrate that highly specific chromatin conformations in brain cells are tightly related to gene regulation mechanisms and specialized functions.© 2021. The Author(s).",
-,No,20211129,ewas,34732256,Epigenetic adaptations of the masticatory mucosa to periodontal inflammation.,Clin Epigenetics,"In mucosal barrier interfaces, flexible responses of gene expression to long-term environmental changes allow adaptation and fine-tuning for the balance of host defense and uncontrolled not-resolving inflammation. Epigenetic modifications of the chromatin confer plasticity to the genetic information and give insight into how tissues use the genetic information to adapt to environmental factors. The oral mucosa is particularly exposed to environmental stressors such as a variable microbiota. Likewise, persistent oral inflammation is the most important intrinsic risk factor for the oral inflammatory disease periodontitis and has strong potential to alter DNA-methylation patterns. The aim of the current study was to identify epigenetic changes of the oral masticatory mucosa in response to long-term inflammation that resulted in periodontitis.Genome-wide CpG methylation of both inflamed and clinically uninflamed solid gingival tissue biopsies of 60 periodontitis cases was analyzed using the Infinium MethylationEPIC BeadChip. We validated and performed cell-type deconvolution for infiltrated immune cells using the EpiDish algorithm. Effect sizes of DMPs in gingival epithelial and fibroblast cells were estimated and adjusted for confounding factors using our recently developed ""intercept-method"". In the current EWAS, we identified various genes that showed significantly different methylation between periodontitis-inflamed and uninflamed oral mucosa in periodontitis patients. The strongest differences were observed for genes with roles in wound healing (ROBO2, PTP4A3), cell adhesion (LPXN) and innate immune response (CCL26, DNAJC1, BPI). Enrichment analyses implied a role of epigenetic changes for vesicle trafficking gene sets.Our results imply specific adaptations of the oral mucosa to a persistent inflammatory environment that involve wound repair, barrier integrity, and innate immune defense.© 2021. The Author(s).",
-,No,20211129,ewas,34799556,Genome-wide differentially methylated genes associated with posttraumatic stress disorder and longitudinal change in methylation in rape survivors.,Transl Psychiatry,"Rape is associated with a high risk for posttraumatic stress disorder (PTSD). DNA methylation changes may confer risk or protection for PTSD following rape by regulating the expression of genes implicated in pathways affected by PTSD. We aimed to: (1) identify epigenome-wide differences in methylation profiles between rape-exposed women with and without PTSD at 3-months post-rape, in a demographically and ethnically similar group, drawn from a low-income setting; (2) validate and replicate the findings of the epigenome-wide analysis in selected genes (BRSK2 and ADCYAP1); and (3) investigate baseline and longitudinal changes in BRSK2 and ADCYAP1 methylation over six months in relation to change in PTSD symptom scores over 6 months, in the combined discovery/validation and replication samples (n = 96). Rape-exposed women (n = 852) were recruited from rape clinics in the Rape Impact Cohort Evaluation (RICE) umbrella study. Epigenome-wide differentially methylated CpG sites between rape-exposed women with (n = 24) and without (n = 24) PTSD at 3-months post-rape were investigated using the Illumina EPIC BeadChip in a discovery cohort (n = 48). Validation (n = 47) and replication (n = 49) of BRSK2 and ADCYAP1 methylation findings were investigated using EpiTYPER technology. Longitudinal change in BRSK2 and ADCYAP1 was also investigated using EpiTYPER technology in the combined sample (n = 96). In the discovery sample, after adjustment for multiple comparisons, one differentially methylated CpG site (chr10: 61385771/ cg01700569, p = 0.049) and thirty-four differentially methylated regions were associated with PTSD status at 3-months post-rape. Decreased BRSK2 and ADCYAP1 methylation at 3-months and 6-months post-rape were associated with increased PTSD scores at the same time points, but these findings did not remain significant in adjusted models. In conclusion, decreased methylation of BRSK2 may result in abnormal neuronal polarization, synaptic development, vesicle formation, and disrupted neurotransmission in individuals with PTSD. PTSD symptoms may also be mediated by differential methylation of the ADCYAP1 gene which is involved in stress regulation. Replication of these findings is required to determine whether ADCYAP1 and BRSK2 are biomarkers of PTSD and potential therapeutic targets.© 2021. The Author(s).",
-,No,20211129,methods,34718752,"EWAS Open Platform: integrated data, knowledge and toolkit for epigenome-wide association study.",Nucleic Acids Res,"Epigenome-Wide Association Study (EWAS) has become a standard strategy to discover DNA methylation variation of different phenotypes. Since 2018, we have developed EWAS Atlas and EWAS Data Hub to integrate a growing volume of EWAS knowledge and data, respectively. Here, we present EWAS Open Platform (https://ngdc.cncb.ac.cn/ewas) that includes EWAS Atlas, EWAS Data Hub and the newly developed EWAS Toolkit. In the current implementation, EWAS Open Platform integrates 617 018 high-quality EWAS associations from 910 publications, covering 51 phenotypes, 275 diseases and 104 environmental factors. It also provides well-normalized DNA methylation array data and the corresponding metadata from 115 852 samples, which involve 707 tissues, 218 cell lines and 528 diseases. Taking advantage of integrated knowledge and data in EWAS Atlas and EWAS Data Hub, EWAS Open Platform equips with EWAS Toolkit, a powerful one-stop site for EWAS enrichment, annotation, and knowledge network construction and visualization. Collectively, EWAS Open Platform provides open access to EWAS knowledge, data and toolkit and thus bears great utility for a broader range of relevant research.© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",
-,No,20211129,methods,34765918,How many markers are needed to robustly determine a cell's type?,iScience,"Our understanding of cell types has advanced considerably with the publication of single-cell atlases. Marker genes play an essential role for experimental validation and computational analyses such as physiological characterization, annotation, and deconvolution. However, a framework for quantifying marker replicability and selecting replicable markers is currently lacking. Here, using high-quality data from the Brain Initiative Cell Census Network (BICCN), we systematically investigate marker replicability for 85 neuronal cell types. We show that, due to dataset-specific noise, we need to combine 5 datasets to obtain robust differentially expressed (DE) genes, particularly for rare populations and lowly expressed genes. We estimate that 10 to 200 meta-analytic markers provide optimal downstream performance and make available replicable marker lists for the 85 BICCN cell types. Replicable marker lists condense interpretable and generalizable information about cell types, opening avenues for downstream applications, including cell type annotation, selection of gene panels, and bulk data deconvolution.© 2021 The Authors.",
-,No,20211129,prediction,34791072,Genome-Scale Methylation Analysis of Circulating Cell-Free DNA in Gastric Cancer Patients.,Clin Chem,"Aberrant DNA hypermethylation of CpG islands (CGIs) occurs frequently and is genome-wide in human gastric cancer (GC). A DNA methylation approach in plasma cell-free DNA (cfDNA) is attractive for the noninvasive detection of GC. Here, we performed genome-scale cfDNA methylation analysis in patients with GC.We used MCTA-Seq, a genome-scale DNA methylation analysis method, on the plasma samples of patients with GC (n = 89) and control participants (n = 82), as well as 28 pairs of GC and adjacent noncancerous tissues. The capacity of the method for detecting GC and discriminating GC from colorectal cancer (CRC) and hepatocellular carcinoma (HCC) was assessed.We identified 153 cfDNA methylation biomarkers, including DOCK10, CABIN1, and KCNQ5, for detecting GC in blood. A panel of these biomarkers gave a sensitivity of 44%, 59%, 78%, and 100% for stage I, II, III, and IV tumors, respectively, at a specificity of 92%. CpG island methylation phenotype (CIMP) tumors and NON-CIMP tumors could be distinguished and detected effectively. We also identified several hundreds of cfDNA biomarkers differentially methylated between GC, CRC, and HCC, and showed that MCTA-Seq can discriminate early-stage GC, CRC, and HCC in blood by using a high specificity (approximately 100%) algorithm.Our comprehensive analyses provided valuable data on cfDNA methylation biomarkers of GC and showed the promise of cfDNA methylation for the blood-based noninvasive detection of GC.© American Association for Clinical Chemistry 2021.",
-,No,20211129,prediction,34789321,"Epigenetic modelling of former, current and never smokers.",Clin Epigenetics,"DNA methylation (DNAm) performs excellently in the discrimination of current and former smokers from never smokers, where AUCs > 0.9 are regularly reported using a single CpG site (cg05575921; AHRR). However, there is a paucity of DNAm models which attempt to distinguish current, former and never smokers as individual classes. Derivation of a robust DNAm model that accurately distinguishes between current, former and never smokers would be particularly valuable to epidemiological research (as a more accurate smoking definition vs. self-report) and could potentially translate to clinical settings. Therefore, we appraise 4 DNAm models of ternary smoking status (that is, current, former and never smokers): methylation at cg05575921 (AHRR model), weighted scores from 13 CpGs created by Maas et al. (Maas model), weighted scores from a LASSO model of candidate smoking CpGs from the literature (candidate CpG LASSO model), and weighted scores from a LASSO model supplied with genome-wide 450K data (agnostic LASSO model). Discrimination is assessed by AUC, whilst classification accuracy is assessed by accuracy and kappa, derived from confusion matrices.We find that DNAm can classify ternary smoking status with reasonable accuracy, including when applied to external data. Ternary classification using only DNAm far exceeds the classification accuracy of simply assigning all classes as the most prevalent class (63.7% vs. 36.4%). Further, we develop a DNAm classifier which performs well in discriminating current from former smokers (agnostic LASSO model AUC in external validation data: 0.744). Finally, across our DNAm models, we show evidence of enrichment for biological pathways and human phenotype ontologies relevant to smoking, such as haemostasis, molybdenum cofactor synthesis, body fatness and social behaviours, providing evidence of the generalisability of our classifiers.Our findings suggest that DNAm can classify ternary smoking status with close to 65% accuracy. Both the ternary smoking status classifiers and current versus former smoking status classifiers address the present lack of former smoker classification in epigenetic literature; essential if DNAm classifiers are to adequately relate to real-world populations. To improve performance further, additional focus on improving discrimination of current from former smokers is necessary.© 2021. The Author(s).",
-,No,20211129,prediction,34780523,A 6-CpG validated methylation risk score model for metabolic syndrome: The HyperGEN and GOLDN studies.,PLoS One,"There has been great interest in genetic risk prediction using risk scores in recent years, however, the utility of scores developed in European populations and later applied to non-European populations has not been successful. The goal of this study was to create a methylation risk score (MRS) for metabolic syndrome (MetS), demonstrating the utility of MRS across race groups using cross-sectional data from the Hypertension Genetic Epidemiology Network (HyperGEN, N = 614 African Americans (AA)) and the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, N = 995 European Americans (EA)). To demonstrate this, we first selected cytosine-guanine dinucleotides (CpG) sites measured on Illumina Methyl450 arrays previously reported to be significantly associated with MetS and/or component conditions in more than one race/ethnic group (CPT1A cg00574958, PHOSPHO1 cg02650017, ABCG1 cg06500161, SREBF1 cg11024682, SOCS3 cg18181703, TXNIP cg19693031). Second, we calculated the parameter estimates for the 6 CpGs in the HyperGEN data (AA) and used the beta estimates as weights to construct a MRS in HyperGEN (AA), which was validated in GOLDN (EA). We performed association analyses using logistic mixed models to test the association between the MRS and MetS, adjusting for covariates. Results showed the MRS was significantly associated with MetS in both populations. In summary, a MRS for MetS was a strong predictor for the condition across two race groups, suggesting MRS may be useful to examine metabolic disease risk or related complications across race/ethnic groups.",
-,No,20211129,prediction,34732805,The relationship of smoking to cg05575921 methylation in blood and saliva DNA samples from several studies.,Sci Rep,"Numerous studies have shown that cg05575921 methylation decreases in response to smoking. However, secondary to methodological issues, the magnitude and dose dependency of that response is as of yet unclear. This lack of certainty is a barrier to the use of DNA methylation clinically to assess and monitor smoking status. To better define this relationship, we conducted a joint analysis of methylation sensitive PCR digital (MSdPCR) assessments of cg05575921 methylation in whole blood and/or saliva DNA to smoking using samples from 421 smokers and 423 biochemically confirmed non-smokers from 4 previously published studies. We found that cg05575921 methylation manifested a curvilinear dose dependent decrease in response to increasing cigarette consumption. In whole blood DNA, the Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) of cg05575921 methylation for predicting daily smoking status was 0.98. In saliva DNA, the gross AUC was 0.91 with correction for cellular heterogeneity improving the AUC to 0.94. Methylation status was significantly associated with the Fagerstrom Test for Nicotine Dependence score, but with significant sampling heterogeneity. We conclude that MSdPCR assessments of cg05575921 methylation are a potentially powerful, clinically implementable tool for the assessment and management of smoking.© 2021. The Author(s).",
-,No,20211129,prediction,34702360,Validating biomarkers and models for epigenetic inference of alcohol consumption from blood.,Clin Epigenetics,"Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories.By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 ± 0.06, while the 5 and 23 CpG models achieved 0.83 ± 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 ± 0.02 in the internal cross-validation and 0.61-0.66 in the external validation datasets.The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications.© 2021. The Author(s).",
-,No,20211129,prediction,34745991,A CpG Methylation Signature as a Potential Marker for Early Diagnosis of Hepatocellular Carcinoma From HBV-Related Liver Disease Using Multiplex Bisulfite Sequencing.,Front Oncol,"Aberrant methylation of CpG sites served as an epigenetic marker for building diagnostic, prognostic, and recurrence models for hepatocellular carcinoma (HCC).Using Illumina 450K and EPIC Beadchip, we identified 34 CpG sites in peripheral blood mononuclear cell (PBMC) DNA that were differentially methylated in early HCC versus HBV-related liver diseases (HBVLD). We employed multiplex bisulfite sequencing (MBS) based on next-generation sequencing (NGS) to measure methylation of 34 CpG sites in PBMC DNA from 654 patients that were divided into a training set (n= 442) and a test set (n= 212). Using the training set, we selected and built a six-CpG-scorer (namely, cg14171514, cg07721852, cg05166871, cg18087306, cg05213896, and cg18772205), applying least absolute shrinkage and selection operator (LASSO) regression. We performed multivariable analyses of four candidate risk predictors (namely, six-CpG-scorer, age, sex, and AFP level), using 20 times imputation of missing data, non-linearly transformed, and backwards feature selection with logistic regression. The final model's regression coefficients were calculated according to ""Rubin's Rules"". The diagnostic accuracy of the model was internally validated with a 10,000 bootstrap validation dataset and then applied to the test set for validation.The area under the receiver operating characteristic curve (AUROC) of the model was 0.81 (95% CI, 0.77-0.85) and it showed good calibration and decision curve analysis. Using enhanced bootstrap validation, adjusted C-statistics and adjusted Brier score were 0.809 and 0.199, respectively. The model also showed an AUROC value of 0.84 (95% CI 0.79-0.88) of diagnosis for early HCC in the test set.Our model based on the six-CpG-scorer was a reliable diagnosis tool for early HCC from HBVLD. The usage of the MBS method can realize large-scale detection of CpG sites in clinical diagnosis of early HCC and benefit the majority of patients.Copyright © 2021 Li, Song, Qin, Li, Jiang, Ren, Zang, Sun, Zhao and Zhang.",
-,No,20211129,prediction,34786085,Combined detection of stool-based methylation indicators for early screening of colorectal neoplasm.,Am J Transl Res,"In the past two decades, several methylated DNA targets, including gene promoters and other intronic markers have been explored in tumors and benign lesions. Therefore, it can be expected that a panel of stool-based biomarkers will become a screening method for colorectal cancer (CRC) and adenoma with better sensitivity and specificity, aiming to decrease the incidence and mortality of CRC. In this study, the methylation of secreted frizzled-related protein 1 (SFRP1), hyperplastic polyposis protein 1 (HPP1), α-internexin (INA), Wnt inhibitory factor 1 (WIF1), tissue factor pathway inhibitor 2 (TFPI2), ikaros family zinc finger protein 1 (IKZF1), and spastic paraplegia 20 (SPG20) were detected in stool samples from patients with CRC, adenoma, polyps, and healthy controls, respectively, and these biomarkers were used to establish a logistic regression model for classification. Receiver operating characteristic (ROC) curves were drawn to assess the importance of each biomarker. Subsequently, a biomarker or combination of biomarkers was analyzed for early screening of high-risk neoplasm. The data showed that when a single biomarker was used for CRC screening, the sensitivity ranged from 63.9% to 76.8%, the area under the curve (AUC) ranged from 0.821 to 0.875, and the accuracy ranged from 77.0% to 84.5%. Finally, the methylation of SFRP1, HPP1, TFPI2, and IKZF1 was selected using a backward stepwise method in the multivariate logistic analysis according to the Akaike Information Criterion. These findings indicate that stool DNA biomarkers have good diagnostic power in discriminating high-risk level of neoplasm from healthy population.AJTR Copyright © 2021.",
-,No,20211129,protein,34765854,The Proteomic Signature of Recombinant Growth Hormone in Recreational Athletes.,J Endocr Soc,"Administration of human growth hormone (hGH) is prohibited in competitive sport and its detection in an athlete's sample triggers an adverse analytical finding. However, the biological processes that are modulated by recombinant hGH are not well characterized and associated blood serum proteins may constitute new biomarkers for hGH misuse.Thirty-five recreational athletes were enrolled in a study to investigate the time- and dose-dependent response of serum protein levels to recombinant hGH administration. Participants were randomly assigned to 4 groups, receiving 1 of 3 different doses of recombinant hGH or a placebo. Bio samples were collected at 22 time points over a period of 13 weeks, starting 4 weeks before treatment, during 3 weeks of treatment, and at 6 weeks' follow-up. A total of 749 serum samples were analyzed for 1305 protein markers using the SOMAscan proteomics platform.We identified 66 proteins that significantly associated with recombinant hGH administration and dosage, including well known hGH targets, such as IGF1, but also previously unknown hGH-related proteins (eg, protease inhibitors, WFIKKN1, and chemokines, CCL2). Network analysis revealed changes in specific biological pathways, mainly related to the immune system and glucose metabolism.Our analysis suggests that hGH administration affects biological processes more strongly than previously acknowledged. Some of the proteins were dysregulated even after hGH treatment and could potentially be developed into biomarkers for hGH misuse. Moreover, our findings suggest new roles for hGH-associated proteins in the etiology of hGH-related diseases and may indicate new risks that may be associated with hGH misuse.© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.",
-,Yes,20211129,ewas,34809630,Genome-wide DNA methylation analysis of pulmonary function in middle and old-aged Chinese monozygotic twins.,Respir Res,"Previous studies have determined the epigenetic association between DNA methylation and pulmonary function among various ethnics, whereas this association is largely unknown in Chinese adults. Thus, we aimed to explore epigenetic relationships between genome-wide DNA methylation levels and pulmonary function among middle-aged Chinese monozygotic twins.The monozygotic twin sample was drawn from the Qingdao Twin Registry. Pulmonary function was measured by three parameters including forced expiratory volume the first second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Linear mixed effect model was used to regress the methylation level of CpG sites on pulmonary function. After that, we applied Genomic Regions Enrichment of Annotations Tool (GREAT) to predict the genomic regions enrichment, and used comb-p python library to detect differentially methylated regions (DMRs). Gene expression analysis was conducted to validate the results of differentially methylated analyses.We identified 112 CpG sites with the level of P < 1 × 10-4which were annotated to 40 genes. We identified 12 common enriched pathways of three pulmonary function parameters. We detected 39 DMRs located at 23 genes, of which PRDM1 was related to decreased pulmonary function, and MPL, LTB4R2, and EPHB3 were related to increased pulmonary function. The gene expression analyses validated DIP2C, ASB2, SLC6A5, and GAS6 related to decreased pulmonary function.Our DNA methylation sequencing analysis on identical twins provides new references for the epigenetic regulation on pulmonary function. Several CpG sites, genes, biological pathways and DMRs are considered as possible crucial to pulmonary function.© 2021. The Author(s).",
-,Yes,20211129,ewas,34798907,"Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals.",Clin Epigenetics,"Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses.Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10-6). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn.Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.© 2021. The Author(s).",
-,No,20211129,prediction,34797422,DNA methylation-based classification of malformations of cortical development in the human brain.,Acta Neuropathol,"Malformations of cortical development (MCD) comprise a broad spectrum of structural brain lesions frequently associated with epilepsy. Disease definition and diagnosis remain challenging and are often prone to arbitrary judgment. Molecular classification of histopathological entities may help rationalize the diagnostic process. We present a retrospective, multi-center analysis of genome-wide DNA methylation from human brain specimens obtained from epilepsy surgery using EPIC 850 K BeadChip arrays. A total of 308 samples were included in the study. In the reference cohort, 239 formalin-fixed and paraffin-embedded (FFPE) tissue samples were histopathologically classified as MCD, including 12 major subtype pathologies. They were compared to 15 FFPE samples from surgical non-MCD cortices and 11 FFPE samples from post-mortem non-epilepsy controls. We applied three different statistical approaches to decipher the DNA methylation pattern of histopathological MCD entities, i.e., pairwise comparison, machine learning, and deep learning algorithms. Our deep learning model, which represented a shallow neuronal network, achieved the highest level of accuracy. A test cohort of 43 independent surgical samples from different epilepsy centers was used to test the precision of our DNA methylation-based MCD classifier. All samples from the test cohort were accurately assigned to their disease classes by the algorithm. These data demonstrate DNA methylation-based MCD classification suitability across major histopathological entities amenable to epilepsy surgery and age groups and will help establish an integrated diagnostic classification scheme for epilepsy-associated MCD.© 2021. The Author(s).",
-,Yes,20211129,ewas,34775485,Epigenome-wide association study of alcohol use disorder in five brain regions.,Neuropsychopharmacology,"Alcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls (n = 58) using a brain-region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted correlation network analysis (WGCNA), gene-set, and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < 0.05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < 0.05) were found in the CN (n = 6), VS (n = 18), and ACC (n = 1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD.© 2021. The Author(s).",
-,Yes,20211129,ewas,34774679,"Blood DNA methylation markers associated with type 2 diabetes, fasting glucose, and HbA1c levels: An epigenome-wide association study in 316 adult twin pairs.",Genomics,"DNA methylation plays an important role in the development and etiology of type 2 diabetes; however, few epigenomic studies have been conducted on twins. Herein, a two-stage study was performed to explore the associations between DNA methylation and type 2 diabetes, fasting plasma glucose, and HbA1c. DNA methylation in 316 twin pairs from the Chinese National Twin Registry (CNTR) was measured using Illumina Infinium BeadChips. In the discovery sample, the results revealed that 63 CpG sites and 6 CpG sites were significantly associated with fasting plasma glucose and HbA1c, respectively. In the replication sample, cg19690313 in TXNIP was associated with both fasting plasma glucose (P = 1.23 × 10-17, FDR < 0.001) and HbA1c (P = 2.29 × 10-18,FDR < 0.001). Furthermore, cg04816311, cg08309687, and cg09249494 may provide new insight in the metabolic mechanism of HbA1c. Our study provides solid evidence that cg19690313 on TXNIP correlates with HbA1c and fasting plasma glucose levels.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
-,Yes,20211129,ewas,34750344,Association between maternal depression during pregnancy and newborn DNA methylation.,Transl Psychiatry,"Around 15-65% of women globally experience depression during pregnancy, prevalence being particularly high in low- and middle-income countries. Prenatal depression has been associated with adverse birth and child development outcomes. DNA methylation (DNAm) may aid in understanding this association. In this project, we analyzed associations between prenatal depression and DNAm from cord blood from participants of the South African Drakenstein Child Health Study. We examined DNAm in an epigenome-wide association study (EWAS) of 248 mother-child pairs. DNAm was measured using the Infinium MethylationEPIC (N = 145) and the Infinium HumanMethylation450 (N = 103) arrays. Prenatal depression scores, obtained with the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory-II (BDI-II), were analyzed as continuous and dichotomized variables. We used linear robust models to estimate associations between depression and newborn DNAm, adjusted for measured (smoking status, household income, sex, preterm birth, cell type proportions, and genetic principal components) and unmeasured confounding using Cate and Bacon algorithms. Bonferroni correction was used to adjust for multiple testing. DMRcate and dmrff were used to test for differentially methylated regions (DMRs). Differential DNAm was significantly associated with BDI-II variables, in cg16473797 (Δ beta = -1.10E-02, p = 6.87E-08), cg23262030 (Δ beta per BDI-II total IQR = 1.47E-03, p = 1.18E-07), and cg04859497 (Δ beta = -6.42E-02, p = 1.06E-09). Five DMRs were associated with at least two depression variables. Further studies are needed to replicate these findings and investigate their biological impact.© 2021. The Author(s).",
-,Yes,20211129,ewas,34738878,Epigenome-wide association study of global cortical volumes in generation Scotland: Scottish family health study.,Epigenetics,"A complex interplay of genetic and environmental risk factors influence global brain structural alterations associated with brain health and disease. Epigenome-wide association studies (EWAS) of global brain imaging phenotypes have the potential to reveal the mechanisms of brain health and disease and can lead to better predictive analytics through the development of risk scores.We perform an EWAS of global brain volumes in Generation Scotland using peripherally measured whole blood DNA methylation (DNAm) from two assessments, (i) at baseline recruitment, ~6 years prior to MRI assessment (N = 672) and (ii) concurrent with MRI assessment (N=565). Four CpGs at baseline were associated with global cerebral white matter, total grey matter, and whole-brain volume (Bonferroni p≤7.41×10-8, βrange= -1.46x10-6to 9.59 × 10-7). These CpGs were annotated to genes implicated in brain-related traits, including psychiatric disorders, development, and ageing. We did not find significant associations in the meta-analysis of the EWAS of the two sets concurrent with imaging at the corrected level.These findings reveal global brain structural changes associated with DNAm measured ~6 years previously, indicating a potential role of early DNAm modifications in brain structure. Although concurrent DNAm was not associated with global brain structure, the nominally significant findings identified here present a rationale for future investigation of associations between DNA methylation and structural brain phenotypes in larger population-based samples.",
-,Yes,20211129,ewas,34732242,Skeletal muscle methylome and transcriptome integration reveals profound sex differences related to muscle function and substrate metabolism.,Clin Epigenetics,"Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation; however, this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle samples (222 males and 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR < 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci; however, these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen (AR), estrogen (ESR1), and glucocorticoid (NR3C1) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16% of sex-biased DNA methylation loci (FDR < 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes (p value = 4.6e-13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes (FOXO3A, ALDH1A1, and GGT7) in the Gene SMART cohort with qPCR. GGT7, involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.© 2021. The Author(s).",
-,Yes,20211129,ewas,34732130,Role of DNA methylation on the association between physical activity and cardiovascular diseases: results from the longitudinal multi-ethnic study of atherosclerosis (MESA) cohort.,BMC Genomics,"The complexity of physical activity (PA) and DNA methylation interaction in the development of cardiovascular disease (CVD) is rarely simultaneously investigated in one study. We examined the role of DNA methylation on the association between PA and CVD.The Multi-Ethnic Study of Atherosclerosis (MESA) cohort Exam 5 data with 1065 participants free of CVD were used for final analysis. The quartile categorical total PA variable was created by activity intensity (METs/week). During a median follow-up of 4.0 years, 69 participants developed CVD. Illumina HumanMethylation450 BeadChip was used to provide genome-wide DNA methylation profiles in purified human monocytes (CD14+). We identified 23 candidate DNA methylation loci to be associated with both PA and CVD. We used the structural equation modeling (SEM) approach to test the complex relationships among multiple variables and the roles of mediators. Three of the 23 identified loci (corresponding to genes VPS13D, PIK3CD and VPS45) remained as significant mediators in the final SEM model along with other covariates. Bridged by the three genes, the 2nd PA quartile (β = - 0.959; 95%CI: - 1.554 to - 0.449) and the 3rd PA quartile (β = - 0.944; 95%CI: - 1.628 to - 0.413) showed the greatest inverse associations with CVD development, while the 4th PA quartile had a relatively weaker inverse association (β = - 0.355; 95%CI: - 0.713 to - 0.124).The current study is among the first to simultaneously examine the relationships among PA, DNA methylation, and CVD in a large cohort with long-term exposure. We identified three DNA methylation loci bridged the association between PA and CVD. The function of the identified genes warrants further investigation in the pathogenesis of CVD.© 2021. The Author(s).",
-,Yes,20211129,ewas,34717175,Short- and intermediate-term exposure to ambient fine particulate elements and leukocyte epigenome-wide DNA methylation in older men: the Normative Aging Study.,Environ Int,"Several epigenome-wide association studies (EWAS) of ambient particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) have been reported. However, EWAS of PM2.5elements (PEs), reflecting different emission sources, are very limited.We performed EWAS of short- and intermediate-term exposure to PM2.5and 13 PEs. We hypothesized that significant changes in DNAm may vary by PM2.5mass and its elements.We repeatedly collected blood samples in the Normative Aging Study and measured leukocyte DNA methylation (DNAm) with the Illumina HumanMethylation450K BeadChip. We collected daily PM2.5and 13 PEs at a fixed central site. To estimate the associations between each PE and DNAm at individual cytosine-phosphate-guanine (CpG) sites, we incorporated a distributed-lag (0-27 d) term in the setting of median regression with subject-specific intercept and examined cumulative lag associations. We also accounted for selection bias due to loss to follow-up and mortality prior to enrollment. Significantly differentially methylated probes (DMPs) were identified using Bonferroni correction for multiple testing. We further conducted regional and pathway analyses to identify significantly differentially methylated regions (DMRs) and pathways.We included 695 men with 1,266 visits between 1999 and 2013. The subjects had a mean age of 75 years. The significant DMPs, DMRs, and pathways varied by to PM2.5total mass and PEs. For example, PM2.5total mass was associated with 2,717 DMPs and 10,470 DMRs whereas Pb was associated with 3,173 DMPs and 637 DMRs. The identified pathways by PM2.5mass were mostly involved in mood disorders, neuroplasticity, immunity, and inflammation, whereas the pathways associated with motor vehicles (BC, Cu, Pb, and Zn) were related with cardiovascular disease and cancer (e.g., ""PPARs signaling"").PM2.5and PE were associated with methylation changes at multiple probes and along multiple pathways, in ways that varied by particle components.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",
-,No,20220131,atac-seq,34774128,A single-cell atlas of chromatin accessibility in the human genome.,Cell,"Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of gene regulatory elements in diverse cell types and tissues in the human body, we applied single-cell chromatin accessibility assays to 30 adult human tissue types from multiple donors. We integrated these datasets with previous single-cell chromatin accessibility data from 15 fetal tissue types to reveal the status of open chromatin for �1.2 million candidate cis-regulatory elements (cCREs) in 222 distinct cell types comprised of >1.3 million nuclei. We used these chromatin accessibility maps to delineate cell-type-specificity of fetal and adult human cCREs and to systematically interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues, life stages, and organ systems.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
-,No,20220131,cell-free dna,34943407,Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm.,Diagnostics (Basel),"Circulating tumor DNA (ctDNA) is a new pan-cancer tumor marker with important applications for patient prognosis, monitoring progression, and assessing the success of the therapeutic response. Another important goal is an early cancer diagnosis. There is currently a debate if ctDNA can be used for early cancer detection due to the small tumor burden and low mutant allele fraction (MAF). We compare our previous calculations on the size of detectable cancers by ctDNA analysis with the latest experimental data from Grail's clinical trial. Current ctDNA-based diagnostic methods could predictably detect tumors of sizes greater than 10-15 mm in diameter. When tumors are of this size or smaller, their MAF is about 0.01% (one tumor DNA molecule admixed with 10,000 normal DNA molecules). The use of 10 mL of blood (4 mL of plasma) will likely contain less than a complete cancer genome, thus rendering the diagnosis of cancer impossible. Grail's new data confirm the low sensitivity for early cancer detection (<30% for Stage I-II tumors, <20% for Stage I tumors), but specificity was high at 99.5%. According to these latest data, the sensitivity of the Grail test is less than 20% in Stage I disease, casting doubt if this test could become a viable pan-cancer clinical screening tool.",
-,No,20220131,dnam age,34962275,Genome-wide association study for four measures of epigenetic age acceleration and two epigenetic surrogate markers using DNA methylation data from Taiwan biobank.,Hum Mol Genet,"To highlight the genetic architecture for epigenetic aging, McCartney et al. recently identified 137 significant SNPs based on genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and two epigenetic surrogate markers. However, none Asian ancestry studies have been included in this or previous meta-analyses. I performed a GWAS on blood DNA methylation (DNAm) levels of 2309 Taiwan Biobank (TWB) participants. Owing to the fact that the sample size of an individual GWAS of DNAm data is still not large, I adopted the ""prioritized subset analysis"" (PSA) method to boost the power of a GWAS. The four epigenetic clocks and the two epigenetic surrogate markers were investigated, respectively. I replicated 21 out of the 137 aging-associated genetic loci by applying the PSA method to the TWB DNAm data. Moreover, I identified five novel loci, including rs117530284 that was associated with the ""epigenetic age acceleration"" (EAA) according to Lu et al.'s GrimAge (called ""GrimEAA""). Considering 16 covariates (sex, BMI, smoking status, drinking status, regular exercise, educational attainment, and the first 10 ancestry principal components), each ""A"" allele of rs117530284 in the IBA57 gene was found to be associated with a 1.5943-year GrimEAA (95% C.I. = [1.0748, 2.1138]). IBA57 is a protein coding gene and is associated with multiple mitochondrial dysfunctions syndromes. A decline in mitochondrial activity and quality is associated with aging and many age-related diseases. This is one of the first DNAm GWAS for individuals of Asian ancestry.© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,No,20220131,dnam age,34980250,Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer.,Clin Epigenetics,"Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed ""epigenetic age acceleration"", has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvath and IEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno), one optimised to predict lifespan (AgeAccelGrim) and a DNA methylation-based predictor of mortality (ZhangScore). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated.IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p = 0.007] and 1.40 [95% CI 1.06, 1.83; p = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069).In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.© 2022. The Author(s).",
-,No,20220131,dnam age,34808433,Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study.,EBioMedicine,"Three DNA methylation (DNAm) based algorithms, DNAm PhenoAge acceleration (AgeAccelPheno), DNAm GrimAge acceleration (AgeAccelGrim), and mortality risk score (MRscore), based on methylation in 513, 1030, and 10 CpGs, respectively, were established to predict health outcomes and mortality. We aimed to compare and validate the predictive ability of these scores and frailty in relation to mortality in a population-based cohort from Germany.DNA methylation in whole blood was measured by the Infinium Methylation EPIC BeadChip kit (EPIC, Illumina, San Diego, CA, USA) in two random subsets of the ESTHER cohort study (n = 741 and n = 1030). AgeAccelPheno, AgeAccelGrim, and a revised MRscore to adapt EPIC, the MRscore with 8 CpGs (MRscore-8CpGs), were calculated. Frailty was assessed by a frailty index (FI).During 17 years of follow-up, 458 deaths were observed. All DNAm algorithms and FI were positively correlated with each other. AgeAccelPheno, AgeAccelGrim, MRscore, and FI showed independent associations with all-cause mortality [hazard ratio (95% CI) per SD increase = 1·32 (1·19-1·46), 1·47 (1·32-1·64), 1·73 (1·49-2·01), and 1·31 (1·20-1·43), respectively]. Harrell's C-statistic was 0·710 for a model predicting mortality by age, sex, and leukocyte composition and increased to 0·759 in a model including MRscore-8CpGs and FI. The predictive performance was further improved (Harrell's C-statistic = 0·766) when additionally including AgeAccelPheno and AgeAccelGrim into the model.The combination of a DNA methylation score based on 8 CpGs only and an easy to ascertain frailty index may strongly enhance mortality prediction beyond age and sex.The ESTHER study was funded by grants from the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany), and the Saarland State Ministry of Health, Social Affairs, Women and the Family (Saarbrücken, Germany). The work of Xiangwei Li was supported by a grant from Fondazione Cariplo (Bando Ricerca Malattie invecchiamento, #2017-0653).Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.",
-,No,20220131,dnam age,34847066,"Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test.",Aging (Albany NY),"The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging in animal models are well established; however, most lack validation in humans. The length of human lifespan makes it impractical to perform survival analysis. Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNAm testing was performed at baseline and by the end of treatment with Rejuvant® supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years (p-value=6.538x10-12). Furthermore, the supplementation with Rejuvant® is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant® is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant® for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.",
-,No,20220131,dnam age,35029144,"DunedinPACE, A DNA methylation biomarker of the Pace of Aging",Elife,"Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al. 2020). Here we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).
+No,20211101,epigenetics,34691960,Evolutionary transition between invertebrates and vertebrates via methylation reprogramming in embryogenesis.,Natl Sci Rev,"Major evolutionary transitions are enigmas, and the most notable enigma is between invertebrates and vertebrates, with numerous spectacular innovations. To search for the molecular connections involved, we asked whether global epigenetic changes may offer a clue by surveying the inheritance and reprogramming of parental DNA methylation across metazoans. We focused on gametes and early embryos, where the methylomes are known to evolve divergently between fish and mammals. Here, we find that methylome reprogramming during embryogenesis occurs neither in pre-bilaterians such as cnidarians nor in protostomes such as insects, but clearly presents in deuterostomes such as echinoderms and invertebrate chordates, and then becomes more evident in vertebrates. Functional association analysis suggests that DNA methylation reprogramming is associated with development, reproduction and adaptive immunity for vertebrates, but not for invertebrates. Interestingly, the single HOX cluster of invertebrates maintains unmethylated status in all stages examined. In contrast, the multiple HOX clusters show dramatic dynamics of DNA methylation during vertebrate embryogenesis. Notably, the methylation dynamics of HOX clusters are associated with their spatiotemporal expression in mammals. Our study reveals that DNA methylation reprogramming has evolved dramatically during animal evolution, especially after the evolutionary transitions from invertebrates to vertebrates, and then to mammals.© The Author(s) 2019. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.",
+Yes,20211101,ewas,34696705,An investigation into DNA methylation patterns associated with risk preference in older individuals.,Epigenetics,"Risk preference is a complex trait governed by psycho-social, environmental and genetic determinants. We aimed to examine how an individual's risk preference associates with their epigenetic profile.Risk preferences were ascertained by asking participants of the Northern Ireland COhort for the Longitudinal study of Ageing to make a series of choices between two hypothetical income scenarios. From these, four risk preference categories were derived, ranging from risk-averse to risk-seeking. Illumina's Infinium High Density Methylation Assay was used to evaluate the status of 862,927 CpGs.Risk preference and DNA methylation data were obtained for 1,656 individuals. The distribution of single site DNA methylation levels between risk-averse and risk-seeking individuals was assessed whilst adjusting for covariates including age, sex and peripheral white cell counts. In this discovery cohort, 55 CpG sites were identified with significantly different levels of methylation (p≤x10-5) between risk-averse and risk-seeking individuals when adjusting for the maximum number of covariates. No CpGs were significantly differentially methylated in any of the risk preference groups at an epigenome-wide association level (p<9x10-8) following covariate adjustment.Protein-coding genesNWD1andLRP1were among the genes in which top-ranked dmCpGs were located for all analyses conducted. Mutations in these genes have previously been linked to neurological conditions.Epigenetic modifications have not previously been linked to risk-aversion using a population cohort but may represent important biomarkers of accumulated, complex determinants of this trait. Several striking results from this study support further analysis of DNA methylation as an important link between measurable biomarkers and health behaviours.",
+Yes,20211101,ewas,34689037,Residential greenness-related DNA methylation changes.,Environ Int,"Residential greenness has been associated with health benefits, but its biological mechanism is largely unknown. Investigation of greenness-related DNA methylation profiles can contribute to mechanistic understanding of the health benefits of residential greenness.To identify DNA methylation profiles associated with greenness in the immediate surroundings of the residence.We analyzed genome-wide DNA methylation in 1938 blood samples (982 participants) from the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). We estimated residential greenness based on normalized difference vegetation index at 30 × 30 m cell (green30) and 500 m buffer (green500) around the residential address. We conducted epigenome-wide association study (EWAS) to identify differentially methylated CpGs and regions, and enrichment tests by comparing to the CpGs that previous EWAS identified as associated with allergy, physical activity, and allostatic load-relevant biomarkers.We identified no genome-wide significant CpGs, but 163 and 56 differentially methylated regions for green30 and green500, respectively. Green30-related DNA methylation profiles showed enrichments in allergy, physical activity, and allostatic load, while green500-related methylation was enriched in allergy and allostatic load.Residential greenness may have health impacts through allergic sensitization, stress coping, or behavioral changes. Exposure to more proximal greenness may be more health-relevant.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",
+Yes,20211101,ewas,34670603,Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: an EWAS in multi-ethnic Asian individuals.,Clin Epigenetics,"The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations.We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined.EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR < 0.05 in 409 Asian samples. We replicated 110 BMI-associated CpGs previously reported in Europeans and identified six novel BMI-associated CpGs and two novel WC-associated CpGs. We observed high consistency in association direction of effect compared to studies in other populations. Causal relationship analyses indicated that BMI was more likely to be the cause of DNA methylation alteration, rather than the consequence. The causal analyses using BMI-associated methylation risk score also suggested that higher levels of the inflammation marker IL-6 were likely the consequence of methylation change.Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.© 2021. The Author(s).",
+Yes,20211101,ewas,34654479,Association of peripheral blood DNA methylation level with Alzheimer's disease progression.,Clin Epigenetics,"Identifying biomarkers associated with Alzheimer's disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.The rate of cognitive decline from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigitand mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. In addition, diagnosis conversion status was assessed using a dichotomized endpoint. Two CpG sites were significantly associated with the slope of mPACC in CN participants (P < 5.79 × 10-8[Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACCdigit, and cg09422696 annotated to RP11-661A12.5 was associated with the slope of CDR-SB. No significant CpG sites associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 19, 13, and 5 differentially methylated regions (DMRs) associated with the slopes of mPACCtrailsB, mPACCdigit, and CDR-SB, respectively, were identified by both comb-p and DMRcate algorithms; these included DMRs annotated to HOXA4. Furthermore, 5 and 19 DMRs were associated with conversion status in CN and MCI participants, respectively. The most significant DMR was annotated to the AD-associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak-corrected P = 7.74 × 10-24), which was associated with both the slope of CDR-SB and the MCI conversion status.Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in participants in the ADNI cohort. While we did not identify a single CpG site with sufficient clinical utility to be used by itself due to the observed effect size, a biosignature composed of DNA methylation changes may have utility as a prognostic biomarker for AD progression.© 2021. The Author(s).",
+No,20211101,prediction,34678958,Prenatal Particulate Matter Exposure Is Associated with Saliva DNA Methylation at Age 15: Applying Cumulative DNA Methylation Scores as an Exposure Biomarker.,Toxics,"Exposure in utero to particulate matter (PM2.5 and PM10) is associated with maladaptive health outcomes. Although exposure to prenatal PM2.5 and PM10 has cord blood DNA methylation signatures at birth, signature persistence into childhood and saliva cross-tissue applicability has not been tested. In the Fragile Families and Child Wellbeing Study, a United States 20-city birth cohort, average residential PM2.5 and PM10 during the three months prior to birth was estimated using air quality monitors with inverse distance weighting. Saliva DNA methylation at ages 9 (n= 749) and 15 (n= 793) was measured using the Illumina HumanMethylation 450 k BeadArray. Cumulative DNA methylation scores for particulate matter were estimated by weighting participant DNA methylation at each site by independent meta-analysis effect estimates and standardizing the sums. Using a mixed-effects regression analysis, we tested the associations between cumulative DNA methylation scores at ages 9 and 15 and PM exposure during pregnancy, adjusted for child sex, age, race/ethnicity, maternal income-to-needs ratio, nonmartial birth status, and saliva cell-type proportions. Our study sample was 50.5% male, 56.3% non-Hispanic Black, and 19.8% Hispanic, with a median income-to-needs ratio of 1.4. Mean exposure levels for PM2.5 were 27.9 ÎĽg/m3/day (standard deviation: 7.0; 23.7% of observations exceeded safety standards) and for PM10 were 15.0 ÎĽg/m3/day (standard deviation: 3.1). An interquartile range increase in PM2.5 exposure (10.73 ÎĽg/m3/day) was associated with a -0.0287 standard deviation lower cumulative DNA methylation score for PM2.5 (95% CI: -0.0732, 0.0158,p= 0.20) across all participants. An interquartile range increase in PM10 exposure (3.20 ÎĽg/m3/day) was associated with a -0.1472 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.3038, 0.0095,p= 0.06) across all participants. The PM10 findings were driven by the age 15 subset where an interquartile range increase in PM10 exposure was associated with a -0.024 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.043, -0.005,p= 0.012). Findings were robust to adjustment for PM exposure at ages 1 and 3. In utero PM10-associated DNA methylation differences were identified at age 15 in saliva. Benchmarking the timing and cell-type generalizability is critical for epigenetic exposure biomarker assessment.",
+Yes,20211101,ewas,34596434,Association of grandmaternal smoking during pregnancy with DNA methylation of grandchildren: the Isle of Wight study.,Epigenomics,"Background:To investigate the intergenerational effects of grandmaternal smoking during pregnancy (GMSDP) on the DNA methylation of grandchildren.Methods:Data from the Isle of Wight birth cohort with information regarding GMSDP and DNA methylation profiling at the birth of grandchildren (n = 161) were used. Differentially methylated CpG sites related to GMSDP were identified using testing-training screening, analysis of variance and multivariate analysis of covariance. The association between identified CpG sites and expression levels of neighboring genes was tested by linear regression.Results:Twenty-three CpG sites were differentially methylated in grandchildren because of GMSDP, and eight of these were associated with expression levels of 13 neighboring genes.Conclusion:GMSDP has an intergenerational effect on the DNA methylation profile of grandchildren independent of maternal smoking during pregnancy.",
+No,20211101,methods,34709110,Comparison of EM-seq and PBAT methylome library methods for low-input DNA.,Epigenetics,"DNA methylation is the most studied epigenetic mark involved in regulation of gene expression. For low input samples, a limited number of methods for quantifying DNA methylation genome-wide has been evaluated. Here, we compared a series of input DNA amounts (1-10ng) from two methylome library preparation protocols, enzymatic methyl-seq (EM-seq) and post-bisulfite adaptor tagging (PBAT) adapted from single-cell PBAT. EM-seq takes advantage of enzymatic activity while PBAT relies on conventional bisulfite conversion for detection of DNA methylation. We found that both methods accurately quantified DNA methylation genome-wide. They produced expected distribution patterns around genomic features, high C-T transition efficiency at non-CpG sites and high correlation between input amounts. However, EM-seq performed better in regard to library and sequencing quality, i.e. EM-seq produced larger insert sizes, higher alignment rates and higher library complexity with lower duplication rate compared to PBAT. Moreover, EM-seq demonstrated higher CpG coverage, better CpG site overlap and higher consistency between input series. In summary, our data suggests that EM-seq overall performed better than PBAT in whole genome methylation quantification of low input samples.",
+No,20211101,methods,34663425,DNA methylation-calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation.,Genome Biol,"Nanopore long-read sequencing technology greatly expands the capacity of long-range, single-molecule DNA-modification detection. A growing number of analytical tools have been developed to detect DNA methylation from nanopore sequencing reads. Here, we assess the performance of different methylation-calling tools to provide a systematic evaluation to guide researchers performing human epigenome-wide studies.We compare seven analytic tools for detecting DNA methylation from nanopore long-read sequencing data generated from human natural DNA at a whole-genome scale. We evaluate the per-read and per-site performance of CpG methylation prediction across different genomic contexts, CpG site coverage, and computational resources consumed by each tool. The seven tools exhibit different performances across the evaluation criteria. We show that the methylation prediction at regions with discordant DNA methylation patterns, intergenic regions, low CG density regions, and repetitive regions show room for improvement across all tools. Furthermore, we demonstrate that 5hmC levels at least partly contribute to the discrepancy between bisulfite and nanopore sequencing. Lastly, we provide an online DNA methylation database ( https://nanome.jax.org ) to display the DNA methylation levels detected by nanopore sequencing and bisulfite sequencing data across different genomic contexts.Our study is the first systematic benchmark of computational methods for detection of mammalian whole-genome DNA modifications in nanopore sequencing. We provide a broad foundation for cross-platform standardization and an evaluation of analytical tools designed for genome-scale modified base detection using nanopore sequencing.© 2021. The Author(s).",
+No,20211101,methods,34651232,A robust mean and variance test with application to high-dimensional phenotypes.,Eur J Epidemiol,"Most studies of continuous health-related outcomes examine differences in mean levels (location) of the outcome by exposure. However, identifying effects on the variability (scale) of an outcome, and combining tests of mean and variability (location-and-scale), could provide additional insights into biological mechanisms. A joint test could improve power for studies of high-dimensional phenotypes, such as epigenome-wide association studies of DNA methylation at CpG sites. One possible cause of heterogeneity of variance is a variable interacting with exposure in its effect on outcome, so a joint test of mean and variability could help in the identification of effect modifiers. Here, we review a scale test, based on the Brown-Forsythe test, for analysing variability of a continuous outcome with respect to both categorical and continuous exposures, and develop a novel joint location-and-scale score (JLSsc) test. These tests were compared to alternatives in simulations and used to test associations of mean and variability of DNA methylation with gender and gestational age using data from the Accessible Resource for Integrated Epigenomics Studies (ARIES). In simulations, the Brown-Forsythe and JLSsc tests retained correct type I error rates when the outcome was not normally distributed in contrast to the other approaches tested which all had inflated type I error rates. These tests also identified > 7500 CpG sites for which either mean or variability in cord blood methylation differed according to gender or gestational age. The Brown-Forsythe test and JLSsc are robust tests that can be used to detect associations not solely driven by a mean effect.© 2021. The Author(s).",
+No,20211101,methods,34663819,Incorporating functional priors improves polygenic prediction accuracy in UK Biobank and 23andMe data sets.,Nat Commun,"Polygenic risk prediction is a widely investigated topic because of its promising clinical applications. Genetic variants in functional regions of the genome are enriched for complex trait heritability. Here, we introduce a method for polygenic prediction, LDpred-funct, that leverages trait-specific functional priors to increase prediction accuracy. We fit priors using the recently developed baseline-LD model, including coding, conserved, regulatory, and LD-related annotations. We analytically estimate posterior mean causal effect sizes and then use cross-validation to regularize these estimates, improving prediction accuracy for sparse architectures. We applied LDpred-funct to predict 21 highly heritable traits in the UK Biobank (avg N = 373 K as training data). LDpred-funct attained a +4.6% relative improvement in average prediction accuracy (avg prediction R2= 0.144; highest R2= 0.413 for height) compared to SBayesR (the best method that does not incorporate functional information). For height, meta-analyzing training data from UK Biobank and 23andMe cohorts (N = 1107 K) increased prediction R2to 0.431. Our results show that incorporating functional priors improves polygenic prediction accuracy, consistent with the functional architecture of complex traits.© 2021. The Author(s).",
+No,20211101,methods,34663458,Guidelines for pre-analytical conditions for assessing the methylation of circulating cell-free DNA.,Clin Epigenetics,"Methylation analysis of circulating cell-free DNA (cirDNA), as a liquid biopsy, has a significant potential to advance the detection, prognosis, and treatment of cancer, as well as many genetic disorders. The role of epigenetics in disease development has been reported in several hereditary disorders, and epigenetic modifications are regarded as one of the earliest and most significant genomic aberrations that arise during carcinogenesis. Liquid biopsy can be employed for the detection of these epigenetic biomarkers. It consists of isolation (pre-analytical) and detection (analytical) phases. The choice of pre-analytical variables comprising cirDNA extraction and bisulfite conversion methods can affect the identification of cirDNA methylation. Indeed, different techniques give a different return of cirDNA, which confirms the importance of pre-analytical procedures in clinical diagnostics. Although novel techniques have been developed for the simplification of methylation analysis, the process remains complex, as the steps of DNA extraction, bisulfite treatment, and methylation detection are each carried out separately. Recent studies have noted the absence of any standard method for the pre-analytical processing of methylated cirDNA. We have therefore conducted a comprehensive and systematic review of the important pre-analytical and analytical variables and the patient-related factors which form the basis of our guidelines for analyzing methylated cirDNA in liquid biopsy.© 2021. The Author(s).",
+No,20211101,methods,34669035,Interpretable machine learning for genomics.,Hum Genet,"High-throughput technologies such as next-generation sequencing allow biologists to observe cell function with unprecedented resolution, but the resulting datasets are too large and complicated for humans to understand without the aid of advanced statistical methods. Machine learning (ML) algorithms, which are designed to automatically find patterns in data, are well suited to this task. Yet these models are often so complex as to be opaque, leaving researchers with few clues about underlying mechanisms. Interpretable machine learning (iML) is a burgeoning subdiscipline of computational statistics devoted to making the predictions of ML models more intelligible to end users. This article is a gentle and critical introduction to iML, with an emphasis on genomic applications. I define relevant concepts, motivate leading methodologies, and provide a simple typology of existing approaches. I survey recent examples of iML in genomics, demonstrating how such techniques are increasingly integrated into research workflows. I argue that iML solutions are required to realize the promise of precision medicine. However, several open challenges remain. I examine the limitations of current state-of-the-art tools and propose a number of directions for future research. While the horizon for iML in genomics is wide and bright, continued progress requires close collaboration across disciplines.© 2021. The Author(s).",
+No,20211101,mirna,34667192,"Faecal miRNA profiles associated with age, sex, BMI, and lifestyle habits in healthy individuals.",Sci Rep,"For their stability and detectability faecal microRNAs represent promising molecules with potential clinical interest as non-invasive diagnostic and prognostic biomarkers. However, there is no evidence on how stool miRNA profiles change according to an individual's age, sex, and body mass index (BMI) or how lifestyle habits influence the expression levels of these molecules. We explored the relationship between the stool miRNA levels and common traits (sex, age, BMI, and menopausal status) or lifestyle habits (physical activity, smoking status, coffee, and alcohol consumption) as derived by a self-reported questionnaire, using small RNA-sequencing data of samples from 335 healthy subjects. We detected 151 differentially expressed miRNAs associated with one variable and 52 associated with at least two. Differences in miR-638 levels were associated with age, sex, BMI, and smoking status. The highest number of differentially expressed miRNAs was associated with BMI (n = 92) and smoking status (n = 84), with several miRNAs shared between them. Functional enrichment analyses revealed the involvement of the miRNA target genes in pathways coherent with the analysed variables. Our findings suggest that miRNA profiles in stool may reflect common traits and lifestyle habits and should be considered in relation to disease and association studies based on faecal miRNA expression.© 2021. The Author(s).",
+No,20211101,tandem repeats,34650204,"Revisiting tandem repeats in psychiatric disorders from perspectives of genetics, physiology, and brain evolution.",Mol Psychiatry,"Genome-wide association studies (GWASs) have revealed substantial genetic components comprised of single nucleotide polymorphisms (SNPs) in the heritable risk of psychiatric disorders. However, genetic risk factors not covered by GWAS also play pivotal roles in these illnesses. Tandem repeats, which are likely functional but frequently overlooked by GWAS, may account for an important proportion in the ""missing heritability"" of psychiatric disorders. Despite difficulties in characterizing and quantifying tandem repeats in the genome, studies have been carried out in an attempt to describe impact of tandem repeats on gene regulation and human phenotypes. In this review, we have introduced recent research progress regarding the genomic distribution and regulatory mechanisms of tandem repeats. We have also summarized the current knowledge of the genetic architecture and biological underpinnings of psychiatric disorders brought by studies of tandem repeats. These findings suggest that tandem repeats, in candidate psychiatric risk genes or in different levels of linkage disequilibrium (LD) with psychiatric GWAS SNPs and haplotypes, may modulate biological phenotypes related to psychiatric disorders (e.g., cognitive function and brain physiology) through regulating alternative splicing, promoter activity, enhancer activity and so on. In addition, many tandem repeats undergo tight natural selection in the human lineage, and likely exert crucial roles in human brain evolution. Taken together, the putative roles of tandem repeats in the pathogenesis of psychiatric disorders is strongly implicated, and using examples from previous literatures, we wish to call for further attention to tandem repeats in the post-GWAS era of psychiatric disorders.© 2021. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20211129,dnam age,34747582,When Anger Remains Unspoken: Anger and Accelerated Epigenetic Aging Among Stress-Exposed Black Americans.,Psychosom Med,"Race-related lifetime stress exposure (LSE) including racial discrimination, trauma, and stressful life events have been shown to contribute to racial health disparities. However, little is known about associations between race-related stressors and premature biological aging that confer the risk of adverse health outcomes. Even less is known about the mechanisms through which race-related stressors may be associated with accelerated aging. Early evidence suggests psychological processes such as anger, and particularly the internalization of anger, may play a role.In a community sample of predominantly low-income Black adults (n = 219; age = 45.91 [12.33] years; 64% female), the present study examined the association of race-related LSE (as defined by exposure to racial discrimination, trauma, and stressful life events) and epigenetic age acceleration through anger expression.Internalized and externalized anger expression were each significantly associated with LSE and age acceleration. Although LSE was not directly associated with age acceleration (ΔR2 = 0.001, p = .64), we found that greater LSE was indirectly associated with age acceleration through increases in internalized, but not externalized, anger (indirect effect: β = 0.03, standard error = 0.02, 95% confidence interval = 0.003 to 0.08; total effect: β = 0.02, 95% confidence interval = -0.25 to 0.31).These results suggest race-related LSE may elicit the internalization of anger, which, along with the externalization of anger, may initiate detrimental epigenetic alterations that confer the risk of adverse health outcomes. These findings lay the groundwork for longitudinal studies of the association between race-related stress and racial health disparities.Copyright © 2021 by the American Psychosomatic Society.",
+No,20211129,epigenetics,34795220,Epromoters function as a hub to recruit key transcription factors required for the inflammatory response.,Nat Commun,"Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results demonstrated that a subset of gene promoters, termed Epromoters, work as bona fide enhancers and regulate distal gene expression. Here, we hypothesized that Epromoters play a key role in the coordination of rapid gene induction during the inflammatory response. Using a high-throughput reporter assay we explored the function of Epromoters in response to type I interferon. We find that clusters of IFNa-induced genes are frequently associated with Epromoters and that these regulatory elements preferentially recruit the STAT1/2 and IRF transcription factors and distally regulate the activation of interferon-response genes. Consistently, we identified and validated the involvement of Epromoter-containing clusters in the regulation of LPS-stimulated macrophages. Our findings suggest that Epromoters function as a local hub recruiting the key TFs required for coordinated regulation of gene clusters during the inflammatory response.© 2021. The Author(s).",
+No,20211129,epigenetics,34789882,Cell-type specialization is encoded by specific chromatin topologies.,Nature,"The three-dimensional (3D) structure of chromatin is intrinsically associated with gene regulation and cell function1-3. Methods based on chromatin conformation capture have mapped chromatin structures in neuronal systems such as in vitro differentiated neurons, neurons isolated through fluorescence-activated cell sorting from cortical tissues pooled from different animals and from dissociated whole hippocampi4-6. However, changes in chromatin organization captured by imaging, such as the relocation of Bdnf away from the nuclear periphery after activation7, are invisible with such approaches8. Here we developed immunoGAM, an extension of genome architecture mapping (GAM)2,9, to map 3D chromatin topology genome-wide in specific brain cell types, without tissue disruption, from single animals. GAM is a ligation-free technology that maps genome topology by sequencing the DNA content from thin (about 220 nm) nuclear cryosections. Chromatin interactions are identified from the increased probability of co-segregation of contacting loci across a collection of nuclear slices. ImmunoGAM expands the scope of GAM to enable the selection of specific cell types using low cell numbers (approximately 1,000 cells) within a complex tissue and avoids tissue dissociation2,10. We report cell-type specialized 3D chromatin structures at multiple genomic scales that relate to patterns of gene expression. We discover extensive 'melting' of long genes when they are highly expressed and/or have high chromatin accessibility. The contacts most specific of neuron subtypes contain genes associated with specialized processes, such as addiction and synaptic plasticity, which harbour putative binding sites for neuronal transcription factors within accessible chromatin regions. Moreover, sensory receptor genes are preferentially found in heterochromatic compartments in brain cells, which establish strong contacts across tens of megabases. Our results demonstrate that highly specific chromatin conformations in brain cells are tightly related to gene regulation mechanisms and specialized functions.© 2021. The Author(s).",
+No,20211129,ewas,34732256,Epigenetic adaptations of the masticatory mucosa to periodontal inflammation.,Clin Epigenetics,"In mucosal barrier interfaces, flexible responses of gene expression to long-term environmental changes allow adaptation and fine-tuning for the balance of host defense and uncontrolled not-resolving inflammation. Epigenetic modifications of the chromatin confer plasticity to the genetic information and give insight into how tissues use the genetic information to adapt to environmental factors. The oral mucosa is particularly exposed to environmental stressors such as a variable microbiota. Likewise, persistent oral inflammation is the most important intrinsic risk factor for the oral inflammatory disease periodontitis and has strong potential to alter DNA-methylation patterns. The aim of the current study was to identify epigenetic changes of the oral masticatory mucosa in response to long-term inflammation that resulted in periodontitis.Genome-wide CpG methylation of both inflamed and clinically uninflamed solid gingival tissue biopsies of 60 periodontitis cases was analyzed using the Infinium MethylationEPIC BeadChip. We validated and performed cell-type deconvolution for infiltrated immune cells using the EpiDish algorithm. Effect sizes of DMPs in gingival epithelial and fibroblast cells were estimated and adjusted for confounding factors using our recently developed ""intercept-method"". In the current EWAS, we identified various genes that showed significantly different methylation between periodontitis-inflamed and uninflamed oral mucosa in periodontitis patients. The strongest differences were observed for genes with roles in wound healing (ROBO2, PTP4A3), cell adhesion (LPXN) and innate immune response (CCL26, DNAJC1, BPI). Enrichment analyses implied a role of epigenetic changes for vesicle trafficking gene sets.Our results imply specific adaptations of the oral mucosa to a persistent inflammatory environment that involve wound repair, barrier integrity, and innate immune defense.© 2021. The Author(s).",
+No,20211129,ewas,34799556,Genome-wide differentially methylated genes associated with posttraumatic stress disorder and longitudinal change in methylation in rape survivors.,Transl Psychiatry,"Rape is associated with a high risk for posttraumatic stress disorder (PTSD). DNA methylation changes may confer risk or protection for PTSD following rape by regulating the expression of genes implicated in pathways affected by PTSD. We aimed to: (1) identify epigenome-wide differences in methylation profiles between rape-exposed women with and without PTSD at 3-months post-rape, in a demographically and ethnically similar group, drawn from a low-income setting; (2) validate and replicate the findings of the epigenome-wide analysis in selected genes (BRSK2 and ADCYAP1); and (3) investigate baseline and longitudinal changes in BRSK2 and ADCYAP1 methylation over six months in relation to change in PTSD symptom scores over 6 months, in the combined discovery/validation and replication samples (n = 96). Rape-exposed women (n = 852) were recruited from rape clinics in the Rape Impact Cohort Evaluation (RICE) umbrella study. Epigenome-wide differentially methylated CpG sites between rape-exposed women with (n = 24) and without (n = 24) PTSD at 3-months post-rape were investigated using the Illumina EPIC BeadChip in a discovery cohort (n = 48). Validation (n = 47) and replication (n = 49) of BRSK2 and ADCYAP1 methylation findings were investigated using EpiTYPER technology. Longitudinal change in BRSK2 and ADCYAP1 was also investigated using EpiTYPER technology in the combined sample (n = 96). In the discovery sample, after adjustment for multiple comparisons, one differentially methylated CpG site (chr10: 61385771/ cg01700569, p = 0.049) and thirty-four differentially methylated regions were associated with PTSD status at 3-months post-rape. Decreased BRSK2 and ADCYAP1 methylation at 3-months and 6-months post-rape were associated with increased PTSD scores at the same time points, but these findings did not remain significant in adjusted models. In conclusion, decreased methylation of BRSK2 may result in abnormal neuronal polarization, synaptic development, vesicle formation, and disrupted neurotransmission in individuals with PTSD. PTSD symptoms may also be mediated by differential methylation of the ADCYAP1 gene which is involved in stress regulation. Replication of these findings is required to determine whether ADCYAP1 and BRSK2 are biomarkers of PTSD and potential therapeutic targets.© 2021. The Author(s).",
+No,20211129,methods,34718752,"EWAS Open Platform: integrated data, knowledge and toolkit for epigenome-wide association study.",Nucleic Acids Res,"Epigenome-Wide Association Study (EWAS) has become a standard strategy to discover DNA methylation variation of different phenotypes. Since 2018, we have developed EWAS Atlas and EWAS Data Hub to integrate a growing volume of EWAS knowledge and data, respectively. Here, we present EWAS Open Platform (https://ngdc.cncb.ac.cn/ewas) that includes EWAS Atlas, EWAS Data Hub and the newly developed EWAS Toolkit. In the current implementation, EWAS Open Platform integrates 617 018 high-quality EWAS associations from 910 publications, covering 51 phenotypes, 275 diseases and 104 environmental factors. It also provides well-normalized DNA methylation array data and the corresponding metadata from 115 852 samples, which involve 707 tissues, 218 cell lines and 528 diseases. Taking advantage of integrated knowledge and data in EWAS Atlas and EWAS Data Hub, EWAS Open Platform equips with EWAS Toolkit, a powerful one-stop site for EWAS enrichment, annotation, and knowledge network construction and visualization. Collectively, EWAS Open Platform provides open access to EWAS knowledge, data and toolkit and thus bears great utility for a broader range of relevant research.© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",
+No,20211129,methods,34765918,How many markers are needed to robustly determine a cell's type?,iScience,"Our understanding of cell types has advanced considerably with the publication of single-cell atlases. Marker genes play an essential role for experimental validation and computational analyses such as physiological characterization, annotation, and deconvolution. However, a framework for quantifying marker replicability and selecting replicable markers is currently lacking. Here, using high-quality data from the Brain Initiative Cell Census Network (BICCN), we systematically investigate marker replicability for 85 neuronal cell types. We show that, due to dataset-specific noise, we need to combine 5 datasets to obtain robust differentially expressed (DE) genes, particularly for rare populations and lowly expressed genes. We estimate that 10 to 200 meta-analytic markers provide optimal downstream performance and make available replicable marker lists for the 85 BICCN cell types. Replicable marker lists condense interpretable and generalizable information about cell types, opening avenues for downstream applications, including cell type annotation, selection of gene panels, and bulk data deconvolution.© 2021 The Authors.",
+No,20211129,prediction,34791072,Genome-Scale Methylation Analysis of Circulating Cell-Free DNA in Gastric Cancer Patients.,Clin Chem,"Aberrant DNA hypermethylation of CpG islands (CGIs) occurs frequently and is genome-wide in human gastric cancer (GC). A DNA methylation approach in plasma cell-free DNA (cfDNA) is attractive for the noninvasive detection of GC. Here, we performed genome-scale cfDNA methylation analysis in patients with GC.We used MCTA-Seq, a genome-scale DNA methylation analysis method, on the plasma samples of patients with GC (n = 89) and control participants (n = 82), as well as 28 pairs of GC and adjacent noncancerous tissues. The capacity of the method for detecting GC and discriminating GC from colorectal cancer (CRC) and hepatocellular carcinoma (HCC) was assessed.We identified 153 cfDNA methylation biomarkers, including DOCK10, CABIN1, and KCNQ5, for detecting GC in blood. A panel of these biomarkers gave a sensitivity of 44%, 59%, 78%, and 100% for stage I, II, III, and IV tumors, respectively, at a specificity of 92%. CpG island methylation phenotype (CIMP) tumors and NON-CIMP tumors could be distinguished and detected effectively. We also identified several hundreds of cfDNA biomarkers differentially methylated between GC, CRC, and HCC, and showed that MCTA-Seq can discriminate early-stage GC, CRC, and HCC in blood by using a high specificity (approximately 100%) algorithm.Our comprehensive analyses provided valuable data on cfDNA methylation biomarkers of GC and showed the promise of cfDNA methylation for the blood-based noninvasive detection of GC.© American Association for Clinical Chemistry 2021.",
+No,20211129,prediction,34789321,"Epigenetic modelling of former, current and never smokers.",Clin Epigenetics,"DNA methylation (DNAm) performs excellently in the discrimination of current and former smokers from never smokers, where AUCs > 0.9 are regularly reported using a single CpG site (cg05575921; AHRR). However, there is a paucity of DNAm models which attempt to distinguish current, former and never smokers as individual classes. Derivation of a robust DNAm model that accurately distinguishes between current, former and never smokers would be particularly valuable to epidemiological research (as a more accurate smoking definition vs. self-report) and could potentially translate to clinical settings. Therefore, we appraise 4 DNAm models of ternary smoking status (that is, current, former and never smokers): methylation at cg05575921 (AHRR model), weighted scores from 13 CpGs created by Maas et al. (Maas model), weighted scores from a LASSO model of candidate smoking CpGs from the literature (candidate CpG LASSO model), and weighted scores from a LASSO model supplied with genome-wide 450K data (agnostic LASSO model). Discrimination is assessed by AUC, whilst classification accuracy is assessed by accuracy and kappa, derived from confusion matrices.We find that DNAm can classify ternary smoking status with reasonable accuracy, including when applied to external data. Ternary classification using only DNAm far exceeds the classification accuracy of simply assigning all classes as the most prevalent class (63.7% vs. 36.4%). Further, we develop a DNAm classifier which performs well in discriminating current from former smokers (agnostic LASSO model AUC in external validation data: 0.744). Finally, across our DNAm models, we show evidence of enrichment for biological pathways and human phenotype ontologies relevant to smoking, such as haemostasis, molybdenum cofactor synthesis, body fatness and social behaviours, providing evidence of the generalisability of our classifiers.Our findings suggest that DNAm can classify ternary smoking status with close to 65% accuracy. Both the ternary smoking status classifiers and current versus former smoking status classifiers address the present lack of former smoker classification in epigenetic literature; essential if DNAm classifiers are to adequately relate to real-world populations. To improve performance further, additional focus on improving discrimination of current from former smokers is necessary.© 2021. The Author(s).",
+No,20211129,prediction,34780523,A 6-CpG validated methylation risk score model for metabolic syndrome: The HyperGEN and GOLDN studies.,PLoS One,"There has been great interest in genetic risk prediction using risk scores in recent years, however, the utility of scores developed in European populations and later applied to non-European populations has not been successful. The goal of this study was to create a methylation risk score (MRS) for metabolic syndrome (MetS), demonstrating the utility of MRS across race groups using cross-sectional data from the Hypertension Genetic Epidemiology Network (HyperGEN, N = 614 African Americans (AA)) and the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, N = 995 European Americans (EA)). To demonstrate this, we first selected cytosine-guanine dinucleotides (CpG) sites measured on Illumina Methyl450 arrays previously reported to be significantly associated with MetS and/or component conditions in more than one race/ethnic group (CPT1A cg00574958, PHOSPHO1 cg02650017, ABCG1 cg06500161, SREBF1 cg11024682, SOCS3 cg18181703, TXNIP cg19693031). Second, we calculated the parameter estimates for the 6 CpGs in the HyperGEN data (AA) and used the beta estimates as weights to construct a MRS in HyperGEN (AA), which was validated in GOLDN (EA). We performed association analyses using logistic mixed models to test the association between the MRS and MetS, adjusting for covariates. Results showed the MRS was significantly associated with MetS in both populations. In summary, a MRS for MetS was a strong predictor for the condition across two race groups, suggesting MRS may be useful to examine metabolic disease risk or related complications across race/ethnic groups.",
+No,20211129,prediction,34732805,The relationship of smoking to cg05575921 methylation in blood and saliva DNA samples from several studies.,Sci Rep,"Numerous studies have shown that cg05575921 methylation decreases in response to smoking. However, secondary to methodological issues, the magnitude and dose dependency of that response is as of yet unclear. This lack of certainty is a barrier to the use of DNA methylation clinically to assess and monitor smoking status. To better define this relationship, we conducted a joint analysis of methylation sensitive PCR digital (MSdPCR) assessments of cg05575921 methylation in whole blood and/or saliva DNA to smoking using samples from 421 smokers and 423 biochemically confirmed non-smokers from 4 previously published studies. We found that cg05575921 methylation manifested a curvilinear dose dependent decrease in response to increasing cigarette consumption. In whole blood DNA, the Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) of cg05575921 methylation for predicting daily smoking status was 0.98. In saliva DNA, the gross AUC was 0.91 with correction for cellular heterogeneity improving the AUC to 0.94. Methylation status was significantly associated with the Fagerstrom Test for Nicotine Dependence score, but with significant sampling heterogeneity. We conclude that MSdPCR assessments of cg05575921 methylation are a potentially powerful, clinically implementable tool for the assessment and management of smoking.© 2021. The Author(s).",
+No,20211129,prediction,34702360,Validating biomarkers and models for epigenetic inference of alcohol consumption from blood.,Clin Epigenetics,"Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories.By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 ± 0.06, while the 5 and 23 CpG models achieved 0.83 ± 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 ± 0.02 in the internal cross-validation and 0.61-0.66 in the external validation datasets.The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications.© 2021. The Author(s).",
+No,20211129,prediction,34745991,A CpG Methylation Signature as a Potential Marker for Early Diagnosis of Hepatocellular Carcinoma From HBV-Related Liver Disease Using Multiplex Bisulfite Sequencing.,Front Oncol,"Aberrant methylation of CpG sites served as an epigenetic marker for building diagnostic, prognostic, and recurrence models for hepatocellular carcinoma (HCC).Using Illumina 450K and EPIC Beadchip, we identified 34 CpG sites in peripheral blood mononuclear cell (PBMC) DNA that were differentially methylated in early HCC versus HBV-related liver diseases (HBVLD). We employed multiplex bisulfite sequencing (MBS) based on next-generation sequencing (NGS) to measure methylation of 34 CpG sites in PBMC DNA from 654 patients that were divided into a training set (n= 442) and a test set (n= 212). Using the training set, we selected and built a six-CpG-scorer (namely, cg14171514, cg07721852, cg05166871, cg18087306, cg05213896, and cg18772205), applying least absolute shrinkage and selection operator (LASSO) regression. We performed multivariable analyses of four candidate risk predictors (namely, six-CpG-scorer, age, sex, and AFP level), using 20 times imputation of missing data, non-linearly transformed, and backwards feature selection with logistic regression. The final model's regression coefficients were calculated according to ""Rubin's Rules"". The diagnostic accuracy of the model was internally validated with a 10,000 bootstrap validation dataset and then applied to the test set for validation.The area under the receiver operating characteristic curve (AUROC) of the model was 0.81 (95% CI, 0.77-0.85) and it showed good calibration and decision curve analysis. Using enhanced bootstrap validation, adjusted C-statistics and adjusted Brier score were 0.809 and 0.199, respectively. The model also showed an AUROC value of 0.84 (95% CI 0.79-0.88) of diagnosis for early HCC in the test set.Our model based on the six-CpG-scorer was a reliable diagnosis tool for early HCC from HBVLD. The usage of the MBS method can realize large-scale detection of CpG sites in clinical diagnosis of early HCC and benefit the majority of patients.Copyright © 2021 Li, Song, Qin, Li, Jiang, Ren, Zang, Sun, Zhao and Zhang.",
+No,20211129,prediction,34786085,Combined detection of stool-based methylation indicators for early screening of colorectal neoplasm.,Am J Transl Res,"In the past two decades, several methylated DNA targets, including gene promoters and other intronic markers have been explored in tumors and benign lesions. Therefore, it can be expected that a panel of stool-based biomarkers will become a screening method for colorectal cancer (CRC) and adenoma with better sensitivity and specificity, aiming to decrease the incidence and mortality of CRC. In this study, the methylation of secreted frizzled-related protein 1 (SFRP1), hyperplastic polyposis protein 1 (HPP1), α-internexin (INA), Wnt inhibitory factor 1 (WIF1), tissue factor pathway inhibitor 2 (TFPI2), ikaros family zinc finger protein 1 (IKZF1), and spastic paraplegia 20 (SPG20) were detected in stool samples from patients with CRC, adenoma, polyps, and healthy controls, respectively, and these biomarkers were used to establish a logistic regression model for classification. Receiver operating characteristic (ROC) curves were drawn to assess the importance of each biomarker. Subsequently, a biomarker or combination of biomarkers was analyzed for early screening of high-risk neoplasm. The data showed that when a single biomarker was used for CRC screening, the sensitivity ranged from 63.9% to 76.8%, the area under the curve (AUC) ranged from 0.821 to 0.875, and the accuracy ranged from 77.0% to 84.5%. Finally, the methylation of SFRP1, HPP1, TFPI2, and IKZF1 was selected using a backward stepwise method in the multivariate logistic analysis according to the Akaike Information Criterion. These findings indicate that stool DNA biomarkers have good diagnostic power in discriminating high-risk level of neoplasm from healthy population.AJTR Copyright © 2021.",
+No,20211129,protein,34765854,The Proteomic Signature of Recombinant Growth Hormone in Recreational Athletes.,J Endocr Soc,"Administration of human growth hormone (hGH) is prohibited in competitive sport and its detection in an athlete's sample triggers an adverse analytical finding. However, the biological processes that are modulated by recombinant hGH are not well characterized and associated blood serum proteins may constitute new biomarkers for hGH misuse.Thirty-five recreational athletes were enrolled in a study to investigate the time- and dose-dependent response of serum protein levels to recombinant hGH administration. Participants were randomly assigned to 4 groups, receiving 1 of 3 different doses of recombinant hGH or a placebo. Bio samples were collected at 22 time points over a period of 13 weeks, starting 4 weeks before treatment, during 3 weeks of treatment, and at 6 weeks' follow-up. A total of 749 serum samples were analyzed for 1305 protein markers using the SOMAscan proteomics platform.We identified 66 proteins that significantly associated with recombinant hGH administration and dosage, including well known hGH targets, such as IGF1, but also previously unknown hGH-related proteins (eg, protease inhibitors, WFIKKN1, and chemokines, CCL2). Network analysis revealed changes in specific biological pathways, mainly related to the immune system and glucose metabolism.Our analysis suggests that hGH administration affects biological processes more strongly than previously acknowledged. Some of the proteins were dysregulated even after hGH treatment and could potentially be developed into biomarkers for hGH misuse. Moreover, our findings suggest new roles for hGH-associated proteins in the etiology of hGH-related diseases and may indicate new risks that may be associated with hGH misuse.© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.",
+Yes,20211129,ewas,34809630,Genome-wide DNA methylation analysis of pulmonary function in middle and old-aged Chinese monozygotic twins.,Respir Res,"Previous studies have determined the epigenetic association between DNA methylation and pulmonary function among various ethnics, whereas this association is largely unknown in Chinese adults. Thus, we aimed to explore epigenetic relationships between genome-wide DNA methylation levels and pulmonary function among middle-aged Chinese monozygotic twins.The monozygotic twin sample was drawn from the Qingdao Twin Registry. Pulmonary function was measured by three parameters including forced expiratory volume the first second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Linear mixed effect model was used to regress the methylation level of CpG sites on pulmonary function. After that, we applied Genomic Regions Enrichment of Annotations Tool (GREAT) to predict the genomic regions enrichment, and used comb-p python library to detect differentially methylated regions (DMRs). Gene expression analysis was conducted to validate the results of differentially methylated analyses.We identified 112 CpG sites with the level of P < 1 × 10-4which were annotated to 40 genes. We identified 12 common enriched pathways of three pulmonary function parameters. We detected 39 DMRs located at 23 genes, of which PRDM1 was related to decreased pulmonary function, and MPL, LTB4R2, and EPHB3 were related to increased pulmonary function. The gene expression analyses validated DIP2C, ASB2, SLC6A5, and GAS6 related to decreased pulmonary function.Our DNA methylation sequencing analysis on identical twins provides new references for the epigenetic regulation on pulmonary function. Several CpG sites, genes, biological pathways and DMRs are considered as possible crucial to pulmonary function.© 2021. The Author(s).",
+Yes,20211129,ewas,34798907,"Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals.",Clin Epigenetics,"Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses.Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10-6). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn.Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.© 2021. The Author(s).",
+No,20211129,prediction,34797422,DNA methylation-based classification of malformations of cortical development in the human brain.,Acta Neuropathol,"Malformations of cortical development (MCD) comprise a broad spectrum of structural brain lesions frequently associated with epilepsy. Disease definition and diagnosis remain challenging and are often prone to arbitrary judgment. Molecular classification of histopathological entities may help rationalize the diagnostic process. We present a retrospective, multi-center analysis of genome-wide DNA methylation from human brain specimens obtained from epilepsy surgery using EPIC 850 K BeadChip arrays. A total of 308 samples were included in the study. In the reference cohort, 239 formalin-fixed and paraffin-embedded (FFPE) tissue samples were histopathologically classified as MCD, including 12 major subtype pathologies. They were compared to 15 FFPE samples from surgical non-MCD cortices and 11 FFPE samples from post-mortem non-epilepsy controls. We applied three different statistical approaches to decipher the DNA methylation pattern of histopathological MCD entities, i.e., pairwise comparison, machine learning, and deep learning algorithms. Our deep learning model, which represented a shallow neuronal network, achieved the highest level of accuracy. A test cohort of 43 independent surgical samples from different epilepsy centers was used to test the precision of our DNA methylation-based MCD classifier. All samples from the test cohort were accurately assigned to their disease classes by the algorithm. These data demonstrate DNA methylation-based MCD classification suitability across major histopathological entities amenable to epilepsy surgery and age groups and will help establish an integrated diagnostic classification scheme for epilepsy-associated MCD.© 2021. The Author(s).",
+Yes,20211129,ewas,34775485,Epigenome-wide association study of alcohol use disorder in five brain regions.,Neuropsychopharmacology,"Alcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls (n = 58) using a brain-region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted correlation network analysis (WGCNA), gene-set, and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < 0.05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < 0.05) were found in the CN (n = 6), VS (n = 18), and ACC (n = 1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD.© 2021. The Author(s).",
+Yes,20211129,ewas,34774679,"Blood DNA methylation markers associated with type 2 diabetes, fasting glucose, and HbA1c levels: An epigenome-wide association study in 316 adult twin pairs.",Genomics,"DNA methylation plays an important role in the development and etiology of type 2 diabetes; however, few epigenomic studies have been conducted on twins. Herein, a two-stage study was performed to explore the associations between DNA methylation and type 2 diabetes, fasting plasma glucose, and HbA1c. DNA methylation in 316 twin pairs from the Chinese National Twin Registry (CNTR) was measured using Illumina Infinium BeadChips. In the discovery sample, the results revealed that 63 CpG sites and 6 CpG sites were significantly associated with fasting plasma glucose and HbA1c, respectively. In the replication sample, cg19690313 in TXNIP was associated with both fasting plasma glucose (P = 1.23 × 10-17, FDR < 0.001) and HbA1c (P = 2.29 × 10-18,FDR < 0.001). Furthermore, cg04816311, cg08309687, and cg09249494 may provide new insight in the metabolic mechanism of HbA1c. Our study provides solid evidence that cg19690313 on TXNIP correlates with HbA1c and fasting plasma glucose levels.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
+Yes,20211129,ewas,34750344,Association between maternal depression during pregnancy and newborn DNA methylation.,Transl Psychiatry,"Around 15-65% of women globally experience depression during pregnancy, prevalence being particularly high in low- and middle-income countries. Prenatal depression has been associated with adverse birth and child development outcomes. DNA methylation (DNAm) may aid in understanding this association. In this project, we analyzed associations between prenatal depression and DNAm from cord blood from participants of the South African Drakenstein Child Health Study. We examined DNAm in an epigenome-wide association study (EWAS) of 248 mother-child pairs. DNAm was measured using the Infinium MethylationEPIC (N = 145) and the Infinium HumanMethylation450 (N = 103) arrays. Prenatal depression scores, obtained with the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory-II (BDI-II), were analyzed as continuous and dichotomized variables. We used linear robust models to estimate associations between depression and newborn DNAm, adjusted for measured (smoking status, household income, sex, preterm birth, cell type proportions, and genetic principal components) and unmeasured confounding using Cate and Bacon algorithms. Bonferroni correction was used to adjust for multiple testing. DMRcate and dmrff were used to test for differentially methylated regions (DMRs). Differential DNAm was significantly associated with BDI-II variables, in cg16473797 (Δ beta = -1.10E-02, p = 6.87E-08), cg23262030 (Δ beta per BDI-II total IQR = 1.47E-03, p = 1.18E-07), and cg04859497 (Δ beta = -6.42E-02, p = 1.06E-09). Five DMRs were associated with at least two depression variables. Further studies are needed to replicate these findings and investigate their biological impact.© 2021. The Author(s).",
+Yes,20211129,ewas,34738878,Epigenome-wide association study of global cortical volumes in generation Scotland: Scottish family health study.,Epigenetics,"A complex interplay of genetic and environmental risk factors influence global brain structural alterations associated with brain health and disease. Epigenome-wide association studies (EWAS) of global brain imaging phenotypes have the potential to reveal the mechanisms of brain health and disease and can lead to better predictive analytics through the development of risk scores.We perform an EWAS of global brain volumes in Generation Scotland using peripherally measured whole blood DNA methylation (DNAm) from two assessments, (i) at baseline recruitment, ~6 years prior to MRI assessment (N = 672) and (ii) concurrent with MRI assessment (N=565). Four CpGs at baseline were associated with global cerebral white matter, total grey matter, and whole-brain volume (Bonferroni p≤7.41×10-8, βrange= -1.46x10-6to 9.59 × 10-7). These CpGs were annotated to genes implicated in brain-related traits, including psychiatric disorders, development, and ageing. We did not find significant associations in the meta-analysis of the EWAS of the two sets concurrent with imaging at the corrected level.These findings reveal global brain structural changes associated with DNAm measured ~6 years previously, indicating a potential role of early DNAm modifications in brain structure. Although concurrent DNAm was not associated with global brain structure, the nominally significant findings identified here present a rationale for future investigation of associations between DNA methylation and structural brain phenotypes in larger population-based samples.",
+Yes,20211129,ewas,34732242,Skeletal muscle methylome and transcriptome integration reveals profound sex differences related to muscle function and substrate metabolism.,Clin Epigenetics,"Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation; however, this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle samples (222 males and 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR < 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci; however, these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen (AR), estrogen (ESR1), and glucocorticoid (NR3C1) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16% of sex-biased DNA methylation loci (FDR < 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes (p value = 4.6e-13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes (FOXO3A, ALDH1A1, and GGT7) in the Gene SMART cohort with qPCR. GGT7, involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.© 2021. The Author(s).",
+Yes,20211129,ewas,34732130,Role of DNA methylation on the association between physical activity and cardiovascular diseases: results from the longitudinal multi-ethnic study of atherosclerosis (MESA) cohort.,BMC Genomics,"The complexity of physical activity (PA) and DNA methylation interaction in the development of cardiovascular disease (CVD) is rarely simultaneously investigated in one study. We examined the role of DNA methylation on the association between PA and CVD.The Multi-Ethnic Study of Atherosclerosis (MESA) cohort Exam 5 data with 1065 participants free of CVD were used for final analysis. The quartile categorical total PA variable was created by activity intensity (METs/week). During a median follow-up of 4.0 years, 69 participants developed CVD. Illumina HumanMethylation450 BeadChip was used to provide genome-wide DNA methylation profiles in purified human monocytes (CD14+). We identified 23 candidate DNA methylation loci to be associated with both PA and CVD. We used the structural equation modeling (SEM) approach to test the complex relationships among multiple variables and the roles of mediators. Three of the 23 identified loci (corresponding to genes VPS13D, PIK3CD and VPS45) remained as significant mediators in the final SEM model along with other covariates. Bridged by the three genes, the 2nd PA quartile (β = - 0.959; 95%CI: - 1.554 to - 0.449) and the 3rd PA quartile (β = - 0.944; 95%CI: - 1.628 to - 0.413) showed the greatest inverse associations with CVD development, while the 4th PA quartile had a relatively weaker inverse association (β = - 0.355; 95%CI: - 0.713 to - 0.124).The current study is among the first to simultaneously examine the relationships among PA, DNA methylation, and CVD in a large cohort with long-term exposure. We identified three DNA methylation loci bridged the association between PA and CVD. The function of the identified genes warrants further investigation in the pathogenesis of CVD.© 2021. The Author(s).",
+Yes,20211129,ewas,34717175,Short- and intermediate-term exposure to ambient fine particulate elements and leukocyte epigenome-wide DNA methylation in older men: the Normative Aging Study.,Environ Int,"Several epigenome-wide association studies (EWAS) of ambient particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) have been reported. However, EWAS of PM2.5elements (PEs), reflecting different emission sources, are very limited.We performed EWAS of short- and intermediate-term exposure to PM2.5and 13 PEs. We hypothesized that significant changes in DNAm may vary by PM2.5mass and its elements.We repeatedly collected blood samples in the Normative Aging Study and measured leukocyte DNA methylation (DNAm) with the Illumina HumanMethylation450K BeadChip. We collected daily PM2.5and 13 PEs at a fixed central site. To estimate the associations between each PE and DNAm at individual cytosine-phosphate-guanine (CpG) sites, we incorporated a distributed-lag (0-27 d) term in the setting of median regression with subject-specific intercept and examined cumulative lag associations. We also accounted for selection bias due to loss to follow-up and mortality prior to enrollment. Significantly differentially methylated probes (DMPs) were identified using Bonferroni correction for multiple testing. We further conducted regional and pathway analyses to identify significantly differentially methylated regions (DMRs) and pathways.We included 695 men with 1,266 visits between 1999 and 2013. The subjects had a mean age of 75 years. The significant DMPs, DMRs, and pathways varied by to PM2.5total mass and PEs. For example, PM2.5total mass was associated with 2,717 DMPs and 10,470 DMRs whereas Pb was associated with 3,173 DMPs and 637 DMRs. The identified pathways by PM2.5mass were mostly involved in mood disorders, neuroplasticity, immunity, and inflammation, whereas the pathways associated with motor vehicles (BC, Cu, Pb, and Zn) were related with cardiovascular disease and cancer (e.g., ""PPARs signaling"").PM2.5and PE were associated with methylation changes at multiple probes and along multiple pathways, in ways that varied by particle components.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",
+No,20220131,atac-seq,34774128,A single-cell atlas of chromatin accessibility in the human genome.,Cell,"Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of gene regulatory elements in diverse cell types and tissues in the human body, we applied single-cell chromatin accessibility assays to 30 adult human tissue types from multiple donors. We integrated these datasets with previous single-cell chromatin accessibility data from 15 fetal tissue types to reveal the status of open chromatin for �1.2 million candidate cis-regulatory elements (cCREs) in 222 distinct cell types comprised of >1.3 million nuclei. We used these chromatin accessibility maps to delineate cell-type-specificity of fetal and adult human cCREs and to systematically interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues, life stages, and organ systems.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
+No,20220131,cell-free dna,34943407,Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm.,Diagnostics (Basel),"Circulating tumor DNA (ctDNA) is a new pan-cancer tumor marker with important applications for patient prognosis, monitoring progression, and assessing the success of the therapeutic response. Another important goal is an early cancer diagnosis. There is currently a debate if ctDNA can be used for early cancer detection due to the small tumor burden and low mutant allele fraction (MAF). We compare our previous calculations on the size of detectable cancers by ctDNA analysis with the latest experimental data from Grail's clinical trial. Current ctDNA-based diagnostic methods could predictably detect tumors of sizes greater than 10-15 mm in diameter. When tumors are of this size or smaller, their MAF is about 0.01% (one tumor DNA molecule admixed with 10,000 normal DNA molecules). The use of 10 mL of blood (4 mL of plasma) will likely contain less than a complete cancer genome, thus rendering the diagnosis of cancer impossible. Grail's new data confirm the low sensitivity for early cancer detection (<30% for Stage I-II tumors, <20% for Stage I tumors), but specificity was high at 99.5%. According to these latest data, the sensitivity of the Grail test is less than 20% in Stage I disease, casting doubt if this test could become a viable pan-cancer clinical screening tool.",
+No,20220131,dnam age,34962275,Genome-wide association study for four measures of epigenetic age acceleration and two epigenetic surrogate markers using DNA methylation data from Taiwan biobank.,Hum Mol Genet,"To highlight the genetic architecture for epigenetic aging, McCartney et al. recently identified 137 significant SNPs based on genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and two epigenetic surrogate markers. However, none Asian ancestry studies have been included in this or previous meta-analyses. I performed a GWAS on blood DNA methylation (DNAm) levels of 2309 Taiwan Biobank (TWB) participants. Owing to the fact that the sample size of an individual GWAS of DNAm data is still not large, I adopted the ""prioritized subset analysis"" (PSA) method to boost the power of a GWAS. The four epigenetic clocks and the two epigenetic surrogate markers were investigated, respectively. I replicated 21 out of the 137 aging-associated genetic loci by applying the PSA method to the TWB DNAm data. Moreover, I identified five novel loci, including rs117530284 that was associated with the ""epigenetic age acceleration"" (EAA) according to Lu et al.'s GrimAge (called ""GrimEAA""). Considering 16 covariates (sex, BMI, smoking status, drinking status, regular exercise, educational attainment, and the first 10 ancestry principal components), each ""A"" allele of rs117530284 in the IBA57 gene was found to be associated with a 1.5943-year GrimEAA (95% C.I. = [1.0748, 2.1138]). IBA57 is a protein coding gene and is associated with multiple mitochondrial dysfunctions syndromes. A decline in mitochondrial activity and quality is associated with aging and many age-related diseases. This is one of the first DNAm GWAS for individuals of Asian ancestry.© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+No,20220131,dnam age,34980250,Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer.,Clin Epigenetics,"Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed ""epigenetic age acceleration"", has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvath and IEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno), one optimised to predict lifespan (AgeAccelGrim) and a DNA methylation-based predictor of mortality (ZhangScore). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated.IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p = 0.007] and 1.40 [95% CI 1.06, 1.83; p = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069).In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.© 2022. The Author(s).",
+No,20220131,dnam age,34808433,Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study.,EBioMedicine,"Three DNA methylation (DNAm) based algorithms, DNAm PhenoAge acceleration (AgeAccelPheno), DNAm GrimAge acceleration (AgeAccelGrim), and mortality risk score (MRscore), based on methylation in 513, 1030, and 10 CpGs, respectively, were established to predict health outcomes and mortality. We aimed to compare and validate the predictive ability of these scores and frailty in relation to mortality in a population-based cohort from Germany.DNA methylation in whole blood was measured by the Infinium Methylation EPIC BeadChip kit (EPIC, Illumina, San Diego, CA, USA) in two random subsets of the ESTHER cohort study (n = 741 and n = 1030). AgeAccelPheno, AgeAccelGrim, and a revised MRscore to adapt EPIC, the MRscore with 8 CpGs (MRscore-8CpGs), were calculated. Frailty was assessed by a frailty index (FI).During 17 years of follow-up, 458 deaths were observed. All DNAm algorithms and FI were positively correlated with each other. AgeAccelPheno, AgeAccelGrim, MRscore, and FI showed independent associations with all-cause mortality [hazard ratio (95% CI) per SD increase = 1·32 (1·19-1·46), 1·47 (1·32-1·64), 1·73 (1·49-2·01), and 1·31 (1·20-1·43), respectively]. Harrell's C-statistic was 0·710 for a model predicting mortality by age, sex, and leukocyte composition and increased to 0·759 in a model including MRscore-8CpGs and FI. The predictive performance was further improved (Harrell's C-statistic = 0·766) when additionally including AgeAccelPheno and AgeAccelGrim into the model.The combination of a DNA methylation score based on 8 CpGs only and an easy to ascertain frailty index may strongly enhance mortality prediction beyond age and sex.The ESTHER study was funded by grants from the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany), and the Saarland State Ministry of Health, Social Affairs, Women and the Family (Saarbrücken, Germany). The work of Xiangwei Li was supported by a grant from Fondazione Cariplo (Bando Ricerca Malattie invecchiamento, #2017-0653).Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.",
+No,20220131,dnam age,34847066,"Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test.",Aging (Albany NY),"The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging in animal models are well established; however, most lack validation in humans. The length of human lifespan makes it impractical to perform survival analysis. Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNAm testing was performed at baseline and by the end of treatment with Rejuvant® supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years (p-value=6.538x10-12). Furthermore, the supplementation with Rejuvant® is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant® is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant® for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.",
+No,20220131,dnam age,35029144,"DunedinPACE, A DNA methylation biomarker of the Pace of Aging",Elife,"Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al. 2020). Here we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).
 
 Methods: We used data from the Dunedin Study 1972-3 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets.
 
 Results: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge.
 
 Conclusions: DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.",
-,No,20220131,dnam score,35023833,Epigenetic scores for the circulating proteome as tools for disease prediction.,Elife,"Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample, (Generation Scotland; n=9,537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore - disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.© 2022, Gadd et al.",
-,No,20220131,epigenetics,35031073,Functional genomics analysis identifies T and NK cell activation as a driver of epigenetic clock progression.,Genome Biol,"Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks.We perform a functional genomics analysis on four epigenetic clocks, including Hannum's blood predictor and Horvath's multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expression in trans. The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells.The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes.© 2022. The Author(s).",
-,No,20220131,epigenetics,34850165,Single-molecule mitochondrial DNA sequencing shows no evidence of CpG methylation in human cells and tissues.,Nucleic Acids Res,"Methylation on CpG residues is one of the most important epigenetic modifications of nuclear DNA, regulating gene expression. Methylation of mitochondrial DNA (mtDNA) has been studied using whole genome bisulfite sequencing (WGBS), but recent evidence has uncovered technical issues which introduce a potential bias during methylation quantification. Here, we validate the technical concerns of WGBS, and develop and assess the accuracy of a new protocol for mtDNA nucleotide variant-specific methylation using single-molecule Oxford Nanopore Sequencing (ONS). Our approach circumvents confounders by enriching for full-length molecules over nuclear DNA. Variant calling analysis against showed that 99.5% of homoplasmic mtDNA variants can be reliably identified providing there is adequate sequencing depth. We show that some of the mtDNA methylation signal detected by ONS is due to sequence-specific false positives introduced by the technique. The residual signal was observed across several human primary and cancer cell lines and multiple human tissues, but was always below the error threshold modelled using negative controls. We conclude that there is no evidence for CpG methylation in human mtDNA, thus resolving previous controversies. Additionally, we developed a reliable protocol to study epigenetic modifications of mtDNA at single-molecule and single-base resolution, with potential applications beyond CpG methylation.© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",
-,No,20220131,epigenetics,34980912,Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues.,Nat Biotechnol,"Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated 'flip-flops' between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).© 2022. The Author(s).",
-,No,20220131,epigenetics,34991667,Universal annotation of the human genome through integration of over a thousand epigenomic datasets.,Genome Biol,"Genome-wide maps of chromatin marks such as histone modifications and open chromatin sites provide valuable information for annotating the non-coding genome, including identifying regulatory elements. Computational approaches such as ChromHMM have been applied to discover and annotate chromatin states defined by combinatorial and spatial patterns of chromatin marks within the same cell type. An alternative ""stacked modeling"" approach was previously suggested, where chromatin states are defined jointly from datasets of multiple cell types to produce a single universal genome annotation based on all datasets. Despite its potential benefits for applications that are not specific to one cell type, such an approach was previously applied only for small-scale specialized purposes. Large-scale applications of stacked modeling have previously posed scalability challenges.Using a version of ChromHMM enhanced for large-scale applications, we apply the stacked modeling approach to produce a universal chromatin state annotation of the human genome using over 1000 datasets from more than 100 cell types, with the learned model denoted as the full-stack model. The full-stack model states show distinct enrichments for external genomic annotations, which we use in characterizing each state. Compared to per-cell-type annotations, the full-stack annotations directly differentiate constitutive from cell type-specific activity and is more predictive of locations of external genomic annotations.The full-stack ChromHMM model provides a universal chromatin state annotation of the genome and a unified global view of over 1000 datasets. We expect this to be a useful resource that complements existing per-cell-type annotations for studying the non-coding human genome.© 2022. The Author(s).",
-,No,20220131,epigenetics,34883445,Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome.,EBioMedicine,"parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing modifiable POE exist.in order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as 'predicted mRNA expression levels' of DNA methylation/imprinting machinery genes and environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315).a set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, 'lifetime smoking status' and 'predicted mRNA expression levels' of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs.the modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases.NSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH.Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.",
-,Yes,20220131,ewas,35046013,DNA methylation analysis of cord blood samples in neonates born to gestational diabetes mothers diagnosed before 24 gestational weeks.,BMJ Open Diabetes Res Care,"Genome-wide methylation analyses of gestational diabetes mellitus (GDM) diagnosed after 24 gestational weeks (late GDM (L-GDM)) using cord blood have been reported. However, epigenetic changes in neonates born to mothers with GDM diagnosed before 24 gestational weeks (early GDM (E-GDM)) have not been reported. We investigated DNA methylation in neonates born to mothers with E-GDM using cord blood samples.Genome-wide DNA methylation analysis was performed using an Illumina EPIC array to compare methylation rates of 754 255 autosomal sites in cord blood samples from term neonates born to 162 mothers with GDM (E-GDM: n=84, L-GDM: n=78) and 60 normal glucose tolerance (normal OGTT) pregnancies. GDM was diagnosed based on Japan Society of Obstetrics and Gynecology criteria modified with International Association of Diabetes in Pregnancy Study Group criteria. In this study, all GDM mothers underwent dietary management, while self-monitoring of blood glucose and insulin administration was initiated when dietary modification did not achieve glycemic control.There were no significant differences in genome-wide DNA methylation of cord blood samples between the GDM (E-GDM and L-GDM) groups and normal OGTT group or between the E-GDM and normal OGTT groups, L-GDM and normal OGTT groups, and E-GDM and L-GDM groups.This is the first report to determine the DNA methylation patterns in neonates born to mothers with E-GDM. Neonates born to mothers with GDM, who were diagnosed based on Japan Society of Obstetrics and Gynecology criteria, may not differ in DNA methylation compared with those born to normal OGTT mothers.© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
-,Yes,20220131,ewas,35036834,Differential DNA Methylation by Hispanic Ethnicity Among Firefighters in the United States.,Epigenet Insights,"Firefighters are exposed to a variety of environmental hazards and are at increased risk for multiple cancers. There is evidence that risks differ by ethnicity, yet the biological or environmental differences underlying these differences are not known. DNA methylation is one type of epigenetic regulation that is altered in cancers. In this pilot study, we profiled DNA methylation with the Infinium MethylationEPIC in blood leukocytes from 31 Hispanic white and 163 non-Hispanic white firefighters. We compared DNA methylation (1) at 12 xenobiotic metabolizing genes and (2) at all loci on the array (>740 000), adjusting for confounders. Five of the xenobiotic metabolizing genes were differentially methylated at a rawP-value <.05 when comparing the 2 ethnic groups, yet were not statistically significant at a 5% false discovery rate (q-value <.05). In the epigenome-wide analysis, 76 loci exhibited DNA methylation differences atq < .05. Among these, 3 CpG sites in the promoter region of the biotransformation geneSULT1C2had lower methylation in Hispanic compared to non-Hispanic firefighters. Other differentially methylated loci included genes that have been implicated in carcinogenesis in published studies (FOXK2, GYLTL1B, ZBTB16, ARHGEF10, and more). In this pilot study, we report differential DNA methylation between Hispanic and non-Hispanic firefighters in xenobiotic metabolism genes and other genes with functions related to cancer. Epigenetic susceptibility by ethnicity merits further study as this may alter risk for cancers linked to toxic exposures.© The Author(s) 2021.",
-,Yes,20220131,ewas,35033200,Epigenome-wide association study of lung function in Latino children and youth with asthma.,Clin Epigenetics,"DNA methylation studies have associated methylation levels at different CpG sites or genomic regions with lung function. Moreover, genetic ancestry has been associated with lung function in Latinos. However, no epigenome-wide association study (EWAS) of lung function has been performed in this population. Here, we aimed to identify DNA methylation patterns associated with lung function in pediatric asthma among Latinos.We conducted an EWAS in whole blood from 250 Puerto Rican and 148 Mexican American children and young adults with asthma. A total of five CpGs exceeded the genome-wide significance threshold of p = 1.17 × 10-7in the combined analyses from Puerto Ricans and Mexican Americans: cg06035600 (MAP3K6, p = 6.13 × 10-8) showed significant association with pre-bronchodilator Tiffeneau-Pinelli index, the probes cg00914963 (TBC1D16, p = 1.04 × 10-7), cg16405908 (MRGPRE, p = 2.05 × 10-8), and cg07428101 (MUC2, p = 5.02 × 10-9) were associated with post-bronchodilator forced vital capacity (FVC), and cg20515679 (KCNJ6) with post-bronchodilator Tiffeneau-Pinelli index (p = 1.13 × 10-8). However, these markers did not show significant associations in publicly available data from Europeans (p > 0.05). A methylation quantitative trait loci analysis revealed that methylation levels at these CpG sites were regulated by genetic variation in Latinos and the Biobank-based Integrative Omics Studies (BIOS) consortium. Additionally, two differentially methylated regions in REXOC and AURKC were associated with pre-bronchodilator Tiffeneau-Pinelli index (adjusted p < 0.05) in Puerto Ricans and Mexican Americans. Moreover, we replicated some of the previous differentially methylated signals associated with lung function in non-Latino populations.We replicated previous associations of epigenetic markers with lung function in whole blood and identified novel population-specific associations shared among Latino subgroups.© 2022. The Author(s).",
-,Yes,20220131,ewas,35032864,Pregnancy exposure to phthalates and DNA methylation in male placenta - An epigenome-wide association study.,Environ Int,"Exposure to phthalates during pregnancy may alter DNA methylation in the placenta, a crucial organ for the growth and development of the fetus.We studied associations between urinary concentrations of phthalate biomarkers during pregnancy and placental DNA methylation.We measured concentrations of 11 phthalate metabolites in maternal spot urine samples collected between 22 and 29 gestational weeks in 202 pregnant women. We analyzed DNA methylation levels in placental tissue (fetal side) collected at delivery. We first investigated changes in global DNA methylation of repetitive elements Alu and LINE-1. We then performed an adjusted epigenome-wide association study using IlluminaHM450 BeadChips and identified differentially methylated regions (DMRs) associated with phthalate exposure.Monobenzyl phthalate concentration was inversely associated with placental methylation of Alu repeats. Moreover, all phthalate biomarkers except for monocarboxy-iso-octyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were associated with at least one DMR. All but three DMRs showed increased DNA methylation with increased phthalate exposure. The largest identified DMR (22 CpGs) was positively associated with monocarboxy-iso-nonyl phthalate and encompassed heat shock proteins (HSPA1A, HSPA1L). The remaining DMRs encompassed transcription factors and nucleotide exchange factors, among other genes.This is the first description of genome-wide modifications of placental DNA methylation in association with pregnancy exposure to phthalates. Our results suggest epigenetic mechanisms by which exposure to these compounds could affect fetal development. Of interest, four identified DMRs had been previously associated with maternal smoking, which may suggest particular sensitivity of these genomic regions to the effect of environmental contaminants.Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.",
-,Yes,20220131,ewas,35028889,Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study.,Neurocrit Care,"Cerebral edema and intracranial hypertension are major contributors to unfavorable prognosis in traumatic brain injury (TBI). Local epigenetic changes, particularly in DNA methylation, may influence gene expression and thus host response/secondary injury after TBI. It remains unknown whether DNA methylation in the central nervous system is associated with cerebral edema severity or intracranial hypertension post TBI. We sought to identify epigenome-wide DNA methylation patterns associated with these forms of secondary injury after TBI.We obtained genome-wide DNA methylation profiles of DNA extracted from ventricular cerebrospinal fluid samples at three different postinjury time points from a prospective cohort of patients with severe TBI (n = 89 patients, 254 samples). Cerebral edema and intracranial pressure (ICP) measures were clustered to generate composite end points of cerebral edema and ICP severity. We performed an unbiased epigenome-wide association study (EWAS) to test associations between DNA methylation at 419,895 cytosine-phosphate-guanine (CpG) sites and cerebral edema/ICP severity categories. Given inflated p values, we conducted permutation tests for top CpG sites to filter out potential false discoveries.Our data-driven hierarchical clustering across six cerebral edema and ICP measures identified two groups differing significantly in ICP based on the EWAS-identified CpG site cg22111818 in RGMA (Repulsive guidance molecule A, permutation p = 4.20 × 10-8). At 3-4 days post TBI, patients with severe intracranial hypertension had significantly lower levels of methylation at cg22111818.We report a novel potential relationship between intracranial hypertension after TBI and an acute, nonsustained reduction in DNA methylation at cg22111818 in the RGMA gene. To our knowledge, this is the largest EWAS in severe TBI. Our findings are further strengthened by previous findings that RGMA modulates axonal repair in other central nervous system disorders, but a role in intracranial hypertension or TBI has not been previously identified. Additional work is warranted to validate and extend these findings, including assessment of its possible role in risk stratification, identification of novel druggable targets, and ultimately our ability to personalize therapy in TBI.© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.",
-,Yes,20220131,ewas,35028426,The genetic and epigenetic profile of serum S100β in the Lothian Birth Cohort 1936 and its relationship to Alzheimer's disease.,Wellcome Open Res,"Background:Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer's disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100β levels in older adults and performed Mendelian randomisation with Alzheimer's disease.Methods:GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100β levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100β. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100β and Alzheimer's disease. Colocalisation between S100β and Alzheimer's disease GWAS loci was also examined.Results:We identified 154 SNPs from chromosome 21 that associated (P<5x10-8) with S100β protein levels. The lead variant was located in theS100βgene (rs8128872, P=5.0x10-17). We found evidence that two independent causal variants existed for both transcription ofS100βand S100β protein levels in our eQTL analyses.No CpG sites were associated with S100β levels at the epigenome-wide significant level (P<3.6x10-8); the lead probe was cg06833709 (P=5.8x10-6), which mapped to theLGI1gene. There was no evidence of a causal association between S100β levels and Alzheimer's disease or vice versa and no evidence for colocalisation betweenS100βand Alzheimer's disease loci.Conclusions:These data provide insight into the molecular regulators of S100β levels. This context may aid in understanding the role of S100β in brain inflammation and neurological disease.Copyright: © 2021 A Gadd D et al.",
-,Yes,20220131,ewas,34996616,"Ascaris exposure and its association with lung function, asthma, and DNA methylation in Northern Europe.",J Allergy Clin Immunol,"Ascaris infections, with a worldwide prevalence above 10%, can cause respiratory pathology. However, long-term effects on lung function in humans are largely unknown.We investigated the associations of Ascaris exposure with lung function, asthma, and DNA methylation.Serum Ascaris IgG antibodies were measured in 671 adults aged 18 to 47 years (46% women) from Aarhus, Bergen, and Tartu RHINESSA study centers. Seropositivity was defined as IgG above the 90th percentile. Linear and logistic regressions were used to analyze Ascaris seropositivity as associated with lung function and asthma, adjusted for age, height, and smoking and clustered by center. DNA methylation in blood was profiled by a commercial methylation assay.Ascaris seropositivity was associated with lower FEV1(-247 mL; 95% CI, -460, -34) and higher odds for asthma (adjusted odds ratio, 5.84; 95% CI, 1.67, 20.37) among men but not women, also after further adjusting for house dust mite sensitivity, consistent across study centers. At a genome-wide level, Ascaris exposure was associated with 23 differentially methylated sites in men and 3 in women. We identified hypermethylation of the MYBPC1 gene, which can regulate airway muscle contraction. We also identified genes linked to asthma pathogenesis such as CRHR1 and GRK1, as well as a differentially methylated region in the PRSS22 gene linked to nematode infection.Ascaris exposure was associated with substantially lower lung function and increased asthma risk among men. Seropositive participants had sex-specific differences in DNA methylation compared to the unexposed, thus suggesting that exposure may lead to sex-specific epigenetic changes associated with lung pathology.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
-,Yes,20220131,ewas,34995380,Newborn DNA methylation and asthma acquisition across adolescence and early adulthood.,Clin Exp Allergy,"Little is known about the association of newborn DNA methylation (DNAm) with asthma acquisition across adolescence and early adult life.We aim to identify epigenetic biomarkers in newborns for asthma acquisition during adolescence or young adulthood.The Isle of Wight Birth Cohort (IOWBC) (n = 1456) data at ages 10, 18 and 26 years were assessed. To screen cytosine-phosphate-guanine site (CpGs) potentially associated with asthma acquisition, at the genome scale, we examined differentially methylated regions (DMR) using dmrff R package and individual CpG sites using linear regression on such associations. For CpGs that passed screening, we examined their enrichment in biological pathways using their mapping genes and tested their associations with asthma acquisitions using logistic regressions. Findings in IOWBC were tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.In total, 2636 unique CpGs passed screening, based on which we identified one biological pathway linked to asthma acquisition during adolescence in females (FDR adjusted p-value = .003 in IOWBC). Via logistic regressions, for females, four CpGs were shown to be associated with asthma acquisition during adolescence, and another four CpGs with asthma acquisition in young adulthood (FDR adjusted p-value < .05 in IOWBC) and these eight CpGs were replicated in ALSPAC (all p-values < .05). DNAm at all the identified CpGs was shown to be temporally consistent, and at six of the CpGs was associated with expressions of adjacent or mapping genes in females (all p-values < .05). For males, 622 CpGs were identified in IOWBC (FDR = 0.01), but these were not tested in ALSPAC due to small sample sizes.Eight CpGs on LHX5, IL22RA2, SOX11, CBX4, ACPT, CFAP46, MUC4, and ATP1B2 genes have the potential to serve as candidate epigenetic biomarkers in newborns for asthma acquisition in females during adolescence or young adulthood.© 2022 John Wiley & Sons Ltd.",
-,Yes,20220131,ewas,34992238,Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress.,Mol Psychiatry,"Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.© 2021. The Author(s), under exclusive licence to Springer Nature Limited.",
-,Yes,20220131,ewas,34944472,Epigenome-Wide Association Study of Prostate Cancer in African Americans Identifies DNA Methylation Biomarkers for Aggressive Disease.,Biomolecules,"DNA methylation plays important roles in prostate cancer (PCa) development and progression. African American men have higher incidence and mortality rates of PCa than other racial groups in U.S. The goal of this study was to identify differentially methylated CpG sites and genes between clinically defined aggressive and nonaggressive PCa in African Americans. We performed genome-wide DNA methylation profiling in leukocyte DNA from 280 African American PCa patients using Illumina MethylationEPIC array that contains about 860K CpG sties. There was a slight increase of overall methylation level (mean β value) with the increasing Gleason scores (GS = 6, GS = 7, GS ≥ 8, P for trend = 0.002). There were 78 differentially methylated CpG sites with P < 10-4and 9 sites with P < 10-5in the trend test. We also found 77 differentially methylated regions/genes (DMRs), including 10 homeobox genes and six zinc finger protein genes. A gene ontology (GO) molecular pathway enrichment analysis of these 77 DMRs found that the main enriched pathway was DNA-binding transcriptional factor activity. A few representative DMRs include HOXD8, SOX11, ZNF-471, and ZNF-577. Our study suggests that leukocyte DNA methylation may be valuable biomarkers for aggressive PCa and the identified differentially methylated genes provide biological insights into the modulation of immune response by aggressive PCa.",
-,Yes,20220131,ewas,34937578,DNA methylation mediates the association between breastfeeding and early-life growth trajectories.,Clin Epigenetics,"The role of breastfeeding in modulating epigenetic factors has been suggested as a possible mechanism conferring its benefits on child development but it lacks evidence. Using extensive DNA methylation data from the ALSPAC child cohort, we characterized the genome-wide landscape of DNA methylation variations associated with the duration of exclusive breastfeeding and assessed whether these variations mediate the association between exclusive breastfeeding and BMI over different epochs of child growth.Exclusive breastfeeding elicits more substantial DNA methylation variations during infancy than at other periods of child growth. At the genome-wide level, 13 CpG sites in girls (miR-21, SNAPC3, ATP6V0A1, DHX15/PPARGC1A, LINC00398/ALOX5AP, FAM238C, NATP/NAT2, CUX1, TRAPPC9, OSBPL1A, ZNF185, FAM84A, PDPK1) and 2 CpG sites in boys (IL16 and NREP), mediate the association between exclusive breastfeeding and longitudinal BMI. We found enrichment of CpG sites located within miRNAs and key pathways (AMPK signaling pathway, insulin signaling pathway, endocytosis). Overall DNA methylation variation corresponding to 3 to 5 months of exclusive breastfeeding was associated with slower BMI growth the first 6 years of life compared to no breastfeeding and in a dose-response manner with exclusive breastfeeding duration.Our study confirmed the early postnatal period as a critical developmental period associated with substantial DNA methylation variations, which in turn could mitigate the development of overweight and obesity from infancy to early childhood. Since an accelerated growth during these developmental periods has been linked to the development of sustained obesity later in life, exclusive breastfeeding could have a major role in preventing the risks of overweight/obesity and children and adults through DNA methylation mechanisms occurring early in life.© 2021. The Author(s).",
-,Yes,20220131,ewas,34930449,Reproductive history and blood cell DNA methylation later in life: the Young Finns Study.,Clin Epigenetics,"Women with a history of complications of pregnancy, including hypertensive disorders, gestational diabetes or an infant fetal growth restriction or preterm birth, are at higher risk for cardiovascular disease later in life. We aimed to examine differences in maternal DNA methylation following pregnancy complications.Data on women participating in the Young Finns study (n = 836) were linked to the national birth registry. DNA methylation in whole blood was assessed using the Infinium Methylation EPIC BeadChip. Epigenome-wide analysis was conducted on differential CpG methylation at 850 K sites. Reproductive history was also modeled as a predictor of four epigenetic age indices.Fourteen significant differentially methylated sites were found associated with both history of pre-eclampsia and overall hypertensive disorders of pregnancy. No associations were found between reproductive history and any epigenetic age acceleration measure.Differences in epigenetic methylation profiles could represent pre-existing risk factors, or changes that occurred as a result of experiencing these complications.© 2021. The Author(s).",
-,Yes,20220131,ewas,34899183,Autism-Associated DNA Methylation at Birth From Multiple Tissues Is Enriched for Autism Genes in the Early Autism Risk Longitudinal Investigation.,Front Mol Neurosci,"Background:Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci.Objectives:To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes.Methods:In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (earlyn= 140 and laten= 75 pregnancy), infant cord blood (n= 133), and placenta (maternaln= 106 and fetaln= 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n= 881) from the Simons Foundation Autism Research Initiative (SFARI) database.Results:No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P< 0.05) in each tissue were highly enriched for SFARI genes (cord bloodP= 7.9 × 10-29, maternal blood early pregnancyP= 6.1 × 10-27, maternal blood late pregnancyP= 2.8 × 10-16, maternal placentaP= 5.6 × 10-15, fetal placentaP= 1.3 × 10-20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes.Conclusion:DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.Copyright © 2021 Bakulski, Dou, Feinberg, Aung, Ladd-Acosta, Volk, Newschaffer, Croen, Hertz-Picciotto, Levy, Landa, Feinberg and Fallin.",
-,Yes,20220131,ewas,34895303,Genome-wide methylation patterns in Marfan syndrome.,Clin Epigenetics,"Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process.The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed.We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP's that associated with clinical events. No significant associations at p < 10-8or p < 10-6were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18-22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before.This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.© 2021. The Author(s).",
-,Yes,20220131,ewas,34895032,Newborn differential DNA methylation and subcortical brain volumes as early signs of severe neurodevelopmental delay in a South African Birth Cohort Study.,World J Biol Psychiatry,"Early detection of neurodevelopmental delay is crucial for intervention and treatment strategies. We analysed associations between newborn DNA methylation (DNAm), neonatal magnetic resonance imaging (MRI) neuroimaging data, and neurodevelopment.Neurodevelopment was assessed in 161 children from the South African Drakenstein Child Health Study at 2 years of age using the Bayley Scales of Infant and Toddler Development III. We performed an epigenome-wide association study of neurodevelopmental delay using DNAm from cord blood. Subsequently, we analysed if associations between DNAm and neurodevelopmental delay were mediated by altered neonatal brain volumes (subset of 51 children).Differential DNAm atSPTBN4(cg26971411,Δbeta = -0.024,p-value = 3.28 × 10-08), and two intergenic regions (chromosome 11: cg00490349,Δbeta = -0.036,p-value = 3.02 × 10-08; chromosome 17: cg15660740,Δbeta = -0.078,p-value = 6.49 × 10-08) were significantly associated with severe neurodevelopmental delay. While these associations were not mediated by neonatal brain volume, neonatal caudate volumes were independently associated with neurodevelopmental delay, particularly in language (Δcaudate volume = 165.30 mm3,p = 0.0443) and motor (Δcaudate volume = 365.36 mm3,p-value = 0.0082) domains.Differential DNAm from cord blood and increased neonatal caudate volumes were independently associated with severe neurodevelopmental delay at 2 years of age. These findings suggest that neurobiological signals for severe developmental delay may be detectable in very early life.",
-,Yes,20220131,ewas,34887417,Meta-analyses identify DNA methylation associated with kidney function and damage.,Nat Commun,"Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.© 2021. The Author(s).",
-,Yes,20220131,ewas,34887389,Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.,Nat Commun,"Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.© 2021. The Author(s).",
-,Yes,20220131,ewas,34857913,Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target.,Mol Psychiatry,"Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10-8) with the five leading probes located in SLC7A11 (p = 7.75 × 10-108), JDP2 (p = 1.44 × 10-56), GAS5 (p = 2.71 × 10-47), TRA2B (p = 3.54 × 10-42), and SLC43A1 (p = 1.18 × 10-40). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer's disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10-09). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10-38and p = 5.41 × 10-14). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p < 10-17). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p < 10-4), increased liver function enzymes (GGT (p = 1.03 × 10-21), ALT (p = 1.29 × 10-6), and AST (p = 1.97 × 10-8)) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention.© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
-,Yes,20220131,ewas,34857876,Differential placental CpG methylation is associated with chronic lung disease of prematurity.,Pediatr Res,"Chronic lung disease (CLD) is the most common pulmonary morbidity in extremely preterm infants. It is unclear to what extent prenatal exposures influence the risk of CLD. Epigenetic variation in placenta DNA methylation may be associated with differential risk of CLD, and these associations may be dependent upon sex.Data were obtained from a multi-center cohort of infants born extremely preterm (<28 weeks' gestation) and an epigenome-wide approach was used to identify associations between placental DNA methylation and CLD (n = 423). Associations were evaluated using robust linear regression adjusting for covariates, with a false discovery rate of 0.05. Analyses stratified by sex were used to assess differences in methylation-CLD associations.CLD was associated with differential methylation at 49 CpG sites representing 46 genes in the placenta. CLD was associated with differential methylation of probes within genes related to pathways involved in fetal lung development, such as p53 signaling and myo-inositol biosynthesis. Associations between CpG methylation and CLD differed by sex.Differential placental methylation within genes with key roles in fetal lung development may reflect complex cell signaling between the placenta and fetus which mediate CLD risk. These pathways appear to be distinct based on fetal sex.In extremely preterm infants, differential methylation of CpG sites within placental genes involved in pathways related to cell signaling, oxidative stress, and trophoblast invasion is associated with chronic lung disease of prematurity. DNA methylation patterns associated with chronic lung disease were distinctly based on fetal sex, suggesting a potential mechanism underlying dimorphic phenotypes. Mechanisms related to fetal hypoxia and placental myo-inositol signaling may play a role in fetal lung programming and the developmental origins of chronic lung disease. Continued research of the relationship between the placental epigenome and chronic lung disease could inform efforts to ameliorate or prevent this condition.© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.",
-,No,20220131,ewas,34841896,Sex- and tissue-specific effects of binge-level prenatal alcohol consumption on DNA methylation at birth.,Epigenomics,"Background:Binge-level prenatal alcohol exposure (PAE) causes developmental abnormalities, which may be mediated in part by epigenetic mechanisms. Despite this, few studies have characterised the association of binge PAE with DNA methylation in offspring.Methods:We investigated the association between binge PAE and genome-wide DNA methylation profiles in a sex-specific manner in neonatal buccal and placental samples.Results:We identified no differentially methylated CpGs or differentially methylated regions (DMRs) at false discovery rate <0.05. However, using a sum-of-ranks approach, we identified a DMR in each tissue of female offspring. The DMR identified in buccal samples is located near regions with previously-reported associations to fetal alcohol spectrum disorder (FASD) and binge PAE.Conclusion:Our findings warrant further replication and highlight a potential epigenetic link between binge PAE and FASD.",
-,Yes,20220131,ewas,34836312,Epigenome-Wide Association Study of Infant Feeding and DNA Methylation in Infancy and Childhood in a Population at Increased Risk for Type 1 Diabetes.,Nutrients,"We assessed associations between infant diet (e.g., breastfeeding and introduction to solid foods) and DNA methylation in infancy and childhood. We measured DNA methylation in peripheral blood collected in infancy (9-15 months of age) in 243 children; and in a subset of 50 children, we also measured methylation in childhood (6-9 years of age) to examine persistence, and at birth (in cord blood) to examine temporality. We performed multivariable linear regression of infant diet on the outcome of methylation using epigenome-wide and candidate site approaches. We identified six novel CpG sites associated with breastfeeding duration using an EWAS approach. One differentially methylated site presented directionally consistent associations with breastfeeding (cg00574958,CPT1A) in infancy and childhood but not at birth. Two differentially methylated sites in infancy (cg19693031,TXNIP; cg23307264,KHSRP) were associated with breastfeeding and were not present at birth; however, these associations did not persist into childhood. Associations between infant diet and methylation in infancy at three sites (cg22369607,AP001525.1; cg2409200,TBCD; cg27173510,PGBD5) were also present at birth, suggesting the influence of exposures other than infant diet. Infant diet exposures are associated with persistent methylation differences inCPT1A, which may be one mechanism behind infant diet's long-term health effects.",
-,Yes,20220131,ewas,35000590,DNA methylation signatures associated with cardiometabolic risk factors in children from India and The Gambia: results from the EMPHASIS study.,Clin Epigenetics,"The prevalence of cardiometabolic disease (CMD) is rising globally, with environmentally induced epigenetic changes suggested to play a role. Few studies have investigated epigenetic associations with CMD risk factors in children from low- and middle-income countries. We sought to identify associations between DNA methylation (DNAm) and CMD risk factors in children from India and The Gambia.Using the Illumina Infinium HumanMethylation 850 K Beadchip array, we interrogated DNAm in 293 Gambian (7-9 years) and 698 Indian (5-7 years) children. We identified differentially methylated CpGs (dmCpGs) associated with systolic blood pressure, fasting insulin, triglycerides and LDL-Cholesterol in the Gambian children; and with insulin sensitivity, insulinogenic index and HDL-Cholesterol in the Indian children. There was no overlap of the dmCpGs between the cohorts. Meta-analysis identified dmCpGs associated with insulin secretion and pulse pressure that were different from cohort-specific dmCpGs. Several differentially methylated regions were associated with diastolic blood pressure, insulin sensitivity and fasting glucose, but these did not overlap with the dmCpGs. We identified significant cis-methQTLs at three LDL-Cholesterol-associated dmCpGs in Gambians; however, methylation did not mediate genotype effects on the CMD outcomes.This study identified cardiometabolic biomarkers associated with differential DNAm in Indian and Gambian children. Most associations were cohort specific, potentially reflecting environmental and ethnic differences.© 2022. The Author(s).",
-,Yes,20220131,ewas,34937574,Associations between DNA methylation and BMI vary by metabolic health status: a potential link to disparate cardiovascular outcomes.,Clin Epigenetics,"Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health.The discovery study population was derived from three Women's Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm β value, the risk of incident CHD increased by 9% in one site and decreased by 6-10% in two sites over 25 years.Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.© 2021. The Author(s).",
-,Yes,20220131,ewas,35039093,Epigenetics of single-site and multi-site atherosclerosis in African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA).,Clin Epigenetics,"DNA methylation, an epigenetic mechanism modulated by lifestyle and environmental factors, may be an important biomarker of complex diseases including cardiovascular diseases (CVD) and subclinical atherosclerosis.DNA methylation in peripheral blood samples from 391 African-Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) was assessed at baseline, and atherosclerosis was assessed 5 and 12 years later. Using linear mixed models, we examined the association between previously identified CpGs for coronary artery calcification (CAC) and carotid plaque, both individually and aggregated into methylation risk scores (MRSCACand MRScarotid), and four measures of atherosclerosis (CAC, abdominal aorta calcification (AAC), ankle-brachial index (ABI), and multi-site atherosclerosis based on gender-specific quartiles of the single-site measures). We also examined the association between four epigenetic age acceleration measures (IEAA, EEAA, PhenoAge acceleration, and GrimAge acceleration) and the four atherosclerosis measures. Finally, we characterized the temporal stability of the epigenetic measures using repeated DNA methylation measured 5 years after baseline (N = 193).After adjusting for CVD risk factors, four CpGs (cg05575921(AHRR), cg09935388 (GFI1), cg21161138 (AHRR), and cg18168448 (LRRC52)) were associated with multi-site atherosclerosis (FDR < 0.1). cg05575921 was also associated with AAC and cg09935388 with ABI. MRSCACwas associated with ABI (Beta = 0.016, P = 0.006), and MRScarotidwas associated with both AAC (Beta = 0.605, equivalent to approximately 1.8-fold increase in the Agatston score of AAC, P = 0.004) and multi-site atherosclerosis (Beta = 0.691, P = 0.002). A 5-year increase in GrimAge acceleration (~ 1 SD) was associated with a 1.6-fold (P = 0.012) increase in the Agatston score of AAC and 0.7 units (P = 0.0003) increase in multi-site atherosclerosis, all after adjusting for CVD risk factors. All epigenetic measures were relatively stable over 5 years, with the highest intraclass correlation coefficients observed for MRScarotidand GrimAge acceleration (0.87 and 0.89, respectively).We found evidence of an association between DNA methylation and atherosclerosis at multiple vascular sites in a sample of African-Americans. Further evaluation of these potential biomarkers is warranted to deepen our understanding of the relationship between epigenetics and atherosclerosis.© 2022. The Author(s).",
-,Yes,20220131,ewas,34835636,Prenatal Exposure to Heavy Metals Affects Gestational Age by Altering DNA Methylation Patterns.,Nanomaterials (Basel),"Environmental exposure is known to have toxic effects. Maternal environmental exposure not only affects mothers but also their fetuses in utero, which may interrupt their early development. Preterm birth, one of the outcomes of prenatal exposure, is a significant factor in lifelong health risks. To understand the effects of prenatal exposome on preterm birth, we studied the association between maternal and prenatal heavy metal exposure and gestational age, using resources from the MOthers' and Children's Environmental Health (MOCEH) study in South Korea. Additionally, a methylation assay was performed to analyze epigenetic mediation using genomic DNA derived from the cord blood of 384 participants in the MOCEH study. The results suggest that maternal cadmium exposure is associated with a decrease in gestational age through an alteration in DNA methylation at a specific CpG site, cg21010642. The CpG site was annotated to a gene involved in early embryonic development. Therefore, irregular methylation patterns at this site may contribute to premature birth by mediating irregular biological mechanisms.",
-,No,20220131,mqtl,34873174,Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome.,Nat Commun,"Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.© 2021. The Author(s).",
-,Yes,20220131,ewas+dnam score,35039062,Blood-based epigenome-wide analyses of cognitive abilities.,Genome Biol,"Blood-based markers of cognitive functioning might provide an accessible way to track neurodegeneration years prior to clinical manifestation of cognitive impairment and dementia.Using blood-based epigenome-wide analyses of general cognitive function, we show that individual differences in DNA methylation (DNAm) explain 35.0% of the variance in general cognitive function (g). A DNAm predictor explains ~4% of the variance, independently of a polygenic score, in two external cohorts. It also associates with circulating levels of neurology- and inflammation-related proteins, global brain imaging metrics, and regional cortical volumes.As sample sizes increase, the ability to assess cognitive function from DNAm data may be informative in settings where cognitive testing is unreliable or unavailable.© 2022. The Author(s).",
-,No,20220131,ewas+dnam score,34906459,DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies.,Genet Med,"Chromatinopathies include more than 50 disorders caused by disease-causing variants of various components of chromatin structure and function. Many of these disorders exhibit unique genome-wide DNA methylation profiles, known as episignatures. In this study, the methylation profile of a large cohort of individuals with chromatinopathies was analyzed for episignature detection.DNA methylation data was generated on extracted blood samples from 129 affected individuals with the Illumina Infinium EPIC arrays and analyzed using an established bioinformatic pipeline.The DNA methylation profiles matched and confirmed the sequence findings in both the discovery and validation cohorts. Twenty-five affected individuals carrying a variant of uncertain significance, did not show a methylation profile matching any of the known episignatures. Three additional variant of uncertain significance cases with an identified KDM6A variant were re-classified as likely pathogenic (n = 2) or re-assigned as Wolf-Hirschhorn syndrome (n = 1). Thirty of the 33 Next Generation Sequencing negative cases did not match a defined episignature while three matched Kabuki syndrome, Rubinstein-Taybi syndrome and BAFopathy respectively.With the expanding clinical utility of the EpiSign assay, DNA methylation analysis should be considered part of the testing cascade for individuals presenting with clinical features of Mendelian chromatinopathy disorders.Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.",
-,Yes,20220131,ewas+dnam score,34880450,Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system.,Mol Psychiatry,"Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 (β = -0.055, pcorrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3, and HEBP2, which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS (N = 3360, β = 0.377, p = 3.12 × 10-11, R2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.© 2021. The Author(s).",
-,Yes,20220131,ewas+dnam score+cell-free dna,34915915,Accurate prediction of acute pancreatitis severity based on genome-wide cell free DNA methylation profiles.,Clin Epigenetics,"Patients with severe acute pancreatitis (SAP) have a high mortality, thus early diagnosis and interventions are critical for improving survival. However, conventional tests are limited in acute pancreatitis (AP) stratification. We aimed to assess AP severity by integrating the informative clinical measurements with cell free DNA (cfDNA) methylation markers.One hundred and seventy-five blood samples were collected from 61 AP patients at multiple time points, plus 24 samples from healthy individuals. Genome-wide cfDNA methylation profiles of all samples were characterized with reduced representative bisulfite sequencing. Clinical blood tests covering 93 biomarkers were performed on AP patients within 24 h. SAP predication models were built based on cfDNA methylation and conventional blood biomarkers separately and in combination.We identified 565 and 59 cfDNA methylation markers informative for acute pancreatitis and its severity. These markers were used to develop prediction models for AP and SAP with area under the receiver operating characteristic of 0.92 and 0.81, respectively. Twelve blood biomarkers were systematically screened for a predictor of SAP with a sensitivity of 87.5% for SAP, and a specificity of 100% in mild acute pancreatitis, significantly higher than existing blood tests. An expanded model integrating 12 conventional blood biomarkers with 59 cfDNA methylation markers further improved the SAP prediction sensitivity to 92.2%.These findings have demonstrated that accurate prediction of SAP by the integration of conventional and novel blood molecular markers, paving the way for early and effective SAP intervention through a non-invasive rapid diagnostic test.© 2021. The Author(s).",
-,Yes,20220131,ewas+longitudinal,34966975,Sex differences in schizophrenia: a longitudinal methylome analysis.,J Neural Transm (Vienna),"DNA methylation analysis at the genome-wide level is a useful tool to explore potential sex differences in SCZ patients. The primary aim of the current study was to identify differentially methylated regions of DNA between males and females with schizophrenia. We collected DNA samples from 134 schizophrenia patients to measure genome-wide methylation at single-base resolution in 96 males and 38 females. We further repeated the analysis in 13 subjects (9 females, 4 males) to confirm the sex differences and to reduce the effect of potential confounders. The longitudinal methylation analysis found significant replication of several genes across the genome. These genes included RFTN1, TLE1, DAZL, PRR4, UTP14C, RNU12, and LOC644649. The overall results showed robust association between autosomal CpG sites and sex. Longitudinal methylation analysis can be used as internal replication to confirm epigenetic variants that are stable over time.© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.",
-,Yes,20220131,ewas+wgbs,34886889,Genome-wide methylation and expression analyses reveal the epigenetic landscape of immune-related diseases for tobacco smoking.,Clin Epigenetics,"Smoking is a major causal risk factor for lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), and is the main preventable cause of deaths in the world. The components of cigarette smoke are involved in immune and inflammatory processes, which may increase the prevalence of cigarette smoke-related diseases. However, the underlying molecular mechanisms linking smoking and diseases have not been well explored. This study was aimed to depict a global map of DNA methylation and gene expression changes induced by tobacco smoking and to explore the molecular mechanisms between smoking and human diseases through whole-genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq).We performed WGBS on 72 samples (36 smokers and 36 nonsmokers) and RNA-seq on 75 samples (38 smokers and 37 nonsmokers), and cytokine immunoassay on plasma from 22 males (9 smokers and 13 nonsmokers) who were recruited from the city of Jincheng in China. By comparing the data of the two groups, we discovered a genome-wide methylation landscape of differentially methylated regions (DMRs) associated with smoking. Functional enrichment analyses revealed that both smoking-related hyper-DMR genes (DMGs) and hypo-DMGs were related to synapse-related pathways, whereas the hypo-DMGs were specifically related to cancer and addiction. The differentially expressed genes (DEGs) revealed by RNA-seq analysis were significantly enriched in the ""immunosuppression"" pathway. Correlation analysis of DMRs with their corresponding gene expression showed that genes affected by tobacco smoking were mostly related to immune system diseases. Finally, by comparing cytokine concentrations between smokers and nonsmokers, we found that vascular endothelial growth factor (VEGF) was significantly upregulated in smokers.In sum, we found that smoking-induced DMRs have different distribution patterns in hypermethylated and hypomethylated areas between smokers and nonsmokers. We further identified and verified smoking-related DMGs and DEGs through multi-omics integration analysis of DNA methylome and transcriptome data. These findings provide us a comprehensive genomic map of the molecular changes induced by smoking which would enhance our understanding of the harms of smoking and its relationship with diseases.© 2021. The Author(s).",
-,No,20220131,hydroxymethylation,35029129,Navigating the hydroxymethylome: experimental biases and quality control tools for the tandem bisulfite and oxidative bisulfite Illumina microarrays.,Epigenomics,"Aim:Tandem bisulfite (BS) and oxidative bisulfite (oxBS) conversion on DNA followed by hybridization to Infinium HumanMethylation BeadChips allows nucleotide resolution of 5-hydroxymethylcytosine genome-wide. Here, the authors compared data quality acquired from BS-treated and oxBS-treated samples.Materials & methods:Raw BeadArray data from 417 pairs of samples across 12 independent datasets were included in the study. Probe call rates were compared between paired BS and oxBS treatments controlling for technical variables.Results:oxBS-treated samples had a significantly lower call rate. Among technical variables, DNA-specific extraction kits performed better with higher call rates after oxBS conversion.Conclusion:The authors emphasize the importance of quality control during oxBS conversion to minimize information loss and recommend using a DNA-specific extraction kit for DNA extraction and an oxBSQC package for data preprocessing.",
-,No,20220131,longitudinal ewas,34903243,Longitudinal DNA methylation dynamics as a practical indicator in clinical epigenetics.,Clin Epigenetics,"One of the fundamental assumptions of DNA methylation in clinical epigenetics is that DNA methylation status can change over time with or without interplay with environmental and clinical conditions. However, little is known about how DNA methylation status changes over time under ordinary environmental and clinical conditions. In this study, we revisited the high frequency longitudinal DNA methylation data of two Japanese males (24 time-points within three months) and characterized the longitudinal dynamics.The results showed that the majority of CpGs on Illumina HumanMethylation450 BeadChip probe set were longitudinally stable over the time period of three months. Focusing on dynamic and stable CpGs extracted from datasets, dynamic CpGs were more likely to be reported as epigenome-wide association study (EWAS) markers of various traits, especially those of immune- and inflammatory-related traits; meanwhile, the stable CpGs were enriched in metabolism-related genes and were less likely to be EWAS markers, indicating that the stable CpGs are stable both in the short-term within individuals and under various environmental and clinical conditions.This study indicates that CpGs with different stabilities are involved in different functions and traits, and thus, they are potential indicators that can be applied for clinical epigenetic studies to outline underlying mechanisms.© 2021. The Author(s).",
-,No,20220131,methods,35013473,The impact of methodology on the reproducibility and rigor of DNA methylation data.,Sci Rep,"Epigenetic modifications are crucial for normal development and implicated in disease pathogenesis. While epigenetics continues to be a burgeoning research area in neuroscience, unaddressed issues related to data reproducibility across laboratories remain. Separating meaningful experimental changes from background variability is a challenge in epigenomic studies. Here we show that seemingly minor experimental variations, even under normal baseline conditions, can have a significant impact on epigenome outcome measures and data interpretation. We examined genome-wide DNA methylation and gene expression profiles of hippocampal tissues from wild-type rats housed in three independent laboratories using nearly identical conditions. Reduced-representation bisulfite sequencing and RNA-seq respectively identified 3852 differentially methylated and 1075 differentially expressed genes between laboratories, even in the absence of experimental intervention. Difficult-to-match factors such as animal vendors and a subset of husbandry and tissue extraction procedures produced quantifiable variations between wild-type animals across the three laboratories. Our study demonstrates that seemingly minor experimental variations, even under normal baseline conditions, can have a significant impact on epigenome outcome measures and data interpretation. This is particularly meaningful for neurological studies in animal models, in which baseline parameters between experimental groups are difficult to control. To enhance scientific rigor, we conclude that strict adherence to protocols is necessary for the execution and interpretation of epigenetic studies and that protocol-sensitive epigenetic changes, amongst naive animals, may confound experimental results.© 2022. The Author(s).",
-,No,20220131,methods,34968257,Ultra-Low DNA Input into Whole Genome Methylation Assays and Detection of Oncogenic Methylation and Copy Number Variants in Circulating Tumour DNA.,Epigenomes,"Abnormal CpG methylation in cancer is ubiquitous and generally detected in tumour specimens using a variety of techniques at a resolution encompassing single CpG loci to genome wide coverage. Analysis of samples with very low DNA inputs, such as formalin fixed (FFPE) biopsy specimens from clinical trials or circulating tumour DNA is challenging at the genome-wide level because of lack of available input. We present the results of low input experiments into the Illumina Infinium HD methylation assay on FFPE specimens and ctDNA samples.For all experiments, the Infinium HD assay for methylation was used. In total, forty-eight FFPE specimens were used at varying concentrations (lowest input 50 ng); eighteen blood derived specimens (lowest input 10 ng) and six matched ctDNA input (lowest input 10 ng)/fresh tumour specimens (lowest input 250 ng) were processed. Downstream analysis was performed in R/Bioconductor for quality control metrics and differential methylation analysis as well as copy number calls.Correlation coefficients for CpG methylation were high at the probe level averaged R2 = 0.99 for blood derived samples and R2 > 0.96 for the FFPE samples. When matched ctDNA/fresh tumour samples were compared, R2 > 0.91 between the two. Results of differential methylation analysis did not vary significantly by DNA input in either the blood or FFPE groups. There were differences seen in the ctDNA group as compared to their paired tumour sample, possibly because of enrichment for tumour material without contaminating normal. Copy number variants observed in the tumour were generally also seen in the paired ctDNA sample with good concordance via DQ plot.The Illumina Infinium HD methylation assay can robustly detect methylation across a range of sample types, including ctDNA, down to an input of 10 ng. It can also reliably detect oncogenic methylation changes and copy number variants in ctDNA. These findings demonstrate that these samples can now be accessed by methylation array technology, allowing analysis of these important sample types.",
-,No,20220131,methods,34886879,The ENmix DNA methylation analysis pipeline for Illumina BeadChip and comparisons with seven other preprocessing pipelines.,Clin Epigenetics,"Illumina DNA methylation arrays are high-throughput platforms for cost-effective genome-wide profiling of individual CpGs. Experimental and technical factors introduce appreciable measurement variation, some of which can be mitigated by careful ""preprocessing"" of raw data.Here we describe the ENmix preprocessing pipeline and compare it to a set of seven published alternative pipelines (ChAMP, Illumina, SWAN, Funnorm, Noob, wateRmelon, and RnBeads). We use two large sets of duplicate sample measurements with 450 K and EPIC arrays, along with mixtures of isogenic methylated and unmethylated cell line DNA to compare raw data and that preprocessed via different pipelines.Our evaluations show that the ENmix pipeline performs the best with significantly higher correlation and lower absolute difference between duplicate pairs, higher intraclass correlation coefficients (ICC) and smaller deviations from expected methylation level in mixture experiments. In addition to the pipeline function, ENmix software provides an integrated set of functions for reading in raw data files from mouse and human arrays, quality control, data preprocessing, visualization, detection of differentially methylated regions (DMRs), estimation of cell type proportions, and calculation of methylation age clocks. ENmix is computationally efficient, flexible and allows parallel computing. To facilitate further evaluations, we make all datasets and evaluation code publicly available.Careful selection of robust data preprocessing methods is critical for DNA methylation array studies. ENmix outperformed other pipelines in our evaluations to minimize experimental variation and to improve data quality and study power.© 2021. The Author(s).",
-,No,20220131,methods,34872606,The SEQC2 epigenomics quality control (EpiQC) study.,Genome Biol,"Cytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA's Epigenomics Quality Control Group.Each sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms.The data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research.© 2021. The Author(s).",
-,No,20220131,methods,34837041,Navigating the pitfalls of applying machine learning in genomics.,Nat Rev Genet,"The scale of genetic, epigenomic, transcriptomic, cheminformatic and proteomic data available today, coupled with easy-to-use machine learning (ML) toolkits, has propelled the application of supervised learning in genomics research. However, the assumptions behind the statistical models and performance evaluations in ML software frequently are not met in biological systems. In this Review, we illustrate the impact of several common pitfalls encountered when applying supervised ML in genomics. We explore how the structure of genomics data can bias performance evaluations and predictions. To address the challenges associated with applying cutting-edge ML methods to genomics, we describe solutions and appropriate use cases where ML modelling shows great potential.© 2021. Springer Nature Limited.",
-,No,20220131,methods,34829962,"Deep Learning for Human Disease Detection, Subtype Classification, and Treatment Response Prediction Using Epigenomic Data",Biomedicines,"Deep learning (DL) is a distinct class of machine learning that has achieved first-class performance in many fields of study. For epigenomics, the application of DL to assist physicians and scientists in human disease-relevant prediction tasks has been relatively unexplored until very recently. In this article, we critically review published studies that employed DL models to predict disease detection, subtype classification, and treatment responses, using epigenomic data. A comprehensive search on PubMed, Scopus, Web of Science, Google Scholar, and arXiv.org was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among 1140 initially identified publications, we included 22 articles in our review. DNA methylation and RNA-sequencing data are most frequently used to train the predictive models. The reviewed models achieved a high accuracy ranged from 88.3% to 100.0% for disease detection tasks, from 69.5% to 97.8% for subtype classification tasks, and from 80.0% to 93.0% for treatment response prediction tasks. We generated a workflow to develop a predictive model that encompasses all steps from first defining human disease-related tasks to finally evaluating model performance. DL holds promise for transforming epigenomic big data into valuable knowledge that will enhance the development of translational epigenomics.",
-,No,20220131,methods,34847877,Predicting environmentally responsive transgenerational differential DNA methylated regions (epimutations) in the genome using a hybrid deep?machine learning approach,BMC Bioinformatics,"Background: Deep learning is an active bioinformatics artificial intelligence field that is useful in solving many biological problems, including predicting altered epigenetics such as DNA methylation regions. Deep learning (DL) can learn an informative representation that addresses the need for defining relevant features. However, deep learning models are computationally expensive, and they require large training datasets to achieve good classification performance.
+No,20220131,dnam score,35023833,Epigenetic scores for the circulating proteome as tools for disease prediction.,Elife,"Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample, (Generation Scotland; n=9,537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore - disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.© 2022, Gadd et al.",
+No,20220131,epigenetics,35031073,Functional genomics analysis identifies T and NK cell activation as a driver of epigenetic clock progression.,Genome Biol,"Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks.We perform a functional genomics analysis on four epigenetic clocks, including Hannum's blood predictor and Horvath's multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expression in trans. The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells.The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes.© 2022. The Author(s).",
+No,20220131,epigenetics,34850165,Single-molecule mitochondrial DNA sequencing shows no evidence of CpG methylation in human cells and tissues.,Nucleic Acids Res,"Methylation on CpG residues is one of the most important epigenetic modifications of nuclear DNA, regulating gene expression. Methylation of mitochondrial DNA (mtDNA) has been studied using whole genome bisulfite sequencing (WGBS), but recent evidence has uncovered technical issues which introduce a potential bias during methylation quantification. Here, we validate the technical concerns of WGBS, and develop and assess the accuracy of a new protocol for mtDNA nucleotide variant-specific methylation using single-molecule Oxford Nanopore Sequencing (ONS). Our approach circumvents confounders by enriching for full-length molecules over nuclear DNA. Variant calling analysis against showed that 99.5% of homoplasmic mtDNA variants can be reliably identified providing there is adequate sequencing depth. We show that some of the mtDNA methylation signal detected by ONS is due to sequence-specific false positives introduced by the technique. The residual signal was observed across several human primary and cancer cell lines and multiple human tissues, but was always below the error threshold modelled using negative controls. We conclude that there is no evidence for CpG methylation in human mtDNA, thus resolving previous controversies. Additionally, we developed a reliable protocol to study epigenetic modifications of mtDNA at single-molecule and single-base resolution, with potential applications beyond CpG methylation.© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",
+No,20220131,epigenetics,34980912,Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues.,Nat Biotechnol,"Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated 'flip-flops' between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).© 2022. The Author(s).",
+No,20220131,epigenetics,34991667,Universal annotation of the human genome through integration of over a thousand epigenomic datasets.,Genome Biol,"Genome-wide maps of chromatin marks such as histone modifications and open chromatin sites provide valuable information for annotating the non-coding genome, including identifying regulatory elements. Computational approaches such as ChromHMM have been applied to discover and annotate chromatin states defined by combinatorial and spatial patterns of chromatin marks within the same cell type. An alternative ""stacked modeling"" approach was previously suggested, where chromatin states are defined jointly from datasets of multiple cell types to produce a single universal genome annotation based on all datasets. Despite its potential benefits for applications that are not specific to one cell type, such an approach was previously applied only for small-scale specialized purposes. Large-scale applications of stacked modeling have previously posed scalability challenges.Using a version of ChromHMM enhanced for large-scale applications, we apply the stacked modeling approach to produce a universal chromatin state annotation of the human genome using over 1000 datasets from more than 100 cell types, with the learned model denoted as the full-stack model. The full-stack model states show distinct enrichments for external genomic annotations, which we use in characterizing each state. Compared to per-cell-type annotations, the full-stack annotations directly differentiate constitutive from cell type-specific activity and is more predictive of locations of external genomic annotations.The full-stack ChromHMM model provides a universal chromatin state annotation of the genome and a unified global view of over 1000 datasets. We expect this to be a useful resource that complements existing per-cell-type annotations for studying the non-coding human genome.© 2022. The Author(s).",
+No,20220131,epigenetics,34883445,Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome.,EBioMedicine,"parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing modifiable POE exist.in order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as 'predicted mRNA expression levels' of DNA methylation/imprinting machinery genes and environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315).a set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, 'lifetime smoking status' and 'predicted mRNA expression levels' of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs.the modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases.NSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH.Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.",
+Yes,20220131,ewas,35046013,DNA methylation analysis of cord blood samples in neonates born to gestational diabetes mothers diagnosed before 24 gestational weeks.,BMJ Open Diabetes Res Care,"Genome-wide methylation analyses of gestational diabetes mellitus (GDM) diagnosed after 24 gestational weeks (late GDM (L-GDM)) using cord blood have been reported. However, epigenetic changes in neonates born to mothers with GDM diagnosed before 24 gestational weeks (early GDM (E-GDM)) have not been reported. We investigated DNA methylation in neonates born to mothers with E-GDM using cord blood samples.Genome-wide DNA methylation analysis was performed using an Illumina EPIC array to compare methylation rates of 754 255 autosomal sites in cord blood samples from term neonates born to 162 mothers with GDM (E-GDM: n=84, L-GDM: n=78) and 60 normal glucose tolerance (normal OGTT) pregnancies. GDM was diagnosed based on Japan Society of Obstetrics and Gynecology criteria modified with International Association of Diabetes in Pregnancy Study Group criteria. In this study, all GDM mothers underwent dietary management, while self-monitoring of blood glucose and insulin administration was initiated when dietary modification did not achieve glycemic control.There were no significant differences in genome-wide DNA methylation of cord blood samples between the GDM (E-GDM and L-GDM) groups and normal OGTT group or between the E-GDM and normal OGTT groups, L-GDM and normal OGTT groups, and E-GDM and L-GDM groups.This is the first report to determine the DNA methylation patterns in neonates born to mothers with E-GDM. Neonates born to mothers with GDM, who were diagnosed based on Japan Society of Obstetrics and Gynecology criteria, may not differ in DNA methylation compared with those born to normal OGTT mothers.© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
+Yes,20220131,ewas,35036834,Differential DNA Methylation by Hispanic Ethnicity Among Firefighters in the United States.,Epigenet Insights,"Firefighters are exposed to a variety of environmental hazards and are at increased risk for multiple cancers. There is evidence that risks differ by ethnicity, yet the biological or environmental differences underlying these differences are not known. DNA methylation is one type of epigenetic regulation that is altered in cancers. In this pilot study, we profiled DNA methylation with the Infinium MethylationEPIC in blood leukocytes from 31 Hispanic white and 163 non-Hispanic white firefighters. We compared DNA methylation (1) at 12 xenobiotic metabolizing genes and (2) at all loci on the array (>740 000), adjusting for confounders. Five of the xenobiotic metabolizing genes were differentially methylated at a rawP-value <.05 when comparing the 2 ethnic groups, yet were not statistically significant at a 5% false discovery rate (q-value <.05). In the epigenome-wide analysis, 76 loci exhibited DNA methylation differences atq < .05. Among these, 3 CpG sites in the promoter region of the biotransformation geneSULT1C2had lower methylation in Hispanic compared to non-Hispanic firefighters. Other differentially methylated loci included genes that have been implicated in carcinogenesis in published studies (FOXK2, GYLTL1B, ZBTB16, ARHGEF10, and more). In this pilot study, we report differential DNA methylation between Hispanic and non-Hispanic firefighters in xenobiotic metabolism genes and other genes with functions related to cancer. Epigenetic susceptibility by ethnicity merits further study as this may alter risk for cancers linked to toxic exposures.© The Author(s) 2021.",
+Yes,20220131,ewas,35033200,Epigenome-wide association study of lung function in Latino children and youth with asthma.,Clin Epigenetics,"DNA methylation studies have associated methylation levels at different CpG sites or genomic regions with lung function. Moreover, genetic ancestry has been associated with lung function in Latinos. However, no epigenome-wide association study (EWAS) of lung function has been performed in this population. Here, we aimed to identify DNA methylation patterns associated with lung function in pediatric asthma among Latinos.We conducted an EWAS in whole blood from 250 Puerto Rican and 148 Mexican American children and young adults with asthma. A total of five CpGs exceeded the genome-wide significance threshold of p = 1.17 × 10-7in the combined analyses from Puerto Ricans and Mexican Americans: cg06035600 (MAP3K6, p = 6.13 × 10-8) showed significant association with pre-bronchodilator Tiffeneau-Pinelli index, the probes cg00914963 (TBC1D16, p = 1.04 × 10-7), cg16405908 (MRGPRE, p = 2.05 × 10-8), and cg07428101 (MUC2, p = 5.02 × 10-9) were associated with post-bronchodilator forced vital capacity (FVC), and cg20515679 (KCNJ6) with post-bronchodilator Tiffeneau-Pinelli index (p = 1.13 × 10-8). However, these markers did not show significant associations in publicly available data from Europeans (p > 0.05). A methylation quantitative trait loci analysis revealed that methylation levels at these CpG sites were regulated by genetic variation in Latinos and the Biobank-based Integrative Omics Studies (BIOS) consortium. Additionally, two differentially methylated regions in REXOC and AURKC were associated with pre-bronchodilator Tiffeneau-Pinelli index (adjusted p < 0.05) in Puerto Ricans and Mexican Americans. Moreover, we replicated some of the previous differentially methylated signals associated with lung function in non-Latino populations.We replicated previous associations of epigenetic markers with lung function in whole blood and identified novel population-specific associations shared among Latino subgroups.© 2022. The Author(s).",
+Yes,20220131,ewas,35032864,Pregnancy exposure to phthalates and DNA methylation in male placenta - An epigenome-wide association study.,Environ Int,"Exposure to phthalates during pregnancy may alter DNA methylation in the placenta, a crucial organ for the growth and development of the fetus.We studied associations between urinary concentrations of phthalate biomarkers during pregnancy and placental DNA methylation.We measured concentrations of 11 phthalate metabolites in maternal spot urine samples collected between 22 and 29 gestational weeks in 202 pregnant women. We analyzed DNA methylation levels in placental tissue (fetal side) collected at delivery. We first investigated changes in global DNA methylation of repetitive elements Alu and LINE-1. We then performed an adjusted epigenome-wide association study using IlluminaHM450 BeadChips and identified differentially methylated regions (DMRs) associated with phthalate exposure.Monobenzyl phthalate concentration was inversely associated with placental methylation of Alu repeats. Moreover, all phthalate biomarkers except for monocarboxy-iso-octyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were associated with at least one DMR. All but three DMRs showed increased DNA methylation with increased phthalate exposure. The largest identified DMR (22 CpGs) was positively associated with monocarboxy-iso-nonyl phthalate and encompassed heat shock proteins (HSPA1A, HSPA1L). The remaining DMRs encompassed transcription factors and nucleotide exchange factors, among other genes.This is the first description of genome-wide modifications of placental DNA methylation in association with pregnancy exposure to phthalates. Our results suggest epigenetic mechanisms by which exposure to these compounds could affect fetal development. Of interest, four identified DMRs had been previously associated with maternal smoking, which may suggest particular sensitivity of these genomic regions to the effect of environmental contaminants.Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.",
+Yes,20220131,ewas,35028889,Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study.,Neurocrit Care,"Cerebral edema and intracranial hypertension are major contributors to unfavorable prognosis in traumatic brain injury (TBI). Local epigenetic changes, particularly in DNA methylation, may influence gene expression and thus host response/secondary injury after TBI. It remains unknown whether DNA methylation in the central nervous system is associated with cerebral edema severity or intracranial hypertension post TBI. We sought to identify epigenome-wide DNA methylation patterns associated with these forms of secondary injury after TBI.We obtained genome-wide DNA methylation profiles of DNA extracted from ventricular cerebrospinal fluid samples at three different postinjury time points from a prospective cohort of patients with severe TBI (n = 89 patients, 254 samples). Cerebral edema and intracranial pressure (ICP) measures were clustered to generate composite end points of cerebral edema and ICP severity. We performed an unbiased epigenome-wide association study (EWAS) to test associations between DNA methylation at 419,895 cytosine-phosphate-guanine (CpG) sites and cerebral edema/ICP severity categories. Given inflated p values, we conducted permutation tests for top CpG sites to filter out potential false discoveries.Our data-driven hierarchical clustering across six cerebral edema and ICP measures identified two groups differing significantly in ICP based on the EWAS-identified CpG site cg22111818 in RGMA (Repulsive guidance molecule A, permutation p = 4.20 × 10-8). At 3-4 days post TBI, patients with severe intracranial hypertension had significantly lower levels of methylation at cg22111818.We report a novel potential relationship between intracranial hypertension after TBI and an acute, nonsustained reduction in DNA methylation at cg22111818 in the RGMA gene. To our knowledge, this is the largest EWAS in severe TBI. Our findings are further strengthened by previous findings that RGMA modulates axonal repair in other central nervous system disorders, but a role in intracranial hypertension or TBI has not been previously identified. Additional work is warranted to validate and extend these findings, including assessment of its possible role in risk stratification, identification of novel druggable targets, and ultimately our ability to personalize therapy in TBI.© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.",
+Yes,20220131,ewas,35028426,The genetic and epigenetic profile of serum S100β in the Lothian Birth Cohort 1936 and its relationship to Alzheimer's disease.,Wellcome Open Res,"Background:Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer's disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100β levels in older adults and performed Mendelian randomisation with Alzheimer's disease.Methods:GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100β levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100β. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100β and Alzheimer's disease. Colocalisation between S100β and Alzheimer's disease GWAS loci was also examined.Results:We identified 154 SNPs from chromosome 21 that associated (P<5x10-8) with S100β protein levels. The lead variant was located in theS100βgene (rs8128872, P=5.0x10-17). We found evidence that two independent causal variants existed for both transcription ofS100βand S100β protein levels in our eQTL analyses.No CpG sites were associated with S100β levels at the epigenome-wide significant level (P<3.6x10-8); the lead probe was cg06833709 (P=5.8x10-6), which mapped to theLGI1gene. There was no evidence of a causal association between S100β levels and Alzheimer's disease or vice versa and no evidence for colocalisation betweenS100βand Alzheimer's disease loci.Conclusions:These data provide insight into the molecular regulators of S100β levels. This context may aid in understanding the role of S100β in brain inflammation and neurological disease.Copyright: © 2021 A Gadd D et al.",
+Yes,20220131,ewas,34996616,"Ascaris exposure and its association with lung function, asthma, and DNA methylation in Northern Europe.",J Allergy Clin Immunol,"Ascaris infections, with a worldwide prevalence above 10%, can cause respiratory pathology. However, long-term effects on lung function in humans are largely unknown.We investigated the associations of Ascaris exposure with lung function, asthma, and DNA methylation.Serum Ascaris IgG antibodies were measured in 671 adults aged 18 to 47 years (46% women) from Aarhus, Bergen, and Tartu RHINESSA study centers. Seropositivity was defined as IgG above the 90th percentile. Linear and logistic regressions were used to analyze Ascaris seropositivity as associated with lung function and asthma, adjusted for age, height, and smoking and clustered by center. DNA methylation in blood was profiled by a commercial methylation assay.Ascaris seropositivity was associated with lower FEV1(-247 mL; 95% CI, -460, -34) and higher odds for asthma (adjusted odds ratio, 5.84; 95% CI, 1.67, 20.37) among men but not women, also after further adjusting for house dust mite sensitivity, consistent across study centers. At a genome-wide level, Ascaris exposure was associated with 23 differentially methylated sites in men and 3 in women. We identified hypermethylation of the MYBPC1 gene, which can regulate airway muscle contraction. We also identified genes linked to asthma pathogenesis such as CRHR1 and GRK1, as well as a differentially methylated region in the PRSS22 gene linked to nematode infection.Ascaris exposure was associated with substantially lower lung function and increased asthma risk among men. Seropositive participants had sex-specific differences in DNA methylation compared to the unexposed, thus suggesting that exposure may lead to sex-specific epigenetic changes associated with lung pathology.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
+Yes,20220131,ewas,34995380,Newborn DNA methylation and asthma acquisition across adolescence and early adulthood.,Clin Exp Allergy,"Little is known about the association of newborn DNA methylation (DNAm) with asthma acquisition across adolescence and early adult life.We aim to identify epigenetic biomarkers in newborns for asthma acquisition during adolescence or young adulthood.The Isle of Wight Birth Cohort (IOWBC) (n = 1456) data at ages 10, 18 and 26 years were assessed. To screen cytosine-phosphate-guanine site (CpGs) potentially associated with asthma acquisition, at the genome scale, we examined differentially methylated regions (DMR) using dmrff R package and individual CpG sites using linear regression on such associations. For CpGs that passed screening, we examined their enrichment in biological pathways using their mapping genes and tested their associations with asthma acquisitions using logistic regressions. Findings in IOWBC were tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.In total, 2636 unique CpGs passed screening, based on which we identified one biological pathway linked to asthma acquisition during adolescence in females (FDR adjusted p-value = .003 in IOWBC). Via logistic regressions, for females, four CpGs were shown to be associated with asthma acquisition during adolescence, and another four CpGs with asthma acquisition in young adulthood (FDR adjusted p-value < .05 in IOWBC) and these eight CpGs were replicated in ALSPAC (all p-values < .05). DNAm at all the identified CpGs was shown to be temporally consistent, and at six of the CpGs was associated with expressions of adjacent or mapping genes in females (all p-values < .05). For males, 622 CpGs were identified in IOWBC (FDR = 0.01), but these were not tested in ALSPAC due to small sample sizes.Eight CpGs on LHX5, IL22RA2, SOX11, CBX4, ACPT, CFAP46, MUC4, and ATP1B2 genes have the potential to serve as candidate epigenetic biomarkers in newborns for asthma acquisition in females during adolescence or young adulthood.© 2022 John Wiley & Sons Ltd.",
+Yes,20220131,ewas,34992238,Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress.,Mol Psychiatry,"Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.© 2021. The Author(s), under exclusive licence to Springer Nature Limited.",
+Yes,20220131,ewas,34944472,Epigenome-Wide Association Study of Prostate Cancer in African Americans Identifies DNA Methylation Biomarkers for Aggressive Disease.,Biomolecules,"DNA methylation plays important roles in prostate cancer (PCa) development and progression. African American men have higher incidence and mortality rates of PCa than other racial groups in U.S. The goal of this study was to identify differentially methylated CpG sites and genes between clinically defined aggressive and nonaggressive PCa in African Americans. We performed genome-wide DNA methylation profiling in leukocyte DNA from 280 African American PCa patients using Illumina MethylationEPIC array that contains about 860K CpG sties. There was a slight increase of overall methylation level (mean β value) with the increasing Gleason scores (GS = 6, GS = 7, GS ≥ 8, P for trend = 0.002). There were 78 differentially methylated CpG sites with P < 10-4and 9 sites with P < 10-5in the trend test. We also found 77 differentially methylated regions/genes (DMRs), including 10 homeobox genes and six zinc finger protein genes. A gene ontology (GO) molecular pathway enrichment analysis of these 77 DMRs found that the main enriched pathway was DNA-binding transcriptional factor activity. A few representative DMRs include HOXD8, SOX11, ZNF-471, and ZNF-577. Our study suggests that leukocyte DNA methylation may be valuable biomarkers for aggressive PCa and the identified differentially methylated genes provide biological insights into the modulation of immune response by aggressive PCa.",
+Yes,20220131,ewas,34937578,DNA methylation mediates the association between breastfeeding and early-life growth trajectories.,Clin Epigenetics,"The role of breastfeeding in modulating epigenetic factors has been suggested as a possible mechanism conferring its benefits on child development but it lacks evidence. Using extensive DNA methylation data from the ALSPAC child cohort, we characterized the genome-wide landscape of DNA methylation variations associated with the duration of exclusive breastfeeding and assessed whether these variations mediate the association between exclusive breastfeeding and BMI over different epochs of child growth.Exclusive breastfeeding elicits more substantial DNA methylation variations during infancy than at other periods of child growth. At the genome-wide level, 13 CpG sites in girls (miR-21, SNAPC3, ATP6V0A1, DHX15/PPARGC1A, LINC00398/ALOX5AP, FAM238C, NATP/NAT2, CUX1, TRAPPC9, OSBPL1A, ZNF185, FAM84A, PDPK1) and 2 CpG sites in boys (IL16 and NREP), mediate the association between exclusive breastfeeding and longitudinal BMI. We found enrichment of CpG sites located within miRNAs and key pathways (AMPK signaling pathway, insulin signaling pathway, endocytosis). Overall DNA methylation variation corresponding to 3 to 5 months of exclusive breastfeeding was associated with slower BMI growth the first 6 years of life compared to no breastfeeding and in a dose-response manner with exclusive breastfeeding duration.Our study confirmed the early postnatal period as a critical developmental period associated with substantial DNA methylation variations, which in turn could mitigate the development of overweight and obesity from infancy to early childhood. Since an accelerated growth during these developmental periods has been linked to the development of sustained obesity later in life, exclusive breastfeeding could have a major role in preventing the risks of overweight/obesity and children and adults through DNA methylation mechanisms occurring early in life.© 2021. The Author(s).",
+Yes,20220131,ewas,34930449,Reproductive history and blood cell DNA methylation later in life: the Young Finns Study.,Clin Epigenetics,"Women with a history of complications of pregnancy, including hypertensive disorders, gestational diabetes or an infant fetal growth restriction or preterm birth, are at higher risk for cardiovascular disease later in life. We aimed to examine differences in maternal DNA methylation following pregnancy complications.Data on women participating in the Young Finns study (n = 836) were linked to the national birth registry. DNA methylation in whole blood was assessed using the Infinium Methylation EPIC BeadChip. Epigenome-wide analysis was conducted on differential CpG methylation at 850 K sites. Reproductive history was also modeled as a predictor of four epigenetic age indices.Fourteen significant differentially methylated sites were found associated with both history of pre-eclampsia and overall hypertensive disorders of pregnancy. No associations were found between reproductive history and any epigenetic age acceleration measure.Differences in epigenetic methylation profiles could represent pre-existing risk factors, or changes that occurred as a result of experiencing these complications.© 2021. The Author(s).",
+Yes,20220131,ewas,34899183,Autism-Associated DNA Methylation at Birth From Multiple Tissues Is Enriched for Autism Genes in the Early Autism Risk Longitudinal Investigation.,Front Mol Neurosci,"Background:Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci.Objectives:To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes.Methods:In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (earlyn= 140 and laten= 75 pregnancy), infant cord blood (n= 133), and placenta (maternaln= 106 and fetaln= 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n= 881) from the Simons Foundation Autism Research Initiative (SFARI) database.Results:No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P< 0.05) in each tissue were highly enriched for SFARI genes (cord bloodP= 7.9 × 10-29, maternal blood early pregnancyP= 6.1 × 10-27, maternal blood late pregnancyP= 2.8 × 10-16, maternal placentaP= 5.6 × 10-15, fetal placentaP= 1.3 × 10-20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes.Conclusion:DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.Copyright © 2021 Bakulski, Dou, Feinberg, Aung, Ladd-Acosta, Volk, Newschaffer, Croen, Hertz-Picciotto, Levy, Landa, Feinberg and Fallin.",
+Yes,20220131,ewas,34895303,Genome-wide methylation patterns in Marfan syndrome.,Clin Epigenetics,"Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process.The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed.We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP's that associated with clinical events. No significant associations at p < 10-8or p < 10-6were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18-22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before.This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.© 2021. The Author(s).",
+Yes,20220131,ewas,34895032,Newborn differential DNA methylation and subcortical brain volumes as early signs of severe neurodevelopmental delay in a South African Birth Cohort Study.,World J Biol Psychiatry,"Early detection of neurodevelopmental delay is crucial for intervention and treatment strategies. We analysed associations between newborn DNA methylation (DNAm), neonatal magnetic resonance imaging (MRI) neuroimaging data, and neurodevelopment.Neurodevelopment was assessed in 161 children from the South African Drakenstein Child Health Study at 2 years of age using the Bayley Scales of Infant and Toddler Development III. We performed an epigenome-wide association study of neurodevelopmental delay using DNAm from cord blood. Subsequently, we analysed if associations between DNAm and neurodevelopmental delay were mediated by altered neonatal brain volumes (subset of 51 children).Differential DNAm atSPTBN4(cg26971411,Δbeta = -0.024,p-value = 3.28 × 10-08), and two intergenic regions (chromosome 11: cg00490349,Δbeta = -0.036,p-value = 3.02 × 10-08; chromosome 17: cg15660740,Δbeta = -0.078,p-value = 6.49 × 10-08) were significantly associated with severe neurodevelopmental delay. While these associations were not mediated by neonatal brain volume, neonatal caudate volumes were independently associated with neurodevelopmental delay, particularly in language (Δcaudate volume = 165.30 mm3,p = 0.0443) and motor (Δcaudate volume = 365.36 mm3,p-value = 0.0082) domains.Differential DNAm from cord blood and increased neonatal caudate volumes were independently associated with severe neurodevelopmental delay at 2 years of age. These findings suggest that neurobiological signals for severe developmental delay may be detectable in very early life.",
+Yes,20220131,ewas,34887417,Meta-analyses identify DNA methylation associated with kidney function and damage.,Nat Commun,"Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.© 2021. The Author(s).",
+Yes,20220131,ewas,34887389,Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.,Nat Commun,"Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.© 2021. The Author(s).",
+Yes,20220131,ewas,34857913,Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target.,Mol Psychiatry,"Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10-8) with the five leading probes located in SLC7A11 (p = 7.75 × 10-108), JDP2 (p = 1.44 × 10-56), GAS5 (p = 2.71 × 10-47), TRA2B (p = 3.54 × 10-42), and SLC43A1 (p = 1.18 × 10-40). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer's disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10-09). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10-38and p = 5.41 × 10-14). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p < 10-17). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p < 10-4), increased liver function enzymes (GGT (p = 1.03 × 10-21), ALT (p = 1.29 × 10-6), and AST (p = 1.97 × 10-8)) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention.© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
+Yes,20220131,ewas,34857876,Differential placental CpG methylation is associated with chronic lung disease of prematurity.,Pediatr Res,"Chronic lung disease (CLD) is the most common pulmonary morbidity in extremely preterm infants. It is unclear to what extent prenatal exposures influence the risk of CLD. Epigenetic variation in placenta DNA methylation may be associated with differential risk of CLD, and these associations may be dependent upon sex.Data were obtained from a multi-center cohort of infants born extremely preterm (<28 weeks' gestation) and an epigenome-wide approach was used to identify associations between placental DNA methylation and CLD (n = 423). Associations were evaluated using robust linear regression adjusting for covariates, with a false discovery rate of 0.05. Analyses stratified by sex were used to assess differences in methylation-CLD associations.CLD was associated with differential methylation at 49 CpG sites representing 46 genes in the placenta. CLD was associated with differential methylation of probes within genes related to pathways involved in fetal lung development, such as p53 signaling and myo-inositol biosynthesis. Associations between CpG methylation and CLD differed by sex.Differential placental methylation within genes with key roles in fetal lung development may reflect complex cell signaling between the placenta and fetus which mediate CLD risk. These pathways appear to be distinct based on fetal sex.In extremely preterm infants, differential methylation of CpG sites within placental genes involved in pathways related to cell signaling, oxidative stress, and trophoblast invasion is associated with chronic lung disease of prematurity. DNA methylation patterns associated with chronic lung disease were distinctly based on fetal sex, suggesting a potential mechanism underlying dimorphic phenotypes. Mechanisms related to fetal hypoxia and placental myo-inositol signaling may play a role in fetal lung programming and the developmental origins of chronic lung disease. Continued research of the relationship between the placental epigenome and chronic lung disease could inform efforts to ameliorate or prevent this condition.© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.",
+No,20220131,ewas,34841896,Sex- and tissue-specific effects of binge-level prenatal alcohol consumption on DNA methylation at birth.,Epigenomics,"Background:Binge-level prenatal alcohol exposure (PAE) causes developmental abnormalities, which may be mediated in part by epigenetic mechanisms. Despite this, few studies have characterised the association of binge PAE with DNA methylation in offspring.Methods:We investigated the association between binge PAE and genome-wide DNA methylation profiles in a sex-specific manner in neonatal buccal and placental samples.Results:We identified no differentially methylated CpGs or differentially methylated regions (DMRs) at false discovery rate <0.05. However, using a sum-of-ranks approach, we identified a DMR in each tissue of female offspring. The DMR identified in buccal samples is located near regions with previously-reported associations to fetal alcohol spectrum disorder (FASD) and binge PAE.Conclusion:Our findings warrant further replication and highlight a potential epigenetic link between binge PAE and FASD.",
+Yes,20220131,ewas,34836312,Epigenome-Wide Association Study of Infant Feeding and DNA Methylation in Infancy and Childhood in a Population at Increased Risk for Type 1 Diabetes.,Nutrients,"We assessed associations between infant diet (e.g., breastfeeding and introduction to solid foods) and DNA methylation in infancy and childhood. We measured DNA methylation in peripheral blood collected in infancy (9-15 months of age) in 243 children; and in a subset of 50 children, we also measured methylation in childhood (6-9 years of age) to examine persistence, and at birth (in cord blood) to examine temporality. We performed multivariable linear regression of infant diet on the outcome of methylation using epigenome-wide and candidate site approaches. We identified six novel CpG sites associated with breastfeeding duration using an EWAS approach. One differentially methylated site presented directionally consistent associations with breastfeeding (cg00574958,CPT1A) in infancy and childhood but not at birth. Two differentially methylated sites in infancy (cg19693031,TXNIP; cg23307264,KHSRP) were associated with breastfeeding and were not present at birth; however, these associations did not persist into childhood. Associations between infant diet and methylation in infancy at three sites (cg22369607,AP001525.1; cg2409200,TBCD; cg27173510,PGBD5) were also present at birth, suggesting the influence of exposures other than infant diet. Infant diet exposures are associated with persistent methylation differences inCPT1A, which may be one mechanism behind infant diet's long-term health effects.",
+Yes,20220131,ewas,35000590,DNA methylation signatures associated with cardiometabolic risk factors in children from India and The Gambia: results from the EMPHASIS study.,Clin Epigenetics,"The prevalence of cardiometabolic disease (CMD) is rising globally, with environmentally induced epigenetic changes suggested to play a role. Few studies have investigated epigenetic associations with CMD risk factors in children from low- and middle-income countries. We sought to identify associations between DNA methylation (DNAm) and CMD risk factors in children from India and The Gambia.Using the Illumina Infinium HumanMethylation 850 K Beadchip array, we interrogated DNAm in 293 Gambian (7-9 years) and 698 Indian (5-7 years) children. We identified differentially methylated CpGs (dmCpGs) associated with systolic blood pressure, fasting insulin, triglycerides and LDL-Cholesterol in the Gambian children; and with insulin sensitivity, insulinogenic index and HDL-Cholesterol in the Indian children. There was no overlap of the dmCpGs between the cohorts. Meta-analysis identified dmCpGs associated with insulin secretion and pulse pressure that were different from cohort-specific dmCpGs. Several differentially methylated regions were associated with diastolic blood pressure, insulin sensitivity and fasting glucose, but these did not overlap with the dmCpGs. We identified significant cis-methQTLs at three LDL-Cholesterol-associated dmCpGs in Gambians; however, methylation did not mediate genotype effects on the CMD outcomes.This study identified cardiometabolic biomarkers associated with differential DNAm in Indian and Gambian children. Most associations were cohort specific, potentially reflecting environmental and ethnic differences.© 2022. The Author(s).",
+Yes,20220131,ewas,34937574,Associations between DNA methylation and BMI vary by metabolic health status: a potential link to disparate cardiovascular outcomes.,Clin Epigenetics,"Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health.The discovery study population was derived from three Women's Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm β value, the risk of incident CHD increased by 9% in one site and decreased by 6-10% in two sites over 25 years.Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.© 2021. The Author(s).",
+Yes,20220131,ewas,35039093,Epigenetics of single-site and multi-site atherosclerosis in African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA).,Clin Epigenetics,"DNA methylation, an epigenetic mechanism modulated by lifestyle and environmental factors, may be an important biomarker of complex diseases including cardiovascular diseases (CVD) and subclinical atherosclerosis.DNA methylation in peripheral blood samples from 391 African-Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) was assessed at baseline, and atherosclerosis was assessed 5 and 12 years later. Using linear mixed models, we examined the association between previously identified CpGs for coronary artery calcification (CAC) and carotid plaque, both individually and aggregated into methylation risk scores (MRSCACand MRScarotid), and four measures of atherosclerosis (CAC, abdominal aorta calcification (AAC), ankle-brachial index (ABI), and multi-site atherosclerosis based on gender-specific quartiles of the single-site measures). We also examined the association between four epigenetic age acceleration measures (IEAA, EEAA, PhenoAge acceleration, and GrimAge acceleration) and the four atherosclerosis measures. Finally, we characterized the temporal stability of the epigenetic measures using repeated DNA methylation measured 5 years after baseline (N = 193).After adjusting for CVD risk factors, four CpGs (cg05575921(AHRR), cg09935388 (GFI1), cg21161138 (AHRR), and cg18168448 (LRRC52)) were associated with multi-site atherosclerosis (FDR < 0.1). cg05575921 was also associated with AAC and cg09935388 with ABI. MRSCACwas associated with ABI (Beta = 0.016, P = 0.006), and MRScarotidwas associated with both AAC (Beta = 0.605, equivalent to approximately 1.8-fold increase in the Agatston score of AAC, P = 0.004) and multi-site atherosclerosis (Beta = 0.691, P = 0.002). A 5-year increase in GrimAge acceleration (~ 1 SD) was associated with a 1.6-fold (P = 0.012) increase in the Agatston score of AAC and 0.7 units (P = 0.0003) increase in multi-site atherosclerosis, all after adjusting for CVD risk factors. All epigenetic measures were relatively stable over 5 years, with the highest intraclass correlation coefficients observed for MRScarotidand GrimAge acceleration (0.87 and 0.89, respectively).We found evidence of an association between DNA methylation and atherosclerosis at multiple vascular sites in a sample of African-Americans. Further evaluation of these potential biomarkers is warranted to deepen our understanding of the relationship between epigenetics and atherosclerosis.© 2022. The Author(s).",
+Yes,20220131,ewas,34835636,Prenatal Exposure to Heavy Metals Affects Gestational Age by Altering DNA Methylation Patterns.,Nanomaterials (Basel),"Environmental exposure is known to have toxic effects. Maternal environmental exposure not only affects mothers but also their fetuses in utero, which may interrupt their early development. Preterm birth, one of the outcomes of prenatal exposure, is a significant factor in lifelong health risks. To understand the effects of prenatal exposome on preterm birth, we studied the association between maternal and prenatal heavy metal exposure and gestational age, using resources from the MOthers' and Children's Environmental Health (MOCEH) study in South Korea. Additionally, a methylation assay was performed to analyze epigenetic mediation using genomic DNA derived from the cord blood of 384 participants in the MOCEH study. The results suggest that maternal cadmium exposure is associated with a decrease in gestational age through an alteration in DNA methylation at a specific CpG site, cg21010642. The CpG site was annotated to a gene involved in early embryonic development. Therefore, irregular methylation patterns at this site may contribute to premature birth by mediating irregular biological mechanisms.",
+No,20220131,mqtl,34873174,Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome.,Nat Commun,"Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.© 2021. The Author(s).",
+Yes,20220131,ewas+dnam score,35039062,Blood-based epigenome-wide analyses of cognitive abilities.,Genome Biol,"Blood-based markers of cognitive functioning might provide an accessible way to track neurodegeneration years prior to clinical manifestation of cognitive impairment and dementia.Using blood-based epigenome-wide analyses of general cognitive function, we show that individual differences in DNA methylation (DNAm) explain 35.0% of the variance in general cognitive function (g). A DNAm predictor explains ~4% of the variance, independently of a polygenic score, in two external cohorts. It also associates with circulating levels of neurology- and inflammation-related proteins, global brain imaging metrics, and regional cortical volumes.As sample sizes increase, the ability to assess cognitive function from DNAm data may be informative in settings where cognitive testing is unreliable or unavailable.© 2022. The Author(s).",
+No,20220131,ewas+dnam score,34906459,DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies.,Genet Med,"Chromatinopathies include more than 50 disorders caused by disease-causing variants of various components of chromatin structure and function. Many of these disorders exhibit unique genome-wide DNA methylation profiles, known as episignatures. In this study, the methylation profile of a large cohort of individuals with chromatinopathies was analyzed for episignature detection.DNA methylation data was generated on extracted blood samples from 129 affected individuals with the Illumina Infinium EPIC arrays and analyzed using an established bioinformatic pipeline.The DNA methylation profiles matched and confirmed the sequence findings in both the discovery and validation cohorts. Twenty-five affected individuals carrying a variant of uncertain significance, did not show a methylation profile matching any of the known episignatures. Three additional variant of uncertain significance cases with an identified KDM6A variant were re-classified as likely pathogenic (n = 2) or re-assigned as Wolf-Hirschhorn syndrome (n = 1). Thirty of the 33 Next Generation Sequencing negative cases did not match a defined episignature while three matched Kabuki syndrome, Rubinstein-Taybi syndrome and BAFopathy respectively.With the expanding clinical utility of the EpiSign assay, DNA methylation analysis should be considered part of the testing cascade for individuals presenting with clinical features of Mendelian chromatinopathy disorders.Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.",
+Yes,20220131,ewas+dnam score,34880450,Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system.,Mol Psychiatry,"Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 (β = -0.055, pcorrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3, and HEBP2, which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS (N = 3360, β = 0.377, p = 3.12 × 10-11, R2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.© 2021. The Author(s).",
+Yes,20220131,ewas+dnam score+cell-free dna,34915915,Accurate prediction of acute pancreatitis severity based on genome-wide cell free DNA methylation profiles.,Clin Epigenetics,"Patients with severe acute pancreatitis (SAP) have a high mortality, thus early diagnosis and interventions are critical for improving survival. However, conventional tests are limited in acute pancreatitis (AP) stratification. We aimed to assess AP severity by integrating the informative clinical measurements with cell free DNA (cfDNA) methylation markers.One hundred and seventy-five blood samples were collected from 61 AP patients at multiple time points, plus 24 samples from healthy individuals. Genome-wide cfDNA methylation profiles of all samples were characterized with reduced representative bisulfite sequencing. Clinical blood tests covering 93 biomarkers were performed on AP patients within 24 h. SAP predication models were built based on cfDNA methylation and conventional blood biomarkers separately and in combination.We identified 565 and 59 cfDNA methylation markers informative for acute pancreatitis and its severity. These markers were used to develop prediction models for AP and SAP with area under the receiver operating characteristic of 0.92 and 0.81, respectively. Twelve blood biomarkers were systematically screened for a predictor of SAP with a sensitivity of 87.5% for SAP, and a specificity of 100% in mild acute pancreatitis, significantly higher than existing blood tests. An expanded model integrating 12 conventional blood biomarkers with 59 cfDNA methylation markers further improved the SAP prediction sensitivity to 92.2%.These findings have demonstrated that accurate prediction of SAP by the integration of conventional and novel blood molecular markers, paving the way for early and effective SAP intervention through a non-invasive rapid diagnostic test.© 2021. The Author(s).",
+Yes,20220131,ewas+longitudinal,34966975,Sex differences in schizophrenia: a longitudinal methylome analysis.,J Neural Transm (Vienna),"DNA methylation analysis at the genome-wide level is a useful tool to explore potential sex differences in SCZ patients. The primary aim of the current study was to identify differentially methylated regions of DNA between males and females with schizophrenia. We collected DNA samples from 134 schizophrenia patients to measure genome-wide methylation at single-base resolution in 96 males and 38 females. We further repeated the analysis in 13 subjects (9 females, 4 males) to confirm the sex differences and to reduce the effect of potential confounders. The longitudinal methylation analysis found significant replication of several genes across the genome. These genes included RFTN1, TLE1, DAZL, PRR4, UTP14C, RNU12, and LOC644649. The overall results showed robust association between autosomal CpG sites and sex. Longitudinal methylation analysis can be used as internal replication to confirm epigenetic variants that are stable over time.© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.",
+Yes,20220131,ewas+wgbs,34886889,Genome-wide methylation and expression analyses reveal the epigenetic landscape of immune-related diseases for tobacco smoking.,Clin Epigenetics,"Smoking is a major causal risk factor for lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), and is the main preventable cause of deaths in the world. The components of cigarette smoke are involved in immune and inflammatory processes, which may increase the prevalence of cigarette smoke-related diseases. However, the underlying molecular mechanisms linking smoking and diseases have not been well explored. This study was aimed to depict a global map of DNA methylation and gene expression changes induced by tobacco smoking and to explore the molecular mechanisms between smoking and human diseases through whole-genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq).We performed WGBS on 72 samples (36 smokers and 36 nonsmokers) and RNA-seq on 75 samples (38 smokers and 37 nonsmokers), and cytokine immunoassay on plasma from 22 males (9 smokers and 13 nonsmokers) who were recruited from the city of Jincheng in China. By comparing the data of the two groups, we discovered a genome-wide methylation landscape of differentially methylated regions (DMRs) associated with smoking. Functional enrichment analyses revealed that both smoking-related hyper-DMR genes (DMGs) and hypo-DMGs were related to synapse-related pathways, whereas the hypo-DMGs were specifically related to cancer and addiction. The differentially expressed genes (DEGs) revealed by RNA-seq analysis were significantly enriched in the ""immunosuppression"" pathway. Correlation analysis of DMRs with their corresponding gene expression showed that genes affected by tobacco smoking were mostly related to immune system diseases. Finally, by comparing cytokine concentrations between smokers and nonsmokers, we found that vascular endothelial growth factor (VEGF) was significantly upregulated in smokers.In sum, we found that smoking-induced DMRs have different distribution patterns in hypermethylated and hypomethylated areas between smokers and nonsmokers. We further identified and verified smoking-related DMGs and DEGs through multi-omics integration analysis of DNA methylome and transcriptome data. These findings provide us a comprehensive genomic map of the molecular changes induced by smoking which would enhance our understanding of the harms of smoking and its relationship with diseases.© 2021. The Author(s).",
+No,20220131,hydroxymethylation,35029129,Navigating the hydroxymethylome: experimental biases and quality control tools for the tandem bisulfite and oxidative bisulfite Illumina microarrays.,Epigenomics,"Aim:Tandem bisulfite (BS) and oxidative bisulfite (oxBS) conversion on DNA followed by hybridization to Infinium HumanMethylation BeadChips allows nucleotide resolution of 5-hydroxymethylcytosine genome-wide. Here, the authors compared data quality acquired from BS-treated and oxBS-treated samples.Materials & methods:Raw BeadArray data from 417 pairs of samples across 12 independent datasets were included in the study. Probe call rates were compared between paired BS and oxBS treatments controlling for technical variables.Results:oxBS-treated samples had a significantly lower call rate. Among technical variables, DNA-specific extraction kits performed better with higher call rates after oxBS conversion.Conclusion:The authors emphasize the importance of quality control during oxBS conversion to minimize information loss and recommend using a DNA-specific extraction kit for DNA extraction and an oxBSQC package for data preprocessing.",
+No,20220131,longitudinal ewas,34903243,Longitudinal DNA methylation dynamics as a practical indicator in clinical epigenetics.,Clin Epigenetics,"One of the fundamental assumptions of DNA methylation in clinical epigenetics is that DNA methylation status can change over time with or without interplay with environmental and clinical conditions. However, little is known about how DNA methylation status changes over time under ordinary environmental and clinical conditions. In this study, we revisited the high frequency longitudinal DNA methylation data of two Japanese males (24 time-points within three months) and characterized the longitudinal dynamics.The results showed that the majority of CpGs on Illumina HumanMethylation450 BeadChip probe set were longitudinally stable over the time period of three months. Focusing on dynamic and stable CpGs extracted from datasets, dynamic CpGs were more likely to be reported as epigenome-wide association study (EWAS) markers of various traits, especially those of immune- and inflammatory-related traits; meanwhile, the stable CpGs were enriched in metabolism-related genes and were less likely to be EWAS markers, indicating that the stable CpGs are stable both in the short-term within individuals and under various environmental and clinical conditions.This study indicates that CpGs with different stabilities are involved in different functions and traits, and thus, they are potential indicators that can be applied for clinical epigenetic studies to outline underlying mechanisms.© 2021. The Author(s).",
+No,20220131,methods,35013473,The impact of methodology on the reproducibility and rigor of DNA methylation data.,Sci Rep,"Epigenetic modifications are crucial for normal development and implicated in disease pathogenesis. While epigenetics continues to be a burgeoning research area in neuroscience, unaddressed issues related to data reproducibility across laboratories remain. Separating meaningful experimental changes from background variability is a challenge in epigenomic studies. Here we show that seemingly minor experimental variations, even under normal baseline conditions, can have a significant impact on epigenome outcome measures and data interpretation. We examined genome-wide DNA methylation and gene expression profiles of hippocampal tissues from wild-type rats housed in three independent laboratories using nearly identical conditions. Reduced-representation bisulfite sequencing and RNA-seq respectively identified 3852 differentially methylated and 1075 differentially expressed genes between laboratories, even in the absence of experimental intervention. Difficult-to-match factors such as animal vendors and a subset of husbandry and tissue extraction procedures produced quantifiable variations between wild-type animals across the three laboratories. Our study demonstrates that seemingly minor experimental variations, even under normal baseline conditions, can have a significant impact on epigenome outcome measures and data interpretation. This is particularly meaningful for neurological studies in animal models, in which baseline parameters between experimental groups are difficult to control. To enhance scientific rigor, we conclude that strict adherence to protocols is necessary for the execution and interpretation of epigenetic studies and that protocol-sensitive epigenetic changes, amongst naive animals, may confound experimental results.© 2022. The Author(s).",
+No,20220131,methods,34968257,Ultra-Low DNA Input into Whole Genome Methylation Assays and Detection of Oncogenic Methylation and Copy Number Variants in Circulating Tumour DNA.,Epigenomes,"Abnormal CpG methylation in cancer is ubiquitous and generally detected in tumour specimens using a variety of techniques at a resolution encompassing single CpG loci to genome wide coverage. Analysis of samples with very low DNA inputs, such as formalin fixed (FFPE) biopsy specimens from clinical trials or circulating tumour DNA is challenging at the genome-wide level because of lack of available input. We present the results of low input experiments into the Illumina Infinium HD methylation assay on FFPE specimens and ctDNA samples.For all experiments, the Infinium HD assay for methylation was used. In total, forty-eight FFPE specimens were used at varying concentrations (lowest input 50 ng); eighteen blood derived specimens (lowest input 10 ng) and six matched ctDNA input (lowest input 10 ng)/fresh tumour specimens (lowest input 250 ng) were processed. Downstream analysis was performed in R/Bioconductor for quality control metrics and differential methylation analysis as well as copy number calls.Correlation coefficients for CpG methylation were high at the probe level averaged R2 = 0.99 for blood derived samples and R2 > 0.96 for the FFPE samples. When matched ctDNA/fresh tumour samples were compared, R2 > 0.91 between the two. Results of differential methylation analysis did not vary significantly by DNA input in either the blood or FFPE groups. There were differences seen in the ctDNA group as compared to their paired tumour sample, possibly because of enrichment for tumour material without contaminating normal. Copy number variants observed in the tumour were generally also seen in the paired ctDNA sample with good concordance via DQ plot.The Illumina Infinium HD methylation assay can robustly detect methylation across a range of sample types, including ctDNA, down to an input of 10 ng. It can also reliably detect oncogenic methylation changes and copy number variants in ctDNA. These findings demonstrate that these samples can now be accessed by methylation array technology, allowing analysis of these important sample types.",
+No,20220131,methods,34886879,The ENmix DNA methylation analysis pipeline for Illumina BeadChip and comparisons with seven other preprocessing pipelines.,Clin Epigenetics,"Illumina DNA methylation arrays are high-throughput platforms for cost-effective genome-wide profiling of individual CpGs. Experimental and technical factors introduce appreciable measurement variation, some of which can be mitigated by careful ""preprocessing"" of raw data.Here we describe the ENmix preprocessing pipeline and compare it to a set of seven published alternative pipelines (ChAMP, Illumina, SWAN, Funnorm, Noob, wateRmelon, and RnBeads). We use two large sets of duplicate sample measurements with 450 K and EPIC arrays, along with mixtures of isogenic methylated and unmethylated cell line DNA to compare raw data and that preprocessed via different pipelines.Our evaluations show that the ENmix pipeline performs the best with significantly higher correlation and lower absolute difference between duplicate pairs, higher intraclass correlation coefficients (ICC) and smaller deviations from expected methylation level in mixture experiments. In addition to the pipeline function, ENmix software provides an integrated set of functions for reading in raw data files from mouse and human arrays, quality control, data preprocessing, visualization, detection of differentially methylated regions (DMRs), estimation of cell type proportions, and calculation of methylation age clocks. ENmix is computationally efficient, flexible and allows parallel computing. To facilitate further evaluations, we make all datasets and evaluation code publicly available.Careful selection of robust data preprocessing methods is critical for DNA methylation array studies. ENmix outperformed other pipelines in our evaluations to minimize experimental variation and to improve data quality and study power.© 2021. The Author(s).",
+No,20220131,methods,34872606,The SEQC2 epigenomics quality control (EpiQC) study.,Genome Biol,"Cytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA's Epigenomics Quality Control Group.Each sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms.The data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research.© 2021. The Author(s).",
+No,20220131,methods,34837041,Navigating the pitfalls of applying machine learning in genomics.,Nat Rev Genet,"The scale of genetic, epigenomic, transcriptomic, cheminformatic and proteomic data available today, coupled with easy-to-use machine learning (ML) toolkits, has propelled the application of supervised learning in genomics research. However, the assumptions behind the statistical models and performance evaluations in ML software frequently are not met in biological systems. In this Review, we illustrate the impact of several common pitfalls encountered when applying supervised ML in genomics. We explore how the structure of genomics data can bias performance evaluations and predictions. To address the challenges associated with applying cutting-edge ML methods to genomics, we describe solutions and appropriate use cases where ML modelling shows great potential.© 2021. Springer Nature Limited.",
+No,20220131,methods,34829962,"Deep Learning for Human Disease Detection, Subtype Classification, and Treatment Response Prediction Using Epigenomic Data",Biomedicines,"Deep learning (DL) is a distinct class of machine learning that has achieved first-class performance in many fields of study. For epigenomics, the application of DL to assist physicians and scientists in human disease-relevant prediction tasks has been relatively unexplored until very recently. In this article, we critically review published studies that employed DL models to predict disease detection, subtype classification, and treatment responses, using epigenomic data. A comprehensive search on PubMed, Scopus, Web of Science, Google Scholar, and arXiv.org was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among 1140 initially identified publications, we included 22 articles in our review. DNA methylation and RNA-sequencing data are most frequently used to train the predictive models. The reviewed models achieved a high accuracy ranged from 88.3% to 100.0% for disease detection tasks, from 69.5% to 97.8% for subtype classification tasks, and from 80.0% to 93.0% for treatment response prediction tasks. We generated a workflow to develop a predictive model that encompasses all steps from first defining human disease-related tasks to finally evaluating model performance. DL holds promise for transforming epigenomic big data into valuable knowledge that will enhance the development of translational epigenomics.",
+No,20220131,methods,34847877,Predicting environmentally responsive transgenerational differential DNA methylated regions (epimutations) in the genome using a hybrid deep?machine learning approach,BMC Bioinformatics,"Background: Deep learning is an active bioinformatics artificial intelligence field that is useful in solving many biological problems, including predicting altered epigenetics such as DNA methylation regions. Deep learning (DL) can learn an informative representation that addresses the need for defining relevant features. However, deep learning models are computationally expensive, and they require large training datasets to achieve good classification performance.
 
 Results: One approach to addressing these challenges is to use a less complex deep learning network for feature selection and Machine Learning (ML) for classification. In the current study, we introduce a hybrid DL-ML approach that uses a deep neural network for extracting molecular features and a non-DL classifier to predict environmentally responsive transgenerational differential DNA methylated regions (DMRs), termed epimutations, based on the extracted DL-based features. Various environmental toxicant induced epigenetic transgenerational inheritance sperm epimutations were used to train the model on the rat genome DNA sequence and use the model to predict transgenerational DMRs (epimutations) across the entire genome.
 
 Conclusion: The approach was also used to predict potential DMRs in the human genome. Experimental results show that the hybrid DL-ML approach outperforms deep learning and traditional machine learning methods.",
-,No,20220131,mqtl,34980917,Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function.,Nat Genet,"We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10-14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20220131,pqtl,34857953,Large-scale integration of the plasma proteome with genetics and disease.,Nat Genet,"The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development.© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20220131,pqtl,34857772,Mapping the serum proteome to neurological diseases using whole genome sequencing.,Nat Commun,"Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.© 2021. The Author(s).",
-,No,20220131,prediction,34915912,Methylation-derived inflammatory measures and lung cancer risk and survival.,Clin Epigenetics,"Examining immunity-related DNA methylation alterations in blood could help elucidate the role of the immune response in lung cancer etiology and aid in discovering factors that are key to lung cancer development and progression. In a nested, matched case-control study, we estimated methylation-derived NLR (mdNLR) and quantified DNA methylation levels at loci previously linked with circulating concentrations of C-reactive protein (CRP). We examined associations between these measures and lung cancer risk and survival.Using conditional logistic regression and further adjusting for BMI, batch effects, and a smoking-based methylation score, we observed a 47% increased risk of non-small cell lung cancer (NSCLC) for one standard deviation (SD) increase in mdNLR (n = 150 pairs; OR: 1.47, 95% CI 1.08, 2.02). Using a similar model, the estimated CRP Scores were inversely associated with risk of NSCLC (e.g., Score 1 OR: 0.57, 95% CI: 0.40, 0.81). Using Cox proportional hazards models adjusting for age, sex, smoking status, methylation-predicted pack-years, BMI, batch effect, and stage, we observed a 28% increased risk of dying from lung cancer (n = 145 deaths in 205 cases; HR: 1.28, 95% CI: 1.09, 1.50) for one SD increase in mdNLR.Our study demonstrates that immunity status measured with DNA methylation markers is associated with lung cancer a decade or more prior to cancer diagnosis. A better understanding of immunity-associated methylation-based biomarkers in lung cancer development could provide insight into critical pathways.© 2021. The Author(s).",
-,No,20220131,review,34863305,"Epigenome-wide association studies: current knowledge, strategies and recommendations.",Clin Epigenetics,"The aetiology and pathophysiology of complex diseases are driven by the interaction between genetic and environmental factors. The variability in risk and outcomes in these diseases are incompletely explained by genetics or environmental risk factors individually. Therefore, researchers are now exploring the epigenome, a biological interface at which genetics and the environment can interact. There is a growing body of evidence supporting the role of epigenetic mechanisms in complex disease pathophysiology. Epigenome-wide association studies (EWASes) investigate the association between a phenotype and epigenetic variants, most commonly DNA methylation. The decreasing cost of measuring epigenome-wide methylation and the increasing accessibility of bioinformatic pipelines have contributed to the rise in EWASes published in recent years. Here, we review the current literature on these EWASes and provide further recommendations and strategies for successfully conducting them. We have constrained our review to studies using methylation data as this is the most studied epigenetic mechanism; microarray-based data as whole-genome bisulphite sequencing remains prohibitively expensive for most laboratories; and blood-based studies due to the non-invasiveness of peripheral blood collection and availability of archived DNA, as well as the accessibility of publicly available blood-cell-based methylation data. Further, we address multiple novel areas of EWAS analysis that have not been covered in previous reviews: (1) longitudinal study designs, (2) the chip analysis methylation pipeline (ChAMP), (3) differentially methylated region (DMR) identification paradigms, (4) methylation quantitative trait loci (methQTL) analysis, (5) methylation age analysis and (6) identifying cell-specific differential methylation from mixed cell data using statistical deconvolution.© 2021. The Author(s).",
-,No,20220131,tissues,10.1101/2022.01.24.477547,A human DNA methylation atlas reveals principles of cell type-specific methylation and identifies thousands of cell type-specific regulatory elements,Biorxiv,"DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 207 healthy tissue samples.
+No,20220131,mqtl,34980917,Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function.,Nat Genet,"We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10-14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20220131,pqtl,34857953,Large-scale integration of the plasma proteome with genetics and disease.,Nat Genet,"The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development.© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20220131,pqtl,34857772,Mapping the serum proteome to neurological diseases using whole genome sequencing.,Nat Commun,"Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.© 2021. The Author(s).",
+No,20220131,prediction,34915912,Methylation-derived inflammatory measures and lung cancer risk and survival.,Clin Epigenetics,"Examining immunity-related DNA methylation alterations in blood could help elucidate the role of the immune response in lung cancer etiology and aid in discovering factors that are key to lung cancer development and progression. In a nested, matched case-control study, we estimated methylation-derived NLR (mdNLR) and quantified DNA methylation levels at loci previously linked with circulating concentrations of C-reactive protein (CRP). We examined associations between these measures and lung cancer risk and survival.Using conditional logistic regression and further adjusting for BMI, batch effects, and a smoking-based methylation score, we observed a 47% increased risk of non-small cell lung cancer (NSCLC) for one standard deviation (SD) increase in mdNLR (n = 150 pairs; OR: 1.47, 95% CI 1.08, 2.02). Using a similar model, the estimated CRP Scores were inversely associated with risk of NSCLC (e.g., Score 1 OR: 0.57, 95% CI: 0.40, 0.81). Using Cox proportional hazards models adjusting for age, sex, smoking status, methylation-predicted pack-years, BMI, batch effect, and stage, we observed a 28% increased risk of dying from lung cancer (n = 145 deaths in 205 cases; HR: 1.28, 95% CI: 1.09, 1.50) for one SD increase in mdNLR.Our study demonstrates that immunity status measured with DNA methylation markers is associated with lung cancer a decade or more prior to cancer diagnosis. A better understanding of immunity-associated methylation-based biomarkers in lung cancer development could provide insight into critical pathways.© 2021. The Author(s).",
+No,20220131,review,34863305,"Epigenome-wide association studies: current knowledge, strategies and recommendations.",Clin Epigenetics,"The aetiology and pathophysiology of complex diseases are driven by the interaction between genetic and environmental factors. The variability in risk and outcomes in these diseases are incompletely explained by genetics or environmental risk factors individually. Therefore, researchers are now exploring the epigenome, a biological interface at which genetics and the environment can interact. There is a growing body of evidence supporting the role of epigenetic mechanisms in complex disease pathophysiology. Epigenome-wide association studies (EWASes) investigate the association between a phenotype and epigenetic variants, most commonly DNA methylation. The decreasing cost of measuring epigenome-wide methylation and the increasing accessibility of bioinformatic pipelines have contributed to the rise in EWASes published in recent years. Here, we review the current literature on these EWASes and provide further recommendations and strategies for successfully conducting them. We have constrained our review to studies using methylation data as this is the most studied epigenetic mechanism; microarray-based data as whole-genome bisulphite sequencing remains prohibitively expensive for most laboratories; and blood-based studies due to the non-invasiveness of peripheral blood collection and availability of archived DNA, as well as the accessibility of publicly available blood-cell-based methylation data. Further, we address multiple novel areas of EWAS analysis that have not been covered in previous reviews: (1) longitudinal study designs, (2) the chip analysis methylation pipeline (ChAMP), (3) differentially methylated region (DMR) identification paradigms, (4) methylation quantitative trait loci (methQTL) analysis, (5) methylation age analysis and (6) identifying cell-specific differential methylation from mixed cell data using statistical deconvolution.© 2021. The Author(s).",
+No,20220131,tissues,10.1101/2022.01.24.477547,A human DNA methylation atlas reveals principles of cell type-specific methylation and identifies thousands of cell type-specific regulatory elements,Biorxiv,"DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 207 healthy tissue samples.
 
 Replicates of the same cell-type are >99.5% identical, demonstrating robustness of cell identity programs to genetic variation and environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny, and identifies methylation patterns retained since gastrulation. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hyper-methylated loci are rare and are enriched for CpG islands, polycomb targets, and CTCF binding sites, suggesting a novel role in shaping cell type-specific chromatin looping. The atlas provides an essential resource for interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.
 
@@ -1460,169 +1460,169 @@ Summary paragraph DNA methylation, a fundamental epigenetic mark, governs chroma
 We present a human methylome atlas based on deep whole-genome bisulfite sequencing of 39 sorted, primary cell types and use this dataset to address fundamental questions in developmental biology, physiology and pathology. Biological replicates are >99.5% identical, demonstrating unappreciated robustness to genetic variation and environmental perturbations. Clustering recapitulates key elements of tissue ontogeny, identifying methylation patterns retained since gastrulation. Loci uniquely unmethylated in individual cell types identify novel transcriptional enhancers and are enriched for tissue-specific transcription factors binding motifs. In contrast, loci uniquely hyper-methylated in specific cell types are rare, enriched for CpG islands and polycomb targets, and overlap CTCF binding sites, suggesting a novel role in shaping cell-type-specific chromatin looping. Finally, the atlas facilitates fragment-level deconvolution of tissue and plasma methylomes across thousands of cell-type specific regions to quantify their individual components at unprecedented resolution.
 
 The human cell-type-specific methylation atlas provides an essential resource for studying gene regulation by defining cell-type-specific distal enhancers and regulators of 3D organization, for identifying pathological changes in DNA methylation, and for the interpretation of methylation-based liquid biopsies.",
-,No,20220131,transgenerational,34983971,Molecular mechanisms of transgenerational epigenetic inheritance.,Nat Rev Genet,"Increasing evidence indicates that non-DNA sequence-based epigenetic information can be inherited across several generations in organisms ranging from yeast to plants to humans. This raises the possibility of heritable 'epimutations' contributing to heritable phenotypic variation and thus to evolution. Recent work has shed light on both the signals that underpin these epimutations, including DNA methylation, histone modifications and non-coding RNAs, and the mechanisms by which they are transmitted across generations at the molecular level. These mechanisms can vary greatly among species and have a more limited effect in mammals than in plants and other animal species. Nevertheless, common principles are emerging, with transmission occurring either via direct replicative mechanisms or indirect reconstruction of the signal in subsequent generations. As these processes become clearer we continue to improve our understanding of the distinctive features and relative contribution of DNA sequence and epigenetic variation to heritable differences in phenotype.© 2022. Springer Nature Limited.",
-,No,20220131,transgenerational,34934526,Epigenetic inheritance of acquired traits through DNA methylation.,Anim Front,NA,
-,No,20220131,methods,35047860,Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders,HGG Adv,"Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.",
-,No,20220214,cancer,35058638,Life histories of myeloproliferative neoplasms inferred from phylogenies.,Nature,"Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617Fwas estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617Fwas the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617Facquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617Facquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20220214,cell counts,35140201,Enhanced cell deconvolution of peripheral blood using DNA methylation for high-resolution immune profiling.,Nat Commun,"DNA methylation microarrays can be employed to interrogate cell-type composition in complex tissues. Here, we expand reference-based deconvolution of blood DNA methylation to include 12 leukocyte subtypes (neutrophils, eosinophils, basophils, monocytes, naïve and memory B cells, naïve and memory CD4 + and CD8 + T cells, natural killer, and T regulatory cells). Including derived variables, our method provides 56 immune profile variables. The IDOL (IDentifying Optimal Libraries) algorithm was used to identify libraries for deconvolution of DNA methylation data for current and previous platforms. The accuracy of deconvolution estimates obtained using our enhanced libraries was validated using artificial mixtures and whole-blood DNA methylation with known cellular composition from flow cytometry. We applied our libraries to deconvolve cancer, aging, and autoimmune disease datasets. In conclusion, these libraries enable a detailed representation of immune-cell profiles in blood using only DNA and facilitate a standardized, thorough investigation of immune profiles in human health and disease.© 2022. The Author(s).",
-,No,20220214,DNAm age,35046594,Turning back time with epigenetic clocks.,Nature,NA,
-,No,20220214,DNAm age,35118376,The relationship between ageing and changes in the human blood and brain methylomes.,NAR Genom Bioinform,"Changes in DNA methylation have been found to be strongly correlated with age, enabling the creation of 'epigenetic clocks'. Previously, studies on the relationship between ageing and DNA methylation have assumed a linear relationship. Here, we show that several markers show a non-linear behaviour. In particular, we observe a tendency for saturation with age, especially in the cerebellum. Further, we show that the relationships between significant methylation changes and ageing are different in different tissues. We suggest a straightforward method of assessing all methylation-age relationships and cluster them according to their relative fold change. Our fold change selection outperforms the most common epigenetic clocks in predicting age for the cerebellum, but not for Blood or the Frontal Cortex. Further, we find that the saturation of methylation observed at older ages for the cerebellum explains why epigenetic clocks consistently underestimate the age there. The findings imply that assuming linear correlations might cause biologically important markers to be missed.© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
-,No,20220214,dnam age,35120273,Age-related DNA methylation on Y chromosome and their associations with total mortality among Chinese males.,Aging Cell,"In view of the sex differences in aging-related diseases, sex chromosomes may play a critical role during aging process. This study aimed to identify age-related DNA methylation changes on Y chromosome (ChrY). A two-stage study design was conducted in this study. The discovery stage contained 419 Chinese males, including 205 from the Wuhan-Zhuhai cohort panel, 107 from the coke oven workers panel, and 107 from the Shiyan panel. The validation stage contained 587 Chinese males from the Dongfeng-Tongji sub-cohort. We used the Illumina HumanMethylation BeadChip to determine genome-wide DNA methylation in peripheral blood of the study participants. The associations between age and methylation levels of ChrY CpGs were investigated by using linear regression models with adjustment for potential confounders. Further, associations of age-related ChrY CpGs with all-cause mortality were tested in the validation stage. We identified the significant associations of 41 ChrY CpGs with age at false discovery rate (FDR) <0.05 in the discovery stage, and 18 of them were validated in the validation stage (p < 0.05). Meta-analysis of both stages confirmed the robust positive associations of 14 CpGs and negative associations of 4 CpGs with age (FDR<0.05). Among them, cg03441493 and cg17816615 were significantly associated with all-cause mortality risk [HR(95% CI) = 1.37 (1.04, 1.79) and 0.70 (0.54, 0.93), respectively]. Our results highlighted the importance of ChrY CpGs on male aging.© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
-,Yes,20220214,ewas,35063012,Immune profiles and DNA methylation alterations related with non-muscle-invasive bladder cancer outcomes.,Clin Epigenetics,"Non-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease. However, screening is invasive, expensive, and associated with significant morbidity making bladder cancer the most expensive cancer to treat per capita. There is an urgent need to expand the understanding of markers related to recurrence and survival outcomes of NMIBC.We used the Illumina HumanMethylationEPIC array to measure peripheral blood DNA methylation profiles of NMIBC patients (N = 603) enrolled in a population-based cohort study in New Hampshire and applied cell type deconvolution to estimate immune cell-type proportions. Using Cox proportional hazard models, we identified that increasing CD4T and CD8T cell proportions were associated with a statistically significant decreased hazard of tumor recurrence or death (CD4T: HR = 0.98, 95% CI = 0.97-1.00; CD8T: HR = 0.97, 95% CI = 0.95-1.00), whereas increasing monocyte proportion and methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) were associated with the increased hazard of tumor recurrence or death (monocyte: HR = 1.04, 95% CI = 1.00-1.07; mdNLR: HR = 1.12, 95% CI = 1.04-1.20). Then, using an epigenome-wide association study (EWAS) approach adjusting for age, sex, smoking status, BCG treatment status, and immune cell profiles, we identified 2528 CpGs associated with the hazard of tumor recurrence or death (P < 0.005). Among these CpGs, the 1572 were associated with an increased hazard and were significantly enriched in open sea regions; the 956 remaining CpGs were associated with a decreased hazard and were significantly enriched in enhancer regions and DNase hypersensitive sites.Our results expand on the knowledge of immune profiles and methylation alteration associated with NMIBC outcomes and represent a first step toward the development of DNA methylation-based biomarkers of tumor recurrence.© 2022. The Author(s).",
-,Yes,20220214,ewas,35063426,Prenatal exposure to PM<sub>10</sub> and changes in DNA methylation and telomere length in cord blood.,Environ Res,"Air pollution exposure in pregnancy can cause molecular level alterations that might influence later disease susceptibility.We investigated DNA methylation (DNAm) and telomere length (TL) in the cord blood in relation to gestational PM10exposure and explored potential gestational windows of susceptibility.Cord blood epigenome-wide DNAm (N = 384) and TL (N = 500) were measured in children of the Italian birth cohort Piccolipiù, using the Infinium Methylation EPIC BeadChip and qPCR, respectively. PM10daily exposure levels, based on maternal residential address, were estimated for different gestational periods using models based on satellite data. Epigenome-wide analysis to identify differentially methylated probes (DMPs) and regions (DMRs) was conducted, followed by a pathway analysis and replication analysis in an second Piccolipiù dataset. Distributed lag models (DLMs) using weekly exposures were used to study the association of PM10exposure across pregnancy with telomere length, as well as with the DMPs that showed robust associations.Gestational PM10exposure was associated with the DNA methylation of more than 250 unique DMPs, most of them identified in early gestation, and 1 DMR. Out of 151 DMPs available in the replication dataset, ten DMPs showed robust associations: eight were associated with exposure during early gestation and 2 with exposure during the whole pregnancy. These exposure windows were supported by the DLM analysis. The PM10exposure between 15th and 20th gestational week seem to be associated with shorter telomeres at birth, while exposure between 24th and 29th was associated with longer telomeres.The early pregnancy period is a potential critical window during which PM10exposure can influence cord blood DNA methylation. The results from the TL analysis were consistent with previous findings and merit further exploration in future studies. The study underlines the importance of considering gestational windows outside of the predefined trimesters that may not always overlap with biologically relevant windows of exposure.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.",
-,Yes,20220214,ewas,35077545,Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci.,Hum Mol Genet,"Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10-9), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.© The Author(s) 2021. Published by Oxford University Press.",
-,No,20220214,longitudinal,35083470,Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage.,Epigenetics Commun,"Following aneurysmal subarachnoid hemorrhage (aSAH), the brain is susceptible to ferroptosis, a type of iron-dependent cell death. Therapeutic intervention targeting the iron homeostasis pathway shows promise for mitigating ferroptosis and improving recovery in animal models, but little work has been conducted in humans. DNA methylation (DNAm) plays a key role in gene expression and brain function, plasticity, and injury recovery, making it a potentially useful biomarker of outcomes or therapeutic target for intervention. Therefore, in this longitudinal, observational study, we examined the relationships between trajectories of DNAm in candidate genes related to iron homeostasis and acute (cerebral vasospasm and delayed cerebral ischemia) and long-term (Glasgow Outcome Scale [GOS, unfavorable = 1-3] and death) patient outcomes after aSAH.Longitudinal, genome-wide DNAm data were generated from DNA extracted from post-aSAH cerebrospinal fluid (n= 260 participants). DNAm trajectories of 637 CpG sites in 36 candidate genes related to iron homeostasis were characterized over 13 days post-aSAH using group-based trajectory analysis, an unsupervised clustering method. Significant associations were identified between inferred DNAm trajectory groups at several CpG sites and acute and long-term outcomes. Among our results, cg25713625 in the STEAP3 metalloreductase gene (STEAP3) stood out. Specifically, in comparing the highest cg25713625 DNAm trajectory group with the lowest, we observed significant associations (i.e., based onp-values less than an empirical significance threshold) with unfavorable GOS at 3 and 12 months (OR= 11.7,p= 0.0006 andOR= 15.6,p= 0.0018, respectively) and death at 3 and 12 months (OR= 19.1,p= 0.0093 andOR= 12.8,p= 0.0041, respectively). These results were replicated in an independent sample (n= 100 participants) observing significant associations with GOS at 3 and 12 months (OR= 8.2,p= 0.001 andOR= 6.3,p= 0.0.0047, respectively) and death at 3 months (OR= 2.3,p= 0.008) and a suggestive association (i.e.,p-value < 0.05 not meeting an empirical significance threshold) with death at 12 months (OR= 2.0,p= 0.0272). In both samples, an additive effect of the DNAm trajectory group was observed as the percentage of participants with unfavorable long-term outcomes increased substantially with higher DNAm trajectory groups.Our results support a role for DNAm of cg25713625/STEAP3in recovery following aSAH. Additional research is needed to further explore the role of DNAm of cg25713625/STEAP3as a biomarker of unfavorable outcomes, or therapeutic target to improve outcomes, to translate these findings clinically.",
-,Yes,20220214,ewas,35104326,Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies.,Diabetes Care,"Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations.To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression.Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] = 0.013 [2.1 × 10-3], P value corrected for false discovery rate [PFDR] = 5.1 × 10-3) and cg02988288 (β [SE]-0.013 [2.3 × 10-3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm.Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.© 2022 by the American Diabetes Association.",
-,Yes,20220214,ewas,35109748,Blood DNA methylation signatures are associated with social determinants of health among survivors of childhood cancer.,Epigenetics,"Social epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5'-cytosine-phosphate-guanine-3' (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH-CpG associations (P< 9 × 10-8), 25 of which were validated in survivors of African ancestry (P< 0.05). Thirteen CpGs were associated with all three SDOH factors and resided at pleiotropic loci in cigarette smoking-related genes (e.g.,CLDND1andCPOX). After accounting for smoking and body mass index, these associations remained significant with attenuated effect sizes. Seven of 13 CpGs were associated with gene expression level based on 57 subsamples with blood RNA sequencing data available. In conclusion, DNAm signatures, many resembling the effect of tobacco use, were associated with SDOH factors among survivors of childhood cancer, thereby suggesting that biologically distal SDOH factors influence health behaviours or related factors, the epigenome, and subsequently survivors' health.",
-,Yes,20220214,ewas,35119793,DNA methylation in blood cells is associated with cortisol levels in offspring of mothers who had prenatal post-traumatic stress disorder.,Stress Health,"Maternal stress during pregnancy is associated with differential DNA methylation in offspring and disrupted cortisol secretion. This study aimed to determine methylation signatures of cortisol levels in children, and whether associations differ based on maternal post-traumatic stress disorder (PTSD). Blood epigenome-wide methylation and fasting cortisol levels were measured in 118 offspring of mothers recruited from the Kosovo Rehabilitation Centre for Torture Victims. Mothers underwent clinically administered assessment for PTSD using Diagnostic and Statistical Manual of Mental Disorders. Correlations between offspring methylation and cortisol levels were examined using epigenome-wide analysis, adjusting for covariates. Subsequent analysis focussed on a priori selected genes involved in the hypothalamic-pituitary-adrenal (HPA) axis stress signalling. Methylation at four sites were correlated with cortisol levels (cg15321696, r = -0.33, cg18105800, r = +0.33, cg00986889, r = -0.25, and cg15920527, r = -0.27). In adjusted multivariable regression, when stratifying based on prenatal PTSD status, significant associations were only found for children born to mothers with prenatal PTSD (p < 0.001). Several sites within HPA axis genes were also associated with cortisol levels in the maternal PTSD group specifically. There is evidence that methylation is associated with cortisol levels, particularly in offspring born to mothers with prenatal PTSD. However, larger studies need to be carried out to independently validate these findings.© 2022 The Authors. Stress and Health published by John Wiley & Sons Ltd.",
-,Yes,20220214,ewas,35123963,Associations between plasma levels of brominated flame retardants and methylation of DNA from peripheral blood: A cross-sectional study in a cohort of French women.,Environ Res,"Brominated flame retardants (BFRs) are organic compounds that are widespread in the environment. Because of their persistence, they are able to bioaccumulate with major impacts on human health. It has been hypothesized that the effect of BFRs on human health is mediated by alterations of DNA methylation.The aim of this study was to examine the association between methylation of DNA extracted from peripheral blood and circulating levels of BFRs measured in plasma.We conducted a methylation wide association study on 336 blood samples from a study within the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) cohort, a long-term longitudinal cohort of French women. DNA methylation at more than 850 000 cytosine-guanine dinucleotide (CpG) sites was measured with the Illumina Infinium HumanMethylation - EPIC BeadChip. Circulating levels of seven BFRs (BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154 and PBB-153) were measured by gas chromatography coupled to high-resolution mass spectrometry in plasma samples. The association between DNA methylation and BFRs plasma levels was assessed through linear mixed-effects models followed by gene-set enrichment analyses (GSEA).We identified 253 CpG sites whose methylation levels were significantly associated with exposure to BFRs after Bonferroni correction. For 50 of these CpGs the p-values were less than 2.2x10-9with the strongest association being between BDE-154 and cg23619365 (4.32x10-13). GSEA of CpG sites associated with exposure to BFRs identified significant enrichment of genes involved in hypoxia, glycolysis and adipogenesis.Exposure to BFRs appears to be related to numerous alterations in DNA methylation. These findings, if replicated in independent studies, provide insights into the biological and health effects of BFRs.Copyright © 2022. Published by Elsevier Inc.",
-,Yes,20220214,ewas,35139887,Aberrant epigenetic and transcriptional events associated with breast cancer risk.,Clin Epigenetics,"Genome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N = 146, median age = 39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina's HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation.Transcriptomic analysis identified 69 differentially expressed genes between women at high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR < 0.05 and fold change ≥ 2. Majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR < 0.01) and primary epithelial cells (p < 0.05) from high-risk breasts. Moreover, 1698 DNA methylation changes were identified in high-risk breast tissues (FDR < 0.05), partially overlapped with cancer-related signatures, and correlated with transcriptional changes (p < 0.05, r ≤ 0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified.Normal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues, and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.© 2022. The Author(s).",
-,Yes,20220214,ewas,35145228,Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.,Mol Psychiatry,"Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.© 2022. The Author(s).",
-,No,20220214,longitudinal,35142878,Early DNA methylation changes in children developing beta cell autoimmunity at a young age.,Diabetologia,"Type 1 diabetes is a chronic autoimmune disease of complex aetiology, including a potential role for epigenetic regulation. Previous epigenomic studies focused mainly on clinically diagnosed individuals. The aim of the study was to assess early DNA methylation changes associated with type 1 diabetes already before the diagnosis or even before the appearance of autoantibodies.Reduced representation bisulphite sequencing (RRBS) was applied to study DNA methylation in purified CD4+T cell, CD8+T cell and CD4-CD8-cell fractions of 226 peripheral blood mononuclear cell samples longitudinally collected from seven type 1 diabetes-specific autoantibody-positive individuals and control individuals matched for age, sex, HLA risk and place of birth. We also explored correlations between DNA methylation and gene expression using RNA sequencing data from the same samples. Technical validation of RRBS results was performed using pyrosequencing.We identified 79, 56 and 45 differentially methylated regions in CD4+T cells, CD8+T cells and CD4-CD8-cell fractions, respectively, between type 1 diabetes-specific autoantibody-positive individuals and control participants. The analysis of pre-seroconversion samples identified DNA methylation signatures at the very early stage of disease, including differential methylation at the promoter of IRF5 in CD4+T cells. Further, we validated RRBS results using pyrosequencing at the following CpG sites: chr19:18118304 in the promoter of ARRDC2; chr21:47307815 in the intron of PCBP3; and chr14:81128398 in the intergenic region near TRAF3 in CD4+T cells.These preliminary results provide novel insights into cell type-specific differential epigenetic regulation of genes, which may contribute to type 1 diabetes pathogenesis at the very early stage of disease development. Should these findings be validated, they may serve as a potential signature useful for disease prediction and management.© 2022. The Author(s).",
-,No,20220214,mechanism,35102554,"Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis.",Int J Cancer,"Alcohol consumption is thought to be one of the modifiable risk factors for colorectal cancer (CRC). However, the causality and mechanisms by which alcohol exerts its carcinogenic effect are unclear. We evaluated the association between alcohol consumption and CRC risk by analyzing data from 32 cohort studies and conducted two-sample Mendelian randomization (MR) analysis to examine for casual relationship. To explore the effect of alcohol related DNA methylation on CRC risk, we performed an epigenetic MR analysis with data from an epigenome-wide association study (EWAS). We additionally performed gene-alcohol interaction analysis nested in the UK Biobank to assess effect modification between alcohol consumption and susceptibility genes. We discovered distinct effects of alcohol on CRC incidence and mortality from the meta-analyses, and genetic predisposition to alcohol drinking was causally associated with an increased CRC risk (OR = 1.79, 95% CI: 1.23-2.61) using two-sample MR approaches. In epigenetic MR analysis, two alcohol-related CpG sites (cg05593667 and cg10045354 mapped to COLCA1/COLCA2 gene) were identified causally associated with an increased CRC risk (P < 8.20 × 10-4). Gene-alcohol interaction analysis revealed that carriage of the risk allele of the eQTL (rs3087967) and mQTL (rs11213823) polymorphism of COLCA1/COLCA2 would interact with alcohol consumption to increase CRC risk (PInteraction = .027 and PInteraction = .016). Our study provides comprehensive evidence to elucidate the role of alcohol in CRC and highlights that the pathogenic effect of alcohol on CRC could be partly attributed to DNA methylation by regulating the expression of COLCA1/COLCA2 gene.© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",
-,No,20220214,mechanism,35119365,Physiological TLR4 regulation in human fetal membranes as an explicative mechanism of a pathological preterm case.,Elife,"The integrity of human fetal membranes is crucial for harmonious fetal development throughout pregnancy. Their premature rupture is often the consequence of a physiological phenomenon that has been exacerbated. Beyond all the implied biological processes, inflammation is of primary importance and is qualified as 'sterile' at the end of pregnancy. In this study, complementary methylomic and transcriptomic strategies on amnion and choriodecidua explants obtained from the altered (cervix zone) and intact fetal membranes at term and before labour were used. By cross-analysing genome-wide studies strengthened by in vitro experiments, we deciphered how the expression of toll-like receptor 4 (TLR4), an actor in pathological fetal membrane rupture, is controlled. Indeed, it is differentially regulated in the altered zone and between both layers by a dual mechanism: (1) the methylation of TLR4 and miRNA promoters and (2) targeting by miRNA (let-7a-2 and miR-125b-1) acting on the 3'-UTR of TLR4. Consequently, this study demonstrates that fine regulation of TLR4 is required for sterile inflammation establishment at the end of pregnancy and that it may be dysregulated in the pathological premature rupture of membranes.© 2022, Belville et al.",
-,No,20220214,methods,35145108,A mammalian methylation array for profiling methylation levels at conserved sequences.,Nat Commun,"Infinium methylation arrays are not available for the vast majority of non-human mammals. Moreover, even if species-specific arrays were available, probe differences between them would confound cross-species comparisons. To address these challenges, we developed the mammalian methylation array, a single custom array that measures up to 36k CpGs per species that are well conserved across many mammalian species. We designed a set of probes that can tolerate specific cross-species mutations. We annotate the array in over 200 species and report CpG island status and chromatin states in select species. Calibration experiments demonstrate the high fidelity in humans, rats, and mice. The mammalian methylation array has several strengths: it applies to all mammalian species even those that have not yet been sequenced, it provides deep coverage of conserved cytosines facilitating the development of epigenetic biomarkers, and it increases the probability that biological insights gained in one species will translate to others.© 2022. The Author(s).",
-,No,20220214,prediction,35045866,A deep learning model for early risk prediction of heart failure with preserved ejection fraction by DNA methylation profiles combined with clinical features.,Clin Epigenetics,"Heart failure with preserved ejection fraction (HFpEF), affected collectively by genetic and environmental factors, is the common subtype of chronic heart failure. Although the available risk assessment methods for HFpEF have achieved some progress, they were based on clinical or genetic features alone. Here, we have developed a deep learning framework, HFmeRisk, using both 5 clinical features and 25 DNA methylation loci to predict the early risk of HFpEF in the Framingham Heart Study Cohort.The framework incorporates Least Absolute Shrinkage and Selection Operator and Extreme Gradient Boosting-based feature selection, as well as a Factorization-Machine based neural network-based recommender system. Model discrimination and calibration were assessed using the AUC and Hosmer-Lemeshow test. HFmeRisk, including 25 CpGs and 5 clinical features, have achieved the AUC of 0.90 (95% confidence interval 0.88-0.92) and Hosmer-Lemeshow statistic was 6.17 (P = 0.632), which outperformed models with clinical characteristics or DNA methylation levels alone, published chronic heart failure risk prediction models and other benchmark machine learning models. Out of them, the DNA methylation levels of two CpGs were significantly correlated with the paired transcriptome levels (R < -0.3, P < 0.05). Besides, DNA methylation locus in HFmeRisk were associated with intercellular signaling and interaction, amino acid metabolism, transport and activation and the clinical variables were all related with the mechanism of occurrence of HFpEF. Together, these findings give new evidence into the HFmeRisk model.Our study proposes an early risk assessment framework for HFpEF integrating both clinical and epigenetic features, providing a promising path for clinical decision making.© 2022. The Author(s).",
-,No,20220214,prediction,35123558,Bladder cancer detection in urine using DNA methylation markers: a technical and prospective preclinical validation.,Clin Epigenetics,"The development of accurate urinary biomarkers for non-invasive and cost-effective detection of primary and recurrent bladder tumours is recognized as one of the major clinical needs in bladder cancer diagnostics. The purposes of this study were (1) to validate the results of a previous technical comparison by determining the diagnostic performance of nine methylation markers in urine pellet compared to full void urine, and (2) to validate the diagnostic performance of the optimal marker panel GHSR/MAL from a previous exploratory study in a preclinical setting.Urine samples of 108 patients with bladder cancer and 100 age- and gender-matched controls were prospectively collected for methylation analysis. Urinary methylation levels of the markers FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST and ZIC1 were determined with quantitative methylation-specific PCR in urine pellet. Area under the curves (AUCs) were determined for individual markers and the marker panel GHSR/MAL. The diagnostic performance of the marker panel GHSR/MAL was evaluated in the total study population and in different subgroups of patients with bladder cancer using the Chi-square test. The diagnostic accuracy was assessed by leave-one-out cross-validation.All nine urinary methylation markers (FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST and ZIC1) showed significantly higher methylation levels in bladder cancer patients than in controls (p < 0.001). Area under the curves (AUCs) of the nine methylation markers tested in urine pellet were similar to AUCs in full void urine of an independent previous cohort. GHSR/MAL reached an AUC of 0.89 (95% confidence interval [CI] 0.84-0.94), at 80% sensitivity and 93% specificity. Sensitivity of GHSR/MAL increased with higher tumour grades, higher tumour stages, in primary vs. recurrent tumours, and in males vs. females.This technical validation supports the robustness of DNA methylation analysis in urine pellet and full void urine for the non-invasive detection of bladder cancer. Subsequent preclinical validation confirmed the diagnostic potential of GHSR/MAL. These findings underline the diagnostic potential of the marker panel GHSR/MAL for future bladder cancer diagnostics.© 2022. The Author(s).",
-,No,20220214,prediction,36008412,Methylation risk scores are associated with a collection of phenotypes within electronic health record systems,NPJ Genom Med,"Inference of clinical phenotypes is a fundamental task in precision medicine, and has therefore been heavily investigated in recent years in the context of electronic health records (EHR) using a large arsenal of machine learning techniques, as well as in the context of genetics using polygenic risk scores (PRS). In this work, we considered the epigenetic analog of PRS, methylation risk scores (MRS), a linear combination of methylation states. Since methylation states are influenced by both environmental and genetic factors, we hypothesized that MRS would complement PRS and EHR-based machine-learning methods, improving overall prediction accuracy. To evaluate this hypothesis, we performed the largest assessment of methylation risk scores in clinical datasets to be conducted to date. We measured methylation across a large cohort (n=831) of diverse samples in the UCLA Health biobank, for which both genetic and complete EHR data are available. We constructed MRS for 607 phenotypes spanning diagnoses, clinical lab tests, and medication prescriptions. When added to a baseline set of predictive features, MRS significantly improved the imputation of 139 outcomes, whereas the PRS improved only 22 (median improvement for methylation 10.74%, 141.52%, and 15.46% in medications, labs and diagnosis codes, respectively, whereas genotypes only improved the labs at a median increase of 18.42%). We added significant MRS to state-of-the-art EHR imputation methods that leverage the entire set of medical records, and found that including MRS as a medical feature in the algorithm significantly improves EHR imputation in 37% of lab tests examined (median R2 increase 47.6%). Finally, we replicated several MRS in multiple external studies of methylation (minimum p-value of 2.72 × 10?7) and replicated 22 of 30 tested MRS internally in two separate cohorts of different ethnicity. In summary, our work provides a comprehensive evaluation of MRS in comparison to PRS and EHR imputation on the largest dataset consisting of methylation, genotype, and EHR data. Our publicly available results and weights show promise for methylation risk scores as clinical and scientific tools.",
-,No,20220214,review,35079149,Seven technologies to watch in 2022.,Nature,NA,
-,No,20220228,cell types,35142607,Human embryoid bodies as a novel system for genomic studies of functionally diverse cell types.,Elife,"Practically all studies of gene expression in humans to date have been performed in a relatively small number of adult tissues. Gene regulation is highly dynamic and context-dependent. In order to better understand the connection between gene regulation and complex phenotypes, including disease, we need to be able to study gene expression in more cell types, tissues, and states that are relevant to human phenotypes. In particular, we need to characterize gene expression in early development cell types, as mutations that affect developmental processes may be of particular relevance to complex traits. To address this challenge, we propose to use embryoid bodies (EBs), which are organoids that contain a multitude of cell types in dynamic states. EBs provide a system in which one can study dynamic regulatory processes at an unprecedentedly high resolution. To explore the utility of EBs, we systematically explored cellular and gene expression heterogeneity in EBs from multiple individuals. We characterized the various cell types that arise from EBs, the extent to which they recapitulate gene expression in vivo, and the relative contribution of technical and biological factors to variability in gene expression, cell composition, and differentiation efficiency. Our results highlight the utility of EBs as a new model system for mapping dynamic inter-individual regulatory differences in a large variety of cell types.© 2022, Rhodes et al.",
-,No,20220228,dnam age,35189945,Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock.,Genome Biol,"A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored.Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women's IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer.Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk.© 2022. The Author(s).",
-,No,20220228,dnam age,35181865,Integrating DNA Methylation Measures of Biological Aging into Social Determinants of Health Research.,Curr Environ Health Rep,"Acceleration of biological processes of aging is hypothesized to drive excess morbidity and mortality in socially disadvantaged populations. DNA methylation measures of biological aging provide tools for testing this hypothesis.Next-generation DNA methylation measures of biological aging developed to predict mortality risk and physiological decline are more predictive of morbidity and mortality than the original epigenetic clocks developed to predict chronological age. These new measures show consistent evidence of more advanced and faster biological aging in people exposed to socioeconomic disadvantage and may be able to record the emergence of socially determined health inequalities as early as childhood. Next-generation DNA methylation measures of biological aging also indicate race/ethnic disparities in biological aging. More research is needed on these measures in samples of non-Western and non-White populations. New DNA methylation measures of biological aging open opportunities for refining inference about the causes of social disparities in health and devising policies to eliminate them. Further refining measures of biological aging by including more diversity in samples used for measurement development is a critical priority for the field.© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.",
-,No,20220228,early detection,35164838,Novel epigenetic network biomarkers for early detection of esophageal cancer.,Clin Epigenetics,"Early detection of esophageal cancer is critical to improve survival. Whilst studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity.Here we applied systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from esophageal adenocarcinoma (EAC) patients and matched normal-adjacent tissue, in order to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity. We identify 12 gene-modules that are epigenetically deregulated in EAC, and are able to validate all 12 modules in 4 independent EAC cohorts. We demonstrate that the epigenetic deregulation is present in the epithelial compartment of EAC-tissue. Using single-cell RNA-Seq data we show that one of these modules, a proto-cadherin module centered around CTNND2, is inactivated in Barrett's Esophagus, a precursor lesion to EAC. By measuring DNA methylation in saliva from EAC cases and controls, we identify a chemokine module centered around CCL20, whose methylation patterns in saliva correlate with EAC status.Given our observations that a CCL20 chemokine network is overactivated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be overactivated in EAC tissue infected with the bacterium F. nucleatum, a bacterium that normally inhabits the oral cavity, our results highlight the possibility of using DNAm measurements in saliva as a proxy for changes occurring in the esophageal epithelium. Both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation.© 2022. The Author(s).",
-,No,20220228,epigenetics,35143483,Slow nucleosome dynamics set the transcriptional speed limit and induce RNA polymerase II traffic jams and bursts.,PLoS Comput Biol,"Nucleosomes are recognized as key regulators of transcription. However, the relationship between slow nucleosome unwrapping dynamics and bulk transcriptional properties has not been thoroughly explored. Here, an agent-based model that we call the dynamic defect Totally Asymmetric Simple Exclusion Process (ddTASEP) was constructed to investigate the effects of nucleosome-induced pausing on transcriptional dynamics. Pausing due to slow nucleosome dynamics induced RNAPII convoy formation, which would cooperatively prevent nucleosome rebinding leading to bursts of transcription. The mean first passage time (MFPT) and the variance of first passage time (VFPT) were analytically expressed in terms of the nucleosome rate constants, allowing for the direct quantification of the effects of nucleosome-induced pausing on pioneering polymerase dynamics. The mean first passage elongation rate γ(hc, ho) is inversely proportional to the MFPT and can be considered to be a new axis of the ddTASEP phase diagram, orthogonal to the classical αβ-plane (where α and β are the initiation and termination rates). Subsequently, we showed that, for β = 1, there is a novel jamming transition in the αγ-plane that separates the ddTASEP dynamics into initiation-limited and nucleosome pausing-limited regions. We propose analytical estimates for the RNAPII density �, average elongation rate v, and transcription flux J and verified them numerically. We demonstrate that the intra-burst RNAPII waiting times tin follow the time-headway distribution of a max flux TASEP and that the average inter-burst interval [Formula: see text] correlates with the index of dispersion De. In the limit γ→0, the average burst size reaches a maximum set by the closing rate hc. When α≪1, the burst sizes are geometrically distributed, allowing large bursts even while the average burst size [Formula: see text] is small. Last, preliminary results on the relative effects of static and dynamic defects are presented to show that dynamic defects can induce equal or greater pausing than static bottle necks.",
-,Yes,20220228,ewas,35213289,Pharmacoepigenetics of hypertension: genome-wide methylation analysis of responsiveness to four classes of antihypertensive drugs using a double-blind crossover study design.,Epigenetics,"Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-relatedACY3gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to theACY3TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (https://clinicaltrials.gov/ct2/show/NCT03276598; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (https://clinicaltrials.gov/ct2/show/NCT00338260; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P < 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to theACY3TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P < 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to theACY3TSS may support the role ofACY3genetic and epigenetic variation in BP response to bisoprolol.",
-,Yes,20220228,ewas,35207690,"DNA Methylation and Asthma Acquisition during Adolescence and Post-Adolescence, an Epigenome-Wide Longitudinal Study.",J Pers Med,"The role of epigenetics in the pathogenesis of asthma acquisition in adolescence and post-adolescence has been unknown. We carried out a longitudinal epigenome-wide association study, using data from the Isle of Wight Birth Cohort (IOWBC). To improve statistical power, we first screened CpGs based on associations of DNA methylation (DNAm) at an age of 10 years (pre-adolescence) with asthma acquisition at 10-18 years (during adolescence). A logistic regression with repeated measures was applied to CpGs that passed screening to examine the associations of pre-adolescence DNAm with asthma acquisition from 10-18 years and 18-26 years, with an interaction term to evaluate transition period specificity. Findings were further tested in an independent birth cohort, ALSPAC. In total, 205 CpGs (with 150 being females) showed associations with asthma acquisition (main or interaction effects) at FDR = 0.05 in IOWBC, of which 112 (90 being females) showed consistent associations in the ALSPAC. Genes that the identified CpGs were mapped to, e.g.,AKAP1andENO1, have been shown to be associated with the risk of asthma. Our findings indicated that DNAm at specific CpGs was associated with asthma acquisition. CpGs showing such associations were likely to be different between males and females and, at certain CpGs, were unique to a specific transition period.",
-,Yes,20220228,ewas,35205218,Variation in Genotype and DNA Methylation Patterns Based on Alcohol Use and CVD in the Korean Genome and Epidemiology Study (KoGES).,Genes (Basel),"Alcohol consumption can increase the risk of chronic diseases, such as myocardial infarction, coronary artery disease, hyperlipidemia, and hypertension. We aimed to assess the association between genotype, DNA methylation patterns, alcohol consumption, and chronic diseases in Korean population. We analyzed 8840 subjects for genotypes and 446 for DNA methylation among the 9351 subjects from the Korean Genome and Epidemiology Study (KoGES). We further divided both groups into two sub-groups according to the presence/absence of chronic diseases. We selected genes whose methylation varied significantly with alcohol consumption, and visualized genotype and DNA methylation patterns specific to each group. Genome-wide association study (GWAS) revealed single nucleotide polymorphisms (SNPs)rs2074356andrs11066280in HECT domain E3 ubiquitin protein ligase 4 (HECTD4) to be significantly associated with alcohol consumption in both the presence. Thers12229654genotype also displayed significantly different patterns with alcohol consumption. Furthermore, we retrieved differentially methylated regions (DMRs) from four groups based on sex and chronic diseases and compared them by drinking status. In genotype analysis, cardiovascular diseases (CVDs) showed a higher proportion in drinker than in non-drinker, but not in DMR analysis. Additionally, we analyzed the enriched Gene Ontology terms and Kyoto Gene and Genome Encyclopedia (KEGG) pathways and visualized the network, heatmap, and upset plot. We show that the pattern of DNA methylation associated with CVD is strongly influenced by alcoholism. Overall, this study identified genetic and epigenetic variants influenced by alcohol consumption and chronic diseases.",
-,Yes,20220228,ewas,35196023,"Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.",Sci Transl Med,"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.",
-,Yes,20220228,ewas,35177594,Epigenome-wide association study of posttraumatic stress disorder identifies novel loci in U.S. military veterans.,Transl Psychiatry,"Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder prevalent in military veterans. Epigenetic mechanisms have been implicated in the etiology of PTSD, with DNA methylation being the most studied to identify novel molecular biomarkers associated with this disorder. We performed one of the largest single-sample epigenome-wide association studies (EWAS) of PTSD to date. Our sample included 1135 male European-American U.S. veterans who participated in the National Health and Resilience in Veterans Study (NHRVS). DNA was collected from saliva samples and the Illumina HumanMethylation EPIC BeadChip was used for the methylation analysis. PTSD was assessed using the PTSD Checklist. An EWAS was conducted using linear regression adjusted for age, cell-type proportions, first 10 principal components, and smoking status. After Bonferroni correction, we identified six genome-wide significant (GWS) CpG sites associated with past-month PTSD and three CpGs with lifetime PTSD (prange = 10-10-10-8). These CpG sites map to genes involved in immune function, transcription regulation, axonal guidance, cell signaling, and protein binding. Among these, SENP7, which is involved in transcription regulation and has been linked to risk-taking behavior and alcohol consumption in genome-wide association studies, replicated in an independent veteran cohort and was downregulated in medial orbitofrontal cortex of PTSD postmortem brain tissue. These findings suggest potential epigenetic biomarkers of PTSD that may help inform the pathophysiology of this disorder in veterans and other trauma-affected populations.© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
-,Yes,20220228,ewas,35169870,Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts.,Diabetologia,"Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts.We conducted a meta-analysis of EWASs in blood collected 7-10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK).The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values <1.1 × 10-7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation.By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development.© 2022. The Author(s).",
-,Yes,20220228,ewas,35163587,Genome-Wide DNA Methylation in Policemen Working in Cities Differing by Major Sources of Air Pollution.,Int J Mol Sci,"DNA methylation is the most studied epigenetic mechanism that regulates gene expression, and it can serve as a useful biomarker of prior environmental exposure and future health outcomes. This study focused on DNA methylation profiles in a human cohort, comprising 125 nonsmoking city policemen (sampled twice), living and working in three localities (Prague, Ostrava and Ceske Budejovice) of the Czech Republic, who spent the majority of their working time outdoors. The main characterization of the localities, differing by major sources of air pollution, was defined by the stationary air pollution monitoring of PM2.5, B[a]P and NO2. DNA methylation was analyzed by a genome-wide microarray method. No season-specific DNA methylation pattern was discovered; however, we identified 13,643 differentially methylated CpG loci (DML) for a comparison between the Prague and Ostrava groups. The most significant DML was cg10123377 (log2FC = -1.92,p= 8.30 Ă— 10-4) and loci annotated toRPTOR(total 20 CpG loci). We also found two hypomethylated loci annotated to the DNA repair geneXRCC5.Groups of DML annotated to the same gene were linked to diabetes mellitus (KCNQ1), respiratory diseases (PTPRN2), the dopaminergic system of the brain and neurodegenerative diseases (NR4A2). The most significant possibly affected pathway was Axon guidance, with 86 potentially deregulated genes near DML. The cluster of gene sets that could be affected by DNA methylation in the Ostrava groups mainly includes the neuronal functions and biological processes of cell junctions and adhesion assembly. The study demonstrates that the differences in the type of air pollution between localities can affect a unique change in DNA methylation profiles across the human genome.",
-,Yes,20220228,ewas,35169479,Immune cell type and DNA methylation vary with reproductive status in women: possible pathways for costs of reproduction.,Evol Med Public Health,"Consistent with evolutionarily theorized costs of reproduction (CoR), reproductive history in women is associated with life expectancy and susceptibility to certain cancers, autoimmune disorders and metabolic disease. Immunological changes originating during reproduction may help explain some of these relationships.To explore the potential role of the immune system in female CoR, we characterized leukocyte composition and regulatory processes using DNA methylation (DNAm) in a cross-sectional cohort of young (20-22 years old) women differing in reproductive status.Compared to nulliparity, pregnancy was characterized by differential methylation at 828 sites, 96% of which were hypomethylated and enriched for genes associated with T-cell activation, innate immunity, pre-eclampsia and neoplasia. Breastfeeding was associated with differential methylation at 1107 sites (71% hypermethylated), enriched for genes involved in metabolism, immune self-recognition and neurogenesis. There were no significant differences in DNAm between nulliparous and parous women. However, compared to nullipara, pregnant women had lower proportions of B, CD4T, CD8T and natural killer (NK) cells, and higher proportions of granulocytes and monocytes. Monocyte counts were lower and NK counts higher among breastfeeding women, and remained so among parous women.Our findings point to widespread differences in DNAm during pregnancy and lactation. These effects appear largely transient, but may accumulate with gravidity become detectable as women age. Nulliparous and parous women differed in leukocyte composition, consistent with more persistent effects of reproduction on cell type. These findings support transient (leukocyte DNAm) and persistent (cell composition) changes associated with reproduction in women, illuminating potential pathways contributing to CoR.Lay Summary:Evolutionary theory and epidemiology support costs of reproduction (CoR) to women's health that may involve changes in immune function. We report differences in immune cell composition and gene regulation during pregnancy and breastfeeding. While many of these differences appear transient, immune cell composition may remain, suggesting mechanisms for female CoR.© The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.",
-,No,20220228,methods,35156895,Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies.,Epigenetics,"Biomedical research has grown increasingly cooperative through the sharing of consortia-level epigenetic data. Since consortia preprocess data prior to distribution, new processing pipelines can lead to different versions of the same dataset. Similarly, analytic frameworks evolve to incorporate cutting-edge methods and best practices. However, it remains unknown how different data and analytic versions alter the results of epigenome-wide analyses, which could influence the replicability of epigenetic associations. Thus, we assessed the impact of these changes using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We analysed DNA methylation from two data versions, processed using separate preprocessing and analytic pipelines, examining associations between seven childhood adversities or prenatal smoking exposure and DNA methylation at age 7. We performed two sets of analyses: (1) epigenome-wide association studies (EWAS); (2) Structured Life Course Modelling Approach (SLCMA), a two-stage method that models time-dependent effects. SLCMA results were also compared across two analytic versions. Data version changes impacted both EWAS and SLCMA analyses, yielding different associations at conventional p-value thresholds. However, the magnitude and direction of associations was generally consistent between data versions, regardless of p-values. Differences were especially apparent in analyses of childhood adversity, while smoking associations were more consistent using significance thresholds. SLCMA analytic versions similarly altered top associations, but time-dependent effects remained concordant. Alterations to data and analytic versions influenced the results of epigenome-wide analyses. Our findings highlight that magnitude and direction are better measures for replication and stability than p-value thresholds.",
-,No,20220228,methods,35172880,"Sustained software development, not number of citations or journal choice, is indicative of accurate bioinformatic software.",Genome Biol,"Computational biology provides software tools for testing and making inferences about biological data. In the face of increasing volumes of data, heuristic methods that trade software speed for accuracy may be employed. We have studied these trade-offs using the results of a large number of independent software benchmarks, and evaluated whether external factors, including speed, author reputation, journal impact, recency and developer efforts, are indicative of accurate software.We find that software speed, author reputation, journal impact, number of citations and age are unreliable predictors of software accuracy. This is unfortunate because these are frequently cited reasons for selecting software tools. However, GitHub-derived statistics and high version numbers show that accurate bioinformatic software tools are generally the product of many improvements over time. We also find an excess of slow and inaccurate bioinformatic software tools, and this is consistent across many sub-disciplines. There are few tools that are middle-of-road in terms of accuracy and speed trade-offs.Our findings indicate that accurate bioinformatic software is primarily the product of long-term commitments to software development. In addition, we hypothesise that bioinformatics software suffers from publication bias. Software that is intermediate in terms of both speed and accuracy may be difficult to publish-possibly due to author, editor and reviewer practises. This leaves an unfortunate hole in the literature, as ideal tools may fall into this gap. High accuracy tools are not always useful if they are slow, while high speed is not useful if the results are also inaccurate.© 2022. The Author(s).",
-,No,20220228,prediction,35124428,The independent prognostic value of global epigenetic alterations: An analysis of single-cell ATAC-seq of circulating leukocytes from trauma patients followed by validation in whole blood leukocyte transcriptomes across three etiologies of critical illness.,EBioMedicine,"While bulk and single cell transcriptomic patterns in circulating leukocytes from trauma patients have been reported, how these relate to changes in open chromatin patterns remain unstudied. Here, we investigated whether single-cell ATAC-seq would provide further resolution of transcriptomic patterns that align with patient outcomes.We performed scATAC-seq on peripheral blood mononuclear cells from four trauma patients at <4 h, 24 h, 72 h post-injury and four matched healthy controls, and extracted the features associated with the global epigenetic alterations. Three large-scale bulk transcriptomic datasets from trauma, burn and sepsis patients were used to validate the scATAC-seq derived signature, explore patient epigenetic heterogeneity (Epigenetic Groups: EG_hi vs. EG_lo), and associate patterns with clinical outcomes in critical illness.Patient subsets with gene expression patterns in blood leukocytes representative of a high global epigenetic signature (EG_hi) had worse outcomes across three etiologies of critical illness. EG_hi designation contributed independent of the known immune leukocyte transcriptomic responses to patient prognosis (Trauma: HR=0.62 [95% CI: 0.43-0.89, event set as recovery], p=0.01, n=167; Burns: HR=4.35 [95% CI: 0.816-23.2, event set as death], p=0.085, n=121; Sepsis: HR=1.60 [95% CI: 1.10-2.33, event set as death], p=0.013, n=479; Cox proportional hazards regression).The inclusion of gene expression patterns that associate with global epigenetic changes in circulating leukocytes improves the resolution of transcriptome-based patient classification in acute critical illnesses. Early detection of both the global epigenetic signature and the known immune transcriptomic patterns associates with the worse prognosis in trauma, burns and sepsis.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.",
-,No,20220228,prediction,35169688,Machine learning for multi-omics data integration in cancer.,iScience,"Multi-omics data analysis is an important aspect of cancer molecular biology studies and has led to ground-breaking discoveries. Many efforts have been made to develop machine learning methods that automatically integrate omics data. Here, we review machine learning tools categorized as either general-purpose or task-specific, covering both supervised and unsupervised learning for integrative analysis of multi-omics data. We benchmark the performance of five machine learning approaches using data from the Cancer Cell Line Encyclopedia, reporting accuracy on cancer type classification and mean absolute error on drug response prediction, and evaluating runtime efficiency. This review provides recommendations to researchers regarding suitable machine learning method selection for their specific applications. It should also promote the development of novel machine learning methodologies for data integration, which will be essential for drug discovery, clinical trial design, and personalized treatments.© 2022 The Author(s).",
-,No,20220228,review,35170363,Evaluating the challenges and reproducibility of studies investigating DNA methylation signatures of psychological stress.,Epigenomics,"Psychological stress can increase the risk of a wide range of negative health outcomes. Studies have been completed to determine if DNA methylation changes occur in the human brain because of stress and are associated with long-term effects and disease, but results have been inconsistent. Human candidate gene studies (150) and epigenome-wide association studies (68) were systematically evaluated to assess how DNA methylation is impacted by stress during the prenatal period, early childhood and adulthood. The association between DNA methylation ofNR3C1exon 1F and child maltreatment and early life adversity was well demonstrated, but other genes did not exhibit a clear association. The reproducibility of individual CpG sites in epigenome-wide association studies was also poor. However, biological pathways, including stress response, brain development and immunity, have been consistently identified across different stressors throughout the life span. Future studies would benefit from the increased sample size, longitudinal design, standardized methodology, optimal quality control, and improved statistical procedures.",
-,No,20220228,sex differences,35177097,Gender-affirming hormone therapy induces specific DNA methylation changes in blood.,Clin Epigenetics,"DNA methylation is an epigenetic mark that is influenced by underlying genetic profile, environment, and ageing. In addition to X-linked DNA methylation, sex-specific methylation patterns are widespread across autosomal chromosomes and can be present from birth or arise over time. In individuals where gender identity and sex assigned at birth are markedly incongruent, as in the case of transgender people, feminization or masculinization may be sought through gender-affirming hormone therapy (GAHT). GAHT is a cornerstone of transgender care, yet no studies to date have investigated its effect on genome-wide methylation. We profiled genome-wide DNA methylation in blood of transgender women (n = 13) and transgender men (n = 13) before and during GAHT (6 months and 12 months into feminizing or masculinizing hormone therapy).We identified several thousand differentially methylated CpG sites (DMPs) (Δβ ≥ 0.02, unadjusted p value < 0.05) and several differentially methylated regions (DMRs) in both people undergoing feminizing and masculinizing GAHT, the vast majority of which were progressive changes over time. X chromosome and sex-specific autosomal DNA methylation patterns established in early development are largely refractory to change in association with GAHT, with only 3% affected (Δβ ≥ 0.02, unadjusted p value < 0.05). The small number of sex-specific DMPs that were affected by GAHT were those that become sex-specific during the lifetime, known as sex-and-age DMPs, including DMRs in PRR4 and VMP1 genes. The GAHT-induced changes at these sex-associated probes consistently demonstrated a shift towards the methylation signature of the GAHT-naïve opposite sex, and we observed enrichment of previously reported adolescence-associated methylation changes.We provide evidence for GAHT inducing a unique blood methylation signature in transgender people. This study advances our understanding of the complex interplay between sex hormones, sex chromosomes, and DNA methylation in the context of immunity. We highlight the need to broaden the field of 'sex-specific' immunity beyond cisgender males and cisgender females, as transgender people on GAHT exhibit a unique molecular profile.© 2022. The Author(s).",
-,No,20220314,dnam age,35255955,Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns.,Epigenetics Chromatin,"The epigenetic age can now be extrapolated from one of several epigenetic clocks, which are based on age-related changes in DNA methylation levels at specific multiple CpG sites. Accelerated aging, calculated from the discrepancy between the chronological age and the epigenetic age, has shown to predict morbidity and mortality rate. We assumed that deconvolution of epigenetic age to its components could shed light on the diversity of epigenetic, and by inference, on inter-individual variability in the causes of biological aging.Using the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the inter-personal variability in epigenetic aging, with CpG sites related to secretagogin and malin being the most variable. We show that equal epigenetic age in different subjects can result from variable contribution size of the same CpG sites to the total epigenetic age. In a healthy cohort, the most variable CpG sites are responsible for accelerated and decelerated epigenetic aging, relative to chronological age.Of the 353 CpG sites that form the basis for the Horvath epigenetic age, we have found the CpG sites that are responsible for accelerated and decelerated epigenetic aging in healthy subjects. However, the relative contribution of each site to aging varies between individuals, leading to variable personal aging patterns. Our findings pave the way to form personalized aging cards allowing the identification of specific genes related to CpG sites, as aging markers, and perhaps treatment of these targets in order to hinder undesirable age drifting.© 2022. The Author(s).",
-,No,20220314,epigenetics,35157611,Ribosomal DNA methylation in human and mouse oocytes increases with age.,Aging (Albany NY),"An age-dependent increase in ribosomal DNA (rDNA) methylation has been observed across a broad spectrum of somatic tissues and the male mammalian germline. Bisulfite pyrosequencing (BPS) was used to determine the methylation levels of the rDNA core promoter and the rDNA upstream control element (UCE) along with two oppositely genomically imprinted control genes (PEG3andGTL2) in individual human germinal vesicle (GV) oocytes from 90 consenting women undergoing fertility treatment because of male infertility. Apart from a few (4%) oocytes with single imprinting defects (in eitherPEG3orGTL2), the analyzed GV oocytes displayed correct imprinting patterns. In 95 GV oocytes from 42 younger women (26-32 years), the mean methylation levels of the rDNA core promoter and UCE were 7.4±4.0% and 9.3±6.1%, respectively. In 79 GV oocytes from 48 older women (33-39 years), methylation levels increased to 9.3±5.3% (P= 0.014) and 11.6±7.4% (P= 0.039), respectively. An age-related increase in oocyte rDNA methylation was also observed in 123 mouse GV oocytes from 29 4-16-months-old animals. Similar to the continuously mitotically dividing male germline, ovarian aging is associated with a gain of rDNA methylation in meiotically arrested oocytes. Oocytes from the same woman can exhibit varying rDNA methylation levels and, by extrapolation, different epigenetic ages.",
-,No,20220314,epigenetics,35166834,"DNA methylation cues in nucleosome geometry, stability and unwrapping.",Nucleic Acids Res,"Cytosine methylation at the 5-carbon position is an essential DNA epigenetic mark in many eukaryotic organisms. Although countless structural and functional studies of cytosine methylation have been reported, our understanding of how it influences the nucleosome assembly, structure, and dynamics remains obscure. Here, we investigate the effects of cytosine methylation at CpG sites on nucleosome dynamics and stability. By applying long molecular dynamics simulations on several microsecond time scale, we generate extensive atomistic conformational ensembles of full nucleosomes. Our results reveal that methylation induces pronounced changes in geometry for both linker and nucleosomal DNA, leading to a more curved, under-twisted DNA, narrowing the adjacent minor grooves, and shifting the population equilibrium of sugar-phosphate backbone geometry. These DNA conformational changes are associated with a considerable enhancement of interactions between methylated DNA and the histone octamer, doubling the number of contacts at some key arginines. H2A and H3 tails play important roles in these interactions, especially for DNA methylated nucleosomes. This, in turn, prevents a spontaneous DNA unwrapping of 3-4 helical turns for the methylated nucleosome with truncated histone tails, otherwise observed in the unmethylated system on several microseconds time scale.Published by Oxford University Press on behalf of Nucleic Acids Research 2022.",
-,No,20220314,epigenetics,35256817,"Means, mechanisms and consequences of adenine methylation in DNA.",Nat Rev Genet,"N6-methyl-2'-deoxyadenosine (6mA or m6dA) has been reported in the DNA of prokaryotes and eukaryotes ranging from unicellular protozoa and algae to multicellular plants and mammals. It has been proposed to modulate DNA structure and transcription, transmit information across generations and have a role in disease, among other functions. However, its existence in more recently evolved eukaryotes remains a topic of debate. Recent technological advancements have facilitated the identification and quantification of 6mA even when the modification is exceptionally rare, but each approach has limitations. Critical assessment of existing data, rigorous design of future studies and further development of methods will be required to confirm the presence and biological functions of 6mA in multicellular eukaryotes.© 2022. Springer Nature Limited.",
-,No,20220314,ewas,35232984,Preterm birth buccal cell epigenetic biomarkers to facilitate preventative medicine.,Sci Rep,"Preterm birth is the major cause of newborn and infant mortality affecting nearly one in every ten live births. The current study was designed to develop an epigenetic biomarker for susceptibility of preterm birth using buccal cells from the mother, father, and child (triads). An epigenome-wide association study (EWAS) was used to identify differential DNA methylation regions (DMRs) using a comparison of control term birth versus preterm birth triads. Epigenetic DMR associations with preterm birth were identified for both the mother and father that were distinct and suggest potential epigenetic contributions from both parents. The mother (165 DMRs) and female child (136 DMRs) at p < 1e-04 had the highest number of DMRs and were highly similar suggesting potential epigenetic inheritance of the epimutations. The male child had negligible DMR associations. The DMR associated genes for each group involve previously identified preterm birth associated genes. Observations identify a potential paternal germline contribution for preterm birth and identify the potential epigenetic inheritance of preterm birth susceptibility for the female child later in life. Although expanded clinical trials and preconception trials are required to optimize the potential epigenetic biomarkers, such epigenetic biomarkers may allow preventative medicine strategies to reduce the incidence of preterm birth.© 2022. The Author(s).",
-,Yes,20220314,ewas,35236238,Maternal Mediterranean diet in pregnancy and newborn DNA methylation: a meta-analysis in the PACE Consortium.,Epigenetics,"Higher adherence to the Mediterranean diet during pregnancy is related to a lower risk of preterm birth and to better offspring cardiometabolic health. DNA methylation may be an underlying biological mechanism. We evaluated whether maternal adherence to the Mediterranean diet was associated with offspring cord blood DNA methylation.We meta-analysed epigenome-wide association studies (EWAS) of maternal adherence to the Mediterranean diet during pregnancy and offspring cord blood DNA methylation in 2802 mother-child pairs from five cohorts. We calculated the relative Mediterranean diet (rMED) score with range 0-18 and an adjusted rMED excluding alcohol (rMEDp, range 0-16). DNA methylation was measured using Illumina 450K arrays. We used robust linear regression modelling adjusted for child sex, maternal education, age, smoking, body mass index, energy intake, batch, and cell types. We performed several functional analyses and examined the persistence of differential DNA methylation into childhood (4.5-7.8 y).rMEDp was associated with cord blood DNA methylation at cg23757341 (0.064% increase in DNA methylation per 1-point increase in the rMEDp score, SE = 0.011,P= 2.41 × 10-8). This cytosine-phosphate-guanine (CpG) site maps toWNT5B, associated with adipogenesis and glycaemic phenotypes. We did not identify associations with childhood gene expression, nor did we find enriched biological pathways. The association did not persist into childhood.In this meta-analysis, maternal adherence to the Mediterranean diet (excluding alcohol) during pregnancy was associated with cord blood DNA methylation level at cg23757341. Potential mediation of DNA methylation in associations with offspring health requires further study.",
-,Yes,20220314,ewas,35236959,Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus.,Mol Psychiatry,"Antipsychotic drugs are the current first-line of treatment for schizophrenia and other psychotic conditions. However, their molecular effects on the human brain are poorly studied, due to difficulty of tissue access and confounders associated with disease status. Here we examine differences in gene expression and DNA methylation associated with positive antipsychotic drug toxicology status in the human caudate nucleus. We find no genome-wide significant differences in DNA methylation, but abundant differences in gene expression. These gene expression differences are overall quite similar to gene expression differences between schizophrenia cases and controls. Interestingly, gene expression differences based on antipsychotic toxicology are different between brain regions, potentially due to affected cell type differences. We finally assess similarities with effects in a mouse model, which finds some overlapping effects but many differences as well. As a first look at the molecular effects of antipsychotics in the human brain, the lack of epigenetic effects is unexpected, possibly because long term treatment effects may be relatively stable for extended periods.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20220314,ewas,35237685,Does DNA methylation mediate the association of age at puberty with forced vital capacity or forced expiratory volume in 1 s?,ERJ Open Res,"Age of pubertal onset is associated with lung function in adulthood. However, the underlying role of epigenetics as a mediator of this association remains unknown.DNA methylation (DNAm) in peripheral blood was measured at age 18 years in the Isle of Wight birth cohort (IOWBC) along with data on age of pubertal events, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) at 26 years. Structural equation models were applied to examine mediation effects of DNAm on the association of age at pubertal events with FVC and FEV1. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.In the IOWBC, for females, 21 cytosine-phosphate-guanine sites (CpGs) were shown to mediate the association of age at puberty with FVC or FEV1at 26 years (p<0.05). In males, DNAm at 20 CpGs was found to mediate the association of age at puberty with FVC (p<0.05). At almost all these CpGs, indirect effects (effects of age at pubertal events on FVC or FEV1viaDNAm) contributed a smaller portion to the total effects compared to direct effects (e.g.at cg08680129, �22% of the estimated total effect of age at menarche on FVC at age 26 was contributed by an indirect effect). Among the IOWBC-discovered CpGs available in ALSPAC, none of them was replicated in ALSPAC (p>0.05).Our findings suggest that post-adolescence DNAm in peripheral blood is likely not to mediate the association of age at pubertal onset with young adulthood FVC or FEV1.Copyright ©The authors 2022.",
-,Yes,20220314,ewas,35237744,Periconception and Prenatal Exposure to Maternal Perceived Stress and Cord Blood DNA Methylation.,Epigenet Insights,"Maternal prenatal stress is associated with physiologic and adverse mental health outcomes in the offspring, but the underlying biologic mechanisms are unknown. We examined the associations of maternal perceived stress, including preconception exposure, with DNA methylation (DNAm) alterations in the cord blood buffy coats of 358 singleton infants.Maternal perceived stress was measured prior to and throughout pregnancy in a cohort of women enrolled in Effects of Aspirin in Gestation and Reproduction Trial (EAGeR) trial. Perceived stress assessments based on a standardized Likert-scale were obtained in periconception (~2 months preconception and 2-8 weeks of gestation) and pregnancy (8-36 weeks of gestation). Cumulative perceived stress was estimated by calculating the predicted area under the curve of stress reported prior to and during pregnancy. DNAm was measured by the Infinium MethylationEPIC BeadChip. Multivariable robust linear regression was used to assess associations of perceived stress with individual CpG probes.Based on a 0 to 3 scale, average reported preconception and early pregnancy stress were 0.76 (0.60) and 0.67 (0.50), respectively. Average mid- to late-pregnancy stress, based on a 0 to 10 scale, was 4.9 (1.6). Neither periconception nor pregnancy perceived stress were associated with individual CpG sites in neonatal cord blood (all false discovery rate [FDR] >5%).No effects of maternal perceived stress exposure on array-wide cord blood neonatal methylation differences were found.© The Author(s) 2022.",
-,No,20220314,ewas,35242787,Role of Age-Related Changes in DNA Methylation in the Disproportionate Susceptibility and Worse Outcomes of Sepsis in Older Adults.,Front Med (Lausanne),"Sepsis, a complex multisystem disorder, is among the top causes of hospitalization and mortality in older adults. However, the mechanisms underlying the disproportionate susceptibility to sepsis and worse outcomes in the elderly are not well understood. Recently, changes in DNA methylation have been shown to be linked to aging processes and age-related diseases. Thus, we postulated that age-related changes in DNA methylation may play a role in the onset and prognosis of sepsis in elderly patients. Here, we performed genome-wide methylation profiling of peripheral blood from patients with sepsis and controls. Among the CpG sites whose methylation changes may contribute to an increase in sepsis susceptibility or mortality, 241 sites that possessed age-related changes in DNA methylation in controls may partly explain the increased risk of sepsis in older adults, and 161 sites whose methylation significantly correlated with age in sepsis group may be the potential mechanisms underlying the worse outcomes of elderly septic patients. Finally, an independent cohort was used to validate our findings. Together, our study demonstrates that age-related changes in DNA methylation may explain in part the disproportionate susceptibility and worse outcomes of sepsis in older adults.Copyright © 2022 Lang, Shen, Zhu, Zhao, Chen, Zhu, Su, Wang, Wang, Neri, Jiang and Chen.",
-,No,20220314,ewas,35243180,Differential DNA methylation in Black and White individuals with chronic low back pain enrich different genomic pathways.,Neurobiol Pain,"Compared to Non-Hispanic Whites (NHWs), individuals who self-identify as Non-Hispanic Blacks (NHBs) in the United States experience more severe and disabling chronic low back pain (cLBP). We hypothesized that differences in DNA methylation (DNAm) play a role in racial disparities in cLBP.To determine the relationship between DNAm levels and racial group differences in adults with cLBP. Our study's secondary purpose was to perform a race-stratified comparison of adults with cLBP and pain-free controls and identify functional genomic pathways enriched by annotated differentially methylated genes.We recruited 49 NHBs and 49 NHWs (49 cLBP and 49 pain-free controls, PFCs), analyzed DNAm from whole blood using reduced representation bisulfite sequencing, and identified enriched genomic pathways.Among participants with cLBP, we identified 2873 differentially methylated loci (DML; methylation differences of at least 10% and p < 0.0001), many of which were annotated to genes of importance to pain pathology. These DMLs significantly enriched pathways to involved in nociception/pain processing (Dopamine-DARPP32 Feedback in cAMP signaling,GABA Receptor Signaling,Opioid Signaling) and neuronal differentiation (e.g.,Calcium Signaling, Axon Guidance Signaling, andEndocannabinoid Neuronal Synapse). Our race stratified analyses of individuals with cLBP versus PFCs revealed 2356 DMLs in NHBs and 772 DMLs in NHWs with p < 0.0001 and > 10% methylation difference. Ingenuity Pathway Analysis revealed that many pathways of significance to pain such asCorticotropin Releasing Hormone Signaling, White Adipose Tissue Browning,andGABA Receptor Signaling pathways, were more significant in NHBs than NHWs.Even though an individual's self-identified race is a social construct, not a biological variable, racism associated with that classification affects virtually every aspect of life, including disease risk. DNAm induced alterations in stress signaling pathways may explain worse pain outcomes in NHBs.© 2022 The Author(s).",
-,No,20220314,ewas,35245816,Genome-wide DNA methylation profiling identifies epigenetic changes in CD4+ and CD14+ cells of multiple sclerosis patients.,Mult Scler Relat Disord,"Multiple sclerosis (MS) is a chronic autoimmune and degenerative disease of the central nervous system, which develops in genetically predisposed individuals upon exposure to environmental influences. Environmental triggers of MS, such as viral infections or smoking, were demonstrated to affect DNA methylation, and thus to involve this important epigenetic mechanism in the development of pathological process. To identify MS-associated DNA methylation hallmarks, we performed genome-wide DNA methylation profiling of two cell populations (CD4+ T-lymphocytes and CD14+ monocytes), collected from the same treatment-naive relapsing-remitting MS patients and healthy subjects, using Illumina 450 K methylation arrays. We revealed significant changes in DNA methylation for both cell populations in MS. In CD4+ cells of MS patients the majority of differentially methylated positions (DMPs) were shown to be hypomethylated, while in CD14+ cells - hypermethylated. Differential methylation of HLA-DRB1 gene in CD4+ and CD14+ cells was associated with carriage of DRB1*15 allele independently from the disease status. Besides, about 20% of identified DMPs were shared between two cell populations and had the same direction of methylation changes; they may be involved in basic epigenetic processes occuring in MS. These findings suggest that the epigenetic mechanism of DNA methylation in immune cells contributes to MS; further studies are now required to validate these results and understand their functional significance.Copyright © 2022. Published by Elsevier B.V.",
-,Yes,20220314,ewas,35266797,Gestational Perfluoroalkyl Substance Exposure and DNA Methylation at Birth and 12 Years of Age: A Longitudinal Epigenome-Wide Association Study.,Environ Health Perspect,"DNA methylation alterations may underlie associations between gestational perfluoroalkyl substances (PFAS) exposure and later-life health outcomes. To the best of our knowledge, no longitudinal studies have examined the associations between gestational PFAS and DNA methylation.We examined associations of gestational PFAS exposure with longitudinal DNA methylation measures at birth and in adolescence using the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006; Cincinnati, Ohio).We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in mothers during pregnancy. We measured DNA methylation in cord blood (n=266) and peripheral leukocytes at 12 years of age (n=160) using the Illumina HumanMethylation EPIC BeadChip. We analyzed associations betweenlog2-transformedPFAS concentrations and repeated DNA methylation measures using linear regression with generalized estimating equations. We included interaction terms between children's age and gestational PFAS. We performed Gene Ontology enrichment analysis to identify molecular pathways. We used Project Viva (1999-2002; Boston, Massachusetts) to replicate significant associations.After adjusting for covariates, 435 cytosine-guanine dinucleotide (CpG) sites were associated with PFAS (false discovery rate,q<0.05). Specifically, we identified 2 CpGs for PFOS, 12 for PFOA, 8 for PFHxS, and 413 for PFNA; none overlapped. Among these, 2 CpGs for PFOA and 4 for PFNA were replicated in Project Viva. Some of the PFAS-associated CpG sites annotated to gene regions related to cancers, cognitive health, cardiovascular disease, and kidney function. We found little evidence that the associations between PFAS and DNA methylation differed by children's age.In these longitudinal data, PFAS biomarkers were associated with differences in several CpGs at birth and at 12 years of age in or near genes linked to some PFAS-associated health outcomes. Future studies should examine whether DNA methylation mediates associations between gestational PFAS exposure and health. https://doi.org/10.1289/EHP10118.",
-,No,20220314,meqtl,35247911,Genetic regulation of DNA methylation yields novel discoveries in GWAS of colorectal cancer.,Cancer Epidemiol Biomarkers Prev,"Colorectal cancer (CRC) has a strong epigenetic component that is accompanied by frequent DNA methylation (DNAm) alterations in addition to heritable genetic risk. It is of interest to understand the interrelationship of germline genetics, DNAm, and CRC risk.We performed a genome-wide methylation quantitative trait locus (meQTL) analysis in 1355 people, assessing the pairwise associations between genetic variants and lymphocytes methylation data. In addition, we used penalized regression with cis-genetic variants +/- 1Mb of methylation to identify genome-wide heritable DNAm. We evaluated the association of genetically predicted methylation with CRC risk based on GWAS of over 125,000 cases and controls using the multivariate sMiST as well as univariately via examination of marginal association with CRC risk.Of the 142 known CRC genome-wide association studies (GWAS) loci, 47 were identified as meQTLs. We identified 4 novel CRC associated loci (NID2, ATXN10, KLHDC10 and CEP41) that reside over 1Mb outside of known CRC loci and 10 secondary signals within 1Mb of known loci.Leveraging information of DNAm regulation into genetic association of CRC risk reveals novel pathways in CRC tumorigenesis. Our summary statistics-based framework sMiST provides a powerful approach by combining information from the effect through methylation and residual direct effects of the meQTLs on disease risk. Further validation and functional follow-up of these novel pathways are needed.Using genotype, DNA methylation, GWAS, we identified four new CRC risk loci. We studied the landscape of genetic regulation of DNA methylation via single-SNP and multi-SNP meQTL analyses.",
-,No,20220314,methods,35245419,Sparse latent factor regression models for genome-wide and epigenome-wide association studies.,Stat Appl Genet Mol Biol,"Association of phenotypes or exposures with genomic and epigenomic data faces important statistical challenges. One of these challenges is to account for variation due to unobserved confounding factors, such as individual ancestry or cell-type composition in tissues. This issue can be addressed with penalized latent factor regression models, where penalties are introduced to cope with high dimension in the data. If a relatively small proportion of genomic or epigenomic markers correlate with the variable of interest, sparsity penalties may help to capture the relevant associations, but the improvement over non-sparse approaches has not been fully evaluated yet. Here, we present least-squares algorithms that jointly estimate effect sizes and confounding factors in sparse latent factor regression models. In simulated data, sparse latent factor regression models generally achieved higher statistical performance than other sparse methods, including the least absolute shrinkage and selection operator and a Bayesian sparse linear mixed model. In generative model simulations, statistical performance was slightly lower (while being comparable) to non-sparse methods, but in simulations based on empirical data, sparse latent factor regression models were more robust to departure from the model than the non-sparse approaches. We applied sparse latent factor regression models to a genome-wide association study of a flowering trait for the plantArabidopsis thalianaand to an epigenome-wide association study of smoking status in pregnant women. For both applications, sparse latent factor regression models facilitated the estimation of non-null effect sizes while overcoming multiple testing issues. The results were not only consistent with previous discoveries, but they also pinpointed new genes with functional annotations relevant to each application.© 2022 Walter de Gruyter GmbH, Berlin/Boston.",
-,No,20220314,omics,35212264,Getting closer to the clinic.,Elife,Associations between plasma protein levels and DNA methylation patterns can be used to predict the onset of age-related chronic disease.,
-,No,20220314,omics,35220969,A guide for the diagnosis of rare and undiagnosed disease: beyond the exome.,Genome Med,"Rare diseases affect 30 million people in the USA and more than 300-400 million worldwide, often causing chronic illness, disability, and premature death. Traditional diagnostic techniques rely heavily on heuristic approaches, coupling clinical experience from prior rare disease presentations with the medical literature. A large number of rare disease patients remain undiagnosed for years and many even die without an accurate diagnosis. In recent years, gene panels, microarrays, and exome sequencing have helped to identify the molecular cause of such rare and undiagnosed diseases. These technologies have allowed diagnoses for a sizable proportion (25-35%) of undiagnosed patients, often with actionable findings. However, a large proportion of these patients remain undiagnosed. In this review, we focus on technologies that can be adopted if exome sequencing is unrevealing. We discuss the benefits of sequencing the whole genome and the additional benefit that may be offered by long-read technology, pan-genome reference, transcriptomics, metabolomics, proteomics, and methyl profiling. We highlight computational methods to help identify regionally distant patients with similar phenotypes or similar genetic mutations. Finally, we describe approaches to automate and accelerate genomic analysis. The strategies discussed here are intended to serve as a guide for clinicians and researchers in the next steps when encountering patients with non-diagnostic exomes.© 2022. The Author(s).",
-,No,20220314,omics,35241783,Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.,Mol Psychiatry,"Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (Ntotal = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20220314,pqtl,35264221,Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes.,Genome Med,"Blood plasma proteins play an important role in immune defense against pathogens, including cytokine signaling, the complement system, and the acute-phase response. Recent large-scale studies have reported genetic (i.e., protein quantitative trait loci, pQTLs) and non-genetic factors, such as age and sex, as major determinants to inter-individual variability in immune response variation. However, the contribution of blood-cell composition to plasma protein heterogeneity has not been fully characterized and may act as a mediating factor in association studies.Here, we evaluated plasma protein levels from 400 unrelated healthy individuals of western European ancestry, who were stratified by sex and two decades of life (20-29 and 60-69 years), from the Milieu Intérieur cohort. We quantified 229 proteins by Luminex in a clinically certified laboratory and their levels of variation were analyzed together with 5.2 million single-nucleotide polymorphisms. With respect to non-genetic variables, we included 254 lifestyle and biochemical factors, as well as counts of seven circulating immune cell populations measured by hemogram and standardized flow cytometry.Collectively, we found 152 significant associations involving 49 proteins and 20 non-genetic variables. Consistent with previous studies, age and sex showed a global, pervasive impact on plasma protein heterogeneity, while body mass index and other health status variables were among the non-genetic factors with the highest number of associations. After controlling for these covariates, we identified 100 and 12 pQTLs acting in cis and trans, respectively, collectively associated with 87 plasma proteins and including 19 novel genetic associations. Genetic factors explained the largest fraction of the variability of plasma protein levels, as compared to non-genetic factors. In addition, blood-cell fractions, including leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, basophils, and platelets, had a larger contribution to inter-individual variability than age and sex and appeared as confounders of specific genetic associations. Finally, we identified new genetic associations with plasma protein levels of five monogenic Mendelian disease genes including two primary immunodeficiency genes (Ficolin-3 and FAS).Our study identified novel genetic and non-genetic factors associated to plasma protein levels which may inform health status and disease management.© 2022. The Author(s).",
-,No,20220314,prediction,35209953,Evidence of accelerated epigenetic aging of breast tissues in patients with breast cancer is driven by CpGs associated with polycomb-related genes.,Clin Epigenetics,"Age is one of the strongest risk factors for the development of breast cancer, however, the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression.Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls).The Levine (p = 0.0037) and Yang clocks (p = 0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb-related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb-related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p = 0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration.Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb-related genes can be used to assess the risk of developing breast cancer among unaffected individuals.© 2022. The Author(s).",
-,No,20220314,prediction,35225958,Opportunities for Early Cancer Detection: The Rise of ctDNA Methylation-Based Pan-Cancer Screening Technologies.,Epigenomes,"The efficiency of conventional screening programs to identify early-stage malignancies can be limited by the low number of cancers recommended for screening as well as the high cumulative false-positive rate, and associated iatrogenic burden, resulting from repeated multimodal testing. The opportunity to use minimally invasive liquid biopsy testing to screen asymptomatic individuals at-risk for multiple cancers simultaneously could benefit from the aggregated diseases prevalence and a fixed specificity. Increasing both latter parameters is paramount to mediate high positive predictive value-a useful metric to evaluate a screening test accuracy and its potential harm-benefit. Thus, the use of a single test for multi-cancer early detection (stMCED) has emerged as an appealing strategy for increasing early cancer detection rate efficiency and benefit population health. A recent flurry of these stMCED technologies have been reported for clinical potential; however, their development is facing unique challenges to effectively improve clinical cost-benefit. One promising avenue is the analysis of circulating tumour DNA (ctDNA) for detecting DNA methylation biomarker fingerprints of malignancies-a hallmark of disease aetiology and progression holding the potential to be tissue- and cancer-type specific. Utilizing panels of epigenetic biomarkers could potentially help to detect earlier stages of malignancies as well as identify a tumour of origin from blood testing, useful information for follow-up clinical decision making and subsequent patient care improvement. Overall, this review collates the latest and most promising stMCED methodologies, summarizes their clinical performances, and discusses the specific requirements multi-cancer tests should meet to be successfully implemented into screening guidelines.",
-,No,20220411,cancer,35331302,Pan-cancer predictions of transcription factors mediating aberrant DNA methylation.,Epigenetics Chromatin,"Aberrant DNA methylation is a hallmark of cancer cells. However, the mechanisms underlying changes in DNA methylation remain elusive. Transcription factors initially thought to be repressed from binding by DNA methylation, have recently emerged as being able to shape DNA methylation patterns.Here, we integrated the massive amount of data available from The Cancer Genome Atlas to predict transcription factors driving aberrant DNA methylation in 13 cancer types. We identified differentially methylated regions between cancer and matching healthy samples, searched for transcription factor motifs enriched in those regions and selected transcription factors with corresponding changes in gene expression. We predict transcription factors known to be involved in cancer as well as novel candidates to drive hypo-methylated regions such as FOXA1 and GATA3 in breast cancer, FOXA1 and TWIST1 in prostate cancer and NFE2L2 in lung cancer. We also predict transcription factors that lead to hyper-methylated regions upon transcription factor loss such as EGR1 in several cancer types. Finally, we validate that FOXA1 and GATA3 mediate hypo-methylated regions in breast cancer cells.Our work highlights the importance of some transcription factors as upstream regulators shaping DNA methylation patterns in cancer.© 2022. The Author(s).",
-,No,20220411,cancer,35354049,Genome-wide identification and analysis of prognostic features in human cancers.,Cell Rep,"Clinical decisions in cancer rely on precisely assessing patient risk. To improve our ability to identify the most aggressive malignancies, we constructed genome-wide survival models using gene expression, copy number, methylation, and mutation data from 10,884 patients. We identified more than 100,000 significant prognostic biomarkers and demonstrate that these genomic features can predict patient outcomes in clinically ambiguous situations. While adverse biomarkers are commonly believed to represent cancer driver genes and promising therapeutic targets, we show that cancer features associated with shorter survival times are not enriched for either oncogenes or for successful drug targets. Instead, the strongest adverse biomarkers represent widely expressed cell-cycle and housekeeping genes, and, correspondingly, nearly all therapies directed against these features have failed in clinical trials. In total, our analysis establishes a rich resource for prognostic biomarker analysis and clarifies the use of patient survival data in preclinical cancer research and therapeutic development.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.",
-,No,20220411,chromatin,35332326,Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.,Nat Neurosci,"Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104-106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20220411,chromatin,35301427,Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose.,Mol Psychiatry,"Opioid use disorder is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. Opioid overdose, the most severe outcome of opioid use disorder, remains the leading cause of accidental death in the United States. We interrogated the effects of opioid overdose on the brain using ChIP-seq to quantify patterns of H3K27 acetylation in dorsolateral prefrontal cortical neurons isolated from 51 opioid-overdose cases and 51 accidental death controls. Among opioid cases, we observed global hypoacetylation and identified 388 putative enhancers consistently depleted for H3K27ac. Machine learning on H3K27ac patterns predicted case-control status with high accuracy. We focused on case-specific regulatory alterations, revealing 81,399 hypoacetylation events, uncovering vast inter-patient heterogeneity. We developed a strategy to decode this heterogeneity based on convergence analysis, which leveraged promoter-capture Hi-C to identify five genes over-burdened by alterations in their regulatory network or ""plexus"": ASTN2, KCNMA1, DUSP4, GABBR2, ENOX1. These convergent loci are enriched for opioid use disorder risk genes and heritability for generalized anxiety, number of sexual partners, and years of education. Overall, our multi-pronged approach uncovers neurobiological aspects of opioid use disorder and captures genetic and environmental factors perpetuating the opioid epidemic.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20220411,dnam age,35313970,Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer.,Genome Med,"Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.For EAA-Horvath, a genome-wide significant association was mapped to the SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to the HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.We identified novel genetic variants in the SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.© 2022. The Author(s).",
-,No,20220411,dnam age,35346416,Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study.,Elife,"Background:Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.Methods:We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (9 single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs) and GrimAge (4 SNPs) on multiple cancers (i.e., breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N=34,710), and for cancer from the UK Biobank (N cases=2,671-13,879; N controls=173,493-372,016), FinnGen (N cases=719-8,401; N controls=74,685-174,006) and several international cancer genetic consortia (N cases=11,348-122,977; N controls=15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.Results:Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR=1.12 per year increase in GrimAge acceleration, 95%CI 1.04-1.20,p=0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR=1.15, 95%CI 1.09-1.21,p=0.006), than rectal cancer (IVW OR=1.05, 95%CI 0.97-1.13,p=0.24). Results were less consistent for associations between other epigenetic clocks and cancers.Conclusions:GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.Funding:FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.© 2022, Morales Berstein et al.",
-,Yes,20220411,eqtm,35302492,Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood.,Elife,"The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children's blood, using data from 832 children of the Human Early Life Exposome (HELIX) project.Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition.We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGene's TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. In 40.4% of the eQTMs, the CpG and the eGene were both associated with at least one genetic variant. The overlap of autosomal cis eQTMs in children's blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants.This catalogue of autosomal cis eQTMs in children's blood can help the biological interpretation of EWAS findings and is publicly available at https://helixomics.isglobal.org/ and at Dryad (doi:10.5061/dryad.fxpnvx0t0).The study has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project); the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project); from the European Union's Horizon 2020 research and innovation programme under grant agreement no 733206 (LIFECYCLE project), and from the European Joint Programming Initiative ""A Healthy Diet for a Healthy Life"" (JPI HDHL and Instituto de Salud Carlos III) under the grant agreement no AC18/00006 (NutriPROGRAM project). The genotyping was supported by the projects PI17/01225 and PI17/01935, funded by the Instituto de Salud Carlos III and co-funded by European Union (ERDF, ""A way to make Europe"") and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; ""Rhea Plus"": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). We acknowledge support from the Spanish Ministry of Science and Innovation through the ""Centro de Excelencia Severo Ochoa 2019-2023"" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. MV-U and CR-A were supported by a FI fellowship from the Catalan Government (FI-DGR 2015 and #016FI_B 00272). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128).© 2022, Ruiz-Arenas et al.",
-,No,20220411,ewas,35305575,DNA methylation changes in cord blood and the developmental origins of health and disease - a systematic review and replication study.,BMC Genomics,"Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance.We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age. We then attempted to replicate these published associations in the Canadian Healthy Infant Longitudinal Development (CHILD) and the South Asian birth cohort (START) cord blood epigenome-wide data.We screened 68 full-text articles and identified a total of 17 cord blood epigenome-wide association studies (EWAS) of the traits of interest. Out of the 290 CpG sites reported, 19 were identified in more than one study; all of them associated with maternal smoking. In CHILD and START EWAS, thousands of sites associated with gestational age were identified and maintained significance after correction for multiple testing. In CHILD, there was differential methylation observed for 8 of the published maternal smoking sites. No other traits tested (i.e., folate levels, gestational diabetes, birthweight) replicated in the CHILD or START cohorts.Maternal smoking during pregnancy and gestational age are strongly associated with differential methylation in offspring cord blood, as assessed in the EWAS literature and our birth cohorts. There are a limited number of reported methylation sites associated in more than two independent studies related to pregnancy. Additional large studies of diverse populations with fine phenotyping are needed to produce robust epigenome-wide data in order to further elucidate the effect of intrauterine exposures on the infants' methylome.© 2022. The Author(s).",
-,Yes,20220411,ewas,35317219,Association of prenatal acetaminophen use and acetaminophen metabolites with DNA methylation of newborns: analysis of two consecutive generations of the Isle of Wight birth cohort.,Environ Epigenet,"Acetaminophen is used by nearly two-thirds of pregnant women. Although considered safe, studies have demonstrated associations between prenatal acetaminophen use and adverse health outcomes in offspring. Since DNA methylation (DNAm) at birth may act as an early indicator of later health, assessments on whether DNAm of newborns is associated with gestational acetaminophen use or its metabolites are needed. Using data from three consecutive generations of the Isle of Wight cohort (F0-grandmothers, F1-mothers, and F2-offspring) we investigated associations between acetaminophen metabolites in F0 serum at delivery with epigenome-wide DNAm in F1 (Guthrie cards) and between acetaminophen use of F1 and F2-cord-serum levels with F2 cord blood DNAm. In epigenome-wide screening, we eliminated non-informative DNAm sites followed by linear regression of informative sites. Based on repeated pregnancies, indication bias analyses tested whether acetaminophen indicated maternal diseases or has a risk in its own right. Considering that individuals with similar intake process acetaminophen differently, metabolites were clustered to distinguish metabolic exposures. Finally, metabolite clusters from F1-maternal and F2-cord sera were tested for their associations with newborn DNAm (F1 and F2). Twenty-one differential DNAm sites in cord blood were associated with reported maternal acetaminophen intake in the F2 generation. For 11 of these cytosine-phosphate-guanine (CpG) sites, an indication bias was excluded and five were replicated in F2 with metabolite clusters. In addition, metabolite clusters showed associations with 25 CpGs in the F0-F1 discovery analysis, of which five CpGs were replicated in the F2-generation. Our results suggest that prenatal acetaminophen use, measured as metabolites, may influence DNAm in newborns.Published by Oxford University Press 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.",
-,Yes,20220411,ewas,35277542,Epigenome-wide association study and epigenetic age acceleration associated with cigarette smoking among Costa Rican adults.,Sci Rep,"Smoking-associated DNA methylation (DNAm) signatures are reproducible among studies of mostly European descent, with mixed evidence if smoking accelerates epigenetic aging and its relationship to longevity. We evaluated smoking-associated DNAm signatures in the Costa Rican Study on Longevity and Healthy Aging (CRELES), including participants from the high longevity region of Nicoya. We measured genome-wide DNAm in leukocytes, tested Epigenetic Age Acceleration (EAA) from five clocks and estimates of telomere length (DNAmTL), and examined effect modification by the high longevity region. 489 participants had a mean (SD) age of 79.4 (10.8) years, and 18% were from Nicoya. Overall, 7.6% reported currently smoking, 35% were former smokers, and 57.4% never smoked. 46 CpGs and five regions (e.g. AHRR, SCARNA6/SNORD39, SNORA20, and F2RL3) were differentially methylated for current smokers. Former smokers had increased Horvath's EAA (1.69-years; 95% CI 0.72, 2.67), Hannum's EAA (0.77-years; 95% CI 0.01, 1.52), GrimAge (2.34-years; 95% CI1.66, 3.02), extrinsic EAA (1.27-years; 95% CI 0.34, 2.21), intrinsic EAA (1.03-years; 95% CI 0.12, 1.94) and shorter DNAmTL (- 0.04-kb; 95% CI - 0.08, - 0.01) relative to non-smokers. There was no evidence of effect modification among residents of Nicoya. Our findings recapitulate previously reported and novel smoking-associated DNAm changes in a Latino cohort.© 2022. The Author(s).",
-,Yes,20220411,ewas,35274472,DNA methylation alterations in muscle of critically ill patients.,J Cachexia Sarcopenia Muscle,"Intensive care unit (ICU)-acquired weakness can persist beyond ICU stay and has been associated with long-term functional impairment of ICU survivors. Recently, DNA methylation alterations were found in the blood of ICU patients, partially explaining long-term developmental impairment of critically ill children. As illness-induced aberrant DNA methylation theoretically could also be involved in long-term weakness, we investigated whether the DNA methylation signature in muscle of adult critically ill patients differs from that in muscle of healthy controls.Genome-wide methylation was determined (Infinium® HumanMethylationEPIC BeadChips) in DNA extracted from skeletal muscle biopsies that had been collected on Day 8 ± 1 in ICU from 172 EPaNIC-trial patients [66% male sex, median age 62.7 years, median body mass index (BMI) 25.9 kg/m2] and 20 matched healthy controls (70% male sex, median age 58.0 years, median BMI 24.4 kg/m2). Methylation status of individual cytosine-phosphate-guanine (CpG) sites of patients and controls was compared with F-tests, using the Benjamini-Hochberg false discovery rate to correct for multiple comparisons. Differential methylation of DNA regions was assessed with bump hunting, with 1000 permutations assessing uncertainty, expressed as family-wise error rate. Gene expression was investigated for 10 representative affected genes.In DNA from ICU patients, 565 CpG sites, associated with 400 unique genes, were differentially methylated as compared with controls (average difference 3.2 ± 0.1% ranging up to 16.9%, P < 0.00005). Many of the associated genes appeared highly relevant for muscle structure and function/weakness, including genes involved in myogenesis, muscle regeneration, nerve/muscle membrane excitability, muscle denervation/re-innervation, axon guidance/myelination/degeneration/regeneration, synapse function, ion channelling with especially calcium signalling, metabolism (glucose, protein, and fat), insulin signalling, neuroendocrine hormone regulation, mitochondrial function, autophagy, apoptosis, oxidative stress, Wnt signalling, transcription regulation, muscle fat infiltration during regeneration, and fibrosis. In patients as compared with controls, we also identified two hypomethylated regions, spanning 18 and 3 CpG sites in the promoters of the HIC1 and NADK2 genes, respectively (average differences 5.8 ± 0.01% and 12.1 ± 0.04%, family-wise error rate <0.05). HIC1 and NADK2 play important roles in muscle regeneration and postsynaptic acetylcholine receptors and in mitochondrial processes, respectively. Nine of 10 investigated genes containing DNA methylation alterations were differentially expressed in patients as compared with controls (P ≤ 0.03).Critically ill patients present with a different DNA methylation signature in skeletal muscle as compared with healthy controls, which in theory could provide a biological basis for long-term persistence of weakness in ICU survivors.ClinicalTrials.gov: NCT00512122, registered on 31 July 2007.© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.",
-,Yes,20220411,ewas,35379837,DNA methylation in peripheral tissues and left-handedness.,Sci Rep,"Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355-0.578]), but inconsistent across tissues (correlation range [- 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.© 2022. The Author(s).",
-,Yes,20220411,ewas,35377194,Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women.,Environ Health Perspect,"Glyphosate is the most commonly used herbicide in the world and is purported to have a variety of health effects, including endocrine disruption and an elevated risk of several types of cancer. Blood DNA methylation has been shown to be associated with many other environmental exposures, but to our knowledge, no studies to date have examined the association between blood DNA methylation and glyphosate exposure.We conducted an epigenome-wide association study to identify DNA methylation loci associated with urinary glyphosate and its metabolite aminomethylphosphonic acid (AMPA) levels. Secondary goals were to determine the association of epigenetic age acceleration with glyphosate and AMPA and develop blood DNA methylation indices to predict urinary glyphosate and AMPA levels.For 392 postmenopausal women, white blood cell DNA methylation was measured using the Illumina Infinium MethylationEPIC BeadChip array. Glyphosate and AMPA were measured in two urine samples per participant using liquid chromatography-tandem mass spectrometry. Methylation differences at the probe and regional level associated with glyphosate and AMPA levels were assessed using a resampling-based approach. Probes and regions that had an false discovery rateq<0.1in≥90%of 1,000 subsamples of the study population were considered differentially methylated. Differentially methylated sites from the probe-specific analysis were combined into a methylation index. Epigenetic age acceleration from three epigenetic clocks and an epigenetic measure of pace of aging were examined for associations with glyphosate and AMPA.We identified 24 CpG sites whose methylation level was associated with urinary glyphosate concentration and two associated with AMPA. Four regions, within the promoters of theMSH4,KCNA6,ABAT, andNDUFAF2/ERCC8genes, were associated with glyphosate levels, along with an association betweenESR1promoter hypomethylation and AMPA. The methylation index accurately predicted glyphosate levels in an internal validation cohort. AMPA, but not glyphosate, was associated with greater epigenetic age acceleration.Glyphosate and AMPA exposure were associated with DNA methylation differences that could promote the development of cancer and other diseases. Further studies are warranted to replicate our results, determine the functional impact of glyphosate- and AMPA-associated differential DNA methylation, and further explore whether DNA methylation could serve as a biomarker of glyphosate exposure. https://doi.org/10.1289/EHP10174.",
-,Yes,20220411,ewas,35354486,DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses.,Genome Med,"Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown.We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined= 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm.Widespread associations (NCpG= 71, pBonferroni< 0.05, p < 6.3 × 10-8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni< 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDRranged from 0.024 to 7.45 × 10-30; depression to DNAm: pFDRranged from 0.028 to 0.003).PRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.© 2022. The Author(s).",
-,Yes,20220411,ewas,35347270,Grandmaternal smoking during pregnancy is associated with differential DNA methylation in peripheral blood of their grandchildren.,Eur J Hum Genet,"The idea that information can be transmitted to subsequent generation(s) by epigenetic means has been studied for decades but remains controversial in humans. Epidemiological studies have established that grandparental exposures are associated with health outcomes in their grandchildren, often with sex-specific effects; however, the mechanism of transmission is still unclear. We conducted Epigenome Wide Association Studies (EWAS) to test whether grandmaternal smoking during pregnancy is associated with altered DNA methylation (DNAm) in peripheral blood from their adolescent grandchildren. We used data from a birth cohort, with discovery and replication datasets of up to 1225 and 708 individuals (respectively, for the maternal line), aged 15-17 years, and tested replication in the same individuals at birth and 7 years. We show for the first time that DNAm at a small number of loci in cord blood is associated with grandmaternal smoking in humans. In adolescents we see suggestive associations in regions of the genome which we hypothesised a priori could be involved in transgenerational transmission - we observe sex-specific associations at two sites on the X chromosome and one in an imprinting control region. All are within transcription factor binding sites (TFBSs), and we observe enrichment for TFBS among the CpG sites with the strongest associations; however, there is limited evidence that the associations we see replicate between timepoints. The implication of this work is that effects of smoking during pregnancy may induce DNAm changes in later generations and that these changes are often sex-specific, in line with epidemiological associations.© 2022. The Author(s).",
-,Yes,20220411,ewas,35346352,Epigenome-wide DNA methylation profiling of conditioned pain modulation in individuals with non-specific chronic low back pain.,Clin Epigenetics,"The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP.In the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM.Based on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group.This is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP.© 2022. The Author(s).",
-,Yes,20220411,ewas,35328979,Prenatal Exposure to Traffic-Related Air Pollution and the DNA Methylation in Cord Blood Cells: MOCEH Study.,Int J Environ Res Public Health,"Particulate matter with a diameter of ≤10 µm (PM10) and nitrogen dioxide (NO2) affect the DNA methylation in the fetus, but epigenetic studies regarding prenatal exposure to air pollution in Asia are lacking. Therefore, this study aimed to assess whether there is any association between the ambient concentrations of PM10and NO2and CpG methylation in the cord blood DNA by using a Korean birth cohort. The concentrations of the air pollutants were incorporated into the final LUR model by using the maternal address data. The methylation level was determined using HumanMethylationEPIC BeadChip and a linear regression analysis model. A multipollutant model including both PM10and NO2and models with single pollutants were used for each trimester exposure. The number of differentially methylated positions was the largest for midpregnancy exposure in both the single pollutant models and the multipollutant regression analysis. Additionally, gene-set analysis regarding midpregnancy exposure revealed four gene ontology terms (cellular response to staurosporine, positive regulation of cytoskeleton organization, neurotransmitter transport, and execution phase of apoptosis). In conclusion, these findings show an association between prenatal PM10and NO2exposure and DNA methylation in several CpG sites in cord blood cells, especially for midpregnancy exposure.",
-,No,20220411,imprinting,35296332,Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences.,Clin Epigenetics,"Imprinting disorders are a group of congenital diseases which are characterized by molecular alterations affecting differentially methylated regions (DMRs). To date, at least twelve imprinting disorders have been defined with overlapping but variable clinical features including growth and metabolic disturbances, cognitive dysfunction, abdominal wall defects and asymmetry. In general, a single specific DMR is affected in an individual with a given imprinting disorder, but there are a growing number of reports on individuals with so-called multilocus imprinting disturbances (MLID), where aberrant imprinting marks (most commonly loss of methylation) occur at multiple DMRs. However, as the literature is fragmented, we reviewed the molecular and clinical data of 55 previously reported or newly identified MLID families with putative pathogenic variants in maternal effect genes (NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6) and in other candidate genes (ZFP57, ARID4A, ZAR1, UHRF1, ZNF445).In 55 families, a total of 68 different candidate pathogenic variants were identified (7 in NLRP2, 16 in NLRP5, 7 in NLRP7, 17 in PADI6, 15 in ZFP57, and a single variant in each of the genes ARID4A, ZAR1, OOEP, UHRF1, KHDC3L and ZNF445). Clinical diagnoses of affected offspring included Beckwith-Wiedemann syndrome spectrum, Silver-Russell syndrome spectrum, transient neonatal diabetes mellitus, or they were suspected for an imprinting disorder (undiagnosed). Some families had recurrent pregnancy loss.Genomic maternal effect and foetal variants causing MLID allow insights into the mechanisms behind the imprinting cycle of life, and the spatial and temporal function of the different factors involved in oocyte maturation and early development. Further basic research together with identification of new MLID families will enable a better understanding of the link between the different reproductive issues such as recurrent miscarriages and preeclampsia in maternal effect variant carriers/families and aneuploidy and the MLID observed in the offsprings. The current knowledge can already be employed in reproductive and genetic counselling in specific situations.© 2022. The Author(s).",
-,No,20220411,metastable epialleles,35355955,Maternal tobacco smoke exposure is associated with increased DNA methylation at human metastable epialleles in infant cord blood.,Environ Epigenet,"Metastable epialleles (MEs) are genomic regions that are stochastically methylated prior to germ layer specification and exhibit high interindividual but low intra-individual variability across tissues. ME methylation is vulnerable to environmental stressors, including diet. Tobacco smoke (TS) exposure during pregnancy is associated with adverse impacts on fetal health and maternal micronutrient levels as well as altered methylation. Our objective was to determine if maternal smoke exposure impacts methylation at MEs. Consistent with prior studies, we observed reductions in one-carbon pathway micronutrients with gestational TS exposure, including maternal folate (P = 0.02) and vitamins B6 (P = 0.05) and B12 (P = 0.007). We examined putative MEsBOLA3, PAX8,andZFYVE28in cord blood specimens from 85 Newborn Epigenetics STudy participants. Gestational TS exposure was associated with elevated DNA methylation atPAX8(+5.22% average methylation; 95% CI: 0.33% to 10.10%;P = 0.037). In human conceptal kidney tissues, higherPAX8transcription was associated with lower methylation (Rs = 0.55;P = 0.07), suggesting that the methylation levels established at MEs, and their environmentally induced perturbation, may have meaningful, tissue-specific functional consequences. This may be particularly important becausePAX8is implicated in several cancers, including pediatric kidney cancer. Our data are the first to indicate vulnerability of human ME methylation establishment to TS exposure, with a general trend of increasing levels of methylation at these loci. Further investigation is needed to determine how TS exposure-mediated changes in DNA methylation at MEs, and consequent expression levels, might affect smoking-related disease risk.© The Author(s) 2022. Published by Oxford University Press.",
-,No,20220411,methods,35235458,Epigenetic MRI: Noninvasive imaging of DNA methylation in the brain.,Proc Natl Acad Sci U S A,"Significance Dynamic epigenetic activity is a fundamental mechanism underpinning how the brain changes its function during development and aging and in response to environmental and disease stimuli. We developed a technology called epigenetic MRI (eMRI) that enables noninvasive imaging of DNA methylation in the brain, a major epigenetic mechanism. eMRI reveals strong regional differences in global DNA methylation in pig brains, a model with stronger resemblance to human brains than are rodents. Given the noninvasive nature of eMRI, our results pave the way for a DNA-methylation imaging paradigm for living human brains. We expect eMRI to enable many studies to unravel the molecular control of brain function and disease.",
-,No,20220411,methods,35361122,ENNGene: an Easy Neural Network model building tool for Genomics.,BMC Genomics,"The recent big data revolution in Genomics, coupled with the emergence of Deep Learning as a set of powerful machine learning methods, has shifted the standard practices of machine learning for Genomics. Even though Deep Learning methods such as Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs) are becoming widespread in Genomics, developing and training such models is outside the ability of most researchers in the field.Here we present ENNGene-Easy Neural Network model building tool for Genomics. This tool simplifies training of custom CNN or hybrid CNN-RNN models on genomic data via an easy-to-use Graphical User Interface. ENNGene allows multiple input branches, including sequence, evolutionary conservation, and secondary structure, and performs all the necessary preprocessing steps, allowing simple input such as genomic coordinates. The network architecture is selected and fully customized by the user, from the number and types of the layers to each layer's precise set-up. ENNGene then deals with all steps of training and evaluation of the model, exporting valuable metrics such as multi-class ROC and precision-recall curve plots or TensorBoard log files. To facilitate interpretation of the predicted results, we deploy Integrated Gradients, providing the user with a graphical representation of an attribution level of each input position. To showcase the usage of ENNGene, we train multiple models on the RBP24 dataset, quickly reaching the state of the art while improving the performance on more than half of the proteins by including the evolutionary conservation score and tuning the network per protein.As the role of DL in big data analysis in the near future is indisputable, it is important to make it available for a broader range of researchers. We believe that an easy-to-use tool such as ENNGene can allow Genomics researchers without a background in Computational Sciences to harness the power of DL to gain better insights into and extract important information from the large amounts of data available in the field.© 2022. The Author(s).",
-,No,20220411,omics,2021.12.17.473125,Integration of public DNA methylation and expression networks via eQTMs improves prediction of functional gene–gene,biorxiv,"Gene co-expression networks can be used to infer functional relationships between genes, but they do not work well for all genes. We investigated whether DNA methylation can provide complementary information for such genes. We first carried out an eQTM meta-analysis of 3,574 gene expression and methylation samples from blood, brain and nasal epithelial brushed cells to identify links between methylated CpG sites and genes. This revealed 6,067 significant eQTM genes, and we observed that histone modification information is predictive of both eQTM direction and presence, enabling us to link many CpG sites to genes. We then generated a co-methylation network – MethylationNetwork – using 27,720 publicly available methylation profiles and integrated it with a public RNA-seq co-expression dataset of 31,499 samples. Here, we observed that MethylationNetwork can identify experimentally validated interacting pairs of genes that could not be identified in the RNA-seq datasets. We then developed a novel integration pipeline based on CCA and used the integrated methylation and gene networks to predict gene pairs reported in the STRING database. The integrated network showed significantly improved prediction performance compared to using a DNA co-methylation or a gene co-expression network alone. This is the first study to integrate data from two -omics layers from unmatched public samples across different tissues and diseases, and our results highlight the issues and potential of integrating public datasets from multiple molecular phenotypes. The eQTMs we identified can be used as an annotation resource for epigenome-wide association, and we believe that our integration pipeline can be used as a framework for future -omics integration analyses of public datasets.
+No,20220131,transgenerational,34983971,Molecular mechanisms of transgenerational epigenetic inheritance.,Nat Rev Genet,"Increasing evidence indicates that non-DNA sequence-based epigenetic information can be inherited across several generations in organisms ranging from yeast to plants to humans. This raises the possibility of heritable 'epimutations' contributing to heritable phenotypic variation and thus to evolution. Recent work has shed light on both the signals that underpin these epimutations, including DNA methylation, histone modifications and non-coding RNAs, and the mechanisms by which they are transmitted across generations at the molecular level. These mechanisms can vary greatly among species and have a more limited effect in mammals than in plants and other animal species. Nevertheless, common principles are emerging, with transmission occurring either via direct replicative mechanisms or indirect reconstruction of the signal in subsequent generations. As these processes become clearer we continue to improve our understanding of the distinctive features and relative contribution of DNA sequence and epigenetic variation to heritable differences in phenotype.© 2022. Springer Nature Limited.",
+No,20220131,transgenerational,34934526,Epigenetic inheritance of acquired traits through DNA methylation.,Anim Front,NA,
+No,20220131,methods,35047860,Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders,HGG Adv,"Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.",
+No,20220214,cancer,35058638,Life histories of myeloproliferative neoplasms inferred from phylogenies.,Nature,"Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617Fwas estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617Fwas the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617Facquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617Facquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20220214,cell counts,35140201,Enhanced cell deconvolution of peripheral blood using DNA methylation for high-resolution immune profiling.,Nat Commun,"DNA methylation microarrays can be employed to interrogate cell-type composition in complex tissues. Here, we expand reference-based deconvolution of blood DNA methylation to include 12 leukocyte subtypes (neutrophils, eosinophils, basophils, monocytes, naïve and memory B cells, naïve and memory CD4 + and CD8 + T cells, natural killer, and T regulatory cells). Including derived variables, our method provides 56 immune profile variables. The IDOL (IDentifying Optimal Libraries) algorithm was used to identify libraries for deconvolution of DNA methylation data for current and previous platforms. The accuracy of deconvolution estimates obtained using our enhanced libraries was validated using artificial mixtures and whole-blood DNA methylation with known cellular composition from flow cytometry. We applied our libraries to deconvolve cancer, aging, and autoimmune disease datasets. In conclusion, these libraries enable a detailed representation of immune-cell profiles in blood using only DNA and facilitate a standardized, thorough investigation of immune profiles in human health and disease.© 2022. The Author(s).",
+No,20220214,DNAm age,35046594,Turning back time with epigenetic clocks.,Nature,NA,
+No,20220214,DNAm age,35118376,The relationship between ageing and changes in the human blood and brain methylomes.,NAR Genom Bioinform,"Changes in DNA methylation have been found to be strongly correlated with age, enabling the creation of 'epigenetic clocks'. Previously, studies on the relationship between ageing and DNA methylation have assumed a linear relationship. Here, we show that several markers show a non-linear behaviour. In particular, we observe a tendency for saturation with age, especially in the cerebellum. Further, we show that the relationships between significant methylation changes and ageing are different in different tissues. We suggest a straightforward method of assessing all methylation-age relationships and cluster them according to their relative fold change. Our fold change selection outperforms the most common epigenetic clocks in predicting age for the cerebellum, but not for Blood or the Frontal Cortex. Further, we find that the saturation of methylation observed at older ages for the cerebellum explains why epigenetic clocks consistently underestimate the age there. The findings imply that assuming linear correlations might cause biologically important markers to be missed.© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
+No,20220214,dnam age,35120273,Age-related DNA methylation on Y chromosome and their associations with total mortality among Chinese males.,Aging Cell,"In view of the sex differences in aging-related diseases, sex chromosomes may play a critical role during aging process. This study aimed to identify age-related DNA methylation changes on Y chromosome (ChrY). A two-stage study design was conducted in this study. The discovery stage contained 419 Chinese males, including 205 from the Wuhan-Zhuhai cohort panel, 107 from the coke oven workers panel, and 107 from the Shiyan panel. The validation stage contained 587 Chinese males from the Dongfeng-Tongji sub-cohort. We used the Illumina HumanMethylation BeadChip to determine genome-wide DNA methylation in peripheral blood of the study participants. The associations between age and methylation levels of ChrY CpGs were investigated by using linear regression models with adjustment for potential confounders. Further, associations of age-related ChrY CpGs with all-cause mortality were tested in the validation stage. We identified the significant associations of 41 ChrY CpGs with age at false discovery rate (FDR) <0.05 in the discovery stage, and 18 of them were validated in the validation stage (p < 0.05). Meta-analysis of both stages confirmed the robust positive associations of 14 CpGs and negative associations of 4 CpGs with age (FDR<0.05). Among them, cg03441493 and cg17816615 were significantly associated with all-cause mortality risk [HR(95% CI) = 1.37 (1.04, 1.79) and 0.70 (0.54, 0.93), respectively]. Our results highlighted the importance of ChrY CpGs on male aging.© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
+Yes,20220214,ewas,35063012,Immune profiles and DNA methylation alterations related with non-muscle-invasive bladder cancer outcomes.,Clin Epigenetics,"Non-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease. However, screening is invasive, expensive, and associated with significant morbidity making bladder cancer the most expensive cancer to treat per capita. There is an urgent need to expand the understanding of markers related to recurrence and survival outcomes of NMIBC.We used the Illumina HumanMethylationEPIC array to measure peripheral blood DNA methylation profiles of NMIBC patients (N = 603) enrolled in a population-based cohort study in New Hampshire and applied cell type deconvolution to estimate immune cell-type proportions. Using Cox proportional hazard models, we identified that increasing CD4T and CD8T cell proportions were associated with a statistically significant decreased hazard of tumor recurrence or death (CD4T: HR = 0.98, 95% CI = 0.97-1.00; CD8T: HR = 0.97, 95% CI = 0.95-1.00), whereas increasing monocyte proportion and methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) were associated with the increased hazard of tumor recurrence or death (monocyte: HR = 1.04, 95% CI = 1.00-1.07; mdNLR: HR = 1.12, 95% CI = 1.04-1.20). Then, using an epigenome-wide association study (EWAS) approach adjusting for age, sex, smoking status, BCG treatment status, and immune cell profiles, we identified 2528 CpGs associated with the hazard of tumor recurrence or death (P < 0.005). Among these CpGs, the 1572 were associated with an increased hazard and were significantly enriched in open sea regions; the 956 remaining CpGs were associated with a decreased hazard and were significantly enriched in enhancer regions and DNase hypersensitive sites.Our results expand on the knowledge of immune profiles and methylation alteration associated with NMIBC outcomes and represent a first step toward the development of DNA methylation-based biomarkers of tumor recurrence.© 2022. The Author(s).",
+Yes,20220214,ewas,35063426,Prenatal exposure to PM<sub>10</sub> and changes in DNA methylation and telomere length in cord blood.,Environ Res,"Air pollution exposure in pregnancy can cause molecular level alterations that might influence later disease susceptibility.We investigated DNA methylation (DNAm) and telomere length (TL) in the cord blood in relation to gestational PM10exposure and explored potential gestational windows of susceptibility.Cord blood epigenome-wide DNAm (N = 384) and TL (N = 500) were measured in children of the Italian birth cohort Piccolipiù, using the Infinium Methylation EPIC BeadChip and qPCR, respectively. PM10daily exposure levels, based on maternal residential address, were estimated for different gestational periods using models based on satellite data. Epigenome-wide analysis to identify differentially methylated probes (DMPs) and regions (DMRs) was conducted, followed by a pathway analysis and replication analysis in an second Piccolipiù dataset. Distributed lag models (DLMs) using weekly exposures were used to study the association of PM10exposure across pregnancy with telomere length, as well as with the DMPs that showed robust associations.Gestational PM10exposure was associated with the DNA methylation of more than 250 unique DMPs, most of them identified in early gestation, and 1 DMR. Out of 151 DMPs available in the replication dataset, ten DMPs showed robust associations: eight were associated with exposure during early gestation and 2 with exposure during the whole pregnancy. These exposure windows were supported by the DLM analysis. The PM10exposure between 15th and 20th gestational week seem to be associated with shorter telomeres at birth, while exposure between 24th and 29th was associated with longer telomeres.The early pregnancy period is a potential critical window during which PM10exposure can influence cord blood DNA methylation. The results from the TL analysis were consistent with previous findings and merit further exploration in future studies. The study underlines the importance of considering gestational windows outside of the predefined trimesters that may not always overlap with biologically relevant windows of exposure.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.",
+Yes,20220214,ewas,35077545,Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci.,Hum Mol Genet,"Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10-9), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.© The Author(s) 2021. Published by Oxford University Press.",
+No,20220214,longitudinal,35083470,Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage.,Epigenetics Commun,"Following aneurysmal subarachnoid hemorrhage (aSAH), the brain is susceptible to ferroptosis, a type of iron-dependent cell death. Therapeutic intervention targeting the iron homeostasis pathway shows promise for mitigating ferroptosis and improving recovery in animal models, but little work has been conducted in humans. DNA methylation (DNAm) plays a key role in gene expression and brain function, plasticity, and injury recovery, making it a potentially useful biomarker of outcomes or therapeutic target for intervention. Therefore, in this longitudinal, observational study, we examined the relationships between trajectories of DNAm in candidate genes related to iron homeostasis and acute (cerebral vasospasm and delayed cerebral ischemia) and long-term (Glasgow Outcome Scale [GOS, unfavorable = 1-3] and death) patient outcomes after aSAH.Longitudinal, genome-wide DNAm data were generated from DNA extracted from post-aSAH cerebrospinal fluid (n= 260 participants). DNAm trajectories of 637 CpG sites in 36 candidate genes related to iron homeostasis were characterized over 13 days post-aSAH using group-based trajectory analysis, an unsupervised clustering method. Significant associations were identified between inferred DNAm trajectory groups at several CpG sites and acute and long-term outcomes. Among our results, cg25713625 in the STEAP3 metalloreductase gene (STEAP3) stood out. Specifically, in comparing the highest cg25713625 DNAm trajectory group with the lowest, we observed significant associations (i.e., based onp-values less than an empirical significance threshold) with unfavorable GOS at 3 and 12 months (OR= 11.7,p= 0.0006 andOR= 15.6,p= 0.0018, respectively) and death at 3 and 12 months (OR= 19.1,p= 0.0093 andOR= 12.8,p= 0.0041, respectively). These results were replicated in an independent sample (n= 100 participants) observing significant associations with GOS at 3 and 12 months (OR= 8.2,p= 0.001 andOR= 6.3,p= 0.0.0047, respectively) and death at 3 months (OR= 2.3,p= 0.008) and a suggestive association (i.e.,p-value < 0.05 not meeting an empirical significance threshold) with death at 12 months (OR= 2.0,p= 0.0272). In both samples, an additive effect of the DNAm trajectory group was observed as the percentage of participants with unfavorable long-term outcomes increased substantially with higher DNAm trajectory groups.Our results support a role for DNAm of cg25713625/STEAP3in recovery following aSAH. Additional research is needed to further explore the role of DNAm of cg25713625/STEAP3as a biomarker of unfavorable outcomes, or therapeutic target to improve outcomes, to translate these findings clinically.",
+Yes,20220214,ewas,35104326,Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies.,Diabetes Care,"Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations.To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression.Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] = 0.013 [2.1 × 10-3], P value corrected for false discovery rate [PFDR] = 5.1 × 10-3) and cg02988288 (β [SE]-0.013 [2.3 × 10-3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm.Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.© 2022 by the American Diabetes Association.",
+Yes,20220214,ewas,35109748,Blood DNA methylation signatures are associated with social determinants of health among survivors of childhood cancer.,Epigenetics,"Social epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5'-cytosine-phosphate-guanine-3' (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH-CpG associations (P< 9 × 10-8), 25 of which were validated in survivors of African ancestry (P< 0.05). Thirteen CpGs were associated with all three SDOH factors and resided at pleiotropic loci in cigarette smoking-related genes (e.g.,CLDND1andCPOX). After accounting for smoking and body mass index, these associations remained significant with attenuated effect sizes. Seven of 13 CpGs were associated with gene expression level based on 57 subsamples with blood RNA sequencing data available. In conclusion, DNAm signatures, many resembling the effect of tobacco use, were associated with SDOH factors among survivors of childhood cancer, thereby suggesting that biologically distal SDOH factors influence health behaviours or related factors, the epigenome, and subsequently survivors' health.",
+Yes,20220214,ewas,35119793,DNA methylation in blood cells is associated with cortisol levels in offspring of mothers who had prenatal post-traumatic stress disorder.,Stress Health,"Maternal stress during pregnancy is associated with differential DNA methylation in offspring and disrupted cortisol secretion. This study aimed to determine methylation signatures of cortisol levels in children, and whether associations differ based on maternal post-traumatic stress disorder (PTSD). Blood epigenome-wide methylation and fasting cortisol levels were measured in 118 offspring of mothers recruited from the Kosovo Rehabilitation Centre for Torture Victims. Mothers underwent clinically administered assessment for PTSD using Diagnostic and Statistical Manual of Mental Disorders. Correlations between offspring methylation and cortisol levels were examined using epigenome-wide analysis, adjusting for covariates. Subsequent analysis focussed on a priori selected genes involved in the hypothalamic-pituitary-adrenal (HPA) axis stress signalling. Methylation at four sites were correlated with cortisol levels (cg15321696, r = -0.33, cg18105800, r = +0.33, cg00986889, r = -0.25, and cg15920527, r = -0.27). In adjusted multivariable regression, when stratifying based on prenatal PTSD status, significant associations were only found for children born to mothers with prenatal PTSD (p < 0.001). Several sites within HPA axis genes were also associated with cortisol levels in the maternal PTSD group specifically. There is evidence that methylation is associated with cortisol levels, particularly in offspring born to mothers with prenatal PTSD. However, larger studies need to be carried out to independently validate these findings.© 2022 The Authors. Stress and Health published by John Wiley & Sons Ltd.",
+Yes,20220214,ewas,35123963,Associations between plasma levels of brominated flame retardants and methylation of DNA from peripheral blood: A cross-sectional study in a cohort of French women.,Environ Res,"Brominated flame retardants (BFRs) are organic compounds that are widespread in the environment. Because of their persistence, they are able to bioaccumulate with major impacts on human health. It has been hypothesized that the effect of BFRs on human health is mediated by alterations of DNA methylation.The aim of this study was to examine the association between methylation of DNA extracted from peripheral blood and circulating levels of BFRs measured in plasma.We conducted a methylation wide association study on 336 blood samples from a study within the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) cohort, a long-term longitudinal cohort of French women. DNA methylation at more than 850 000 cytosine-guanine dinucleotide (CpG) sites was measured with the Illumina Infinium HumanMethylation - EPIC BeadChip. Circulating levels of seven BFRs (BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154 and PBB-153) were measured by gas chromatography coupled to high-resolution mass spectrometry in plasma samples. The association between DNA methylation and BFRs plasma levels was assessed through linear mixed-effects models followed by gene-set enrichment analyses (GSEA).We identified 253 CpG sites whose methylation levels were significantly associated with exposure to BFRs after Bonferroni correction. For 50 of these CpGs the p-values were less than 2.2x10-9with the strongest association being between BDE-154 and cg23619365 (4.32x10-13). GSEA of CpG sites associated with exposure to BFRs identified significant enrichment of genes involved in hypoxia, glycolysis and adipogenesis.Exposure to BFRs appears to be related to numerous alterations in DNA methylation. These findings, if replicated in independent studies, provide insights into the biological and health effects of BFRs.Copyright © 2022. Published by Elsevier Inc.",
+Yes,20220214,ewas,35139887,Aberrant epigenetic and transcriptional events associated with breast cancer risk.,Clin Epigenetics,"Genome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N = 146, median age = 39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina's HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation.Transcriptomic analysis identified 69 differentially expressed genes between women at high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR < 0.05 and fold change ≥ 2. Majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR < 0.01) and primary epithelial cells (p < 0.05) from high-risk breasts. Moreover, 1698 DNA methylation changes were identified in high-risk breast tissues (FDR < 0.05), partially overlapped with cancer-related signatures, and correlated with transcriptional changes (p < 0.05, r ≤ 0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified.Normal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues, and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.© 2022. The Author(s).",
+Yes,20220214,ewas,35145228,Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.,Mol Psychiatry,"Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.© 2022. The Author(s).",
+No,20220214,longitudinal,35142878,Early DNA methylation changes in children developing beta cell autoimmunity at a young age.,Diabetologia,"Type 1 diabetes is a chronic autoimmune disease of complex aetiology, including a potential role for epigenetic regulation. Previous epigenomic studies focused mainly on clinically diagnosed individuals. The aim of the study was to assess early DNA methylation changes associated with type 1 diabetes already before the diagnosis or even before the appearance of autoantibodies.Reduced representation bisulphite sequencing (RRBS) was applied to study DNA methylation in purified CD4+T cell, CD8+T cell and CD4-CD8-cell fractions of 226 peripheral blood mononuclear cell samples longitudinally collected from seven type 1 diabetes-specific autoantibody-positive individuals and control individuals matched for age, sex, HLA risk and place of birth. We also explored correlations between DNA methylation and gene expression using RNA sequencing data from the same samples. Technical validation of RRBS results was performed using pyrosequencing.We identified 79, 56 and 45 differentially methylated regions in CD4+T cells, CD8+T cells and CD4-CD8-cell fractions, respectively, between type 1 diabetes-specific autoantibody-positive individuals and control participants. The analysis of pre-seroconversion samples identified DNA methylation signatures at the very early stage of disease, including differential methylation at the promoter of IRF5 in CD4+T cells. Further, we validated RRBS results using pyrosequencing at the following CpG sites: chr19:18118304 in the promoter of ARRDC2; chr21:47307815 in the intron of PCBP3; and chr14:81128398 in the intergenic region near TRAF3 in CD4+T cells.These preliminary results provide novel insights into cell type-specific differential epigenetic regulation of genes, which may contribute to type 1 diabetes pathogenesis at the very early stage of disease development. Should these findings be validated, they may serve as a potential signature useful for disease prediction and management.© 2022. The Author(s).",
+No,20220214,mechanism,35102554,"Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis.",Int J Cancer,"Alcohol consumption is thought to be one of the modifiable risk factors for colorectal cancer (CRC). However, the causality and mechanisms by which alcohol exerts its carcinogenic effect are unclear. We evaluated the association between alcohol consumption and CRC risk by analyzing data from 32 cohort studies and conducted two-sample Mendelian randomization (MR) analysis to examine for casual relationship. To explore the effect of alcohol related DNA methylation on CRC risk, we performed an epigenetic MR analysis with data from an epigenome-wide association study (EWAS). We additionally performed gene-alcohol interaction analysis nested in the UK Biobank to assess effect modification between alcohol consumption and susceptibility genes. We discovered distinct effects of alcohol on CRC incidence and mortality from the meta-analyses, and genetic predisposition to alcohol drinking was causally associated with an increased CRC risk (OR = 1.79, 95% CI: 1.23-2.61) using two-sample MR approaches. In epigenetic MR analysis, two alcohol-related CpG sites (cg05593667 and cg10045354 mapped to COLCA1/COLCA2 gene) were identified causally associated with an increased CRC risk (P < 8.20 × 10-4). Gene-alcohol interaction analysis revealed that carriage of the risk allele of the eQTL (rs3087967) and mQTL (rs11213823) polymorphism of COLCA1/COLCA2 would interact with alcohol consumption to increase CRC risk (PInteraction = .027 and PInteraction = .016). Our study provides comprehensive evidence to elucidate the role of alcohol in CRC and highlights that the pathogenic effect of alcohol on CRC could be partly attributed to DNA methylation by regulating the expression of COLCA1/COLCA2 gene.© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",
+No,20220214,mechanism,35119365,Physiological TLR4 regulation in human fetal membranes as an explicative mechanism of a pathological preterm case.,Elife,"The integrity of human fetal membranes is crucial for harmonious fetal development throughout pregnancy. Their premature rupture is often the consequence of a physiological phenomenon that has been exacerbated. Beyond all the implied biological processes, inflammation is of primary importance and is qualified as 'sterile' at the end of pregnancy. In this study, complementary methylomic and transcriptomic strategies on amnion and choriodecidua explants obtained from the altered (cervix zone) and intact fetal membranes at term and before labour were used. By cross-analysing genome-wide studies strengthened by in vitro experiments, we deciphered how the expression of toll-like receptor 4 (TLR4), an actor in pathological fetal membrane rupture, is controlled. Indeed, it is differentially regulated in the altered zone and between both layers by a dual mechanism: (1) the methylation of TLR4 and miRNA promoters and (2) targeting by miRNA (let-7a-2 and miR-125b-1) acting on the 3'-UTR of TLR4. Consequently, this study demonstrates that fine regulation of TLR4 is required for sterile inflammation establishment at the end of pregnancy and that it may be dysregulated in the pathological premature rupture of membranes.© 2022, Belville et al.",
+No,20220214,methods,35145108,A mammalian methylation array for profiling methylation levels at conserved sequences.,Nat Commun,"Infinium methylation arrays are not available for the vast majority of non-human mammals. Moreover, even if species-specific arrays were available, probe differences between them would confound cross-species comparisons. To address these challenges, we developed the mammalian methylation array, a single custom array that measures up to 36k CpGs per species that are well conserved across many mammalian species. We designed a set of probes that can tolerate specific cross-species mutations. We annotate the array in over 200 species and report CpG island status and chromatin states in select species. Calibration experiments demonstrate the high fidelity in humans, rats, and mice. The mammalian methylation array has several strengths: it applies to all mammalian species even those that have not yet been sequenced, it provides deep coverage of conserved cytosines facilitating the development of epigenetic biomarkers, and it increases the probability that biological insights gained in one species will translate to others.© 2022. The Author(s).",
+No,20220214,prediction,35045866,A deep learning model for early risk prediction of heart failure with preserved ejection fraction by DNA methylation profiles combined with clinical features.,Clin Epigenetics,"Heart failure with preserved ejection fraction (HFpEF), affected collectively by genetic and environmental factors, is the common subtype of chronic heart failure. Although the available risk assessment methods for HFpEF have achieved some progress, they were based on clinical or genetic features alone. Here, we have developed a deep learning framework, HFmeRisk, using both 5 clinical features and 25 DNA methylation loci to predict the early risk of HFpEF in the Framingham Heart Study Cohort.The framework incorporates Least Absolute Shrinkage and Selection Operator and Extreme Gradient Boosting-based feature selection, as well as a Factorization-Machine based neural network-based recommender system. Model discrimination and calibration were assessed using the AUC and Hosmer-Lemeshow test. HFmeRisk, including 25 CpGs and 5 clinical features, have achieved the AUC of 0.90 (95% confidence interval 0.88-0.92) and Hosmer-Lemeshow statistic was 6.17 (P = 0.632), which outperformed models with clinical characteristics or DNA methylation levels alone, published chronic heart failure risk prediction models and other benchmark machine learning models. Out of them, the DNA methylation levels of two CpGs were significantly correlated with the paired transcriptome levels (R < -0.3, P < 0.05). Besides, DNA methylation locus in HFmeRisk were associated with intercellular signaling and interaction, amino acid metabolism, transport and activation and the clinical variables were all related with the mechanism of occurrence of HFpEF. Together, these findings give new evidence into the HFmeRisk model.Our study proposes an early risk assessment framework for HFpEF integrating both clinical and epigenetic features, providing a promising path for clinical decision making.© 2022. The Author(s).",
+No,20220214,prediction,35123558,Bladder cancer detection in urine using DNA methylation markers: a technical and prospective preclinical validation.,Clin Epigenetics,"The development of accurate urinary biomarkers for non-invasive and cost-effective detection of primary and recurrent bladder tumours is recognized as one of the major clinical needs in bladder cancer diagnostics. The purposes of this study were (1) to validate the results of a previous technical comparison by determining the diagnostic performance of nine methylation markers in urine pellet compared to full void urine, and (2) to validate the diagnostic performance of the optimal marker panel GHSR/MAL from a previous exploratory study in a preclinical setting.Urine samples of 108 patients with bladder cancer and 100 age- and gender-matched controls were prospectively collected for methylation analysis. Urinary methylation levels of the markers FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST and ZIC1 were determined with quantitative methylation-specific PCR in urine pellet. Area under the curves (AUCs) were determined for individual markers and the marker panel GHSR/MAL. The diagnostic performance of the marker panel GHSR/MAL was evaluated in the total study population and in different subgroups of patients with bladder cancer using the Chi-square test. The diagnostic accuracy was assessed by leave-one-out cross-validation.All nine urinary methylation markers (FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST and ZIC1) showed significantly higher methylation levels in bladder cancer patients than in controls (p < 0.001). Area under the curves (AUCs) of the nine methylation markers tested in urine pellet were similar to AUCs in full void urine of an independent previous cohort. GHSR/MAL reached an AUC of 0.89 (95% confidence interval [CI] 0.84-0.94), at 80% sensitivity and 93% specificity. Sensitivity of GHSR/MAL increased with higher tumour grades, higher tumour stages, in primary vs. recurrent tumours, and in males vs. females.This technical validation supports the robustness of DNA methylation analysis in urine pellet and full void urine for the non-invasive detection of bladder cancer. Subsequent preclinical validation confirmed the diagnostic potential of GHSR/MAL. These findings underline the diagnostic potential of the marker panel GHSR/MAL for future bladder cancer diagnostics.© 2022. The Author(s).",
+No,20220214,prediction,36008412,Methylation risk scores are associated with a collection of phenotypes within electronic health record systems,NPJ Genom Med,"Inference of clinical phenotypes is a fundamental task in precision medicine, and has therefore been heavily investigated in recent years in the context of electronic health records (EHR) using a large arsenal of machine learning techniques, as well as in the context of genetics using polygenic risk scores (PRS). In this work, we considered the epigenetic analog of PRS, methylation risk scores (MRS), a linear combination of methylation states. Since methylation states are influenced by both environmental and genetic factors, we hypothesized that MRS would complement PRS and EHR-based machine-learning methods, improving overall prediction accuracy. To evaluate this hypothesis, we performed the largest assessment of methylation risk scores in clinical datasets to be conducted to date. We measured methylation across a large cohort (n=831) of diverse samples in the UCLA Health biobank, for which both genetic and complete EHR data are available. We constructed MRS for 607 phenotypes spanning diagnoses, clinical lab tests, and medication prescriptions. When added to a baseline set of predictive features, MRS significantly improved the imputation of 139 outcomes, whereas the PRS improved only 22 (median improvement for methylation 10.74%, 141.52%, and 15.46% in medications, labs and diagnosis codes, respectively, whereas genotypes only improved the labs at a median increase of 18.42%). We added significant MRS to state-of-the-art EHR imputation methods that leverage the entire set of medical records, and found that including MRS as a medical feature in the algorithm significantly improves EHR imputation in 37% of lab tests examined (median R2 increase 47.6%). Finally, we replicated several MRS in multiple external studies of methylation (minimum p-value of 2.72 × 10?7) and replicated 22 of 30 tested MRS internally in two separate cohorts of different ethnicity. In summary, our work provides a comprehensive evaluation of MRS in comparison to PRS and EHR imputation on the largest dataset consisting of methylation, genotype, and EHR data. Our publicly available results and weights show promise for methylation risk scores as clinical and scientific tools.",
+No,20220214,review,35079149,Seven technologies to watch in 2022.,Nature,NA,
+No,20220228,cell types,35142607,Human embryoid bodies as a novel system for genomic studies of functionally diverse cell types.,Elife,"Practically all studies of gene expression in humans to date have been performed in a relatively small number of adult tissues. Gene regulation is highly dynamic and context-dependent. In order to better understand the connection between gene regulation and complex phenotypes, including disease, we need to be able to study gene expression in more cell types, tissues, and states that are relevant to human phenotypes. In particular, we need to characterize gene expression in early development cell types, as mutations that affect developmental processes may be of particular relevance to complex traits. To address this challenge, we propose to use embryoid bodies (EBs), which are organoids that contain a multitude of cell types in dynamic states. EBs provide a system in which one can study dynamic regulatory processes at an unprecedentedly high resolution. To explore the utility of EBs, we systematically explored cellular and gene expression heterogeneity in EBs from multiple individuals. We characterized the various cell types that arise from EBs, the extent to which they recapitulate gene expression in vivo, and the relative contribution of technical and biological factors to variability in gene expression, cell composition, and differentiation efficiency. Our results highlight the utility of EBs as a new model system for mapping dynamic inter-individual regulatory differences in a large variety of cell types.© 2022, Rhodes et al.",
+No,20220228,dnam age,35189945,Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock.,Genome Biol,"A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored.Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women's IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer.Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk.© 2022. The Author(s).",
+No,20220228,dnam age,35181865,Integrating DNA Methylation Measures of Biological Aging into Social Determinants of Health Research.,Curr Environ Health Rep,"Acceleration of biological processes of aging is hypothesized to drive excess morbidity and mortality in socially disadvantaged populations. DNA methylation measures of biological aging provide tools for testing this hypothesis.Next-generation DNA methylation measures of biological aging developed to predict mortality risk and physiological decline are more predictive of morbidity and mortality than the original epigenetic clocks developed to predict chronological age. These new measures show consistent evidence of more advanced and faster biological aging in people exposed to socioeconomic disadvantage and may be able to record the emergence of socially determined health inequalities as early as childhood. Next-generation DNA methylation measures of biological aging also indicate race/ethnic disparities in biological aging. More research is needed on these measures in samples of non-Western and non-White populations. New DNA methylation measures of biological aging open opportunities for refining inference about the causes of social disparities in health and devising policies to eliminate them. Further refining measures of biological aging by including more diversity in samples used for measurement development is a critical priority for the field.© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.",
+No,20220228,early detection,35164838,Novel epigenetic network biomarkers for early detection of esophageal cancer.,Clin Epigenetics,"Early detection of esophageal cancer is critical to improve survival. Whilst studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity.Here we applied systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from esophageal adenocarcinoma (EAC) patients and matched normal-adjacent tissue, in order to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity. We identify 12 gene-modules that are epigenetically deregulated in EAC, and are able to validate all 12 modules in 4 independent EAC cohorts. We demonstrate that the epigenetic deregulation is present in the epithelial compartment of EAC-tissue. Using single-cell RNA-Seq data we show that one of these modules, a proto-cadherin module centered around CTNND2, is inactivated in Barrett's Esophagus, a precursor lesion to EAC. By measuring DNA methylation in saliva from EAC cases and controls, we identify a chemokine module centered around CCL20, whose methylation patterns in saliva correlate with EAC status.Given our observations that a CCL20 chemokine network is overactivated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be overactivated in EAC tissue infected with the bacterium F. nucleatum, a bacterium that normally inhabits the oral cavity, our results highlight the possibility of using DNAm measurements in saliva as a proxy for changes occurring in the esophageal epithelium. Both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation.© 2022. The Author(s).",
+No,20220228,epigenetics,35143483,Slow nucleosome dynamics set the transcriptional speed limit and induce RNA polymerase II traffic jams and bursts.,PLoS Comput Biol,"Nucleosomes are recognized as key regulators of transcription. However, the relationship between slow nucleosome unwrapping dynamics and bulk transcriptional properties has not been thoroughly explored. Here, an agent-based model that we call the dynamic defect Totally Asymmetric Simple Exclusion Process (ddTASEP) was constructed to investigate the effects of nucleosome-induced pausing on transcriptional dynamics. Pausing due to slow nucleosome dynamics induced RNAPII convoy formation, which would cooperatively prevent nucleosome rebinding leading to bursts of transcription. The mean first passage time (MFPT) and the variance of first passage time (VFPT) were analytically expressed in terms of the nucleosome rate constants, allowing for the direct quantification of the effects of nucleosome-induced pausing on pioneering polymerase dynamics. The mean first passage elongation rate γ(hc, ho) is inversely proportional to the MFPT and can be considered to be a new axis of the ddTASEP phase diagram, orthogonal to the classical αβ-plane (where α and β are the initiation and termination rates). Subsequently, we showed that, for β = 1, there is a novel jamming transition in the αγ-plane that separates the ddTASEP dynamics into initiation-limited and nucleosome pausing-limited regions. We propose analytical estimates for the RNAPII density �, average elongation rate v, and transcription flux J and verified them numerically. We demonstrate that the intra-burst RNAPII waiting times tin follow the time-headway distribution of a max flux TASEP and that the average inter-burst interval [Formula: see text] correlates with the index of dispersion De. In the limit γ→0, the average burst size reaches a maximum set by the closing rate hc. When α≪1, the burst sizes are geometrically distributed, allowing large bursts even while the average burst size [Formula: see text] is small. Last, preliminary results on the relative effects of static and dynamic defects are presented to show that dynamic defects can induce equal or greater pausing than static bottle necks.",
+Yes,20220228,ewas,35213289,Pharmacoepigenetics of hypertension: genome-wide methylation analysis of responsiveness to four classes of antihypertensive drugs using a double-blind crossover study design.,Epigenetics,"Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-relatedACY3gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to theACY3TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (https://clinicaltrials.gov/ct2/show/NCT03276598; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (https://clinicaltrials.gov/ct2/show/NCT00338260; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P < 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to theACY3TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P < 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to theACY3TSS may support the role ofACY3genetic and epigenetic variation in BP response to bisoprolol.",
+Yes,20220228,ewas,35207690,"DNA Methylation and Asthma Acquisition during Adolescence and Post-Adolescence, an Epigenome-Wide Longitudinal Study.",J Pers Med,"The role of epigenetics in the pathogenesis of asthma acquisition in adolescence and post-adolescence has been unknown. We carried out a longitudinal epigenome-wide association study, using data from the Isle of Wight Birth Cohort (IOWBC). To improve statistical power, we first screened CpGs based on associations of DNA methylation (DNAm) at an age of 10 years (pre-adolescence) with asthma acquisition at 10-18 years (during adolescence). A logistic regression with repeated measures was applied to CpGs that passed screening to examine the associations of pre-adolescence DNAm with asthma acquisition from 10-18 years and 18-26 years, with an interaction term to evaluate transition period specificity. Findings were further tested in an independent birth cohort, ALSPAC. In total, 205 CpGs (with 150 being females) showed associations with asthma acquisition (main or interaction effects) at FDR = 0.05 in IOWBC, of which 112 (90 being females) showed consistent associations in the ALSPAC. Genes that the identified CpGs were mapped to, e.g.,AKAP1andENO1, have been shown to be associated with the risk of asthma. Our findings indicated that DNAm at specific CpGs was associated with asthma acquisition. CpGs showing such associations were likely to be different between males and females and, at certain CpGs, were unique to a specific transition period.",
+Yes,20220228,ewas,35205218,Variation in Genotype and DNA Methylation Patterns Based on Alcohol Use and CVD in the Korean Genome and Epidemiology Study (KoGES).,Genes (Basel),"Alcohol consumption can increase the risk of chronic diseases, such as myocardial infarction, coronary artery disease, hyperlipidemia, and hypertension. We aimed to assess the association between genotype, DNA methylation patterns, alcohol consumption, and chronic diseases in Korean population. We analyzed 8840 subjects for genotypes and 446 for DNA methylation among the 9351 subjects from the Korean Genome and Epidemiology Study (KoGES). We further divided both groups into two sub-groups according to the presence/absence of chronic diseases. We selected genes whose methylation varied significantly with alcohol consumption, and visualized genotype and DNA methylation patterns specific to each group. Genome-wide association study (GWAS) revealed single nucleotide polymorphisms (SNPs)rs2074356andrs11066280in HECT domain E3 ubiquitin protein ligase 4 (HECTD4) to be significantly associated with alcohol consumption in both the presence. Thers12229654genotype also displayed significantly different patterns with alcohol consumption. Furthermore, we retrieved differentially methylated regions (DMRs) from four groups based on sex and chronic diseases and compared them by drinking status. In genotype analysis, cardiovascular diseases (CVDs) showed a higher proportion in drinker than in non-drinker, but not in DMR analysis. Additionally, we analyzed the enriched Gene Ontology terms and Kyoto Gene and Genome Encyclopedia (KEGG) pathways and visualized the network, heatmap, and upset plot. We show that the pattern of DNA methylation associated with CVD is strongly influenced by alcoholism. Overall, this study identified genetic and epigenetic variants influenced by alcohol consumption and chronic diseases.",
+Yes,20220228,ewas,35196023,"Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.",Sci Transl Med,"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.",
+Yes,20220228,ewas,35177594,Epigenome-wide association study of posttraumatic stress disorder identifies novel loci in U.S. military veterans.,Transl Psychiatry,"Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder prevalent in military veterans. Epigenetic mechanisms have been implicated in the etiology of PTSD, with DNA methylation being the most studied to identify novel molecular biomarkers associated with this disorder. We performed one of the largest single-sample epigenome-wide association studies (EWAS) of PTSD to date. Our sample included 1135 male European-American U.S. veterans who participated in the National Health and Resilience in Veterans Study (NHRVS). DNA was collected from saliva samples and the Illumina HumanMethylation EPIC BeadChip was used for the methylation analysis. PTSD was assessed using the PTSD Checklist. An EWAS was conducted using linear regression adjusted for age, cell-type proportions, first 10 principal components, and smoking status. After Bonferroni correction, we identified six genome-wide significant (GWS) CpG sites associated with past-month PTSD and three CpGs with lifetime PTSD (prange = 10-10-10-8). These CpG sites map to genes involved in immune function, transcription regulation, axonal guidance, cell signaling, and protein binding. Among these, SENP7, which is involved in transcription regulation and has been linked to risk-taking behavior and alcohol consumption in genome-wide association studies, replicated in an independent veteran cohort and was downregulated in medial orbitofrontal cortex of PTSD postmortem brain tissue. These findings suggest potential epigenetic biomarkers of PTSD that may help inform the pathophysiology of this disorder in veterans and other trauma-affected populations.© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
+Yes,20220228,ewas,35169870,Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts.,Diabetologia,"Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts.We conducted a meta-analysis of EWASs in blood collected 7-10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK).The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values <1.1 × 10-7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation.By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development.© 2022. The Author(s).",
+Yes,20220228,ewas,35163587,Genome-Wide DNA Methylation in Policemen Working in Cities Differing by Major Sources of Air Pollution.,Int J Mol Sci,"DNA methylation is the most studied epigenetic mechanism that regulates gene expression, and it can serve as a useful biomarker of prior environmental exposure and future health outcomes. This study focused on DNA methylation profiles in a human cohort, comprising 125 nonsmoking city policemen (sampled twice), living and working in three localities (Prague, Ostrava and Ceske Budejovice) of the Czech Republic, who spent the majority of their working time outdoors. The main characterization of the localities, differing by major sources of air pollution, was defined by the stationary air pollution monitoring of PM2.5, B[a]P and NO2. DNA methylation was analyzed by a genome-wide microarray method. No season-specific DNA methylation pattern was discovered; however, we identified 13,643 differentially methylated CpG loci (DML) for a comparison between the Prague and Ostrava groups. The most significant DML was cg10123377 (log2FC = -1.92,p= 8.30 Ă— 10-4) and loci annotated toRPTOR(total 20 CpG loci). We also found two hypomethylated loci annotated to the DNA repair geneXRCC5.Groups of DML annotated to the same gene were linked to diabetes mellitus (KCNQ1), respiratory diseases (PTPRN2), the dopaminergic system of the brain and neurodegenerative diseases (NR4A2). The most significant possibly affected pathway was Axon guidance, with 86 potentially deregulated genes near DML. The cluster of gene sets that could be affected by DNA methylation in the Ostrava groups mainly includes the neuronal functions and biological processes of cell junctions and adhesion assembly. The study demonstrates that the differences in the type of air pollution between localities can affect a unique change in DNA methylation profiles across the human genome.",
+Yes,20220228,ewas,35169479,Immune cell type and DNA methylation vary with reproductive status in women: possible pathways for costs of reproduction.,Evol Med Public Health,"Consistent with evolutionarily theorized costs of reproduction (CoR), reproductive history in women is associated with life expectancy and susceptibility to certain cancers, autoimmune disorders and metabolic disease. Immunological changes originating during reproduction may help explain some of these relationships.To explore the potential role of the immune system in female CoR, we characterized leukocyte composition and regulatory processes using DNA methylation (DNAm) in a cross-sectional cohort of young (20-22 years old) women differing in reproductive status.Compared to nulliparity, pregnancy was characterized by differential methylation at 828 sites, 96% of which were hypomethylated and enriched for genes associated with T-cell activation, innate immunity, pre-eclampsia and neoplasia. Breastfeeding was associated with differential methylation at 1107 sites (71% hypermethylated), enriched for genes involved in metabolism, immune self-recognition and neurogenesis. There were no significant differences in DNAm between nulliparous and parous women. However, compared to nullipara, pregnant women had lower proportions of B, CD4T, CD8T and natural killer (NK) cells, and higher proportions of granulocytes and monocytes. Monocyte counts were lower and NK counts higher among breastfeeding women, and remained so among parous women.Our findings point to widespread differences in DNAm during pregnancy and lactation. These effects appear largely transient, but may accumulate with gravidity become detectable as women age. Nulliparous and parous women differed in leukocyte composition, consistent with more persistent effects of reproduction on cell type. These findings support transient (leukocyte DNAm) and persistent (cell composition) changes associated with reproduction in women, illuminating potential pathways contributing to CoR.Lay Summary:Evolutionary theory and epidemiology support costs of reproduction (CoR) to women's health that may involve changes in immune function. We report differences in immune cell composition and gene regulation during pregnancy and breastfeeding. While many of these differences appear transient, immune cell composition may remain, suggesting mechanisms for female CoR.© The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.",
+No,20220228,methods,35156895,Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies.,Epigenetics,"Biomedical research has grown increasingly cooperative through the sharing of consortia-level epigenetic data. Since consortia preprocess data prior to distribution, new processing pipelines can lead to different versions of the same dataset. Similarly, analytic frameworks evolve to incorporate cutting-edge methods and best practices. However, it remains unknown how different data and analytic versions alter the results of epigenome-wide analyses, which could influence the replicability of epigenetic associations. Thus, we assessed the impact of these changes using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We analysed DNA methylation from two data versions, processed using separate preprocessing and analytic pipelines, examining associations between seven childhood adversities or prenatal smoking exposure and DNA methylation at age 7. We performed two sets of analyses: (1) epigenome-wide association studies (EWAS); (2) Structured Life Course Modelling Approach (SLCMA), a two-stage method that models time-dependent effects. SLCMA results were also compared across two analytic versions. Data version changes impacted both EWAS and SLCMA analyses, yielding different associations at conventional p-value thresholds. However, the magnitude and direction of associations was generally consistent between data versions, regardless of p-values. Differences were especially apparent in analyses of childhood adversity, while smoking associations were more consistent using significance thresholds. SLCMA analytic versions similarly altered top associations, but time-dependent effects remained concordant. Alterations to data and analytic versions influenced the results of epigenome-wide analyses. Our findings highlight that magnitude and direction are better measures for replication and stability than p-value thresholds.",
+No,20220228,methods,35172880,"Sustained software development, not number of citations or journal choice, is indicative of accurate bioinformatic software.",Genome Biol,"Computational biology provides software tools for testing and making inferences about biological data. In the face of increasing volumes of data, heuristic methods that trade software speed for accuracy may be employed. We have studied these trade-offs using the results of a large number of independent software benchmarks, and evaluated whether external factors, including speed, author reputation, journal impact, recency and developer efforts, are indicative of accurate software.We find that software speed, author reputation, journal impact, number of citations and age are unreliable predictors of software accuracy. This is unfortunate because these are frequently cited reasons for selecting software tools. However, GitHub-derived statistics and high version numbers show that accurate bioinformatic software tools are generally the product of many improvements over time. We also find an excess of slow and inaccurate bioinformatic software tools, and this is consistent across many sub-disciplines. There are few tools that are middle-of-road in terms of accuracy and speed trade-offs.Our findings indicate that accurate bioinformatic software is primarily the product of long-term commitments to software development. In addition, we hypothesise that bioinformatics software suffers from publication bias. Software that is intermediate in terms of both speed and accuracy may be difficult to publish-possibly due to author, editor and reviewer practises. This leaves an unfortunate hole in the literature, as ideal tools may fall into this gap. High accuracy tools are not always useful if they are slow, while high speed is not useful if the results are also inaccurate.© 2022. The Author(s).",
+No,20220228,prediction,35124428,The independent prognostic value of global epigenetic alterations: An analysis of single-cell ATAC-seq of circulating leukocytes from trauma patients followed by validation in whole blood leukocyte transcriptomes across three etiologies of critical illness.,EBioMedicine,"While bulk and single cell transcriptomic patterns in circulating leukocytes from trauma patients have been reported, how these relate to changes in open chromatin patterns remain unstudied. Here, we investigated whether single-cell ATAC-seq would provide further resolution of transcriptomic patterns that align with patient outcomes.We performed scATAC-seq on peripheral blood mononuclear cells from four trauma patients at <4 h, 24 h, 72 h post-injury and four matched healthy controls, and extracted the features associated with the global epigenetic alterations. Three large-scale bulk transcriptomic datasets from trauma, burn and sepsis patients were used to validate the scATAC-seq derived signature, explore patient epigenetic heterogeneity (Epigenetic Groups: EG_hi vs. EG_lo), and associate patterns with clinical outcomes in critical illness.Patient subsets with gene expression patterns in blood leukocytes representative of a high global epigenetic signature (EG_hi) had worse outcomes across three etiologies of critical illness. EG_hi designation contributed independent of the known immune leukocyte transcriptomic responses to patient prognosis (Trauma: HR=0.62 [95% CI: 0.43-0.89, event set as recovery], p=0.01, n=167; Burns: HR=4.35 [95% CI: 0.816-23.2, event set as death], p=0.085, n=121; Sepsis: HR=1.60 [95% CI: 1.10-2.33, event set as death], p=0.013, n=479; Cox proportional hazards regression).The inclusion of gene expression patterns that associate with global epigenetic changes in circulating leukocytes improves the resolution of transcriptome-based patient classification in acute critical illnesses. Early detection of both the global epigenetic signature and the known immune transcriptomic patterns associates with the worse prognosis in trauma, burns and sepsis.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.",
+No,20220228,prediction,35169688,Machine learning for multi-omics data integration in cancer.,iScience,"Multi-omics data analysis is an important aspect of cancer molecular biology studies and has led to ground-breaking discoveries. Many efforts have been made to develop machine learning methods that automatically integrate omics data. Here, we review machine learning tools categorized as either general-purpose or task-specific, covering both supervised and unsupervised learning for integrative analysis of multi-omics data. We benchmark the performance of five machine learning approaches using data from the Cancer Cell Line Encyclopedia, reporting accuracy on cancer type classification and mean absolute error on drug response prediction, and evaluating runtime efficiency. This review provides recommendations to researchers regarding suitable machine learning method selection for their specific applications. It should also promote the development of novel machine learning methodologies for data integration, which will be essential for drug discovery, clinical trial design, and personalized treatments.© 2022 The Author(s).",
+No,20220228,review,35170363,Evaluating the challenges and reproducibility of studies investigating DNA methylation signatures of psychological stress.,Epigenomics,"Psychological stress can increase the risk of a wide range of negative health outcomes. Studies have been completed to determine if DNA methylation changes occur in the human brain because of stress and are associated with long-term effects and disease, but results have been inconsistent. Human candidate gene studies (150) and epigenome-wide association studies (68) were systematically evaluated to assess how DNA methylation is impacted by stress during the prenatal period, early childhood and adulthood. The association between DNA methylation ofNR3C1exon 1F and child maltreatment and early life adversity was well demonstrated, but other genes did not exhibit a clear association. The reproducibility of individual CpG sites in epigenome-wide association studies was also poor. However, biological pathways, including stress response, brain development and immunity, have been consistently identified across different stressors throughout the life span. Future studies would benefit from the increased sample size, longitudinal design, standardized methodology, optimal quality control, and improved statistical procedures.",
+No,20220228,sex differences,35177097,Gender-affirming hormone therapy induces specific DNA methylation changes in blood.,Clin Epigenetics,"DNA methylation is an epigenetic mark that is influenced by underlying genetic profile, environment, and ageing. In addition to X-linked DNA methylation, sex-specific methylation patterns are widespread across autosomal chromosomes and can be present from birth or arise over time. In individuals where gender identity and sex assigned at birth are markedly incongruent, as in the case of transgender people, feminization or masculinization may be sought through gender-affirming hormone therapy (GAHT). GAHT is a cornerstone of transgender care, yet no studies to date have investigated its effect on genome-wide methylation. We profiled genome-wide DNA methylation in blood of transgender women (n = 13) and transgender men (n = 13) before and during GAHT (6 months and 12 months into feminizing or masculinizing hormone therapy).We identified several thousand differentially methylated CpG sites (DMPs) (Δβ ≥ 0.02, unadjusted p value < 0.05) and several differentially methylated regions (DMRs) in both people undergoing feminizing and masculinizing GAHT, the vast majority of which were progressive changes over time. X chromosome and sex-specific autosomal DNA methylation patterns established in early development are largely refractory to change in association with GAHT, with only 3% affected (Δβ ≥ 0.02, unadjusted p value < 0.05). The small number of sex-specific DMPs that were affected by GAHT were those that become sex-specific during the lifetime, known as sex-and-age DMPs, including DMRs in PRR4 and VMP1 genes. The GAHT-induced changes at these sex-associated probes consistently demonstrated a shift towards the methylation signature of the GAHT-naïve opposite sex, and we observed enrichment of previously reported adolescence-associated methylation changes.We provide evidence for GAHT inducing a unique blood methylation signature in transgender people. This study advances our understanding of the complex interplay between sex hormones, sex chromosomes, and DNA methylation in the context of immunity. We highlight the need to broaden the field of 'sex-specific' immunity beyond cisgender males and cisgender females, as transgender people on GAHT exhibit a unique molecular profile.© 2022. The Author(s).",
+No,20220314,dnam age,35255955,Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns.,Epigenetics Chromatin,"The epigenetic age can now be extrapolated from one of several epigenetic clocks, which are based on age-related changes in DNA methylation levels at specific multiple CpG sites. Accelerated aging, calculated from the discrepancy between the chronological age and the epigenetic age, has shown to predict morbidity and mortality rate. We assumed that deconvolution of epigenetic age to its components could shed light on the diversity of epigenetic, and by inference, on inter-individual variability in the causes of biological aging.Using the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the inter-personal variability in epigenetic aging, with CpG sites related to secretagogin and malin being the most variable. We show that equal epigenetic age in different subjects can result from variable contribution size of the same CpG sites to the total epigenetic age. In a healthy cohort, the most variable CpG sites are responsible for accelerated and decelerated epigenetic aging, relative to chronological age.Of the 353 CpG sites that form the basis for the Horvath epigenetic age, we have found the CpG sites that are responsible for accelerated and decelerated epigenetic aging in healthy subjects. However, the relative contribution of each site to aging varies between individuals, leading to variable personal aging patterns. Our findings pave the way to form personalized aging cards allowing the identification of specific genes related to CpG sites, as aging markers, and perhaps treatment of these targets in order to hinder undesirable age drifting.© 2022. The Author(s).",
+No,20220314,epigenetics,35157611,Ribosomal DNA methylation in human and mouse oocytes increases with age.,Aging (Albany NY),"An age-dependent increase in ribosomal DNA (rDNA) methylation has been observed across a broad spectrum of somatic tissues and the male mammalian germline. Bisulfite pyrosequencing (BPS) was used to determine the methylation levels of the rDNA core promoter and the rDNA upstream control element (UCE) along with two oppositely genomically imprinted control genes (PEG3andGTL2) in individual human germinal vesicle (GV) oocytes from 90 consenting women undergoing fertility treatment because of male infertility. Apart from a few (4%) oocytes with single imprinting defects (in eitherPEG3orGTL2), the analyzed GV oocytes displayed correct imprinting patterns. In 95 GV oocytes from 42 younger women (26-32 years), the mean methylation levels of the rDNA core promoter and UCE were 7.4±4.0% and 9.3±6.1%, respectively. In 79 GV oocytes from 48 older women (33-39 years), methylation levels increased to 9.3±5.3% (P= 0.014) and 11.6±7.4% (P= 0.039), respectively. An age-related increase in oocyte rDNA methylation was also observed in 123 mouse GV oocytes from 29 4-16-months-old animals. Similar to the continuously mitotically dividing male germline, ovarian aging is associated with a gain of rDNA methylation in meiotically arrested oocytes. Oocytes from the same woman can exhibit varying rDNA methylation levels and, by extrapolation, different epigenetic ages.",
+No,20220314,epigenetics,35166834,"DNA methylation cues in nucleosome geometry, stability and unwrapping.",Nucleic Acids Res,"Cytosine methylation at the 5-carbon position is an essential DNA epigenetic mark in many eukaryotic organisms. Although countless structural and functional studies of cytosine methylation have been reported, our understanding of how it influences the nucleosome assembly, structure, and dynamics remains obscure. Here, we investigate the effects of cytosine methylation at CpG sites on nucleosome dynamics and stability. By applying long molecular dynamics simulations on several microsecond time scale, we generate extensive atomistic conformational ensembles of full nucleosomes. Our results reveal that methylation induces pronounced changes in geometry for both linker and nucleosomal DNA, leading to a more curved, under-twisted DNA, narrowing the adjacent minor grooves, and shifting the population equilibrium of sugar-phosphate backbone geometry. These DNA conformational changes are associated with a considerable enhancement of interactions between methylated DNA and the histone octamer, doubling the number of contacts at some key arginines. H2A and H3 tails play important roles in these interactions, especially for DNA methylated nucleosomes. This, in turn, prevents a spontaneous DNA unwrapping of 3-4 helical turns for the methylated nucleosome with truncated histone tails, otherwise observed in the unmethylated system on several microseconds time scale.Published by Oxford University Press on behalf of Nucleic Acids Research 2022.",
+No,20220314,epigenetics,35256817,"Means, mechanisms and consequences of adenine methylation in DNA.",Nat Rev Genet,"N6-methyl-2'-deoxyadenosine (6mA or m6dA) has been reported in the DNA of prokaryotes and eukaryotes ranging from unicellular protozoa and algae to multicellular plants and mammals. It has been proposed to modulate DNA structure and transcription, transmit information across generations and have a role in disease, among other functions. However, its existence in more recently evolved eukaryotes remains a topic of debate. Recent technological advancements have facilitated the identification and quantification of 6mA even when the modification is exceptionally rare, but each approach has limitations. Critical assessment of existing data, rigorous design of future studies and further development of methods will be required to confirm the presence and biological functions of 6mA in multicellular eukaryotes.© 2022. Springer Nature Limited.",
+No,20220314,ewas,35232984,Preterm birth buccal cell epigenetic biomarkers to facilitate preventative medicine.,Sci Rep,"Preterm birth is the major cause of newborn and infant mortality affecting nearly one in every ten live births. The current study was designed to develop an epigenetic biomarker for susceptibility of preterm birth using buccal cells from the mother, father, and child (triads). An epigenome-wide association study (EWAS) was used to identify differential DNA methylation regions (DMRs) using a comparison of control term birth versus preterm birth triads. Epigenetic DMR associations with preterm birth were identified for both the mother and father that were distinct and suggest potential epigenetic contributions from both parents. The mother (165 DMRs) and female child (136 DMRs) at p < 1e-04 had the highest number of DMRs and were highly similar suggesting potential epigenetic inheritance of the epimutations. The male child had negligible DMR associations. The DMR associated genes for each group involve previously identified preterm birth associated genes. Observations identify a potential paternal germline contribution for preterm birth and identify the potential epigenetic inheritance of preterm birth susceptibility for the female child later in life. Although expanded clinical trials and preconception trials are required to optimize the potential epigenetic biomarkers, such epigenetic biomarkers may allow preventative medicine strategies to reduce the incidence of preterm birth.© 2022. The Author(s).",
+Yes,20220314,ewas,35236238,Maternal Mediterranean diet in pregnancy and newborn DNA methylation: a meta-analysis in the PACE Consortium.,Epigenetics,"Higher adherence to the Mediterranean diet during pregnancy is related to a lower risk of preterm birth and to better offspring cardiometabolic health. DNA methylation may be an underlying biological mechanism. We evaluated whether maternal adherence to the Mediterranean diet was associated with offspring cord blood DNA methylation.We meta-analysed epigenome-wide association studies (EWAS) of maternal adherence to the Mediterranean diet during pregnancy and offspring cord blood DNA methylation in 2802 mother-child pairs from five cohorts. We calculated the relative Mediterranean diet (rMED) score with range 0-18 and an adjusted rMED excluding alcohol (rMEDp, range 0-16). DNA methylation was measured using Illumina 450K arrays. We used robust linear regression modelling adjusted for child sex, maternal education, age, smoking, body mass index, energy intake, batch, and cell types. We performed several functional analyses and examined the persistence of differential DNA methylation into childhood (4.5-7.8 y).rMEDp was associated with cord blood DNA methylation at cg23757341 (0.064% increase in DNA methylation per 1-point increase in the rMEDp score, SE = 0.011,P= 2.41 × 10-8). This cytosine-phosphate-guanine (CpG) site maps toWNT5B, associated with adipogenesis and glycaemic phenotypes. We did not identify associations with childhood gene expression, nor did we find enriched biological pathways. The association did not persist into childhood.In this meta-analysis, maternal adherence to the Mediterranean diet (excluding alcohol) during pregnancy was associated with cord blood DNA methylation level at cg23757341. Potential mediation of DNA methylation in associations with offspring health requires further study.",
+Yes,20220314,ewas,35236959,Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus.,Mol Psychiatry,"Antipsychotic drugs are the current first-line of treatment for schizophrenia and other psychotic conditions. However, their molecular effects on the human brain are poorly studied, due to difficulty of tissue access and confounders associated with disease status. Here we examine differences in gene expression and DNA methylation associated with positive antipsychotic drug toxicology status in the human caudate nucleus. We find no genome-wide significant differences in DNA methylation, but abundant differences in gene expression. These gene expression differences are overall quite similar to gene expression differences between schizophrenia cases and controls. Interestingly, gene expression differences based on antipsychotic toxicology are different between brain regions, potentially due to affected cell type differences. We finally assess similarities with effects in a mouse model, which finds some overlapping effects but many differences as well. As a first look at the molecular effects of antipsychotics in the human brain, the lack of epigenetic effects is unexpected, possibly because long term treatment effects may be relatively stable for extended periods.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20220314,ewas,35237685,Does DNA methylation mediate the association of age at puberty with forced vital capacity or forced expiratory volume in 1 s?,ERJ Open Res,"Age of pubertal onset is associated with lung function in adulthood. However, the underlying role of epigenetics as a mediator of this association remains unknown.DNA methylation (DNAm) in peripheral blood was measured at age 18 years in the Isle of Wight birth cohort (IOWBC) along with data on age of pubertal events, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) at 26 years. Structural equation models were applied to examine mediation effects of DNAm on the association of age at pubertal events with FVC and FEV1. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.In the IOWBC, for females, 21 cytosine-phosphate-guanine sites (CpGs) were shown to mediate the association of age at puberty with FVC or FEV1at 26 years (p<0.05). In males, DNAm at 20 CpGs was found to mediate the association of age at puberty with FVC (p<0.05). At almost all these CpGs, indirect effects (effects of age at pubertal events on FVC or FEV1viaDNAm) contributed a smaller portion to the total effects compared to direct effects (e.g.at cg08680129, �22% of the estimated total effect of age at menarche on FVC at age 26 was contributed by an indirect effect). Among the IOWBC-discovered CpGs available in ALSPAC, none of them was replicated in ALSPAC (p>0.05).Our findings suggest that post-adolescence DNAm in peripheral blood is likely not to mediate the association of age at pubertal onset with young adulthood FVC or FEV1.Copyright ©The authors 2022.",
+Yes,20220314,ewas,35237744,Periconception and Prenatal Exposure to Maternal Perceived Stress and Cord Blood DNA Methylation.,Epigenet Insights,"Maternal prenatal stress is associated with physiologic and adverse mental health outcomes in the offspring, but the underlying biologic mechanisms are unknown. We examined the associations of maternal perceived stress, including preconception exposure, with DNA methylation (DNAm) alterations in the cord blood buffy coats of 358 singleton infants.Maternal perceived stress was measured prior to and throughout pregnancy in a cohort of women enrolled in Effects of Aspirin in Gestation and Reproduction Trial (EAGeR) trial. Perceived stress assessments based on a standardized Likert-scale were obtained in periconception (~2 months preconception and 2-8 weeks of gestation) and pregnancy (8-36 weeks of gestation). Cumulative perceived stress was estimated by calculating the predicted area under the curve of stress reported prior to and during pregnancy. DNAm was measured by the Infinium MethylationEPIC BeadChip. Multivariable robust linear regression was used to assess associations of perceived stress with individual CpG probes.Based on a 0 to 3 scale, average reported preconception and early pregnancy stress were 0.76 (0.60) and 0.67 (0.50), respectively. Average mid- to late-pregnancy stress, based on a 0 to 10 scale, was 4.9 (1.6). Neither periconception nor pregnancy perceived stress were associated with individual CpG sites in neonatal cord blood (all false discovery rate [FDR] >5%).No effects of maternal perceived stress exposure on array-wide cord blood neonatal methylation differences were found.© The Author(s) 2022.",
+No,20220314,ewas,35242787,Role of Age-Related Changes in DNA Methylation in the Disproportionate Susceptibility and Worse Outcomes of Sepsis in Older Adults.,Front Med (Lausanne),"Sepsis, a complex multisystem disorder, is among the top causes of hospitalization and mortality in older adults. However, the mechanisms underlying the disproportionate susceptibility to sepsis and worse outcomes in the elderly are not well understood. Recently, changes in DNA methylation have been shown to be linked to aging processes and age-related diseases. Thus, we postulated that age-related changes in DNA methylation may play a role in the onset and prognosis of sepsis in elderly patients. Here, we performed genome-wide methylation profiling of peripheral blood from patients with sepsis and controls. Among the CpG sites whose methylation changes may contribute to an increase in sepsis susceptibility or mortality, 241 sites that possessed age-related changes in DNA methylation in controls may partly explain the increased risk of sepsis in older adults, and 161 sites whose methylation significantly correlated with age in sepsis group may be the potential mechanisms underlying the worse outcomes of elderly septic patients. Finally, an independent cohort was used to validate our findings. Together, our study demonstrates that age-related changes in DNA methylation may explain in part the disproportionate susceptibility and worse outcomes of sepsis in older adults.Copyright © 2022 Lang, Shen, Zhu, Zhao, Chen, Zhu, Su, Wang, Wang, Neri, Jiang and Chen.",
+No,20220314,ewas,35243180,Differential DNA methylation in Black and White individuals with chronic low back pain enrich different genomic pathways.,Neurobiol Pain,"Compared to Non-Hispanic Whites (NHWs), individuals who self-identify as Non-Hispanic Blacks (NHBs) in the United States experience more severe and disabling chronic low back pain (cLBP). We hypothesized that differences in DNA methylation (DNAm) play a role in racial disparities in cLBP.To determine the relationship between DNAm levels and racial group differences in adults with cLBP. Our study's secondary purpose was to perform a race-stratified comparison of adults with cLBP and pain-free controls and identify functional genomic pathways enriched by annotated differentially methylated genes.We recruited 49 NHBs and 49 NHWs (49 cLBP and 49 pain-free controls, PFCs), analyzed DNAm from whole blood using reduced representation bisulfite sequencing, and identified enriched genomic pathways.Among participants with cLBP, we identified 2873 differentially methylated loci (DML; methylation differences of at least 10% and p < 0.0001), many of which were annotated to genes of importance to pain pathology. These DMLs significantly enriched pathways to involved in nociception/pain processing (Dopamine-DARPP32 Feedback in cAMP signaling,GABA Receptor Signaling,Opioid Signaling) and neuronal differentiation (e.g.,Calcium Signaling, Axon Guidance Signaling, andEndocannabinoid Neuronal Synapse). Our race stratified analyses of individuals with cLBP versus PFCs revealed 2356 DMLs in NHBs and 772 DMLs in NHWs with p < 0.0001 and > 10% methylation difference. Ingenuity Pathway Analysis revealed that many pathways of significance to pain such asCorticotropin Releasing Hormone Signaling, White Adipose Tissue Browning,andGABA Receptor Signaling pathways, were more significant in NHBs than NHWs.Even though an individual's self-identified race is a social construct, not a biological variable, racism associated with that classification affects virtually every aspect of life, including disease risk. DNAm induced alterations in stress signaling pathways may explain worse pain outcomes in NHBs.© 2022 The Author(s).",
+No,20220314,ewas,35245816,Genome-wide DNA methylation profiling identifies epigenetic changes in CD4+ and CD14+ cells of multiple sclerosis patients.,Mult Scler Relat Disord,"Multiple sclerosis (MS) is a chronic autoimmune and degenerative disease of the central nervous system, which develops in genetically predisposed individuals upon exposure to environmental influences. Environmental triggers of MS, such as viral infections or smoking, were demonstrated to affect DNA methylation, and thus to involve this important epigenetic mechanism in the development of pathological process. To identify MS-associated DNA methylation hallmarks, we performed genome-wide DNA methylation profiling of two cell populations (CD4+ T-lymphocytes and CD14+ monocytes), collected from the same treatment-naive relapsing-remitting MS patients and healthy subjects, using Illumina 450 K methylation arrays. We revealed significant changes in DNA methylation for both cell populations in MS. In CD4+ cells of MS patients the majority of differentially methylated positions (DMPs) were shown to be hypomethylated, while in CD14+ cells - hypermethylated. Differential methylation of HLA-DRB1 gene in CD4+ and CD14+ cells was associated with carriage of DRB1*15 allele independently from the disease status. Besides, about 20% of identified DMPs were shared between two cell populations and had the same direction of methylation changes; they may be involved in basic epigenetic processes occuring in MS. These findings suggest that the epigenetic mechanism of DNA methylation in immune cells contributes to MS; further studies are now required to validate these results and understand their functional significance.Copyright © 2022. Published by Elsevier B.V.",
+Yes,20220314,ewas,35266797,Gestational Perfluoroalkyl Substance Exposure and DNA Methylation at Birth and 12 Years of Age: A Longitudinal Epigenome-Wide Association Study.,Environ Health Perspect,"DNA methylation alterations may underlie associations between gestational perfluoroalkyl substances (PFAS) exposure and later-life health outcomes. To the best of our knowledge, no longitudinal studies have examined the associations between gestational PFAS and DNA methylation.We examined associations of gestational PFAS exposure with longitudinal DNA methylation measures at birth and in adolescence using the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006; Cincinnati, Ohio).We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in mothers during pregnancy. We measured DNA methylation in cord blood (n=266) and peripheral leukocytes at 12 years of age (n=160) using the Illumina HumanMethylation EPIC BeadChip. We analyzed associations betweenlog2-transformedPFAS concentrations and repeated DNA methylation measures using linear regression with generalized estimating equations. We included interaction terms between children's age and gestational PFAS. We performed Gene Ontology enrichment analysis to identify molecular pathways. We used Project Viva (1999-2002; Boston, Massachusetts) to replicate significant associations.After adjusting for covariates, 435 cytosine-guanine dinucleotide (CpG) sites were associated with PFAS (false discovery rate,q<0.05). Specifically, we identified 2 CpGs for PFOS, 12 for PFOA, 8 for PFHxS, and 413 for PFNA; none overlapped. Among these, 2 CpGs for PFOA and 4 for PFNA were replicated in Project Viva. Some of the PFAS-associated CpG sites annotated to gene regions related to cancers, cognitive health, cardiovascular disease, and kidney function. We found little evidence that the associations between PFAS and DNA methylation differed by children's age.In these longitudinal data, PFAS biomarkers were associated with differences in several CpGs at birth and at 12 years of age in or near genes linked to some PFAS-associated health outcomes. Future studies should examine whether DNA methylation mediates associations between gestational PFAS exposure and health. https://doi.org/10.1289/EHP10118.",
+No,20220314,meqtl,35247911,Genetic regulation of DNA methylation yields novel discoveries in GWAS of colorectal cancer.,Cancer Epidemiol Biomarkers Prev,"Colorectal cancer (CRC) has a strong epigenetic component that is accompanied by frequent DNA methylation (DNAm) alterations in addition to heritable genetic risk. It is of interest to understand the interrelationship of germline genetics, DNAm, and CRC risk.We performed a genome-wide methylation quantitative trait locus (meQTL) analysis in 1355 people, assessing the pairwise associations between genetic variants and lymphocytes methylation data. In addition, we used penalized regression with cis-genetic variants +/- 1Mb of methylation to identify genome-wide heritable DNAm. We evaluated the association of genetically predicted methylation with CRC risk based on GWAS of over 125,000 cases and controls using the multivariate sMiST as well as univariately via examination of marginal association with CRC risk.Of the 142 known CRC genome-wide association studies (GWAS) loci, 47 were identified as meQTLs. We identified 4 novel CRC associated loci (NID2, ATXN10, KLHDC10 and CEP41) that reside over 1Mb outside of known CRC loci and 10 secondary signals within 1Mb of known loci.Leveraging information of DNAm regulation into genetic association of CRC risk reveals novel pathways in CRC tumorigenesis. Our summary statistics-based framework sMiST provides a powerful approach by combining information from the effect through methylation and residual direct effects of the meQTLs on disease risk. Further validation and functional follow-up of these novel pathways are needed.Using genotype, DNA methylation, GWAS, we identified four new CRC risk loci. We studied the landscape of genetic regulation of DNA methylation via single-SNP and multi-SNP meQTL analyses.",
+No,20220314,methods,35245419,Sparse latent factor regression models for genome-wide and epigenome-wide association studies.,Stat Appl Genet Mol Biol,"Association of phenotypes or exposures with genomic and epigenomic data faces important statistical challenges. One of these challenges is to account for variation due to unobserved confounding factors, such as individual ancestry or cell-type composition in tissues. This issue can be addressed with penalized latent factor regression models, where penalties are introduced to cope with high dimension in the data. If a relatively small proportion of genomic or epigenomic markers correlate with the variable of interest, sparsity penalties may help to capture the relevant associations, but the improvement over non-sparse approaches has not been fully evaluated yet. Here, we present least-squares algorithms that jointly estimate effect sizes and confounding factors in sparse latent factor regression models. In simulated data, sparse latent factor regression models generally achieved higher statistical performance than other sparse methods, including the least absolute shrinkage and selection operator and a Bayesian sparse linear mixed model. In generative model simulations, statistical performance was slightly lower (while being comparable) to non-sparse methods, but in simulations based on empirical data, sparse latent factor regression models were more robust to departure from the model than the non-sparse approaches. We applied sparse latent factor regression models to a genome-wide association study of a flowering trait for the plantArabidopsis thalianaand to an epigenome-wide association study of smoking status in pregnant women. For both applications, sparse latent factor regression models facilitated the estimation of non-null effect sizes while overcoming multiple testing issues. The results were not only consistent with previous discoveries, but they also pinpointed new genes with functional annotations relevant to each application.© 2022 Walter de Gruyter GmbH, Berlin/Boston.",
+No,20220314,omics,35212264,Getting closer to the clinic.,Elife,Associations between plasma protein levels and DNA methylation patterns can be used to predict the onset of age-related chronic disease.,
+No,20220314,omics,35220969,A guide for the diagnosis of rare and undiagnosed disease: beyond the exome.,Genome Med,"Rare diseases affect 30 million people in the USA and more than 300-400 million worldwide, often causing chronic illness, disability, and premature death. Traditional diagnostic techniques rely heavily on heuristic approaches, coupling clinical experience from prior rare disease presentations with the medical literature. A large number of rare disease patients remain undiagnosed for years and many even die without an accurate diagnosis. In recent years, gene panels, microarrays, and exome sequencing have helped to identify the molecular cause of such rare and undiagnosed diseases. These technologies have allowed diagnoses for a sizable proportion (25-35%) of undiagnosed patients, often with actionable findings. However, a large proportion of these patients remain undiagnosed. In this review, we focus on technologies that can be adopted if exome sequencing is unrevealing. We discuss the benefits of sequencing the whole genome and the additional benefit that may be offered by long-read technology, pan-genome reference, transcriptomics, metabolomics, proteomics, and methyl profiling. We highlight computational methods to help identify regionally distant patients with similar phenotypes or similar genetic mutations. Finally, we describe approaches to automate and accelerate genomic analysis. The strategies discussed here are intended to serve as a guide for clinicians and researchers in the next steps when encountering patients with non-diagnostic exomes.© 2022. The Author(s).",
+No,20220314,omics,35241783,Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.,Mol Psychiatry,"Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (Ntotal = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20220314,pqtl,35264221,Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes.,Genome Med,"Blood plasma proteins play an important role in immune defense against pathogens, including cytokine signaling, the complement system, and the acute-phase response. Recent large-scale studies have reported genetic (i.e., protein quantitative trait loci, pQTLs) and non-genetic factors, such as age and sex, as major determinants to inter-individual variability in immune response variation. However, the contribution of blood-cell composition to plasma protein heterogeneity has not been fully characterized and may act as a mediating factor in association studies.Here, we evaluated plasma protein levels from 400 unrelated healthy individuals of western European ancestry, who were stratified by sex and two decades of life (20-29 and 60-69 years), from the Milieu Intérieur cohort. We quantified 229 proteins by Luminex in a clinically certified laboratory and their levels of variation were analyzed together with 5.2 million single-nucleotide polymorphisms. With respect to non-genetic variables, we included 254 lifestyle and biochemical factors, as well as counts of seven circulating immune cell populations measured by hemogram and standardized flow cytometry.Collectively, we found 152 significant associations involving 49 proteins and 20 non-genetic variables. Consistent with previous studies, age and sex showed a global, pervasive impact on plasma protein heterogeneity, while body mass index and other health status variables were among the non-genetic factors with the highest number of associations. After controlling for these covariates, we identified 100 and 12 pQTLs acting in cis and trans, respectively, collectively associated with 87 plasma proteins and including 19 novel genetic associations. Genetic factors explained the largest fraction of the variability of plasma protein levels, as compared to non-genetic factors. In addition, blood-cell fractions, including leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, basophils, and platelets, had a larger contribution to inter-individual variability than age and sex and appeared as confounders of specific genetic associations. Finally, we identified new genetic associations with plasma protein levels of five monogenic Mendelian disease genes including two primary immunodeficiency genes (Ficolin-3 and FAS).Our study identified novel genetic and non-genetic factors associated to plasma protein levels which may inform health status and disease management.© 2022. The Author(s).",
+No,20220314,prediction,35209953,Evidence of accelerated epigenetic aging of breast tissues in patients with breast cancer is driven by CpGs associated with polycomb-related genes.,Clin Epigenetics,"Age is one of the strongest risk factors for the development of breast cancer, however, the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression.Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls).The Levine (p = 0.0037) and Yang clocks (p = 0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb-related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb-related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p = 0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration.Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb-related genes can be used to assess the risk of developing breast cancer among unaffected individuals.© 2022. The Author(s).",
+No,20220314,prediction,35225958,Opportunities for Early Cancer Detection: The Rise of ctDNA Methylation-Based Pan-Cancer Screening Technologies.,Epigenomes,"The efficiency of conventional screening programs to identify early-stage malignancies can be limited by the low number of cancers recommended for screening as well as the high cumulative false-positive rate, and associated iatrogenic burden, resulting from repeated multimodal testing. The opportunity to use minimally invasive liquid biopsy testing to screen asymptomatic individuals at-risk for multiple cancers simultaneously could benefit from the aggregated diseases prevalence and a fixed specificity. Increasing both latter parameters is paramount to mediate high positive predictive value-a useful metric to evaluate a screening test accuracy and its potential harm-benefit. Thus, the use of a single test for multi-cancer early detection (stMCED) has emerged as an appealing strategy for increasing early cancer detection rate efficiency and benefit population health. A recent flurry of these stMCED technologies have been reported for clinical potential; however, their development is facing unique challenges to effectively improve clinical cost-benefit. One promising avenue is the analysis of circulating tumour DNA (ctDNA) for detecting DNA methylation biomarker fingerprints of malignancies-a hallmark of disease aetiology and progression holding the potential to be tissue- and cancer-type specific. Utilizing panels of epigenetic biomarkers could potentially help to detect earlier stages of malignancies as well as identify a tumour of origin from blood testing, useful information for follow-up clinical decision making and subsequent patient care improvement. Overall, this review collates the latest and most promising stMCED methodologies, summarizes their clinical performances, and discusses the specific requirements multi-cancer tests should meet to be successfully implemented into screening guidelines.",
+No,20220411,cancer,35331302,Pan-cancer predictions of transcription factors mediating aberrant DNA methylation.,Epigenetics Chromatin,"Aberrant DNA methylation is a hallmark of cancer cells. However, the mechanisms underlying changes in DNA methylation remain elusive. Transcription factors initially thought to be repressed from binding by DNA methylation, have recently emerged as being able to shape DNA methylation patterns.Here, we integrated the massive amount of data available from The Cancer Genome Atlas to predict transcription factors driving aberrant DNA methylation in 13 cancer types. We identified differentially methylated regions between cancer and matching healthy samples, searched for transcription factor motifs enriched in those regions and selected transcription factors with corresponding changes in gene expression. We predict transcription factors known to be involved in cancer as well as novel candidates to drive hypo-methylated regions such as FOXA1 and GATA3 in breast cancer, FOXA1 and TWIST1 in prostate cancer and NFE2L2 in lung cancer. We also predict transcription factors that lead to hyper-methylated regions upon transcription factor loss such as EGR1 in several cancer types. Finally, we validate that FOXA1 and GATA3 mediate hypo-methylated regions in breast cancer cells.Our work highlights the importance of some transcription factors as upstream regulators shaping DNA methylation patterns in cancer.© 2022. The Author(s).",
+No,20220411,cancer,35354049,Genome-wide identification and analysis of prognostic features in human cancers.,Cell Rep,"Clinical decisions in cancer rely on precisely assessing patient risk. To improve our ability to identify the most aggressive malignancies, we constructed genome-wide survival models using gene expression, copy number, methylation, and mutation data from 10,884 patients. We identified more than 100,000 significant prognostic biomarkers and demonstrate that these genomic features can predict patient outcomes in clinically ambiguous situations. While adverse biomarkers are commonly believed to represent cancer driver genes and promising therapeutic targets, we show that cancer features associated with shorter survival times are not enriched for either oncogenes or for successful drug targets. Instead, the strongest adverse biomarkers represent widely expressed cell-cycle and housekeeping genes, and, correspondingly, nearly all therapies directed against these features have failed in clinical trials. In total, our analysis establishes a rich resource for prognostic biomarker analysis and clarifies the use of patient survival data in preclinical cancer research and therapeutic development.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.",
+No,20220411,chromatin,35332326,Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.,Nat Neurosci,"Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104-106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20220411,chromatin,35301427,Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose.,Mol Psychiatry,"Opioid use disorder is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. Opioid overdose, the most severe outcome of opioid use disorder, remains the leading cause of accidental death in the United States. We interrogated the effects of opioid overdose on the brain using ChIP-seq to quantify patterns of H3K27 acetylation in dorsolateral prefrontal cortical neurons isolated from 51 opioid-overdose cases and 51 accidental death controls. Among opioid cases, we observed global hypoacetylation and identified 388 putative enhancers consistently depleted for H3K27ac. Machine learning on H3K27ac patterns predicted case-control status with high accuracy. We focused on case-specific regulatory alterations, revealing 81,399 hypoacetylation events, uncovering vast inter-patient heterogeneity. We developed a strategy to decode this heterogeneity based on convergence analysis, which leveraged promoter-capture Hi-C to identify five genes over-burdened by alterations in their regulatory network or ""plexus"": ASTN2, KCNMA1, DUSP4, GABBR2, ENOX1. These convergent loci are enriched for opioid use disorder risk genes and heritability for generalized anxiety, number of sexual partners, and years of education. Overall, our multi-pronged approach uncovers neurobiological aspects of opioid use disorder and captures genetic and environmental factors perpetuating the opioid epidemic.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20220411,dnam age,35313970,Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer.,Genome Med,"Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.For EAA-Horvath, a genome-wide significant association was mapped to the SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to the HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.We identified novel genetic variants in the SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.© 2022. The Author(s).",
+No,20220411,dnam age,35346416,Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study.,Elife,"Background:Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.Methods:We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (9 single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs) and GrimAge (4 SNPs) on multiple cancers (i.e., breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N=34,710), and for cancer from the UK Biobank (N cases=2,671-13,879; N controls=173,493-372,016), FinnGen (N cases=719-8,401; N controls=74,685-174,006) and several international cancer genetic consortia (N cases=11,348-122,977; N controls=15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.Results:Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR=1.12 per year increase in GrimAge acceleration, 95%CI 1.04-1.20,p=0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR=1.15, 95%CI 1.09-1.21,p=0.006), than rectal cancer (IVW OR=1.05, 95%CI 0.97-1.13,p=0.24). Results were less consistent for associations between other epigenetic clocks and cancers.Conclusions:GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.Funding:FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.© 2022, Morales Berstein et al.",
+Yes,20220411,eqtm,35302492,Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood.,Elife,"The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children's blood, using data from 832 children of the Human Early Life Exposome (HELIX) project.Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition.We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGene's TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. In 40.4% of the eQTMs, the CpG and the eGene were both associated with at least one genetic variant. The overlap of autosomal cis eQTMs in children's blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants.This catalogue of autosomal cis eQTMs in children's blood can help the biological interpretation of EWAS findings and is publicly available at https://helixomics.isglobal.org/ and at Dryad (doi:10.5061/dryad.fxpnvx0t0).The study has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project); the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project); from the European Union's Horizon 2020 research and innovation programme under grant agreement no 733206 (LIFECYCLE project), and from the European Joint Programming Initiative ""A Healthy Diet for a Healthy Life"" (JPI HDHL and Instituto de Salud Carlos III) under the grant agreement no AC18/00006 (NutriPROGRAM project). The genotyping was supported by the projects PI17/01225 and PI17/01935, funded by the Instituto de Salud Carlos III and co-funded by European Union (ERDF, ""A way to make Europe"") and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; ""Rhea Plus"": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). We acknowledge support from the Spanish Ministry of Science and Innovation through the ""Centro de Excelencia Severo Ochoa 2019-2023"" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. MV-U and CR-A were supported by a FI fellowship from the Catalan Government (FI-DGR 2015 and #016FI_B 00272). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128).© 2022, Ruiz-Arenas et al.",
+No,20220411,ewas,35305575,DNA methylation changes in cord blood and the developmental origins of health and disease - a systematic review and replication study.,BMC Genomics,"Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance.We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age. We then attempted to replicate these published associations in the Canadian Healthy Infant Longitudinal Development (CHILD) and the South Asian birth cohort (START) cord blood epigenome-wide data.We screened 68 full-text articles and identified a total of 17 cord blood epigenome-wide association studies (EWAS) of the traits of interest. Out of the 290 CpG sites reported, 19 were identified in more than one study; all of them associated with maternal smoking. In CHILD and START EWAS, thousands of sites associated with gestational age were identified and maintained significance after correction for multiple testing. In CHILD, there was differential methylation observed for 8 of the published maternal smoking sites. No other traits tested (i.e., folate levels, gestational diabetes, birthweight) replicated in the CHILD or START cohorts.Maternal smoking during pregnancy and gestational age are strongly associated with differential methylation in offspring cord blood, as assessed in the EWAS literature and our birth cohorts. There are a limited number of reported methylation sites associated in more than two independent studies related to pregnancy. Additional large studies of diverse populations with fine phenotyping are needed to produce robust epigenome-wide data in order to further elucidate the effect of intrauterine exposures on the infants' methylome.© 2022. The Author(s).",
+Yes,20220411,ewas,35317219,Association of prenatal acetaminophen use and acetaminophen metabolites with DNA methylation of newborns: analysis of two consecutive generations of the Isle of Wight birth cohort.,Environ Epigenet,"Acetaminophen is used by nearly two-thirds of pregnant women. Although considered safe, studies have demonstrated associations between prenatal acetaminophen use and adverse health outcomes in offspring. Since DNA methylation (DNAm) at birth may act as an early indicator of later health, assessments on whether DNAm of newborns is associated with gestational acetaminophen use or its metabolites are needed. Using data from three consecutive generations of the Isle of Wight cohort (F0-grandmothers, F1-mothers, and F2-offspring) we investigated associations between acetaminophen metabolites in F0 serum at delivery with epigenome-wide DNAm in F1 (Guthrie cards) and between acetaminophen use of F1 and F2-cord-serum levels with F2 cord blood DNAm. In epigenome-wide screening, we eliminated non-informative DNAm sites followed by linear regression of informative sites. Based on repeated pregnancies, indication bias analyses tested whether acetaminophen indicated maternal diseases or has a risk in its own right. Considering that individuals with similar intake process acetaminophen differently, metabolites were clustered to distinguish metabolic exposures. Finally, metabolite clusters from F1-maternal and F2-cord sera were tested for their associations with newborn DNAm (F1 and F2). Twenty-one differential DNAm sites in cord blood were associated with reported maternal acetaminophen intake in the F2 generation. For 11 of these cytosine-phosphate-guanine (CpG) sites, an indication bias was excluded and five were replicated in F2 with metabolite clusters. In addition, metabolite clusters showed associations with 25 CpGs in the F0-F1 discovery analysis, of which five CpGs were replicated in the F2-generation. Our results suggest that prenatal acetaminophen use, measured as metabolites, may influence DNAm in newborns.Published by Oxford University Press 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.",
+Yes,20220411,ewas,35277542,Epigenome-wide association study and epigenetic age acceleration associated with cigarette smoking among Costa Rican adults.,Sci Rep,"Smoking-associated DNA methylation (DNAm) signatures are reproducible among studies of mostly European descent, with mixed evidence if smoking accelerates epigenetic aging and its relationship to longevity. We evaluated smoking-associated DNAm signatures in the Costa Rican Study on Longevity and Healthy Aging (CRELES), including participants from the high longevity region of Nicoya. We measured genome-wide DNAm in leukocytes, tested Epigenetic Age Acceleration (EAA) from five clocks and estimates of telomere length (DNAmTL), and examined effect modification by the high longevity region. 489 participants had a mean (SD) age of 79.4 (10.8) years, and 18% were from Nicoya. Overall, 7.6% reported currently smoking, 35% were former smokers, and 57.4% never smoked. 46 CpGs and five regions (e.g. AHRR, SCARNA6/SNORD39, SNORA20, and F2RL3) were differentially methylated for current smokers. Former smokers had increased Horvath's EAA (1.69-years; 95% CI 0.72, 2.67), Hannum's EAA (0.77-years; 95% CI 0.01, 1.52), GrimAge (2.34-years; 95% CI1.66, 3.02), extrinsic EAA (1.27-years; 95% CI 0.34, 2.21), intrinsic EAA (1.03-years; 95% CI 0.12, 1.94) and shorter DNAmTL (- 0.04-kb; 95% CI - 0.08, - 0.01) relative to non-smokers. There was no evidence of effect modification among residents of Nicoya. Our findings recapitulate previously reported and novel smoking-associated DNAm changes in a Latino cohort.© 2022. The Author(s).",
+Yes,20220411,ewas,35274472,DNA methylation alterations in muscle of critically ill patients.,J Cachexia Sarcopenia Muscle,"Intensive care unit (ICU)-acquired weakness can persist beyond ICU stay and has been associated with long-term functional impairment of ICU survivors. Recently, DNA methylation alterations were found in the blood of ICU patients, partially explaining long-term developmental impairment of critically ill children. As illness-induced aberrant DNA methylation theoretically could also be involved in long-term weakness, we investigated whether the DNA methylation signature in muscle of adult critically ill patients differs from that in muscle of healthy controls.Genome-wide methylation was determined (Infinium® HumanMethylationEPIC BeadChips) in DNA extracted from skeletal muscle biopsies that had been collected on Day 8 ± 1 in ICU from 172 EPaNIC-trial patients [66% male sex, median age 62.7 years, median body mass index (BMI) 25.9 kg/m2] and 20 matched healthy controls (70% male sex, median age 58.0 years, median BMI 24.4 kg/m2). Methylation status of individual cytosine-phosphate-guanine (CpG) sites of patients and controls was compared with F-tests, using the Benjamini-Hochberg false discovery rate to correct for multiple comparisons. Differential methylation of DNA regions was assessed with bump hunting, with 1000 permutations assessing uncertainty, expressed as family-wise error rate. Gene expression was investigated for 10 representative affected genes.In DNA from ICU patients, 565 CpG sites, associated with 400 unique genes, were differentially methylated as compared with controls (average difference 3.2 ± 0.1% ranging up to 16.9%, P < 0.00005). Many of the associated genes appeared highly relevant for muscle structure and function/weakness, including genes involved in myogenesis, muscle regeneration, nerve/muscle membrane excitability, muscle denervation/re-innervation, axon guidance/myelination/degeneration/regeneration, synapse function, ion channelling with especially calcium signalling, metabolism (glucose, protein, and fat), insulin signalling, neuroendocrine hormone regulation, mitochondrial function, autophagy, apoptosis, oxidative stress, Wnt signalling, transcription regulation, muscle fat infiltration during regeneration, and fibrosis. In patients as compared with controls, we also identified two hypomethylated regions, spanning 18 and 3 CpG sites in the promoters of the HIC1 and NADK2 genes, respectively (average differences 5.8 ± 0.01% and 12.1 ± 0.04%, family-wise error rate <0.05). HIC1 and NADK2 play important roles in muscle regeneration and postsynaptic acetylcholine receptors and in mitochondrial processes, respectively. Nine of 10 investigated genes containing DNA methylation alterations were differentially expressed in patients as compared with controls (P ≤ 0.03).Critically ill patients present with a different DNA methylation signature in skeletal muscle as compared with healthy controls, which in theory could provide a biological basis for long-term persistence of weakness in ICU survivors.ClinicalTrials.gov: NCT00512122, registered on 31 July 2007.© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.",
+Yes,20220411,ewas,35379837,DNA methylation in peripheral tissues and left-handedness.,Sci Rep,"Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355-0.578]), but inconsistent across tissues (correlation range [- 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.© 2022. The Author(s).",
+Yes,20220411,ewas,35377194,Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women.,Environ Health Perspect,"Glyphosate is the most commonly used herbicide in the world and is purported to have a variety of health effects, including endocrine disruption and an elevated risk of several types of cancer. Blood DNA methylation has been shown to be associated with many other environmental exposures, but to our knowledge, no studies to date have examined the association between blood DNA methylation and glyphosate exposure.We conducted an epigenome-wide association study to identify DNA methylation loci associated with urinary glyphosate and its metabolite aminomethylphosphonic acid (AMPA) levels. Secondary goals were to determine the association of epigenetic age acceleration with glyphosate and AMPA and develop blood DNA methylation indices to predict urinary glyphosate and AMPA levels.For 392 postmenopausal women, white blood cell DNA methylation was measured using the Illumina Infinium MethylationEPIC BeadChip array. Glyphosate and AMPA were measured in two urine samples per participant using liquid chromatography-tandem mass spectrometry. Methylation differences at the probe and regional level associated with glyphosate and AMPA levels were assessed using a resampling-based approach. Probes and regions that had an false discovery rateq<0.1in≥90%of 1,000 subsamples of the study population were considered differentially methylated. Differentially methylated sites from the probe-specific analysis were combined into a methylation index. Epigenetic age acceleration from three epigenetic clocks and an epigenetic measure of pace of aging were examined for associations with glyphosate and AMPA.We identified 24 CpG sites whose methylation level was associated with urinary glyphosate concentration and two associated with AMPA. Four regions, within the promoters of theMSH4,KCNA6,ABAT, andNDUFAF2/ERCC8genes, were associated with glyphosate levels, along with an association betweenESR1promoter hypomethylation and AMPA. The methylation index accurately predicted glyphosate levels in an internal validation cohort. AMPA, but not glyphosate, was associated with greater epigenetic age acceleration.Glyphosate and AMPA exposure were associated with DNA methylation differences that could promote the development of cancer and other diseases. Further studies are warranted to replicate our results, determine the functional impact of glyphosate- and AMPA-associated differential DNA methylation, and further explore whether DNA methylation could serve as a biomarker of glyphosate exposure. https://doi.org/10.1289/EHP10174.",
+Yes,20220411,ewas,35354486,DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses.,Genome Med,"Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown.We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined= 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm.Widespread associations (NCpG= 71, pBonferroni< 0.05, p < 6.3 × 10-8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni< 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDRranged from 0.024 to 7.45 × 10-30; depression to DNAm: pFDRranged from 0.028 to 0.003).PRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.© 2022. The Author(s).",
+Yes,20220411,ewas,35347270,Grandmaternal smoking during pregnancy is associated with differential DNA methylation in peripheral blood of their grandchildren.,Eur J Hum Genet,"The idea that information can be transmitted to subsequent generation(s) by epigenetic means has been studied for decades but remains controversial in humans. Epidemiological studies have established that grandparental exposures are associated with health outcomes in their grandchildren, often with sex-specific effects; however, the mechanism of transmission is still unclear. We conducted Epigenome Wide Association Studies (EWAS) to test whether grandmaternal smoking during pregnancy is associated with altered DNA methylation (DNAm) in peripheral blood from their adolescent grandchildren. We used data from a birth cohort, with discovery and replication datasets of up to 1225 and 708 individuals (respectively, for the maternal line), aged 15-17 years, and tested replication in the same individuals at birth and 7 years. We show for the first time that DNAm at a small number of loci in cord blood is associated with grandmaternal smoking in humans. In adolescents we see suggestive associations in regions of the genome which we hypothesised a priori could be involved in transgenerational transmission - we observe sex-specific associations at two sites on the X chromosome and one in an imprinting control region. All are within transcription factor binding sites (TFBSs), and we observe enrichment for TFBS among the CpG sites with the strongest associations; however, there is limited evidence that the associations we see replicate between timepoints. The implication of this work is that effects of smoking during pregnancy may induce DNAm changes in later generations and that these changes are often sex-specific, in line with epidemiological associations.© 2022. The Author(s).",
+Yes,20220411,ewas,35346352,Epigenome-wide DNA methylation profiling of conditioned pain modulation in individuals with non-specific chronic low back pain.,Clin Epigenetics,"The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP.In the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM.Based on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group.This is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP.© 2022. The Author(s).",
+Yes,20220411,ewas,35328979,Prenatal Exposure to Traffic-Related Air Pollution and the DNA Methylation in Cord Blood Cells: MOCEH Study.,Int J Environ Res Public Health,"Particulate matter with a diameter of ≤10 µm (PM10) and nitrogen dioxide (NO2) affect the DNA methylation in the fetus, but epigenetic studies regarding prenatal exposure to air pollution in Asia are lacking. Therefore, this study aimed to assess whether there is any association between the ambient concentrations of PM10and NO2and CpG methylation in the cord blood DNA by using a Korean birth cohort. The concentrations of the air pollutants were incorporated into the final LUR model by using the maternal address data. The methylation level was determined using HumanMethylationEPIC BeadChip and a linear regression analysis model. A multipollutant model including both PM10and NO2and models with single pollutants were used for each trimester exposure. The number of differentially methylated positions was the largest for midpregnancy exposure in both the single pollutant models and the multipollutant regression analysis. Additionally, gene-set analysis regarding midpregnancy exposure revealed four gene ontology terms (cellular response to staurosporine, positive regulation of cytoskeleton organization, neurotransmitter transport, and execution phase of apoptosis). In conclusion, these findings show an association between prenatal PM10and NO2exposure and DNA methylation in several CpG sites in cord blood cells, especially for midpregnancy exposure.",
+No,20220411,imprinting,35296332,Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences.,Clin Epigenetics,"Imprinting disorders are a group of congenital diseases which are characterized by molecular alterations affecting differentially methylated regions (DMRs). To date, at least twelve imprinting disorders have been defined with overlapping but variable clinical features including growth and metabolic disturbances, cognitive dysfunction, abdominal wall defects and asymmetry. In general, a single specific DMR is affected in an individual with a given imprinting disorder, but there are a growing number of reports on individuals with so-called multilocus imprinting disturbances (MLID), where aberrant imprinting marks (most commonly loss of methylation) occur at multiple DMRs. However, as the literature is fragmented, we reviewed the molecular and clinical data of 55 previously reported or newly identified MLID families with putative pathogenic variants in maternal effect genes (NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6) and in other candidate genes (ZFP57, ARID4A, ZAR1, UHRF1, ZNF445).In 55 families, a total of 68 different candidate pathogenic variants were identified (7 in NLRP2, 16 in NLRP5, 7 in NLRP7, 17 in PADI6, 15 in ZFP57, and a single variant in each of the genes ARID4A, ZAR1, OOEP, UHRF1, KHDC3L and ZNF445). Clinical diagnoses of affected offspring included Beckwith-Wiedemann syndrome spectrum, Silver-Russell syndrome spectrum, transient neonatal diabetes mellitus, or they were suspected for an imprinting disorder (undiagnosed). Some families had recurrent pregnancy loss.Genomic maternal effect and foetal variants causing MLID allow insights into the mechanisms behind the imprinting cycle of life, and the spatial and temporal function of the different factors involved in oocyte maturation and early development. Further basic research together with identification of new MLID families will enable a better understanding of the link between the different reproductive issues such as recurrent miscarriages and preeclampsia in maternal effect variant carriers/families and aneuploidy and the MLID observed in the offsprings. The current knowledge can already be employed in reproductive and genetic counselling in specific situations.© 2022. The Author(s).",
+No,20220411,metastable epialleles,35355955,Maternal tobacco smoke exposure is associated with increased DNA methylation at human metastable epialleles in infant cord blood.,Environ Epigenet,"Metastable epialleles (MEs) are genomic regions that are stochastically methylated prior to germ layer specification and exhibit high interindividual but low intra-individual variability across tissues. ME methylation is vulnerable to environmental stressors, including diet. Tobacco smoke (TS) exposure during pregnancy is associated with adverse impacts on fetal health and maternal micronutrient levels as well as altered methylation. Our objective was to determine if maternal smoke exposure impacts methylation at MEs. Consistent with prior studies, we observed reductions in one-carbon pathway micronutrients with gestational TS exposure, including maternal folate (P = 0.02) and vitamins B6 (P = 0.05) and B12 (P = 0.007). We examined putative MEsBOLA3, PAX8,andZFYVE28in cord blood specimens from 85 Newborn Epigenetics STudy participants. Gestational TS exposure was associated with elevated DNA methylation atPAX8(+5.22% average methylation; 95% CI: 0.33% to 10.10%;P = 0.037). In human conceptal kidney tissues, higherPAX8transcription was associated with lower methylation (Rs = 0.55;P = 0.07), suggesting that the methylation levels established at MEs, and their environmentally induced perturbation, may have meaningful, tissue-specific functional consequences. This may be particularly important becausePAX8is implicated in several cancers, including pediatric kidney cancer. Our data are the first to indicate vulnerability of human ME methylation establishment to TS exposure, with a general trend of increasing levels of methylation at these loci. Further investigation is needed to determine how TS exposure-mediated changes in DNA methylation at MEs, and consequent expression levels, might affect smoking-related disease risk.© The Author(s) 2022. Published by Oxford University Press.",
+No,20220411,methods,35235458,Epigenetic MRI: Noninvasive imaging of DNA methylation in the brain.,Proc Natl Acad Sci U S A,"Significance Dynamic epigenetic activity is a fundamental mechanism underpinning how the brain changes its function during development and aging and in response to environmental and disease stimuli. We developed a technology called epigenetic MRI (eMRI) that enables noninvasive imaging of DNA methylation in the brain, a major epigenetic mechanism. eMRI reveals strong regional differences in global DNA methylation in pig brains, a model with stronger resemblance to human brains than are rodents. Given the noninvasive nature of eMRI, our results pave the way for a DNA-methylation imaging paradigm for living human brains. We expect eMRI to enable many studies to unravel the molecular control of brain function and disease.",
+No,20220411,methods,35361122,ENNGene: an Easy Neural Network model building tool for Genomics.,BMC Genomics,"The recent big data revolution in Genomics, coupled with the emergence of Deep Learning as a set of powerful machine learning methods, has shifted the standard practices of machine learning for Genomics. Even though Deep Learning methods such as Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs) are becoming widespread in Genomics, developing and training such models is outside the ability of most researchers in the field.Here we present ENNGene-Easy Neural Network model building tool for Genomics. This tool simplifies training of custom CNN or hybrid CNN-RNN models on genomic data via an easy-to-use Graphical User Interface. ENNGene allows multiple input branches, including sequence, evolutionary conservation, and secondary structure, and performs all the necessary preprocessing steps, allowing simple input such as genomic coordinates. The network architecture is selected and fully customized by the user, from the number and types of the layers to each layer's precise set-up. ENNGene then deals with all steps of training and evaluation of the model, exporting valuable metrics such as multi-class ROC and precision-recall curve plots or TensorBoard log files. To facilitate interpretation of the predicted results, we deploy Integrated Gradients, providing the user with a graphical representation of an attribution level of each input position. To showcase the usage of ENNGene, we train multiple models on the RBP24 dataset, quickly reaching the state of the art while improving the performance on more than half of the proteins by including the evolutionary conservation score and tuning the network per protein.As the role of DL in big data analysis in the near future is indisputable, it is important to make it available for a broader range of researchers. We believe that an easy-to-use tool such as ENNGene can allow Genomics researchers without a background in Computational Sciences to harness the power of DL to gain better insights into and extract important information from the large amounts of data available in the field.© 2022. The Author(s).",
+No,20220411,omics,2021.12.17.473125,Integration of public DNA methylation and expression networks via eQTMs improves prediction of functional gene–gene,biorxiv,"Gene co-expression networks can be used to infer functional relationships between genes, but they do not work well for all genes. We investigated whether DNA methylation can provide complementary information for such genes. We first carried out an eQTM meta-analysis of 3,574 gene expression and methylation samples from blood, brain and nasal epithelial brushed cells to identify links between methylated CpG sites and genes. This revealed 6,067 significant eQTM genes, and we observed that histone modification information is predictive of both eQTM direction and presence, enabling us to link many CpG sites to genes. We then generated a co-methylation network – MethylationNetwork – using 27,720 publicly available methylation profiles and integrated it with a public RNA-seq co-expression dataset of 31,499 samples. Here, we observed that MethylationNetwork can identify experimentally validated interacting pairs of genes that could not be identified in the RNA-seq datasets. We then developed a novel integration pipeline based on CCA and used the integrated methylation and gene networks to predict gene pairs reported in the STRING database. The integrated network showed significantly improved prediction performance compared to using a DNA co-methylation or a gene co-expression network alone. This is the first study to integrate data from two -omics layers from unmatched public samples across different tissues and diseases, and our results highlight the issues and potential of integrating public datasets from multiple molecular phenotypes. The eQTMs we identified can be used as an annotation resource for epigenome-wide association, and we believe that our integration pipeline can be used as a framework for future -omics integration analyses of public datasets.
 
 We provide supporting materials and results, including the harmonized DNA methylation data from multiple tissues and diseases in https://data.harmjanwestra.nl/comethylation/, the discovered and predicted eQTMs, the corresponding CCA components and the trained prediction models in a Zenodo repository (https://zenodo.org/record/4666994). We provide notebooks to facilitate use of the proposed pipeline in a GitHub repository (https://github.com/molgenis/methylationnetwork).",
-,No,20220411,omics,35259029,Multi-Omics Integration in a Twin Cohort and Predictive Modeling of Blood Pressure Values.,OMICS,"Abnormal blood pressure is strongly associated with risk of high-prevalence diseases, making the study of blood pressure a major public health challenge. Although biological mechanisms underlying hypertension at the single omic level have been discovered, multi-omics integrative analyses using continuous variations in blood pressure values remain limited. We used a multi-omics regression-based method, called sparse multi-block partial least square, for integrative, explanatory, and predictive interests in study of systolic and diastolic blood pressure values. Various datasets were obtained from the Finnish Twin Cohort for up to 444 twins. Blocks of omics-including transcriptomic, methylation, metabolomic-data as well as polygenic risk scores and clinical data were integrated into the modeling and supported by cross-validation. The predictive contribution of each omics block when predicting blood pressure values was investigated using external participants from the Young Finns Study. In addition to revealing interesting inter-omics associations, we found that each block of omics heterogeneously improved the predictions of blood pressure values once the multi-omics data were integrated. The modeling revealed a plurality of clinical, transcriptomic, and metabolomic factors consistent with the literature and that play a leading role in explaining unit variations in blood pressure. These findings demonstrate (1) the robustness of our integrative method to harness results obtained by single omics discriminant analyses, and (2) the added value of predictive and exploratory gains of a multi-omics approach in studies of complex phenotypes such as blood pressure.",
-,No,20220411,prediction,35304597,DNA methylation-based predictors of health: applications and statistical considerations.,Nat Rev Genet,"DNA methylation data have become a valuable source of information for biomarker development, because, unlike static genetic risk estimates, DNA methylation varies dynamically in relation to diverse exogenous and endogenous factors, including environmental risk factors and complex disease pathology. Reliable methods for genome-wide measurement at scale have led to the proliferation of epigenome-wide association studies and subsequently to the development of DNA methylation-based predictors across a wide range of health-related applications, from the identification of risk factors or exposures, such as age and smoking, to early detection of disease or progression in cancer, cardiovascular and neurological disease. This Review evaluates the progress of existing DNA methylation-based predictors, including the contribution of machine learning techniques, and assesses the uptake of key statistical best practices needed to ensure their reliable performance, such as data-driven feature selection, elimination of data leakage in performance estimates and use of generalizable, adequately powered training samples.© 2022. Springer Nature Limited.",
-,No,20220411,prediction,35283726,DNA Methylation Markers and Prediction Model for Depression and Their Contribution for Breast Cancer Risk.,Front Mol Neurosci,"Major depressive disorder (MDD) has become a leading cause of disability worldwide. However, the diagnosis of the disorder is dependent on clinical experience and inventory. At present, there are no reliable biomarkers to help with diagnosis and treatment. DNA methylation patterns may be a promising approach for elucidating the etiology of MDD and predicting patient susceptibility. Our overarching aim was to identify biomarkers based on DNA methylation, and then use it to propose a methylation prediction score for MDD, which we hope will help us evaluate the risk of breast cancer.Methylation data from 533 samples were extracted from the Gene Expression Omnibus (GEO) database, of which, 324 individuals were diagnosed with MDD. Statistical difference of DNA Methylation between Promoter and Other body region (SIMPO) score for each gene was calculated based on the DNA methylation data. Based on SIMPO scores, we selected the top genes that showed a correlation with MDD in random resampling, then proposed a methylation-derived Depression Index (mDI) by combining the SIMPO of the selected genes to predict MDD. A validation analysis was then performed using additional DNA methylation data from 194 samples extracted from the GEO database. Furthermore, we applied the mDI to construct a prediction model for the risk of breast cancer using stepwise regression and random forest methods.The optimal mDI was derived from 426 genes, which included 245 positive and 181 negative correlations. It was constructed to predict MDD with high predictive power (AUC of 0.88) in the discovery dataset. In addition, we observed moderate power for mDI in the validation dataset with an OR of 1.79. Biological function assessment of the 426 genes showed that they were functionally enriched in Eph Ephrin signaling and beta-catenin Wnt signaling pathways. The mDI was then used to construct a predictive model for breast cancer that had an AUC ranging from 0.70 to 0.67.Our results indicated that DNA methylation could help to explain the pathogenesis of MDD and assist with its diagnosis.Copyright © 2022 Wang, Sun, Pang, Zheng, Liang, He, Tang, Yu, Xiong and Chang.",
-,No,20220411,reference,35277705,A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution.,Nat Methods,"Bulk-tissue DNA methylomes represent an average over many different cell types, hampering our understanding of cell-type-specific contributions to disease development. As single-cell methylomics is not scalable to large cohorts of individuals, cost-effective computational solutions are needed, yet current methods are limited to tissues such as blood. Here we leverage the high-resolution nature of tissue-specific single-cell RNA-sequencing datasets to construct a DNA methylation atlas defined for 13 solid tissue types and 40 cell types. We comprehensively validate this atlas in independent bulk and single-nucleus DNA methylation datasets. We demonstrate that it correctly predicts the cell of origin of diverse cancer types and discovers new prognostic associations in olfactory neuroblastoma and stage 2 melanoma. In brain, the atlas predicts a neuronal origin for schizophrenia, with neuron-specific differential DNA methylation enriched for corresponding genome-wide association study risk loci. In summary, the DNA methylation atlas enables the decomposition of 13 different human tissue types at a high cellular resolution, paving the way for an improved interpretation of epigenetic data.© 2022. The Author(s).",
-,No,20220411,translation,35337378,Ethical implications of epigenetics in the era of personalized medicine.,Clin Epigenetics,"Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatization as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all populations equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflection on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determinism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into society.© 2022. The Author(s).",
-,No,20220411,twins,35301182,Early life affects late-life health through determining DNA methylation across the lifespan: A twin study.,EBioMedicine,"Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time.1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included. Familial correlations (i.e., correlations between twins) for 353,681 methylation sites were estimated and modelled as a function of twin pair cohabitation history.The methylome average familial correlation was around zero at birth (MZ pair: -0.01; DZ pair: -0.04), increased with the time of twins living together during childhood at rates of 0.16 (95%CI: 0.12-0.20) for MZ pairs and 0.13 (95%CI: 0.07-0.20) for DZ pairs per decade, and decreased with the time of living apart during adulthood at rates of 0.026 (95%CI: 0.019-0.033) for MZ pairs and 0.027 (95%CI: 0.011-0.043) for DZ pairs per decade. Neither the increasing nor decreasing rate differed by zygosity (both P>0.1), consistent with cohabitation environment shared by twins, rather than genetic factors, influencing the methylation familial correlation changes. Familial correlations for 6.6% (23,386/353,681) sites changed with twin pair cohabitation history. These sites were enriched for high heritability, proximal promoters, and epigenetic/genetic associations with various early-life factors and late-life health conditions.Early life strongly influences DNA methylation variation across the lifespan, and the effects are stronger for heritable sites and sites biologically relevant to the regulation of gene expression. Early life could affect late-life health through influencing DNA methylation.Victorian Cancer Agency, Cancer Australia, Cure Cancer Foundation.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.",
-,Yes,20220523,ewas,35546478,Integrative analysis of clinical and epigenetic biomarkers of mortality.,Aging Cell,"DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7, of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR = 4.1 × 10-4) and negatively associated with longevity (Beta = -1.9, PMR = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.",
-,No,20220523,dnam age,35501397,Making sense of the ageing methylome.,Nat Rev Genet,"Over time, the human DNA methylation landscape accrues substantial damage, which has been associated with a broad range of age-related diseases, including cardiovascular disease and cancer. Various age-related DNA methylation changes have been described, including at the level of individual CpGs, such as differential and variable methylation, and at the level of the whole methylome, including entropy and correlation networks. Here, we review these changes in the ageing methylome as well as the statistical tools that can be used to quantify them. We detail the evidence linking DNA methylation to ageing phenotypes and the longevity strategies aimed at altering both DNA methylation patterns and machinery to extend healthspan and lifespan. Lastly, we discuss theories on the mechanistic causes of epigenetic ageing.© 2022. Springer Nature Limited.",
-,No,20220523,dnam age,35481978,The aging epigenome.,Elife,"A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer.© 2022, Pierce.",
-,No,20220523,dnam age,35522643,eClock: An ensemble-based method to accurately predict ages with a biased distribution from DNA methylation data.,PLoS One,"DNA methylation is closely related to senescence, so it has been used to develop statistical models, called clock models, to predict chronological ages accurately. However, because the training data always have a biased age distribution, the model performance becomes weak for the samples with a small age distribution density. To solve this problem, we developed the R package eClock, which uses a bagging-SMOTE method to adjust the biased distribution and predict age with an ensemble model. Moreover, it also provides a bootstrapped model based on bagging only and a traditional clock model. The performance on three datasets showed that the bagging-SMOTE model significantly improved rare sample age prediction. In addition to model construction, the package also provides other functions such as data visualization and methylation feature conversion to facilitate the research in relevant areas.",
-,No,20220523,dnam score,35550596,The early-life exposome modulates the effect of polymorphic inversions on DNA methylation.,Commun Biol,"Polymorphic genomic inversions are chromosomal variants with intrinsic variability that play important roles in evolution, environmental adaptation, and complex traits. We investigated the DNA methylation patterns of three common human inversions, at 8p23.1, 16p11.2, and 17q21.31 in 1,009 blood samples from children from the Human Early Life Exposome (HELIX) project and in 39 prenatal heart tissue samples. We found inversion-state specific methylation patterns within and nearby flanking each inversion region in both datasets. Additionally, numerous inversion-exposure interactions on methylation levels were identified from early-life exposome data comprising 64 exposures. For instance, children homozygous at inv-8p23.1 and higher meat intake were more susceptible to TDH hypermethylation (P = 3.8 × 10-22); being the inversion, exposure, and gene known risk factors for adult obesity. Inv-8p23.1 associated hypermethylation of GATA4 was also detected across numerous exposures. Our data suggests that the pleiotropic influence of inversions during development and lifetime could be substantially mediated by allele-specific methylation patterns which can be modulated by the exposome.© 2022. The Author(s).",
-,No,20220523,dnam scores,35513492,Epigenetics of type 2 diabetes mellitus and weight change - a tool for precision medicine?,Nat Rev Endocrinol,"Pioneering studies performed over the past few decades demonstrate links between epigenetics and type 2 diabetes mellitus (T2DM), the metabolic disorder with the most rapidly increasing prevalence in the world. Importantly, these studies identified epigenetic modifications, including altered DNA methylation, in pancreatic islets, adipose tissue, skeletal muscle and the liver from individuals with T2DM. As non-genetic factors that affect the risk of T2DM, such as obesity, unhealthy diet, physical inactivity, ageing and the intrauterine environment, have been associated with epigenetic modifications in healthy individuals, epigenetics probably also contributes to T2DM development. In addition, genetic factors associated with T2DM and obesity affect the epigenome in human tissues. Notably, causal mediation analyses found DNA methylation to be a potential mediator of genetic associations with metabolic traits and disease. In the past few years, translational studies have identified blood-based epigenetic markers that might be further developed and used for precision medicine to help patients with T2DM receive optimal therapy and to identify patients at risk of complications. This Review focuses on epigenetic mechanisms in the development of T2DM and the regulation of body weight in humans, with a special focus on precision medicine.© 2022. Springer Nature Limited.",
-,No,20220523,epigenetics,35473573,Comprehensive enhancer-target gene assignments improve gene set level interpretation of genome-wide regulatory data.,Genome Biol,"Revealing the gene targets of distal regulatory elements is challenging yet critical for interpreting regulome data. Experiment-derived enhancer-gene links are restricted to a small set of enhancers and/or cell types, while the accuracy of genome-wide approaches remains elusive due to the lack of a systematic evaluation. We combined multiple spatial and in silico approaches for defining enhancer locations and linking them to their target genes aggregated across >500 cell types, generating 1860 human genome-wide distal enhancer-to-target gene definitions (EnTDefs). To evaluate performance, we used gene set enrichment (GSE) testing on 87 independent ENCODE ChIP-seq datasets of 34 transcription factors (TFs) and assessed concordance of results with known TF Gene Ontology annotations, and other benchmarks.The top ranked 741 (40%) EnTDefs significantly outperform the common, naïve approach of linking distal regions to the nearest genes, and the top 10 EnTDefs perform well when applied to ChIP-seq data of other cell types. The GSE-based ranking of EnTDefs is highly concordant with ranking based on overlap with curated benchmarks of enhancer-gene interactions. Both our top general EnTDef and cell-type-specific EnTDefs significantly outperform seven independent computational and experiment-based enhancer-gene pair datasets. We show that using our top EnTDefs for GSE with either genome-wide DNA methylation or ATAC-seq data is able to better recapitulate the biological processes changed in gene expression data performed in parallel for the same experiment than our lower-ranked EnTDefs.Our findings illustrate the power of our approach to provide genome-wide interpretation regardless of cell type.© 2022. The Author(s).",
-,No,20220523,epigenetics,35488174,The Placental Epigenome as a Molecular Link Between Prenatal Exposures and Fetal Health Outcomes Through the DOHaD Hypothesis.,Curr Environ Health Rep,"The developmental origins of health and disease (DOHaD) hypothesis posits that the perinatal environment can impact fetal and later life health. The placenta is uniquely situated to assess prenatal exposures in the context of DOHaD because it is an essential ephemeral fetal organ that manages the transport of oxygen, nutrients, waste, and endocrine signals between the mother and fetus. The purpose of this review is to summarize recent studies that evaluated the DOHaD hypothesis in human placentas using epigenomics, including DNA methylation and transcriptomic studies of mRNA, lncRNA, and microRNAs.Between 2016 and 2021, 28 articles evaluated associations between prenatal exposures and placental epigenomics across broad exposure categories including maternal smoking, psychosocial stressors, chemicals, air pollution, and metals. Sixteen of these studies connected exposures to health outcome such as birth weight, fetal growth, or infant neurobehavior through mediation analysis, identification of shared associations between exposure and outcome, or network analysis. These aspects of infant and childhood health serve as a foundation for future studies that aim to use placental epigenetics to understand relationships between the prenatal environment and perinatal complications (such as preterm birth or fetal growth restriction) or later life childhood health. Placental DNA methylation and RNA expression have been linked to numerous prenatal exposures, such as PM2.5 air pollution, metals, and maternal smoking, as well as infant and childhood health outcomes, including fetal growth and birth weight. Placental epigenomics provides a unique opportunity to expand the DOHaD premise, particularly if research applies novel methodologies such as multi-omics analysis, sequencing of non-coding RNAs, mixtures analysis, and assessment of health outcomes beyond early childhood.© 2022. The Author(s).",
-,No,20220523,epigenetics,35527238,An optimal variant to gene distance window derived from an empirical definition of cis and trans protein QTLs.,BMC Bioinformatics,"A genome-wide association study (GWAS) correlates variation in the genotype with variation in the phenotype across a cohort, but the causal gene mediating that impact is often unclear. When the phenotype is protein abundance, a reasonable hypothesis is that the gene encoding that protein is the causal gene. However, as variants impacting protein levels can occur thousands or even millions of base pairs from the gene encoding the protein, it is unclear at what distance this simple hypothesis breaks down.By making the simple assumption that cis-pQTLs should be distance dependent while trans-pQTLs are distance independent, we arrive at a simple and empirical distance cutoff separating cis- and trans-pQTLs. Analyzing a recent large-scale pQTL study (Pietzner in Science 374:eabj1541, 2021) we arrive at an estimated distance cutoff of 944 kilobasepairs (95% confidence interval: 767-1,161) separating the cis and trans regimes.We demonstrate that this simple model can be applied to other molecular GWAS traits. Since much of biology is built on molecular traits like protein, transcript and metabolite abundance, we posit that the mathematical models for cis and trans distance distributions derived here will also apply to more complex phenotypes and traits.© 2022. The Author(s).",
-,Yes,20220523,ewas,35536696,Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis.,Am J Respir Crit Care Med,"Methylation integrates factors present at birth and modifiable across life that can influence pulmonary function. Studies are limited in scope and replication.To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function.Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multi-ancestry epigenome-wide meta-analyses (17,503 individuals: 14,761 European; 2,549 African; and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics.We identified 1,267 CpGs (1,042 genes) differentially methylated (FDR<0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to COPD (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that EWAS signals capture causal regulatory genomic loci.We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies providing insights into lung pathogenesis.",
-,Yes,20220523,ewas,35513368,Maternal prenatal depressive symptoms and toddler behavior: an umbilical cord blood epigenome-wide association study.,Transl Psychiatry,"Children of mothers with prenatal depressive symptoms (PND) have a higher risk of behavioral problems; fetal programming through DNA methylation is a possible underlying mechanism. This study investigated DNA methylation in cord blood to identify possible ""at birth"" signatures that may indicate susceptibility to behavioral problems at 18 months of age. Cord blood was collected from 256 children of mothers who had self-reported on symptoms of depression during pregnancy and the behavior of their child at 18 months of age. Whole genome DNA methylation was assessed using Illumina MethylationEPIC assay. The mother and child pairs were categorized into four groups, based on both self-reported depressive symptoms, PND or Healthy control (HC), and scores from the Child Behavior checklist (high or low for internalizing, externalizing, and total scores). Adjustments were made for batch effects, cell-type, and clinical covariates. Differentially methylated sites were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p values < 0.05 were considered significant. The analysis was also stratified by sex of the child. Among boys, we observed higher and correlated DNA methylation of one CpG-site in the promoter region of TPP1 in the HC group, with high externalizing scores compared to HC with low externalizing scores. Boys in the PND group showed lower DNA methylation in NUDT15 among those with high, compared to low, internalizing scores; the DNA methylation levels of CpGs in this gene were positively correlated with the CBCL scores. Hence, the differentially methylated CpG sites could be of interest for resilience, regardless of maternal mental health during pregnancy. The findings are in a relatively healthy study cohort, thus limiting the possibility of detecting strong effects associated with behavioral difficulties. This is the first investigation of cord blood DNA methylation signs of fetal programming of PND on child behavior at 18 months of age and thus calls for independent replications.© 2022. The Author(s).",
-,Yes,20220523,ewas,35505416,Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis.,Clin Epigenetics,"Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother-newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation.Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs.Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.© 2022. The Author(s).",
-,Yes,20220523,ewas,35504910,DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases.,Nat Commun,"We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.© 2022. The Author(s).",
-,Yes,20220523,ewas,35501310,An epigenetic association analysis of childhood trauma in psychosis reveals possible overlap with methylation changes associated with PTSD.,Transl Psychiatry,"Patients with a severe mental disorder report significantly higher levels of childhood trauma (CT) than healthy individuals. Studies have suggested that CT may affect brain plasticity through epigenetic mechanisms and contribute to developing various psychiatric disorders. We performed a blood-based epigenome-wide association study using the Childhood Trauma Questionnaire-short form in 602 patients with a current severe mental illness, investigating DNA methylation association separately for five trauma subtypes and the total trauma score. The median trauma score was set as the predefined cutoff for determining whether the trauma was present or not. Additionally, we compared our genome-wide results with methylation probes annotated to candidate genes previously associated with CT. Of the patients, 83.2% reported CT above the cutoff in one or more trauma subtypes, and emotional neglect was the trauma subtype most frequently reported. We identified one significant differently methylated position associated with the gene TANGO6 for physical neglect. Seventeen differentially methylated regions (DMRs) were associated with different trauma categories. Several of these DMRs were annotated to genes previously associated with neuropsychiatric disorders such as post-traumatic stress disorder and cognitive impairments. Our results support a biomolecular association between CT and severe mental disorders. Genes that were previously identified as differentially methylated in CT-exposed subjects with and without psychosis did not show methylation differences in our analysis. We discuss this inconsistency, the relevance of our findings, and the limitations of our study.© 2022. The Author(s).",
-,Yes,20220523,ewas,35500859,Gaseous air pollutants and DNA methylation in a methylome-wide association study of an ethnically and environmentally diverse population of U.S. adults.,Environ Res,"Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (PCochran's Q > 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.Copyright © 2022 Elsevier Inc. All rights reserved.",
-,Yes,20220523,ewas,35477560,Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder.,Clin Epigenetics,"Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD.DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association.Two CpG-sites presented with p-values below 1 × 10-05in PD: cg09738429 (p = 6.40 × 10-06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10-06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes.This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.© 2022. The Author(s).",
-,Yes,20220523,ewas,35475137,Genome- and epigenome-wide studies of plasma protein biomarkers for Alzheimer's disease implicate TBCA and TREM2 in disease risk.,Alzheimers Dement (Amst),"The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms.Genome-wide and epigenome-wide studies (nindividuals≤1064) were performed on plasma levels of 282 AD-associated proteins, identified by a structured literature review. Bayesian penalized regression estimated contributions of genetic and epigenetic variation toward inter-individual differences in plasma protein levels. Mendelian randomization (MR) and co-localization tested associations between proteins and disease-related phenotypes.Sixty-four independent genetic and 26 epigenetic loci were associated with 45 proteins. Novel findings included an association between plasma triggering receptor expressed on myeloid cells 2 (TREM2) levels and a polymorphism and cytosine-phosphate-guanine (CpG) site within theMS4A4Alocus. Higher plasma tubulin-specific chaperone A (TBCA) and TREM2 levels were significantly associated with lower AD risk.Our data inform the regulation of biomarker levels and their relationships with AD.© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.",
-,No,20220523,ewas,35455681,Epigenetic Signatures of Smoking in Five Brain Regions.,J Pers Med,"(1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which may contribute to the pathophysiology of addictive behavior observed in chronic smokers. (2) Methods: We investigated the similarity of DNAm signatures in matched blood and postmortem brain samples (n= 10). In addition, we performed EWASs in five brain regions belonging to the neurocircuitry of addiction: anterior cingulate cortex (ACC), Brodmann Area 9, caudate nucleus, putamen, and ventral striatum (n= 38-72). (3) Results: cg15925993 within theLOC339975gene was epigenome-wide significant in the ACC. Of 16 identified differentially methylated regions, two (PRSS50andLINC00612/A2M-AS1) overlapped between multiple brain regions. Functional enrichment was detected for biological processes related to neuronal development, inflammatory signaling and immune cell migration. Additionally, our results indicate the association of the well-knownAHRRCpG site cg05575921 with smoking in the brain. (4) Conclusion: The present study provides further evidence of the strong relationship between aberrant DNAm and smoking.",
-,No,20220523,ewas,35454993,Epigenome-Wide Analysis of DNA Methylation in Parkinson's Disease Cortex.,Life (Basel),"Epigenetic factors including DNA methylation contribute to specific patterns of gene expression. Gene-environment interactions can change the methylation status in the brain, and accumulation of these epigenetic changes over a lifespan may be co-responsible for a neurodegenerative disease like Parkinson's disease, which that is characterised by a late onset in life.To determine epigenetic modifications in the brains of Parkinson's disease patients.DNA methylation patterns were compared in the cortex tissue of 14 male PD patients and 10 male healthy individuals using the Illumina Methylation 450 K chip. Subsequently, DNA methylation of candidate genes was evaluated using bisulphite pyrosequencing, and DNA methylation of cytochrome P450 2E1 (CYP2E1) was characterized in DNA from blood mononuclear cells (259 PD patients and 182 healthy controls) and skin fibroblasts (10 PD patients and 5 healthy controls). Protein levels ofCYP2E1were analysed using Western blot in human cortex andknock-outmice brain samples.We found 35 hypomethylated and 22 hypermethylated genes with a methylation M-value difference &gt;0.5. Decreased methylation of cytochrome P450 2E1 (CYP2E1) was associated with increased protein levels in PD brains, but in peripheral tissues, i.e., in blood cells and skin fibroblasts, DNA methylation ofCYP2E1was unchanged. InCYP2E1 knock-outmice brain alpha-synuclein (SNCA) protein levels were down-regulated compared to wild-type mice, whereas treatment with trichloroethylene (TCE) up-regulatedCYP2E1protein in a dose-dependent manner in cultured cells. We further identified an interconnected group of genes associated with oxidative stress, such as Methionine sulfoxide reductase A (MSRA) and tumour protein 73 (TP73) in the brain, which again were not paralleled in other tissues and appeared to indicate brain-specific changes.Our study revealed surprisingly few dysmethylated genes in a brain region less affected in PD. We confirmed hypomethylation ofCYP2E1.",
-,Yes,20220523,ewas,35568878,Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array.,Clin Epigenetics,"Sex differences are known to play a role in disease aetiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and females in some tissues, including differences in DNA methylation patterns. Here, we report for the first time an analysis of autosomal sex differences in DNAme using the Illumina EPIC array in human whole blood by performing a discovery (n = 1171) and validation (n = 2471) analysis.We identified and validated 396 sex-associated differentially methylated CpG sites (saDMPs) with the majority found to be female-biased CpGs (74%). These saDMP's are enriched in CpG islands and CpG shores and located preferentially at 5'UTRs, 3'UTRs and enhancers. Additionally, we identified 266 significant sex-associated differentially methylated regions overlapping genes, which have previously been shown to exhibit epigenetic sex differences, and novel genes. Transcription factor binding site enrichment revealed enrichment of transcription factors related to critical developmental processes and sex determination such as SRY and ESR1.Our study reports a reliable catalogue of sex-associated CpG sites and elucidates several characteristics of these sites using large-scale discovery and validation data sets. This resource will benefit future studies aiming to investigate sex specific epigenetic signatures and further our understanding of the role of DNA methylation in sex differences in human whole blood.© 2022. The Author(s).",
-,No,20220523,ewas,35578268,"Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms.",Clin Epigenetics,"We previously showed that continued folic acid (FA) supplementation beyond the first trimester of pregnancy appears to have beneficial effects on neurocognitive performance in children followed for up to 11 years, but the biological mechanism for this effect has remained unclear. Using samples from our randomized controlled trial of folic acid supplementation in second and third trimester (FASSTT), where significant improvements in cognitive and psychosocial performance were demonstrated in children from mothers supplemented in pregnancy with 400 µg/day FA compared with placebo, we examined methylation patterns from cord blood (CB) using the EPIC array which covers approximately 850,000 cytosine-guanine (CG) sites across the genome. Genes showing significant differences were verified using pyrosequencing and mechanistic approaches used in vitro to determine effects on transcription.FA supplementation resulted in significant differences in methylation, particularly at brain-related genes. Further analysis showed these genes split into two groups. In one group, which included the CES1 gene, methylation changes at the promoters were important for regulating transcription. We also identified a second group which had a characteristic bimodal profile, with low promoter and high gene body (GB) methylation. In the latter, loss of methylation in the GB is linked to decreases in transcription: this group included the PRKAR1B/HEATR2 genes and the dopamine receptor regulator PDE4C. Overall, methylation in CB also showed good correlation with methylation profiles seen in a published data set of late gestation foetal brain samples.We show here clear alterations in DNA methylation at specific classes of neurodevelopmental genes in the same cohort of children, born to FA-supplemented mothers, who previously showed improved cognitive and psychosocial performance. Our results show measurable differences at neural genes which are important for transcriptional regulation and add to the supporting evidence for continued FA supplementation throughout later gestation. This trial was registered on 15 May 2013 at www.isrctn.com as ISRCTN19917787.© 2022. The Author(s).",
-,No,20220523,ewas,35577912,"Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants.",Mol Psychiatry,"The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events that precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers' attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 106individual CpG dinucleotides, using clustering-based significance criteria to control for multiple comparisons. We found that tens of thousands of individual infant CpGs were alternatively methylated in association with maternal attachment insecurity, maltreatment in childhood, and antenatal and postpartum depressive symptoms, including genes implicated in developmental patterning, cell-cell communication, hormonal regulation, immune function/inflammatory response, and neurotransmission. Density of DNA methylation at selected genes from the result set was also significantly associated with toddler socioemotional and behavioral problems. This is the first report to identify novel regions of the human infant genome at which DNA methylation patterns are associated longitudinally both with maternal characteristics and with offspring socioemotional and behavioral problems in toddlerhood.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20220523,meqtl,35488087,Incorporating local ancestry improves identification of ancestry-associated methylation signatures and meQTLs in African Americans.,Commun Biol,"Here we report three epigenome-wide association studies (EWAS) of DNA methylation on self-reported race, global genetic ancestry, and local genetic ancestry in admixed Americans from three sets of samples, including internal and external replications (Ntotal = 1224). Our EWAS on local ancestry (LA) identified the largest number of ancestry-associated DNA methylation sites and also featured the highest replication rate. Furthermore, by incorporating ancestry origins of genetic variations, we identified 36 methylation quantitative trait loci (meQTL) clumps for LA-associated CpGs that cannot be captured by a model that assumes identical genetic effects across ancestry origins. Lead SNPs at 152 meQTL clumps had significantly different genetic effects in the context of an African or European ancestry background. Local ancestry information enables superior capture of ancestry-associated methylation signatures and identification of ancestry-specific genetic effects on DNA methylation. These findings highlight the importance of incorporating local ancestry for EWAS in admixed samples from multi-ancestry cohorts.© 2022. The Author(s).",
-,No,20220523,methods,35567415,Evaluation of nanopore sequencing for epigenetic epidemiology: a comparison with DNA methylation microarrays.,Hum Mol Genet,"Most epigenetic epidemiology to date has utilized microarrays to identify positions in the genome where variation in DNA methylation is associated with environmental exposures or disease. However, these profile less than 3% of DNA methylation sites in the human genome, potentially missing affected loci and preventing the discovery of disrupted biological pathways. Third generation sequencing technologies, including Nanopore sequencing, have the potential to revolutionise the generation of epigenetic data, not only by providing genuine genome-wide coverage but profiling epigenetic modifications direct from native DNA. Here we assess the viability of using Nanopore sequencing for epidemiology by performing a comparison with DNA methylation quantified using the most comprehensive microarray available, the Illumina EPIC array. We implemented a CRISPR-Cas9 targeted sequencing approach in concert with Nanopore sequencing to profile DNA methylation in three genomic regions to attempt to rediscover genomic positions that existing technologies have shown are differentially methylated in tobacco smokers. Using Nanopore sequencing reads, DNA methylation was quantified at 1779 CpGs across three regions, providing a finer resolution of DNA methylation patterns compared to the EPIC array. The correlation of estimated levels of DNA methylation between platforms was high. Furthermore, we identified 12 CpGs where hypomethylation was significantly associated with smoking status, including 10 within the AHRR gene. In summary, Nanopore sequencing is a valid option for identifying genomic loci where large differences in DNAm are associated with a phenotype and has the potential to advance our understanding of the role differential methylation plays in the aetiology of complex disease.© The Author(s) 2022. Published by Oxford University Press.",
-,No,20220523,methods,35505215,BCurve: Bayesian Curve Credible Bands Approach for the Detection of Differentially Methylated Regions.,Methods Mol Biol,"High-throughput assays have been developed to measure DNA methylation, among which bisulfite-based sequencing (BS-seq) and microarray technologies are the most popular for genome-wide profiling. A major goal in DNA methylation analysis is the detection of differentially methylated genomic regions under two different conditions. To accomplish this, many state-of-the-art methods have been proposed in the past few years; only a handful of these methods are capable of analyzing both types of data (BS-seq and microarray), though. On the other hand, covariates, such as sex and age, are known to be potentially influential on DNA methylation; and thus, it would be important to adjust for their effects on differential methylation analysis. In this chapter, we describe a Bayesian curve credible bands approach and the accompanying software, BCurve, for detecting differentially methylated regions for data generated from either microarray or BS-Seq. The unified theme underlying the analysis of these two different types of data is the model that accounts for correlation between DNA methylation in nearby sites, covariates, and between-sample variability. The BCurve R software package also provides tools for simulating both microarray and BS-seq data, which can be useful for facilitating comparisons of methods given the known ""gold standard"" in the simulated data. We provide detailed description of the main functions in BCurve and demonstrate the utility of the package for analyzing data from both platforms using simulated data from the functions provided in the package. Analyses of two real datasets, one from BS-seq and one from microarray, are also furnished to further illustrate the capability of BCurve.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35505213,DNA Methylation Imputation Across Platforms.,Methods Mol Biol,"In this chapter, we will provide a review on imputation in the context of DNA methylation, specifically focusing on a penalized functional regression (PFR) method we have previously developed. We will start with a brief review of DNA methylation, genomic and epigenomic contexts where imputation has proven beneficial in practice, and statistical or computational methods proposed for DNA methylation in the recent literature (Subheading 1). The rest of the chapter (Subheadings 2-4) will provide a detailed review of our PFR method proposed for across-platform imputation, which incorporates nonlocal information using a penalized functional regression framework. Subheading 2 introduces commonly employed technologies for DNA methylation measurement and describes the real dataset we have used in the development of our method: the acute myeloid leukemia (AML) dataset from The Cancer Genome Atlas (TCGA) project. Subheading 3 comprehensively reviews our method, encompassing data harmonization prior to model building, the actual building of penalized functional regression model, post-imputation quality filter, and imputation quality assessment. Subheading 4 shows the performance of our method in both simulation and the TCGA AML dataset, demonstrating that our penalized functional regression model is a valuable across-platform imputation tool for DNA methylation data, particularly because of its ability to boost statistical power for subsequent epigenome-wide association study. Finally, Subheading 5 provides future perspectives on imputation for DNA methylation data.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35505212,A Review of High-Dimensional Mediation Analyses in DNA Methylation Studies.,Methods Mol Biol,"DNA methylation alterations have been widely studied as mediators of environmentally induced disease risks. With new advances in technique, epigenome-wide DNA methylation data (EWAS) have become the new standard for epigenetic studies in human populations. However, to date most epigenetic studies of mediation effects only involve selected (gene-specific) candidate methylation markers. There is an urgent need for appropriate analytical methods for EWAS mediation analysis. In this chapter, we provide an overview of recent advances on high-dimensional mediation analysis, with application to two DNA methylation data.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35505211,Increase the Power of Epigenome-Wide Association Testing Using ICC-Based Hypothesis Weighting.,Methods Mol Biol,"For large-scale hypothesis testing such as epigenome-wide association testing, adaptively focusing power on the more promising hypotheses can lead to a much more powerful multiple testing procedure. In this chapter, we introduce a multiple testing procedure that weights each hypothesis based on the intraclass correlation coefficient (ICC), a measure of ""noisiness"" of CpG methylation measurement, to increase the power of epigenome-wide association testing. Compared to the traditional multiple testing procedure on a filtered CpG set, the proposed procedure circumvents the difficulty to determine the optimal ICC cutoff value and is overall more powerful. We illustrate the procedure and compare the power to classical multiple testing procedures using an example data.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35505210,Meta-Analysis for Epigenome-Wide Association Studies.,Methods Mol Biol,"With the rapid development of methylation profiling technology, many datasets are generated to quantify genome-wide methylation patterns. Given the heavy burden of multiple testing of hundreds of thousands of DNA methylation markers, individual studies often have limited sample sizes and power. The EWAS meta-analysis is an approach that combines results from multiple studies on the same scientific question. It helps to improve statistical power by combining information from individual studies and reduce the chances of false positives. This chapter introduces commonly used meta-analysis methods and analytical tools with application to EWAS data.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35505208,Controlling Batch Effect in Epigenome-Wide Association Study.,Methods Mol Biol,"Methylation data, similar to other omics data, is susceptible to various technical issues that are potentially associated with unexplained or unrelated factors. Any difference in the measurement of DNA methylation, such as laboratory operation and sequencing platform, may lead to batch effects. With the accumulation of large-scale omics data, scientists are making joint efforts to generate and analyze omics data to answer various scientific questions. However, batch effects are inevitable in practice, and careful adjustment is needed. Multiple statistical methods for controlling bias and inflation between batches have been developed either by correcting based on known batch factors or by estimating directly from the output data. In this chapter, we will review and demonstrate several popular methods for batch effect correction and make practical recommendations in epigenome-wide association studies (EWAS).© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35505207,Cell Type-Specific Signal Analysis in Epigenome-Wide Association Studies.,Methods Mol Biol,"Hundreds of epigenome-wide association studies (EWAS) have been performed, successfully identifying replicated epigenomic signals in processes such as aging and smoking. Despite this progress, it remains a major challenge in EWAS to detect both cell type-specific and cell type confounding effects impacting study results. One way to identify these effects is through eFORGE (experimentally derived Functional element Overlap analysis of ReGions from EWAS), a published tool that uses 815 datasets from large-scale mapping studies to detect enriched tissues, cell types, and genomic regions. Here, I show that eFORGE analysis can be extended to EWAS differentially variable positions (DVPs), identifying target cell types and tissues. In addition, I also show that eFORGE tissue-specific enrichment can be detected for sites below EWAS significance threshold. I develop on these and other analysis examples, extending our knowledge of eFORGE cell type- and tissue-specific enrichment results for different EWAS.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35505205,Accurate Measurement of DNA Methylation: Challenges and Bias Correction.,Methods Mol Biol,"DNA methylation is a key epigenetic modification involved in gene regulation whose contribution to disease susceptibility is still not fully understood. As the cost of genome sequencing technologies continues to drop, it will soon become commonplace to perform genome-wide quantification of DNA methylation at a single base-pair resolution. However, the demand for its accurate quantification might vary across studies. When the scope of the analysis is to detect regions of the genome with different methylation patterns between two or more conditions, e.g., case vs control; treatments vs placebo, accuracy is not crucial. This is the case in epigenome-wide association studies used as genome-wide screening of methylation changes to detect new candidate genes and regions associated with a specific disease or condition. If the aim of the analysis is to use DNA methylation measurements as a biomarker for diseases diagnosis and treatment (Laird, Nat Rev Cancer 3:253-266, 2003; Bock, Epigenomics 1:99-110, 2009), it is instead recommended to produce accurate methylation measurements. Furthermore, if the objective is the detection of DNA methylation in subclonal tumor cell populations or in circulating tumor DNA or in any case of mosaicism, the importance of accuracy becomes critical. The aim of this chapter is to describe the factors that could affect the precise measurement of methylation levels and a recent Bayesian statistical method called MethylCal and its extension that have been proposed to minimize this problem.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35505204,Evaluating Reliability of DNA Methylation Measurement.,Methods Mol Biol,"DNA methylation is a widely studied epigenetic phenomenon. Alterations in methylation patterns influence human phenotypes and risk of disease. The Illumina Infinium HumanMethylation450 (HM450) and MethylationEPIC (EPIC) BeadChip are widely used microarray-based platforms for epigenome-wide association studies (EWASs). In this chapter, we will discuss the use of intraclass correlation coefficient (ICC) for assessing technical variations induced by methylation arrays at single-CpG level. ICC compares variation of methylation levels within- and between-replicate measurements, ranging between 0 and 1. We further characterize the distribution of ICCs using a mixture of truncated normal and normal distributions, and cluster CpG sites on the arrays into low- and high-reliability groups. In practice, we recommend that extra caution needs to be taken for associations at the CpG sites with low ICC values.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20220523,methods,35488315,"Batch-effect detection, correction and characterisation in Illumina HumanMethylation450 and MethylationEPIC BeadChip array data.",Clin Epigenetics,"Genomic technologies can be subject to significant batch-effects which are known to reduce experimental power and to potentially create false positive results. The Illumina Infinium Methylation BeadChip is a popular technology choice for epigenome-wide association studies (EWAS), but presently, little is known about the nature of batch-effects on these designs. Given the subtlety of biological phenotypes in many EWAS, control for batch-effects should be a consideration.Using the batch-effect removal approaches in the ComBat and Harman software, we examined two in-house datasets and compared results with three large publicly available datasets, (1214 HumanMethylation450 and 1094 MethylationEPIC BeadChips in total), and find that despite various forms of preprocessing, some batch-effects persist. This residual batch-effect is associated with the day of processing, the individual glass slide and the position of the array on the slide. Consistently across all datasets, 4649 probes required high amounts of correction. To understand the impact of this set to EWAS studies, we explored the literature and found three instances where persistently batch-effect prone probes have been reported in abstracts as key sites of differential methylation. As well as batch-effect susceptible probes, we also discover a set of probes which are erroneously corrected. We provide batch-effect workflows for Infinium Methylation data and provide reference matrices of batch-effect prone and erroneously corrected features across the five datasets spanning regionally diverse populations and three commonly collected biosamples (blood, buccal and saliva).Batch-effects are ever present, even in high-quality data, and a strategy to deal with them should be part of experimental design, particularly for EWAS. Batch-effect removal tools are useful to reduce technical variance in Infinium Methylation data, but they need to be applied with care and make use of post hoc diagnostic measures.© 2022. The Author(s).",
-,No,20220523,methods,35450213,High-Dimensional DNA Methylation Mediates the Effect of Smoking on Crohn's Disease.,Front Genet,"Epigenome-wide mediation analysis aims to identify high-dimensional DNA methylation at cytosine-phosphate-guanine (CpG) sites that mediate the causal effect of linking smoking with Crohn's disease (CD) outcome. Studies have shown that smoking has significant detrimental effects on the course of CD. So we assessed whether DNA methylation mediates the association between smoking and CD. Among 103 CD cases and 174 controls, we estimated whether the effects of smoking on CD are mediated through DNA methylation CpG sites, which we referred to as causal mediation effect. Based on the causal diagram, we first implemented sure independence screening (SIS) to reduce the pool of potential mediator CpGs from a very large to a moderate number; then, we implemented variable selection with de-sparsifying the LASSO regression. Finally, we carried out a comprehensive mediation analysis and conducted sensitivity analysis, which was adjusted for potential confounders of age, sex, and blood cell type proportions to estimate the mediation effects. Smoking was significantly associated with CD under odds ratio (OR) of 2.319 (95% CI: 1.603, 3.485,p < 0.001) after adjustment for confounders. Ninety-nine mediator CpGs were selected from SIS, and then, seven candidate CpGs were obtained by de-sparsifying the LASSO regression. Four of these CpGs showed statistical significance, and the average causal mediation effects (ACME) were attenuated from 0.066 to 0.126. Notably, three significant mediator CpGs had absolute sensitivity parameters of 0.40, indicating that these mediation effects were robust even when the assumptions were slightly violated. Genes (BCL3 and FKBP5) harboring these four CpGs were related to CD. These findings suggest that changes in methylation are involved in the mechanism by which smoking increases risk of CD.Copyright © 2022 Wang, Xia and Su.",
-,No,20220523,methods,35440009,Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach.,Clin Epigenetics,"DNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R2Methylation) towards childhood phenotypes is unknown. An estimate of R2Methylationwould provide context regarding the importance of DNA methylation explaining variance in health outcomes. We therefore estimated the variance explained by epigenome-wide cord blood methylation (R2Methylation) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n = 775) and Generation R (n = 1382).Using information from > 470,000 autosomal probes we estimated that DNA methylation at birth explains 32% (SDCV = 0.06) of gestational age variance and 5% (SDCV = 0.02) of birth weight variance. The R2Methylationestimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations.The results suggest that cord blood methylation explains a moderate degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the true R2Methylationfor these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth.© 2022. The Author(s).",
-,No,20220523,methods,35501393,Multi-omics single-cell data integration and regulatory inference with graph-linked embedding.,Nat Biotechnol,"Despite the emergence of experimental methods for simultaneous measurement of multiple omics modalities in single cells, most single-cell datasets include only one modality. A major obstacle in integrating omics data from multiple modalities is that different omics layers typically have distinct feature spaces. Here, we propose a computational framework called GLUE (graph-linked unified embedding), which bridges the gap by modeling regulatory interactions across omics layers explicitly. Systematic benchmarking demonstrated that GLUE is more accurate, robust and scalable than state-of-the-art tools for heterogeneous single-cell multi-omics data. We applied GLUE to various challenging tasks, including triple-omics integration, integrative regulatory inference and multi-omics human cell atlas construction over millions of cells, where GLUE was able to correct previous annotations. GLUE features a modular design that can be flexibly extended and enhanced for new analysis tasks. The full package is available online at https://github.com/gao-lab/GLUE .© 2022. The Author(s).",
-,No,20220523,prediction,35523767,Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum.,Transl Psychiatry,"Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR < 0.05), but not the ventral striatum of AUD cases. In the VS, DE genes at FDR < 0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune- and inflammation-related processes in AUD.© 2022. The Author(s).",
-,No,20220523,prediction,35490552,Complex trait methylation scores in the prediction of major depressive disorder.,EBioMedicine,"DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions.Here, we calculated methylation scores (MS) at multiple p-value thresholds for lifestyle (BMI, smoking, alcohol consumption, and educational attainment) and biochemical (high-density lipoprotein (HDL) and total cholesterol) factors in Generation Scotland (GS) (N=9,502) and in a replication cohort (ALSPACadults, N=565), using CpG sites reported in previous well-powered methylome-wide association studies. We also compared their predictive accuracy for MDD to a MDD MS in an independent GS sub-sample (N=4,432).Each trait MS was significantly associated with its corresponding phenotype in GS (βrange=0.089-1.457) and in ALSPAC (βrange=0.078-2.533). Each MS was also significantly associated with MDD before and after adjustment for its corresponding phenotype in GS (βrange=0.053-0.145). After accounting for relevant lifestyle factors, MS for educational attainment (β=0.094) and alcohol consumption (MSp-value<0.01-0.5; βrange=-0.069-0.083) remained significantly associated with MDD in GS. Smoking (AUC=0.569) and educational attainment (AUC=0.585) MSs could discriminate MDD from controls better than the MDD MS (AUC=0.553) in the independent GS sub-sample. Analyses implicating MDD did not replicate across ALSPAC, although the direction of effect was consistent for all traits when adjusting for the MS corresponding phenotypes.We showed that lifestyle and biochemical MS were associated with MDD before and after adjustment for their corresponding phenotypes (pnominal<0.05), but not when smoking, alcohol consumption, and BMI were also included as covariates. MDD results did not replicate in the smaller, female-only independent ALSPAC cohort (NALSPAC=565; NGS=9,502), potentially due to demographic differences or low statistical power, but effect sizes were consistent with the direction reported in GS. DNAm scores for modifiable MDD risk factors may contribute to disease vulnerability and, in some cases, explain additional variance to their observed phenotypes.Wellcome Trust.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.",
-,No,20220523,prediction,35473556,Accurate and highly interpretable prediction of gene expression from histone modifications.,BMC Bioinformatics,"Histone Mark Modifications (HMs) are crucial actors in gene regulation, as they actively remodel chromatin to modulate transcriptional activity: aberrant combinatorial patterns of HMs have been connected with several diseases, including cancer. HMs are, however, reversible modifications: understanding their role in disease would allow the design of 'epigenetic drugs' for specific, non-invasive treatments. Standard statistical techniques were not entirely successful in extracting representative features from raw HM signals over gene locations. On the other hand, deep learning approaches allow for effective automatic feature extraction, but at the expense of model interpretation.Here, we propose ShallowChrome, a novel computational pipeline to model transcriptional regulation via HMs in both an accurate and interpretable way. We attain state-of-the-art results on the binary classification of gene transcriptional states over 56 cell-types from the REMC database, largely outperforming recent deep learning approaches. We interpret our models by extracting insightful gene-specific regulative patterns, and we analyse them for the specific case of the PAX5 gene over three differentiated blood cell lines. Finally, we compare the patterns we obtained with the characteristic emission patterns of ChromHMM, and show that ShallowChrome is able to coherently rank groups of chromatin states w.r.t. their transcriptional activity.In this work we demonstrate that it is possible to model HM-modulated gene expression regulation in a highly accurate, yet interpretable way. Our feature extraction algorithm leverages on data downstream the identification of enriched regions to retrieve gene-wise, statistically significant and dynamically located features for each HM. These features are highly predictive of gene transcriptional state, and allow for accurate modeling by computationally efficient logistic regression models. These models allow a direct inspection and a rigorous interpretation, helping to formulate quantifiable hypotheses.© 2022. The Author(s).",
-,No,20220523,pwas,35544531,Cardiovascular disease protein biomarkers are associated with kidney function: The Framingham Heart Study.,PLoS One,"Biomarkers common to chronic kidney disease (CKD) and cardiovascular disease (CVD) may reflect early impairments underlying both diseases.We evaluated associations of 71 CVD-related plasma proteins measured in 2,873 Framingham Heart Study (FHS) Offspring cohort participants with cross-sectional continuous eGFR and with longitudinal change in eGFR from baseline to follow-up (ΔeGFR). We also evaluated the associations of the 71 CVD proteins with the following dichotomous secondary outcomes: prevalent CKD stage ≥3 (cross-sectional), new-onset CKD stage ≥3 (longitudinal), and rapid decline in eGFR (longitudinal). Proteins significantly associated with eGFR and ΔeGFR were subsequently validated in 3,951 FHS Third Generation cohort participants and were tested using Mendelian randomization (MR) analysis to infer putatively causal relations between plasma protein biomarkers and kidney function.In cross-sectional analysis, 37 protein biomarkers were significantly associated with eGFR at FDR<0.05 in the FHS Offspring cohort and 20 of these validated in the FHS Third Generation cohort at p<0.05/37. In longitudinal analysis, 27 protein biomarkers were significantly associated with ΔeGFR at FDR<0.05 and 12 of these were validated in the FHS Third Generation cohort at p<0.05/27. Additionally, 35 protein biomarkers were significantly associated with prevalent CKD, five were significantly associated with new-onset CKD, and 17 were significantly associated with rapid decline in eGFR. MR suggested putatively causal relations of melanoma cell adhesion molecule (MCAM; -0.011±0.003 mL/min/1.73m2, p = 5.11E-5) and epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1; -0.006±0.002 mL/min/1.73m2, p = 0.0001) concentration with eGFR.Eight protein biomarkers were consistently associated with eGFR in cross-sectional and longitudinal analysis in both cohorts and may capture early kidney impairment; others were implicated in association and causal inference analyses. A subset of CVD protein biomarkers may contribute causally to the pathogenesis of kidney impairment and should be studied as targets for CKD treatment and early prevention.",
-,No,20220523,somatic,35444284,Somatic genomic changes in single Alzheimer's disease neurons.,Nature,"Dementia in Alzheimer's disease progresses alongside neurodegeneration1-4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5at rates similar to those of dividing cells6,7which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells6-10. In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20220620,dnam age,35681159,Cardiovascular health and four epigenetic clocks.,Clin Epigenetics,"Cardiovascular health (CVH) was defined by the American Heart Association as an integrative idealness of seven clinical or lifestyle factors. Based on populations of European ancestry, recent studies have shown that ideal CVH is associated with a slower aging rate. The aging rate is measured by levels of epigenetic age acceleration (EAA), usually obtained from the residuals of regressing DNA methylation (DNAm) age on chronological age. However, little has been known about the association of CVH with biological aging in Asian populations.We here analyzed blood DNAm data and clinical/lifestyle factors of 2474 Taiwan Biobank (TWB) participants, to investigate the association of CVH with EAA. CVH was assessed by seven components: smoking status, physical activity, dietary habits, body mass index, total cholesterol, fasting glucose, and blood pressure levels. Four measures of EAA were applied, among which two were based on the first-generation DNAm clocks (HannumEAA and IEAA) and two were based on the second-generation clocks (PhenoEAA and GrimEAA). After excluding 276 individuals with cardiovascular diseases, we regressed EAA on the CVH score (ranging from 0 to 7, integrating the abovementioned seven components) while adjusting for sex, drinking status, and educational attainment. Our results showed that a decrease in one point in the CVH score was associated with a 0.350-year PhenoEAA (p = 4.5E-4) and a 0.499-year GrimEAA (p = 4.2E-15). By contrast, HannumEAA and IEAA were not significantly associated with the CVH score. We have obtained consistent results within each generation of epigenetic clocks.This is one of the first studies to comprehensively investigate the associations of CVH with four epigenetic clocks. Our TWB data showed that ideal CVH is associated with lower levels of EAA calculated according to the second-generation epigenetic clocks (PhenoEAA and GrimEAA). Having an ideal CVH status can lower EAA and reduce the risk of aging-related disorders.© 2022. The Author(s).",
-,No,20220620,dnam age,35681206,Evaluation of short-term epigenetic age fluctuation.,Clin Epigenetics,"Considerable effort has been spent on lowering and maintaining the epigenetic age. However, the extent to which epigenetic age fluctuates under normal conditions is poorly understood. Therefore, we analyzed methylation data from monocytes and peripheral blood mononuclear cells collected from two Japanese men. The ranges of the Pan-tissue, Skin and blood, and DNAm PhenoAge epigenetic age during 3 months were ≥ 5.62, ≥ 3.04, and ≥ 8.23 years, and the maximum daily changes were 5.21, 3.20, and 6.53 years, respectively. These fluctuations were not suppressed by correcting for cell-type composition. Although the underlying biological mechanism remains unclear, there was a nonnegligible degree of age fluctuation which should inform personalized clinical applications.© 2022. The Author(s).",
-,No,20220620,epigenetics,35608069,Large-scale integration of DNA methylation and gene expression array platforms identifies both <i>cis</i> and <i>trans</i> relationships.,Epigenetics,"Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE inciswere enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated withtransGE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming acisDNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented. An in-depth characterization of GE-associated CpG sites could improve predictions of the downstream functional impact of altered DNAm and inform best practices for interpreting DNAm-trait associations generated by EWAS.",
-,No,20220620,epigenetics,35672318,Integrating 3D genomic and epigenomic data to enhance target gene discovery and drug repurposing in transcriptome-wide association studies.,Nat Commun,"Transcriptome-wide association studies (TWAS) are popular approaches to test for association between imputed gene expression levels and traits of interest. Here, we propose an integrative method PUMICE (Prediction Using Models Informed by Chromatin conformations and Epigenomics) to integrate 3D genomic and epigenomic data with expression quantitative trait loci (eQTL) to more accurately predict gene expressions. PUMICE helps define and prioritize regions that harbor cis-regulatory variants, which outperforms competing methods. We further describe an extension to our method PUMICE +, which jointly combines TWAS results from single- and multi-tissue models. Across 79 traits, PUMICE + identifies 22% more independent novel genes and increases median chi-square statistics values at known loci by 35% compared to the second-best method, as well as achieves the narrowest credible interval size. Lastly, we perform computational drug repurposing and confirm that PUMICE + outperforms other TWAS methods.© 2022. The Author(s).",
-,No,20220620,epigenetics,35614216,Divergent transcriptional regulation of astrocyte reactivity across disorders.,Nature,"Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20220620,epigenetics,35710981,"Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease",Nat Genet,"More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability analysis reveals that methylation variation explains a larger fraction of heritability than gene expression. We present a multi-stage prioritization strategy and prioritize target genes for 87% of kidney function loci. We highlight key roles of proximal tubules and metabolism in kidney function regulation. Furthermore, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.",
-,No,20220620,methods,35592546,The EWAS Catalog: a database of epigenome-wide association studies.,Wellcome Open Res,"Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p<1x10-4) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From January 7, 2022, The EWAS Catalog contained 1,737,746 associations from 2,686 EWAS. This includes 1,345,398 associations from 342 peer-reviewed publications. In addition, it also contains summary statistics for 392,348 associations from 427 EWAS, performed on data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Omnibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to query EWAS associations quickly and easily, and gain insight into the molecular underpinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog data extraction team continue to update the database monthly and we encourage any EWAS authors to upload their summary statistics to our website. Details of how to upload data can be found here: http://www.ewascatalog.org/upload. The EWAS Catalog is available at http://www.ewascatalog.org.Copyright: © 2022 Battram T et al.",
-,No,20220620,prediction,35681440,Artificial Intelligence and Circulating Cell-Free DNA Methylation Profiling: Mechanism and Detection of Alzheimer's Disease.,Cells,"Despite extensive efforts, significant gaps remain in our understanding of Alzheimer's disease (AD) pathophysiology. Novel approaches using circulating cell-free DNA (cfDNA) have the potential to revolutionize our understanding of neurodegenerative disorders.We performed DNA methylation profiling of cfDNA from AD patients and compared them to cognitively normal controls. Six Artificial Intelligence (AI) platforms were utilized for the diagnosis of AD while enrichment analysis was used to elucidate the pathogenesis of AD.A total of 3684 CpGs were significantly (adj.p-value &lt; 0.05) differentially methylated in AD versus controls. All six AI algorithms achieved high predictive accuracy (AUC = 0.949-0.998) in an independent test group. As an example, Deep Learning (DL) achieved an AUC (95% CI) = 0.99 (0.95-1.0), with 94.5% sensitivity and specificity.We describe numerous epigenetically altered genes which were previously reported to be differentially expressed in the brain of AD sufferers. Genes identified by AI to be the best predictors of AD were either known to be expressed in the brain or have been previously linked to AD. We highlight enrichment in the Calcium signaling pathway, Glutamatergic synapse, Hedgehog signaling pathway, Axon guidance and Olfactory transduction in AD sufferers. To the best of our knowledge, this is the first reported genome-wide DNA methylation study using cfDNA to detect AD.",
-,No,20220620,telomeres,35681050,"Genetic, parental and lifestyle factors influence telomere length.",Commun Biol,"The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.© 2022. The Author(s).",
-,Yes,20220620,ewas,35703085,"DNA methylation in people with Anorexia Nervosa: Epigenome-wide patterns in actively ill, long-term remitted, and healthy-eater women.",World J Biol Psychiatry,"Objectives:Recent studies have reported altered methylation levels at disorder-relevant DNA sites in people who are ill with Anorexia Nervosa (AN) compared to findings in people with no eating disorder (ED) or in whom AN has remitted. The preceding implies state-related influences upon gene expression in people with AN. The present study further examined this notion.Methods:We measured genome-wide DNA methylation in 145 women with active AN, 49 showing stable one-year remission of AN, and 64 with no ED.Results:Comparisons revealed 205 differentially methylated sites between active and no ED groups, and 162 differentially methylated sites between active and remitted groups (Q < 0.01). Probes tended to map onto genes relevant to psychiatric, metabolic and immune functions. Notably, several of the genes identified here as being differentially methylated in people with AN (e.g.,SYNJ2, PRKAG2, STAT3,CSGALNACT1, NEGR1,NR1H3) have figured in previous studies on AN. Effects also associated illness chronicity and lower BMI with more pronounced DNA methylation alterations, and remission of AN with normalization of DNA methylation.Conclusions:Findings corroborate earlier results suggesting reversible DNA methylation alterations in AN, and point to particular genes at which epigenetic mechanisms may act to shape AN phenomenology.",
-,Yes,20220620,ewas,35700439,Epigenome-wide Association Study Identified VTI1A DNA Methylation Associated with Accelerometer-assessed Physical Activity.,Med Sci Sports Exerc,"Health benefits of physical activity (PA) may be mediated by DNA methylation alterations. The purpose of the current study was to comprehensively identify CpG sites whose methylation levels were associated with accelerometer-assessed total PA in a general Japanese population.The study participants were from the baseline survey of Saga Japan Multi-institutional Collaborative Cohort. PA was objectively measured by a single-axis accelerometer for seven days. We employed a two-stage strategy. In the discovery stage, we performed a meta-analysis of two epigenome-wide association studies (EWAS) of total PA in 898 individuals (a combination of random sample [n = 507] and case-control study sample [n = 391]. Peripheral blood DNA methylation levels were measured using Infinium EPIC or HM450 arrays. In the replication stage, we subsequently examined whether CpG sites significantly associated (P < 1 × 10-5) with total PA were replicated in another sample (n = 1711), in which methylation levels were measured by pyrosequencing. A multiple linear regression was performed to determine the cross-sectional association between total PA and methylation levels with adjustment for potential confounders, including BMI. A fixed-effects model was used in the meta-analysis. Correlations between total PA-associated DNA methylation and several inflammatory markers, such as hs-CRP, were also conducted.In the meta-analysis, nine CpG sites were significantly associated with total PA (P < 1 × 10-5). Among the nine sites, one site cg07030336 (annotated to VTI1A/ZDHHC6 gene) was successfully replicated (P = 0.009).The current study showed that greater accelerometer-assessed total PA was associated with higher DNA methylation levels at cg07030336 (VTI1A/ZDHHC6) in the general population. Additionally, we found a divergent relationship between the methylation levels at cg07030336 and several inflammatory biomarkers.Copyright © 2022 by the American College of Sports Medicine.",
-,Yes,20220620,ewas,35692099,DNA methylation patterns reflect individual's lifestyle independent of obesity.,Clin Transl Med,"Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects on blood DNA methylation in participants of the LIFE-Adult study, a well-characterised population-based cohort from Germany.Lifestyle scores (LS) based on diet, physical activity, smoking and alcohol intake were calculated in 4107 participants of the LIFE-Adult study. Fifty subjects with an extremely healthy lifestyle and 50 with an extremely unhealthy lifestyle (5th and 95th percentiles LS) were selected for genome-wide DNA methylation analysis in blood samples employing Illumina Infinium® Methylation EPIC BeadChip system technology.Differences in DNA methylation patterns between body mass index groups (<25 vs. >30 kg/m2) were rather marginal compared to inter-lifestyle differences (0 vs. 145 differentially methylated positions [DMPs]), which identified 4682 differentially methylated regions (DMRs; false discovery rate [FDR <5%) annotated to 4426 unique genes. A DMR annotated to the glutamine-fructose-6-phosphate transaminase 2 (GFPT2) locus showed the strongest hypomethylation (�6.9%), and one annotated to glutamate rich 1 (ERICH1) showed the strongest hypermethylation (�5.4%) in healthy compared to unhealthy lifestyle individuals. Intersection analysis showed that diet, physical activity, smoking and alcohol intake equally contributed to the observed differences, which affected, among others, pathways related to glutamatergic synapses (adj. p < .01) and axon guidance (adj. p < .05). We showed that methylation age correlates with chronological age and waist-to-hip ratio with lower DNA methylation age (DNAmAge) acceleration distances in participants with healthy lifestyles. Finally, two identified top DMPs for the alanyl aminopeptidase (ANPEP) locus also showed the strongest expression quantitative trait methylation in blood.DNA methylation patterns help discriminate individuals with a healthy versus unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.",
-,Yes,20220620,ewas,35690418,Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.,Mutat Res Rev Mutat Res,"Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits.We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268).In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction.This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.",
-,Yes,20220620,ewas,35681244,An epigenome-wide study of DNA methylation profiles and lung function among American Indians in the Strong Heart Study.,Clin Epigenetics,"Epigenetic modifications, including DNA methylation (DNAm), are often related to environmental exposures, and are increasingly recognized as key processes in the pathogenesis of chronic lung disease. American Indian communities have a high burden of lung disease compared to the national average. The objective of this study was to investigate the association of DNAm and lung function in the Strong Heart Study (SHS). We conducted a cross-sectional study of American Indian adults, 45-74 years of age who participated in the SHS. DNAm was measured using the Illumina Infinium Human MethylationEPIC platform at baseline (1989-1991). Lung function was measured via spirometry, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), at visit 2 (1993-1995). Airflow limitation was defined as FEV1 < 70% predicted and FEV1/FVC < 0.7, restriction was defined as FEV1/FVC > 0.7 and FVC < 80% predicted, and normal spirometry was defined as FEV1/FVC > 0.7, FEV1 > 70% predicted, FVC > 80% predicted. We used elastic-net models to select relevant CpGs for lung function and spirometry-defined lung disease. We also conducted bioinformatic analyses to evaluate the biological plausibility of the findings.Among 1677 participants, 21.2% had spirometry-defined airflow limitation and 13.6% had spirometry-defined restrictive pattern lung function. Elastic-net models selected 1118 Differentially Methylated Positions (DMPs) as predictors of airflow limitation and 1385 for restrictive pattern lung function. A total of 12 DMPs overlapped between airflow limitation and restrictive pattern. EGFR, MAPK1 and PRPF8 genes were the most connected nodes in the protein-protein interaction network. Many of the DMPs targeted genes with biological roles related to lung function such as protein kinases.We found multiple differentially methylated CpG sites associated with chronic lung disease. These signals could contribute to better understand molecular mechanisms involved in lung disease, as assessed systemically, as well as to identify patterns that could be useful for diagnostic purposes. Further experimental and longitudinal studies are needed to assess whether DNA methylation has a causal role in lung disease.© 2022. The Author(s).",
-,Yes,20220620,ewas,35679866,An epigenome-wide view of osteoarthritis in primary tissues.,Am J Hum Genet,"Osteoarthritis is a complex degenerative joint disease. Here, we investigate matched genotype and methylation profiles of primary chondrocytes from macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage and from synoviocytes collected from 98 osteoarthritis-affected individuals undergoing knee replacement surgery. We perform an epigenome-wide association study of knee cartilage degeneration and report robustly replicating methylation markers, which reveal an etiologic mechanism linked to the migration of epithelial cells. Using machine learning, we derive methylation models of cartilage degeneration, which we validate with 82% accuracy in independent data. We report a genome-wide methylation quantitative trait locus (mQTL) map of articular cartilage and synovium and identify 18 disease-grade-specific mQTLs in osteoarthritis cartilage. We resolve osteoarthritis GWAS loci through causal inference and colocalization analyses and decipher the epigenetic mechanisms that mediate the effect of genotype on disease risk. Together, our findings provide enhanced insights into epigenetic mechanisms underlying osteoarthritis in primary tissues.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.",
-,Yes,20220620,ewas,35672357,Large-scale placenta DNA methylation integrated analysis reveals fetal sex-specific differentially methylated CpG sites and regions.,Sci Rep,"Although male-female differences in placental structure and function have been observed, little is understood about their molecular underpinnings. Here, we present a mega-analysis of 14 publicly available placenta DNA methylation (DNAm) microarray datasets to identify individual CpGs and regions associated with fetal sex. In the discovery dataset of placentas from full term pregnancies (N = 532 samples), 5212 CpGs met genome-wide significance (p < 1E-8) and were enriched in pathways such as keratinization (FDR p-value = 7.37E-14), chemokine activity (FDR p-value = 1.56E-2), and eosinophil migration (FDR p-value = 1.83E-2). Nine differentially methylated regions were identified (fwerArea < 0.1) including a region in the promoter of ZNF300 that showed consistent differential DNAm in samples from earlier timepoints in pregnancy and appeared to be driven predominately by effects in the trophoblast cell type. We describe the largest study of fetal sex differences in placenta DNAm performed to date, revealing genes and pathways characterizing sex-specific placenta function and health outcomes later in life.© 2022. The Author(s).",
-,Yes,20220620,ewas,35665255,DNA Methylation Mediates the Association Between Individual and Neighborhood Social Disadvantage and Cardiovascular Risk Factors.,Front Cardiovasc Med,"Low socioeconomic status (SES) and living in a disadvantaged neighborhood are associated with poor cardiovascular health. Multiple lines of evidence have linked DNA methylation to both cardiovascular risk factors and social disadvantage indicators. However, limited research has investigated the role of DNA methylation in mediating the associations of individual- and neighborhood-level disadvantage with multiple cardiovascular risk factors in large, multi-ethnic, population-based cohorts. We examined whether disadvantage at the individual level (childhood and adult SES) and neighborhood level (summary neighborhood SES as assessed by Census data and social environment as assessed by perceptions of aesthetic quality, safety, and social cohesion) were associated with 11 cardiovascular risk factors including measures of obesity, diabetes, lipids, and hypertension in 1,154 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). For significant associations, we conducted epigenome-wide mediation analysis to identify methylation sites mediating the relationship between individual/neighborhood disadvantage and cardiovascular risk factors using the JT-Comp method that assesses sparse mediation effects under a composite null hypothesis. In models adjusting for age, sex, race/ethnicity, smoking, medication use, and genetic principal components of ancestry, epigenetic mediation was detected for the associations of adult SES with body mass index (BMI), insulin, and high-density lipoprotein cholesterol (HDL-C), as well as for the association between neighborhood socioeconomic disadvantage and HDL-C at FDRq< 0.05. The 410 CpG mediators identified for the SES-BMI association were enriched for CpGs associated with gene expression (expression quantitative trait methylation loci, or eQTMs), and corresponding genes were enriched in antigen processing and presentation pathways. For cardiovascular risk factors other than BMI, most of the epigenetic mediators lost significance after controlling for BMI. However, 43 methylation sites showed evidence of mediating the neighborhood socioeconomic disadvantage and HDL-C association after BMI adjustment. The identified mediators were enriched for eQTMs, and corresponding genes were enriched in inflammatory and apoptotic pathways. Our findings support the hypothesis that DNA methylation acts as a mediator between individual- and neighborhood-level disadvantage and cardiovascular risk factors, and shed light on the potential underlying epigenetic pathways. Future studies are needed to fully elucidate the biological mechanisms that link social disadvantage to poor cardiovascular health.Copyright © 2022 Wang, Zhao, Ammous, Song, Du, Shang, Ratliff, Moore, Kelly, Needham, Diez Roux, Liu, Butler, Kardia, Mukherjee, Zhou and Smith.",
-,Yes,20220620,ewas,35654255,Epigenome-wide DNA methylation signature of plasma zinc and their mediation roles in the association of zinc with lung cancer risk.,Environ Pollut,"Essential trace element zinc is associated with decreased lung cancer risk, but underlying mechanisms remain unclear. This study aimed to investigate role of DNA methylation in zinc-lung cancer association. We conducted a case-cohort study within prospective Dongfeng-Tongji cohort, including 359 incident lung cancer cases and a randomly selected sub-cohort of 1399 participants. Epigenome-wide association study (EWAS) was used to examine association of plasma zinc with DNA methylation in peripheral blood. For the zinc-related CpGs, their mediation effects on zinc-lung cancer association were assessed; their diagnostic performance for lung cancer was testified in the case-cohort study and further validated in another 126 pairs of lung cancer case-control study. We identified 28 CpGs associated with plasma zinc at P < 1.0 × 10-5and seven of them (cg07077080, cg01077808, cg17749033, cg15554270, cg26125625, cg10669424, and cg15409013 annotated to GSR, CALR3, SLC16A3, PHLPP2, SLC12A8, VGLL4, and ADAMTS16, respectively) were associated with incident risk of lung cancer. Moreover, the above seven CpGs were differently methylated between 126 pairs of lung cancer and adjacent normal lung tissues and had the same directions with EWAS of zinc. They could mediate a separate 7.05%�22.65% and a joint 29.42% of zinc-lung cancer association. Compared to using traditional factors, addition of methylation risk score exerted improved discriminations for lung cancer both in case-cohort study [area under the curve (AUC) = 0.818 vs. 0.738] and in case-control study (AUC = 0.816 vs. 0.646). Our results provide new insights for the biological role of DNA methylation in the inverse association of zinc with incident lung cancer.Copyright © 2022 Elsevier Ltd. All rights reserved.",
-,Yes,20220620,ewas,35652342,Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study.,Circulation,"Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD.In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events.We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age.CPT1A,ABCG1, andSREBF1appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genesSARS1,SOCS3, andLINC-PINTstatistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87;P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28;P=1.22E-05).Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.",
-,Yes,20220620,ewas,35650177,Epigenome-wide DNA methylation in obsessive-compulsive disorder.,Transl Psychiatry,"In adult patients with obsessive-compulsive disorder (OCD), altered DNA methylation has been discerned in several candidate genes, while DNA methylation on an epigenome-wide level has been investigated in only one Chinese study so far. Here, an epigenome-wide association study (EWAS) was performed in a sample of 76 OCD patients of European ancestry (37 women, age ± SD: 33.51 ± 10.92 years) and 76 sex- and age-matched healthy controls for the first time using the Illumina MethylationEPIC BeadChip. After quality control, nine epigenome-wide significant quantitative trait methylation sites (QTMs) and 21 suggestive hits were discerned in the final sample of 68 patients and 68 controls. The top hit (cg24159721) and four other significant QTMs (cg11894324, cg01070250, cg11330075, cg15174812) map to the region of the microRNA 12136 gene (MIR12136). Two additional significant CpG sites (cg05740793, cg20450977) are located in the flanking region of the MT-RNR2 (humanin) like 8 gene (MT-RNRL8), while two further QTMs (cg16267121, cg15890734) map to the regions of the MT-RNR2 (humanin) like 3 (MT-RNRL3) and MT-RNR2 (humanin) like 2 (MT-RNRL2) genes. Provided replication of the present findings in larger samples, the identified QTMs might provide more biological insight into the pathogenesis of OCD and thereby could in the future serve as peripheral epigenetic markers of OCD risk with the potential to inform targeted preventive and therapeutic efforts.© 2022. The Author(s).",
-,Yes,20220620,ewas,35635730,The dynamics of methylation of CpG sites associated with SLE subtypes in a longitudinal cohort.,Arthritis Rheumatol,"Cross-sectional studies have revealed associations between DNA methylation and systemic lupus erythematosus (SLE) outcomes. To study the dynamics of DNA methylation, we examined participants from a SLE longitudinal cohort sampled at two time-points.One hundred and one participants from the California Lupus Epidemiology Study were studied. DNA extracted from blood at cohort enrollment and after two years was analyzed using the Illumina EPIC BeadChip. Paired t-tests were utilized to identify changes at 256 CpG sites previously associated with SLE subtypes as well as genome-wide. Mixed linear models were developed to understand the relationship between DNA methylation and disease activity, medication use and sample cell proportions, adjusting for age, sex and genetic principal components.The majority of CpGs that were previously associated with SLE subtypes remained stable over two years (185 CpGs (72.3%), t-test FDR >0.05). Compared to background genome-wide methylation, there was an enrichment of SLE subtype associated CpGs that changed over time (27.7% vs 0.34%). Changes in cell proportion were associated with changes at 67 CpGs (p<2.70E-05) and 15 CpGs had at least one significant association with use of an immunosuppressive medication.In this longitudinal cohort of SLE, we identified a subset of SLE subtype associated CpGs that were stable over time and may be useful as biomarkers of disease subtypes. Another subset of SLE subtype-associated CpGs changed at a higher proportion compared to the genome-wide methylome. Additional studies are needed to understand the etiology and impact of these methylation changes in SLE-associated CpGs.This article is protected by copyright. All rights reserved.",
-,Yes,20220620,ewas,35627945,Differential Methylation Analysis of Suicidal Ideation Severity in Schizophrenia with the Illumina MethylationEPIC Array.,Healthcare (Basel),"There is a multitude of factors that makes difficult to identify those at risk for suicide, especially among schizophrenia patients. Suicide cannot be explained by genetics alone, therefore epigenetic mechanisms including DNA methylation are thought to play a role. DNA methylation could be a valuable tool in helping predict those at-risk individuals. This cross-sectional study comprised 112 subjects diagnosed with schizophrenia spectrum disorders, and were grouped according to the current suicidal ideation severity. DNA methylation across the genome was measured with the Infinium®MethylationEPIC BeadChip. We utilized the dmpFinder and bumphunter functions within the Bioconductor minfi package to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs), respectively. Following quality control, we removed one sample from the analysis and reported the most significant DMPs and DMRs associated with suicidal ideation severity. All positions and regions identified in this analysis were only found to have suggestive levels of significance at the genome-wide level. The present study was one of the first to investigate genome-wide methylation and suicidal ideation severity. While there were many strengths of our study, including investigating both differentially methylated positions and regions, further larger-scale studies are necessary to replicate, support, and validate our findings presented here.",
-,Yes,20220620,ewas,35596190,The mediating effect of DNA methylation in the association between maternal sleep during pregnancy and offspring adiposity status: a prospective cohort study.,Clin Epigenetics,"Childhood overweight/obesity is a global public health concern. It is important to identify its early-life risk factors. Maternal poor sleep is common in late pregnancy, and previous studies indicated that poor sleep may influence the offspring's adiposity status. However, very few studies in humans investigated the effect of the different sleep parameters (sleep quantity, quality, and timing) on the offspring's adiposity indicators, and long-term studies are even more scarce. In addition, the underlying mechanism remains unclear. The present study therefore aimed to examine the association between the three maternal sleep dimensions in the late pregnancy and the offspring adiposity indicators and to explore the potential mediating effect of the cord blood DNA methylation in the above association.Included participants in the current study were 2211 healthy pregnant women with singleton gestation from the Shanghai Birth Cohort (SBC) and Shanghai Sleep Birth Cohort (SSBC). Maternal nighttime sleep duration, quality, and midpoint (an indicator of circadian rhythm) were assessed by the same instrument in both cohorts during late pregnancy, and the offspring's body mass index (BMI) and subcutaneous fat (SF) were measured at 2 years old. Additionally, in 231 SSBC samples, the genome-wide DNA methylation levels were measured using the Illumina Infinium Methylation EPIC BeadChip. The multivariate linear regression was used to determine the associations between the maternal sleep parameters and the offspring adiposity indicators. The epigenome-wide association study was conducted to identify the maternal sleep-related CpG sites. The mediation analysis was performed to evaluate the potential intermediate role of DNA methylation in the association between maternal sleep and offspring adiposity indicators.The mean maternal nighttime sleep duration and the sleep midpoint for combined cohorts were 9.24 ± 1.13 h and 3.02 ± 0.82, respectively, and 24.5% of pregnant women experienced poor sleep quality in late pregnancy. After adjusting for the covariates, the maternal later sleep midpoint was associated with the increased SF in offspring (Coef. = 0.62, 95% CI 0.37-0.87, p < 0.001) at 2 years old. However, no significant associations of the nighttime sleep duration or sleep quality with the offspring adiposity indicators were found. In the SSBC sample, 45 differential methylated probes (DMPs) were associated with the maternal sleep midpoint, and then, we observed 10 and 3 DMPs that were also associated with the offspring's SF and BMI at 2 years, of which cg04351668 (MARCH9) and cg12232388 significantly mediated the relationship of sleep midpoint and SF and cg12232388 and cg12225226 mediated the sleep midpoint-BMI association, respectively.Maternal later sleep timing in late pregnancy was associated with higher childhood adiposity in the offspring. Cord blood DNA methylation may play a mediation role in that relationship.© 2022. The Author(s).",
-,Yes,20220620,ewas,35595947,Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking.,Eur J Epidemiol,"Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients.© 2022. The Author(s).",
-,No,20220815,prediction,35064064,AHRR (cg05575921) Methylation Safely Improves Specificity of Lung Cancer Screening Eligibility Criteria: A Cohort Study,Cancer Epidemiol Biomarkers Prev.,"Background: Screening reduces lung cancer mortality, but specificities of eligibility criteria are low. We tested if leukocyte AHRR(cg05575921) methylation improves specificity of lung cancer screening eligibility criteria.
+No,20220411,omics,35259029,Multi-Omics Integration in a Twin Cohort and Predictive Modeling of Blood Pressure Values.,OMICS,"Abnormal blood pressure is strongly associated with risk of high-prevalence diseases, making the study of blood pressure a major public health challenge. Although biological mechanisms underlying hypertension at the single omic level have been discovered, multi-omics integrative analyses using continuous variations in blood pressure values remain limited. We used a multi-omics regression-based method, called sparse multi-block partial least square, for integrative, explanatory, and predictive interests in study of systolic and diastolic blood pressure values. Various datasets were obtained from the Finnish Twin Cohort for up to 444 twins. Blocks of omics-including transcriptomic, methylation, metabolomic-data as well as polygenic risk scores and clinical data were integrated into the modeling and supported by cross-validation. The predictive contribution of each omics block when predicting blood pressure values was investigated using external participants from the Young Finns Study. In addition to revealing interesting inter-omics associations, we found that each block of omics heterogeneously improved the predictions of blood pressure values once the multi-omics data were integrated. The modeling revealed a plurality of clinical, transcriptomic, and metabolomic factors consistent with the literature and that play a leading role in explaining unit variations in blood pressure. These findings demonstrate (1) the robustness of our integrative method to harness results obtained by single omics discriminant analyses, and (2) the added value of predictive and exploratory gains of a multi-omics approach in studies of complex phenotypes such as blood pressure.",
+No,20220411,prediction,35304597,DNA methylation-based predictors of health: applications and statistical considerations.,Nat Rev Genet,"DNA methylation data have become a valuable source of information for biomarker development, because, unlike static genetic risk estimates, DNA methylation varies dynamically in relation to diverse exogenous and endogenous factors, including environmental risk factors and complex disease pathology. Reliable methods for genome-wide measurement at scale have led to the proliferation of epigenome-wide association studies and subsequently to the development of DNA methylation-based predictors across a wide range of health-related applications, from the identification of risk factors or exposures, such as age and smoking, to early detection of disease or progression in cancer, cardiovascular and neurological disease. This Review evaluates the progress of existing DNA methylation-based predictors, including the contribution of machine learning techniques, and assesses the uptake of key statistical best practices needed to ensure their reliable performance, such as data-driven feature selection, elimination of data leakage in performance estimates and use of generalizable, adequately powered training samples.© 2022. Springer Nature Limited.",
+No,20220411,prediction,35283726,DNA Methylation Markers and Prediction Model for Depression and Their Contribution for Breast Cancer Risk.,Front Mol Neurosci,"Major depressive disorder (MDD) has become a leading cause of disability worldwide. However, the diagnosis of the disorder is dependent on clinical experience and inventory. At present, there are no reliable biomarkers to help with diagnosis and treatment. DNA methylation patterns may be a promising approach for elucidating the etiology of MDD and predicting patient susceptibility. Our overarching aim was to identify biomarkers based on DNA methylation, and then use it to propose a methylation prediction score for MDD, which we hope will help us evaluate the risk of breast cancer.Methylation data from 533 samples were extracted from the Gene Expression Omnibus (GEO) database, of which, 324 individuals were diagnosed with MDD. Statistical difference of DNA Methylation between Promoter and Other body region (SIMPO) score for each gene was calculated based on the DNA methylation data. Based on SIMPO scores, we selected the top genes that showed a correlation with MDD in random resampling, then proposed a methylation-derived Depression Index (mDI) by combining the SIMPO of the selected genes to predict MDD. A validation analysis was then performed using additional DNA methylation data from 194 samples extracted from the GEO database. Furthermore, we applied the mDI to construct a prediction model for the risk of breast cancer using stepwise regression and random forest methods.The optimal mDI was derived from 426 genes, which included 245 positive and 181 negative correlations. It was constructed to predict MDD with high predictive power (AUC of 0.88) in the discovery dataset. In addition, we observed moderate power for mDI in the validation dataset with an OR of 1.79. Biological function assessment of the 426 genes showed that they were functionally enriched in Eph Ephrin signaling and beta-catenin Wnt signaling pathways. The mDI was then used to construct a predictive model for breast cancer that had an AUC ranging from 0.70 to 0.67.Our results indicated that DNA methylation could help to explain the pathogenesis of MDD and assist with its diagnosis.Copyright © 2022 Wang, Sun, Pang, Zheng, Liang, He, Tang, Yu, Xiong and Chang.",
+No,20220411,reference,35277705,A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution.,Nat Methods,"Bulk-tissue DNA methylomes represent an average over many different cell types, hampering our understanding of cell-type-specific contributions to disease development. As single-cell methylomics is not scalable to large cohorts of individuals, cost-effective computational solutions are needed, yet current methods are limited to tissues such as blood. Here we leverage the high-resolution nature of tissue-specific single-cell RNA-sequencing datasets to construct a DNA methylation atlas defined for 13 solid tissue types and 40 cell types. We comprehensively validate this atlas in independent bulk and single-nucleus DNA methylation datasets. We demonstrate that it correctly predicts the cell of origin of diverse cancer types and discovers new prognostic associations in olfactory neuroblastoma and stage 2 melanoma. In brain, the atlas predicts a neuronal origin for schizophrenia, with neuron-specific differential DNA methylation enriched for corresponding genome-wide association study risk loci. In summary, the DNA methylation atlas enables the decomposition of 13 different human tissue types at a high cellular resolution, paving the way for an improved interpretation of epigenetic data.© 2022. The Author(s).",
+No,20220411,translation,35337378,Ethical implications of epigenetics in the era of personalized medicine.,Clin Epigenetics,"Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatization as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all populations equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflection on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determinism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into society.© 2022. The Author(s).",
+No,20220411,twins,35301182,Early life affects late-life health through determining DNA methylation across the lifespan: A twin study.,EBioMedicine,"Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time.1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included. Familial correlations (i.e., correlations between twins) for 353,681 methylation sites were estimated and modelled as a function of twin pair cohabitation history.The methylome average familial correlation was around zero at birth (MZ pair: -0.01; DZ pair: -0.04), increased with the time of twins living together during childhood at rates of 0.16 (95%CI: 0.12-0.20) for MZ pairs and 0.13 (95%CI: 0.07-0.20) for DZ pairs per decade, and decreased with the time of living apart during adulthood at rates of 0.026 (95%CI: 0.019-0.033) for MZ pairs and 0.027 (95%CI: 0.011-0.043) for DZ pairs per decade. Neither the increasing nor decreasing rate differed by zygosity (both P>0.1), consistent with cohabitation environment shared by twins, rather than genetic factors, influencing the methylation familial correlation changes. Familial correlations for 6.6% (23,386/353,681) sites changed with twin pair cohabitation history. These sites were enriched for high heritability, proximal promoters, and epigenetic/genetic associations with various early-life factors and late-life health conditions.Early life strongly influences DNA methylation variation across the lifespan, and the effects are stronger for heritable sites and sites biologically relevant to the regulation of gene expression. Early life could affect late-life health through influencing DNA methylation.Victorian Cancer Agency, Cancer Australia, Cure Cancer Foundation.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.",
+Yes,20220523,ewas,35546478,Integrative analysis of clinical and epigenetic biomarkers of mortality.,Aging Cell,"DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7, of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR = 4.1 × 10-4) and negatively associated with longevity (Beta = -1.9, PMR = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.",
+No,20220523,dnam age,35501397,Making sense of the ageing methylome.,Nat Rev Genet,"Over time, the human DNA methylation landscape accrues substantial damage, which has been associated with a broad range of age-related diseases, including cardiovascular disease and cancer. Various age-related DNA methylation changes have been described, including at the level of individual CpGs, such as differential and variable methylation, and at the level of the whole methylome, including entropy and correlation networks. Here, we review these changes in the ageing methylome as well as the statistical tools that can be used to quantify them. We detail the evidence linking DNA methylation to ageing phenotypes and the longevity strategies aimed at altering both DNA methylation patterns and machinery to extend healthspan and lifespan. Lastly, we discuss theories on the mechanistic causes of epigenetic ageing.© 2022. Springer Nature Limited.",
+No,20220523,dnam age,35481978,The aging epigenome.,Elife,"A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer.© 2022, Pierce.",
+No,20220523,dnam age,35522643,eClock: An ensemble-based method to accurately predict ages with a biased distribution from DNA methylation data.,PLoS One,"DNA methylation is closely related to senescence, so it has been used to develop statistical models, called clock models, to predict chronological ages accurately. However, because the training data always have a biased age distribution, the model performance becomes weak for the samples with a small age distribution density. To solve this problem, we developed the R package eClock, which uses a bagging-SMOTE method to adjust the biased distribution and predict age with an ensemble model. Moreover, it also provides a bootstrapped model based on bagging only and a traditional clock model. The performance on three datasets showed that the bagging-SMOTE model significantly improved rare sample age prediction. In addition to model construction, the package also provides other functions such as data visualization and methylation feature conversion to facilitate the research in relevant areas.",
+No,20220523,dnam score,35550596,The early-life exposome modulates the effect of polymorphic inversions on DNA methylation.,Commun Biol,"Polymorphic genomic inversions are chromosomal variants with intrinsic variability that play important roles in evolution, environmental adaptation, and complex traits. We investigated the DNA methylation patterns of three common human inversions, at 8p23.1, 16p11.2, and 17q21.31 in 1,009 blood samples from children from the Human Early Life Exposome (HELIX) project and in 39 prenatal heart tissue samples. We found inversion-state specific methylation patterns within and nearby flanking each inversion region in both datasets. Additionally, numerous inversion-exposure interactions on methylation levels were identified from early-life exposome data comprising 64 exposures. For instance, children homozygous at inv-8p23.1 and higher meat intake were more susceptible to TDH hypermethylation (P = 3.8 × 10-22); being the inversion, exposure, and gene known risk factors for adult obesity. Inv-8p23.1 associated hypermethylation of GATA4 was also detected across numerous exposures. Our data suggests that the pleiotropic influence of inversions during development and lifetime could be substantially mediated by allele-specific methylation patterns which can be modulated by the exposome.© 2022. The Author(s).",
+No,20220523,dnam scores,35513492,Epigenetics of type 2 diabetes mellitus and weight change - a tool for precision medicine?,Nat Rev Endocrinol,"Pioneering studies performed over the past few decades demonstrate links between epigenetics and type 2 diabetes mellitus (T2DM), the metabolic disorder with the most rapidly increasing prevalence in the world. Importantly, these studies identified epigenetic modifications, including altered DNA methylation, in pancreatic islets, adipose tissue, skeletal muscle and the liver from individuals with T2DM. As non-genetic factors that affect the risk of T2DM, such as obesity, unhealthy diet, physical inactivity, ageing and the intrauterine environment, have been associated with epigenetic modifications in healthy individuals, epigenetics probably also contributes to T2DM development. In addition, genetic factors associated with T2DM and obesity affect the epigenome in human tissues. Notably, causal mediation analyses found DNA methylation to be a potential mediator of genetic associations with metabolic traits and disease. In the past few years, translational studies have identified blood-based epigenetic markers that might be further developed and used for precision medicine to help patients with T2DM receive optimal therapy and to identify patients at risk of complications. This Review focuses on epigenetic mechanisms in the development of T2DM and the regulation of body weight in humans, with a special focus on precision medicine.© 2022. Springer Nature Limited.",
+No,20220523,epigenetics,35473573,Comprehensive enhancer-target gene assignments improve gene set level interpretation of genome-wide regulatory data.,Genome Biol,"Revealing the gene targets of distal regulatory elements is challenging yet critical for interpreting regulome data. Experiment-derived enhancer-gene links are restricted to a small set of enhancers and/or cell types, while the accuracy of genome-wide approaches remains elusive due to the lack of a systematic evaluation. We combined multiple spatial and in silico approaches for defining enhancer locations and linking them to their target genes aggregated across >500 cell types, generating 1860 human genome-wide distal enhancer-to-target gene definitions (EnTDefs). To evaluate performance, we used gene set enrichment (GSE) testing on 87 independent ENCODE ChIP-seq datasets of 34 transcription factors (TFs) and assessed concordance of results with known TF Gene Ontology annotations, and other benchmarks.The top ranked 741 (40%) EnTDefs significantly outperform the common, naïve approach of linking distal regions to the nearest genes, and the top 10 EnTDefs perform well when applied to ChIP-seq data of other cell types. The GSE-based ranking of EnTDefs is highly concordant with ranking based on overlap with curated benchmarks of enhancer-gene interactions. Both our top general EnTDef and cell-type-specific EnTDefs significantly outperform seven independent computational and experiment-based enhancer-gene pair datasets. We show that using our top EnTDefs for GSE with either genome-wide DNA methylation or ATAC-seq data is able to better recapitulate the biological processes changed in gene expression data performed in parallel for the same experiment than our lower-ranked EnTDefs.Our findings illustrate the power of our approach to provide genome-wide interpretation regardless of cell type.© 2022. The Author(s).",
+No,20220523,epigenetics,35488174,The Placental Epigenome as a Molecular Link Between Prenatal Exposures and Fetal Health Outcomes Through the DOHaD Hypothesis.,Curr Environ Health Rep,"The developmental origins of health and disease (DOHaD) hypothesis posits that the perinatal environment can impact fetal and later life health. The placenta is uniquely situated to assess prenatal exposures in the context of DOHaD because it is an essential ephemeral fetal organ that manages the transport of oxygen, nutrients, waste, and endocrine signals between the mother and fetus. The purpose of this review is to summarize recent studies that evaluated the DOHaD hypothesis in human placentas using epigenomics, including DNA methylation and transcriptomic studies of mRNA, lncRNA, and microRNAs.Between 2016 and 2021, 28 articles evaluated associations between prenatal exposures and placental epigenomics across broad exposure categories including maternal smoking, psychosocial stressors, chemicals, air pollution, and metals. Sixteen of these studies connected exposures to health outcome such as birth weight, fetal growth, or infant neurobehavior through mediation analysis, identification of shared associations between exposure and outcome, or network analysis. These aspects of infant and childhood health serve as a foundation for future studies that aim to use placental epigenetics to understand relationships between the prenatal environment and perinatal complications (such as preterm birth or fetal growth restriction) or later life childhood health. Placental DNA methylation and RNA expression have been linked to numerous prenatal exposures, such as PM2.5 air pollution, metals, and maternal smoking, as well as infant and childhood health outcomes, including fetal growth and birth weight. Placental epigenomics provides a unique opportunity to expand the DOHaD premise, particularly if research applies novel methodologies such as multi-omics analysis, sequencing of non-coding RNAs, mixtures analysis, and assessment of health outcomes beyond early childhood.© 2022. The Author(s).",
+No,20220523,epigenetics,35527238,An optimal variant to gene distance window derived from an empirical definition of cis and trans protein QTLs.,BMC Bioinformatics,"A genome-wide association study (GWAS) correlates variation in the genotype with variation in the phenotype across a cohort, but the causal gene mediating that impact is often unclear. When the phenotype is protein abundance, a reasonable hypothesis is that the gene encoding that protein is the causal gene. However, as variants impacting protein levels can occur thousands or even millions of base pairs from the gene encoding the protein, it is unclear at what distance this simple hypothesis breaks down.By making the simple assumption that cis-pQTLs should be distance dependent while trans-pQTLs are distance independent, we arrive at a simple and empirical distance cutoff separating cis- and trans-pQTLs. Analyzing a recent large-scale pQTL study (Pietzner in Science 374:eabj1541, 2021) we arrive at an estimated distance cutoff of 944 kilobasepairs (95% confidence interval: 767-1,161) separating the cis and trans regimes.We demonstrate that this simple model can be applied to other molecular GWAS traits. Since much of biology is built on molecular traits like protein, transcript and metabolite abundance, we posit that the mathematical models for cis and trans distance distributions derived here will also apply to more complex phenotypes and traits.© 2022. The Author(s).",
+Yes,20220523,ewas,35536696,Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis.,Am J Respir Crit Care Med,"Methylation integrates factors present at birth and modifiable across life that can influence pulmonary function. Studies are limited in scope and replication.To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function.Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multi-ancestry epigenome-wide meta-analyses (17,503 individuals: 14,761 European; 2,549 African; and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics.We identified 1,267 CpGs (1,042 genes) differentially methylated (FDR<0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to COPD (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that EWAS signals capture causal regulatory genomic loci.We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies providing insights into lung pathogenesis.",
+Yes,20220523,ewas,35513368,Maternal prenatal depressive symptoms and toddler behavior: an umbilical cord blood epigenome-wide association study.,Transl Psychiatry,"Children of mothers with prenatal depressive symptoms (PND) have a higher risk of behavioral problems; fetal programming through DNA methylation is a possible underlying mechanism. This study investigated DNA methylation in cord blood to identify possible ""at birth"" signatures that may indicate susceptibility to behavioral problems at 18 months of age. Cord blood was collected from 256 children of mothers who had self-reported on symptoms of depression during pregnancy and the behavior of their child at 18 months of age. Whole genome DNA methylation was assessed using Illumina MethylationEPIC assay. The mother and child pairs were categorized into four groups, based on both self-reported depressive symptoms, PND or Healthy control (HC), and scores from the Child Behavior checklist (high or low for internalizing, externalizing, and total scores). Adjustments were made for batch effects, cell-type, and clinical covariates. Differentially methylated sites were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p values < 0.05 were considered significant. The analysis was also stratified by sex of the child. Among boys, we observed higher and correlated DNA methylation of one CpG-site in the promoter region of TPP1 in the HC group, with high externalizing scores compared to HC with low externalizing scores. Boys in the PND group showed lower DNA methylation in NUDT15 among those with high, compared to low, internalizing scores; the DNA methylation levels of CpGs in this gene were positively correlated with the CBCL scores. Hence, the differentially methylated CpG sites could be of interest for resilience, regardless of maternal mental health during pregnancy. The findings are in a relatively healthy study cohort, thus limiting the possibility of detecting strong effects associated with behavioral difficulties. This is the first investigation of cord blood DNA methylation signs of fetal programming of PND on child behavior at 18 months of age and thus calls for independent replications.© 2022. The Author(s).",
+Yes,20220523,ewas,35505416,Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis.,Clin Epigenetics,"Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother-newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation.Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs.Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.© 2022. The Author(s).",
+Yes,20220523,ewas,35504910,DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases.,Nat Commun,"We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.© 2022. The Author(s).",
+Yes,20220523,ewas,35501310,An epigenetic association analysis of childhood trauma in psychosis reveals possible overlap with methylation changes associated with PTSD.,Transl Psychiatry,"Patients with a severe mental disorder report significantly higher levels of childhood trauma (CT) than healthy individuals. Studies have suggested that CT may affect brain plasticity through epigenetic mechanisms and contribute to developing various psychiatric disorders. We performed a blood-based epigenome-wide association study using the Childhood Trauma Questionnaire-short form in 602 patients with a current severe mental illness, investigating DNA methylation association separately for five trauma subtypes and the total trauma score. The median trauma score was set as the predefined cutoff for determining whether the trauma was present or not. Additionally, we compared our genome-wide results with methylation probes annotated to candidate genes previously associated with CT. Of the patients, 83.2% reported CT above the cutoff in one or more trauma subtypes, and emotional neglect was the trauma subtype most frequently reported. We identified one significant differently methylated position associated with the gene TANGO6 for physical neglect. Seventeen differentially methylated regions (DMRs) were associated with different trauma categories. Several of these DMRs were annotated to genes previously associated with neuropsychiatric disorders such as post-traumatic stress disorder and cognitive impairments. Our results support a biomolecular association between CT and severe mental disorders. Genes that were previously identified as differentially methylated in CT-exposed subjects with and without psychosis did not show methylation differences in our analysis. We discuss this inconsistency, the relevance of our findings, and the limitations of our study.© 2022. The Author(s).",
+Yes,20220523,ewas,35500859,Gaseous air pollutants and DNA methylation in a methylome-wide association study of an ethnically and environmentally diverse population of U.S. adults.,Environ Res,"Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (PCochran's Q > 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.Copyright © 2022 Elsevier Inc. All rights reserved.",
+Yes,20220523,ewas,35477560,Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder.,Clin Epigenetics,"Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD.DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association.Two CpG-sites presented with p-values below 1 × 10-05in PD: cg09738429 (p = 6.40 × 10-06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10-06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes.This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.© 2022. The Author(s).",
+Yes,20220523,ewas,35475137,Genome- and epigenome-wide studies of plasma protein biomarkers for Alzheimer's disease implicate TBCA and TREM2 in disease risk.,Alzheimers Dement (Amst),"The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms.Genome-wide and epigenome-wide studies (nindividuals≤1064) were performed on plasma levels of 282 AD-associated proteins, identified by a structured literature review. Bayesian penalized regression estimated contributions of genetic and epigenetic variation toward inter-individual differences in plasma protein levels. Mendelian randomization (MR) and co-localization tested associations between proteins and disease-related phenotypes.Sixty-four independent genetic and 26 epigenetic loci were associated with 45 proteins. Novel findings included an association between plasma triggering receptor expressed on myeloid cells 2 (TREM2) levels and a polymorphism and cytosine-phosphate-guanine (CpG) site within theMS4A4Alocus. Higher plasma tubulin-specific chaperone A (TBCA) and TREM2 levels were significantly associated with lower AD risk.Our data inform the regulation of biomarker levels and their relationships with AD.© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.",
+No,20220523,ewas,35455681,Epigenetic Signatures of Smoking in Five Brain Regions.,J Pers Med,"(1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which may contribute to the pathophysiology of addictive behavior observed in chronic smokers. (2) Methods: We investigated the similarity of DNAm signatures in matched blood and postmortem brain samples (n= 10). In addition, we performed EWASs in five brain regions belonging to the neurocircuitry of addiction: anterior cingulate cortex (ACC), Brodmann Area 9, caudate nucleus, putamen, and ventral striatum (n= 38-72). (3) Results: cg15925993 within theLOC339975gene was epigenome-wide significant in the ACC. Of 16 identified differentially methylated regions, two (PRSS50andLINC00612/A2M-AS1) overlapped between multiple brain regions. Functional enrichment was detected for biological processes related to neuronal development, inflammatory signaling and immune cell migration. Additionally, our results indicate the association of the well-knownAHRRCpG site cg05575921 with smoking in the brain. (4) Conclusion: The present study provides further evidence of the strong relationship between aberrant DNAm and smoking.",
+No,20220523,ewas,35454993,Epigenome-Wide Analysis of DNA Methylation in Parkinson's Disease Cortex.,Life (Basel),"Epigenetic factors including DNA methylation contribute to specific patterns of gene expression. Gene-environment interactions can change the methylation status in the brain, and accumulation of these epigenetic changes over a lifespan may be co-responsible for a neurodegenerative disease like Parkinson's disease, which that is characterised by a late onset in life.To determine epigenetic modifications in the brains of Parkinson's disease patients.DNA methylation patterns were compared in the cortex tissue of 14 male PD patients and 10 male healthy individuals using the Illumina Methylation 450 K chip. Subsequently, DNA methylation of candidate genes was evaluated using bisulphite pyrosequencing, and DNA methylation of cytochrome P450 2E1 (CYP2E1) was characterized in DNA from blood mononuclear cells (259 PD patients and 182 healthy controls) and skin fibroblasts (10 PD patients and 5 healthy controls). Protein levels ofCYP2E1were analysed using Western blot in human cortex andknock-outmice brain samples.We found 35 hypomethylated and 22 hypermethylated genes with a methylation M-value difference &gt;0.5. Decreased methylation of cytochrome P450 2E1 (CYP2E1) was associated with increased protein levels in PD brains, but in peripheral tissues, i.e., in blood cells and skin fibroblasts, DNA methylation ofCYP2E1was unchanged. InCYP2E1 knock-outmice brain alpha-synuclein (SNCA) protein levels were down-regulated compared to wild-type mice, whereas treatment with trichloroethylene (TCE) up-regulatedCYP2E1protein in a dose-dependent manner in cultured cells. We further identified an interconnected group of genes associated with oxidative stress, such as Methionine sulfoxide reductase A (MSRA) and tumour protein 73 (TP73) in the brain, which again were not paralleled in other tissues and appeared to indicate brain-specific changes.Our study revealed surprisingly few dysmethylated genes in a brain region less affected in PD. We confirmed hypomethylation ofCYP2E1.",
+Yes,20220523,ewas,35568878,Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array.,Clin Epigenetics,"Sex differences are known to play a role in disease aetiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and females in some tissues, including differences in DNA methylation patterns. Here, we report for the first time an analysis of autosomal sex differences in DNAme using the Illumina EPIC array in human whole blood by performing a discovery (n = 1171) and validation (n = 2471) analysis.We identified and validated 396 sex-associated differentially methylated CpG sites (saDMPs) with the majority found to be female-biased CpGs (74%). These saDMP's are enriched in CpG islands and CpG shores and located preferentially at 5'UTRs, 3'UTRs and enhancers. Additionally, we identified 266 significant sex-associated differentially methylated regions overlapping genes, which have previously been shown to exhibit epigenetic sex differences, and novel genes. Transcription factor binding site enrichment revealed enrichment of transcription factors related to critical developmental processes and sex determination such as SRY and ESR1.Our study reports a reliable catalogue of sex-associated CpG sites and elucidates several characteristics of these sites using large-scale discovery and validation data sets. This resource will benefit future studies aiming to investigate sex specific epigenetic signatures and further our understanding of the role of DNA methylation in sex differences in human whole blood.© 2022. The Author(s).",
+No,20220523,ewas,35578268,"Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms.",Clin Epigenetics,"We previously showed that continued folic acid (FA) supplementation beyond the first trimester of pregnancy appears to have beneficial effects on neurocognitive performance in children followed for up to 11 years, but the biological mechanism for this effect has remained unclear. Using samples from our randomized controlled trial of folic acid supplementation in second and third trimester (FASSTT), where significant improvements in cognitive and psychosocial performance were demonstrated in children from mothers supplemented in pregnancy with 400 µg/day FA compared with placebo, we examined methylation patterns from cord blood (CB) using the EPIC array which covers approximately 850,000 cytosine-guanine (CG) sites across the genome. Genes showing significant differences were verified using pyrosequencing and mechanistic approaches used in vitro to determine effects on transcription.FA supplementation resulted in significant differences in methylation, particularly at brain-related genes. Further analysis showed these genes split into two groups. In one group, which included the CES1 gene, methylation changes at the promoters were important for regulating transcription. We also identified a second group which had a characteristic bimodal profile, with low promoter and high gene body (GB) methylation. In the latter, loss of methylation in the GB is linked to decreases in transcription: this group included the PRKAR1B/HEATR2 genes and the dopamine receptor regulator PDE4C. Overall, methylation in CB also showed good correlation with methylation profiles seen in a published data set of late gestation foetal brain samples.We show here clear alterations in DNA methylation at specific classes of neurodevelopmental genes in the same cohort of children, born to FA-supplemented mothers, who previously showed improved cognitive and psychosocial performance. Our results show measurable differences at neural genes which are important for transcriptional regulation and add to the supporting evidence for continued FA supplementation throughout later gestation. This trial was registered on 15 May 2013 at www.isrctn.com as ISRCTN19917787.© 2022. The Author(s).",
+No,20220523,ewas,35577912,"Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants.",Mol Psychiatry,"The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events that precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers' attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 106individual CpG dinucleotides, using clustering-based significance criteria to control for multiple comparisons. We found that tens of thousands of individual infant CpGs were alternatively methylated in association with maternal attachment insecurity, maltreatment in childhood, and antenatal and postpartum depressive symptoms, including genes implicated in developmental patterning, cell-cell communication, hormonal regulation, immune function/inflammatory response, and neurotransmission. Density of DNA methylation at selected genes from the result set was also significantly associated with toddler socioemotional and behavioral problems. This is the first report to identify novel regions of the human infant genome at which DNA methylation patterns are associated longitudinally both with maternal characteristics and with offspring socioemotional and behavioral problems in toddlerhood.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20220523,meqtl,35488087,Incorporating local ancestry improves identification of ancestry-associated methylation signatures and meQTLs in African Americans.,Commun Biol,"Here we report three epigenome-wide association studies (EWAS) of DNA methylation on self-reported race, global genetic ancestry, and local genetic ancestry in admixed Americans from three sets of samples, including internal and external replications (Ntotal = 1224). Our EWAS on local ancestry (LA) identified the largest number of ancestry-associated DNA methylation sites and also featured the highest replication rate. Furthermore, by incorporating ancestry origins of genetic variations, we identified 36 methylation quantitative trait loci (meQTL) clumps for LA-associated CpGs that cannot be captured by a model that assumes identical genetic effects across ancestry origins. Lead SNPs at 152 meQTL clumps had significantly different genetic effects in the context of an African or European ancestry background. Local ancestry information enables superior capture of ancestry-associated methylation signatures and identification of ancestry-specific genetic effects on DNA methylation. These findings highlight the importance of incorporating local ancestry for EWAS in admixed samples from multi-ancestry cohorts.© 2022. The Author(s).",
+No,20220523,methods,35567415,Evaluation of nanopore sequencing for epigenetic epidemiology: a comparison with DNA methylation microarrays.,Hum Mol Genet,"Most epigenetic epidemiology to date has utilized microarrays to identify positions in the genome where variation in DNA methylation is associated with environmental exposures or disease. However, these profile less than 3% of DNA methylation sites in the human genome, potentially missing affected loci and preventing the discovery of disrupted biological pathways. Third generation sequencing technologies, including Nanopore sequencing, have the potential to revolutionise the generation of epigenetic data, not only by providing genuine genome-wide coverage but profiling epigenetic modifications direct from native DNA. Here we assess the viability of using Nanopore sequencing for epidemiology by performing a comparison with DNA methylation quantified using the most comprehensive microarray available, the Illumina EPIC array. We implemented a CRISPR-Cas9 targeted sequencing approach in concert with Nanopore sequencing to profile DNA methylation in three genomic regions to attempt to rediscover genomic positions that existing technologies have shown are differentially methylated in tobacco smokers. Using Nanopore sequencing reads, DNA methylation was quantified at 1779 CpGs across three regions, providing a finer resolution of DNA methylation patterns compared to the EPIC array. The correlation of estimated levels of DNA methylation between platforms was high. Furthermore, we identified 12 CpGs where hypomethylation was significantly associated with smoking status, including 10 within the AHRR gene. In summary, Nanopore sequencing is a valid option for identifying genomic loci where large differences in DNAm are associated with a phenotype and has the potential to advance our understanding of the role differential methylation plays in the aetiology of complex disease.© The Author(s) 2022. Published by Oxford University Press.",
+No,20220523,methods,35505215,BCurve: Bayesian Curve Credible Bands Approach for the Detection of Differentially Methylated Regions.,Methods Mol Biol,"High-throughput assays have been developed to measure DNA methylation, among which bisulfite-based sequencing (BS-seq) and microarray technologies are the most popular for genome-wide profiling. A major goal in DNA methylation analysis is the detection of differentially methylated genomic regions under two different conditions. To accomplish this, many state-of-the-art methods have been proposed in the past few years; only a handful of these methods are capable of analyzing both types of data (BS-seq and microarray), though. On the other hand, covariates, such as sex and age, are known to be potentially influential on DNA methylation; and thus, it would be important to adjust for their effects on differential methylation analysis. In this chapter, we describe a Bayesian curve credible bands approach and the accompanying software, BCurve, for detecting differentially methylated regions for data generated from either microarray or BS-Seq. The unified theme underlying the analysis of these two different types of data is the model that accounts for correlation between DNA methylation in nearby sites, covariates, and between-sample variability. The BCurve R software package also provides tools for simulating both microarray and BS-seq data, which can be useful for facilitating comparisons of methods given the known ""gold standard"" in the simulated data. We provide detailed description of the main functions in BCurve and demonstrate the utility of the package for analyzing data from both platforms using simulated data from the functions provided in the package. Analyses of two real datasets, one from BS-seq and one from microarray, are also furnished to further illustrate the capability of BCurve.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35505213,DNA Methylation Imputation Across Platforms.,Methods Mol Biol,"In this chapter, we will provide a review on imputation in the context of DNA methylation, specifically focusing on a penalized functional regression (PFR) method we have previously developed. We will start with a brief review of DNA methylation, genomic and epigenomic contexts where imputation has proven beneficial in practice, and statistical or computational methods proposed for DNA methylation in the recent literature (Subheading 1). The rest of the chapter (Subheadings 2-4) will provide a detailed review of our PFR method proposed for across-platform imputation, which incorporates nonlocal information using a penalized functional regression framework. Subheading 2 introduces commonly employed technologies for DNA methylation measurement and describes the real dataset we have used in the development of our method: the acute myeloid leukemia (AML) dataset from The Cancer Genome Atlas (TCGA) project. Subheading 3 comprehensively reviews our method, encompassing data harmonization prior to model building, the actual building of penalized functional regression model, post-imputation quality filter, and imputation quality assessment. Subheading 4 shows the performance of our method in both simulation and the TCGA AML dataset, demonstrating that our penalized functional regression model is a valuable across-platform imputation tool for DNA methylation data, particularly because of its ability to boost statistical power for subsequent epigenome-wide association study. Finally, Subheading 5 provides future perspectives on imputation for DNA methylation data.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35505212,A Review of High-Dimensional Mediation Analyses in DNA Methylation Studies.,Methods Mol Biol,"DNA methylation alterations have been widely studied as mediators of environmentally induced disease risks. With new advances in technique, epigenome-wide DNA methylation data (EWAS) have become the new standard for epigenetic studies in human populations. However, to date most epigenetic studies of mediation effects only involve selected (gene-specific) candidate methylation markers. There is an urgent need for appropriate analytical methods for EWAS mediation analysis. In this chapter, we provide an overview of recent advances on high-dimensional mediation analysis, with application to two DNA methylation data.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35505211,Increase the Power of Epigenome-Wide Association Testing Using ICC-Based Hypothesis Weighting.,Methods Mol Biol,"For large-scale hypothesis testing such as epigenome-wide association testing, adaptively focusing power on the more promising hypotheses can lead to a much more powerful multiple testing procedure. In this chapter, we introduce a multiple testing procedure that weights each hypothesis based on the intraclass correlation coefficient (ICC), a measure of ""noisiness"" of CpG methylation measurement, to increase the power of epigenome-wide association testing. Compared to the traditional multiple testing procedure on a filtered CpG set, the proposed procedure circumvents the difficulty to determine the optimal ICC cutoff value and is overall more powerful. We illustrate the procedure and compare the power to classical multiple testing procedures using an example data.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35505210,Meta-Analysis for Epigenome-Wide Association Studies.,Methods Mol Biol,"With the rapid development of methylation profiling technology, many datasets are generated to quantify genome-wide methylation patterns. Given the heavy burden of multiple testing of hundreds of thousands of DNA methylation markers, individual studies often have limited sample sizes and power. The EWAS meta-analysis is an approach that combines results from multiple studies on the same scientific question. It helps to improve statistical power by combining information from individual studies and reduce the chances of false positives. This chapter introduces commonly used meta-analysis methods and analytical tools with application to EWAS data.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35505208,Controlling Batch Effect in Epigenome-Wide Association Study.,Methods Mol Biol,"Methylation data, similar to other omics data, is susceptible to various technical issues that are potentially associated with unexplained or unrelated factors. Any difference in the measurement of DNA methylation, such as laboratory operation and sequencing platform, may lead to batch effects. With the accumulation of large-scale omics data, scientists are making joint efforts to generate and analyze omics data to answer various scientific questions. However, batch effects are inevitable in practice, and careful adjustment is needed. Multiple statistical methods for controlling bias and inflation between batches have been developed either by correcting based on known batch factors or by estimating directly from the output data. In this chapter, we will review and demonstrate several popular methods for batch effect correction and make practical recommendations in epigenome-wide association studies (EWAS).© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35505207,Cell Type-Specific Signal Analysis in Epigenome-Wide Association Studies.,Methods Mol Biol,"Hundreds of epigenome-wide association studies (EWAS) have been performed, successfully identifying replicated epigenomic signals in processes such as aging and smoking. Despite this progress, it remains a major challenge in EWAS to detect both cell type-specific and cell type confounding effects impacting study results. One way to identify these effects is through eFORGE (experimentally derived Functional element Overlap analysis of ReGions from EWAS), a published tool that uses 815 datasets from large-scale mapping studies to detect enriched tissues, cell types, and genomic regions. Here, I show that eFORGE analysis can be extended to EWAS differentially variable positions (DVPs), identifying target cell types and tissues. In addition, I also show that eFORGE tissue-specific enrichment can be detected for sites below EWAS significance threshold. I develop on these and other analysis examples, extending our knowledge of eFORGE cell type- and tissue-specific enrichment results for different EWAS.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35505205,Accurate Measurement of DNA Methylation: Challenges and Bias Correction.,Methods Mol Biol,"DNA methylation is a key epigenetic modification involved in gene regulation whose contribution to disease susceptibility is still not fully understood. As the cost of genome sequencing technologies continues to drop, it will soon become commonplace to perform genome-wide quantification of DNA methylation at a single base-pair resolution. However, the demand for its accurate quantification might vary across studies. When the scope of the analysis is to detect regions of the genome with different methylation patterns between two or more conditions, e.g., case vs control; treatments vs placebo, accuracy is not crucial. This is the case in epigenome-wide association studies used as genome-wide screening of methylation changes to detect new candidate genes and regions associated with a specific disease or condition. If the aim of the analysis is to use DNA methylation measurements as a biomarker for diseases diagnosis and treatment (Laird, Nat Rev Cancer 3:253-266, 2003; Bock, Epigenomics 1:99-110, 2009), it is instead recommended to produce accurate methylation measurements. Furthermore, if the objective is the detection of DNA methylation in subclonal tumor cell populations or in circulating tumor DNA or in any case of mosaicism, the importance of accuracy becomes critical. The aim of this chapter is to describe the factors that could affect the precise measurement of methylation levels and a recent Bayesian statistical method called MethylCal and its extension that have been proposed to minimize this problem.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35505204,Evaluating Reliability of DNA Methylation Measurement.,Methods Mol Biol,"DNA methylation is a widely studied epigenetic phenomenon. Alterations in methylation patterns influence human phenotypes and risk of disease. The Illumina Infinium HumanMethylation450 (HM450) and MethylationEPIC (EPIC) BeadChip are widely used microarray-based platforms for epigenome-wide association studies (EWASs). In this chapter, we will discuss the use of intraclass correlation coefficient (ICC) for assessing technical variations induced by methylation arrays at single-CpG level. ICC compares variation of methylation levels within- and between-replicate measurements, ranging between 0 and 1. We further characterize the distribution of ICCs using a mixture of truncated normal and normal distributions, and cluster CpG sites on the arrays into low- and high-reliability groups. In practice, we recommend that extra caution needs to be taken for associations at the CpG sites with low ICC values.© 2022. Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20220523,methods,35488315,"Batch-effect detection, correction and characterisation in Illumina HumanMethylation450 and MethylationEPIC BeadChip array data.",Clin Epigenetics,"Genomic technologies can be subject to significant batch-effects which are known to reduce experimental power and to potentially create false positive results. The Illumina Infinium Methylation BeadChip is a popular technology choice for epigenome-wide association studies (EWAS), but presently, little is known about the nature of batch-effects on these designs. Given the subtlety of biological phenotypes in many EWAS, control for batch-effects should be a consideration.Using the batch-effect removal approaches in the ComBat and Harman software, we examined two in-house datasets and compared results with three large publicly available datasets, (1214 HumanMethylation450 and 1094 MethylationEPIC BeadChips in total), and find that despite various forms of preprocessing, some batch-effects persist. This residual batch-effect is associated with the day of processing, the individual glass slide and the position of the array on the slide. Consistently across all datasets, 4649 probes required high amounts of correction. To understand the impact of this set to EWAS studies, we explored the literature and found three instances where persistently batch-effect prone probes have been reported in abstracts as key sites of differential methylation. As well as batch-effect susceptible probes, we also discover a set of probes which are erroneously corrected. We provide batch-effect workflows for Infinium Methylation data and provide reference matrices of batch-effect prone and erroneously corrected features across the five datasets spanning regionally diverse populations and three commonly collected biosamples (blood, buccal and saliva).Batch-effects are ever present, even in high-quality data, and a strategy to deal with them should be part of experimental design, particularly for EWAS. Batch-effect removal tools are useful to reduce technical variance in Infinium Methylation data, but they need to be applied with care and make use of post hoc diagnostic measures.© 2022. The Author(s).",
+No,20220523,methods,35450213,High-Dimensional DNA Methylation Mediates the Effect of Smoking on Crohn's Disease.,Front Genet,"Epigenome-wide mediation analysis aims to identify high-dimensional DNA methylation at cytosine-phosphate-guanine (CpG) sites that mediate the causal effect of linking smoking with Crohn's disease (CD) outcome. Studies have shown that smoking has significant detrimental effects on the course of CD. So we assessed whether DNA methylation mediates the association between smoking and CD. Among 103 CD cases and 174 controls, we estimated whether the effects of smoking on CD are mediated through DNA methylation CpG sites, which we referred to as causal mediation effect. Based on the causal diagram, we first implemented sure independence screening (SIS) to reduce the pool of potential mediator CpGs from a very large to a moderate number; then, we implemented variable selection with de-sparsifying the LASSO regression. Finally, we carried out a comprehensive mediation analysis and conducted sensitivity analysis, which was adjusted for potential confounders of age, sex, and blood cell type proportions to estimate the mediation effects. Smoking was significantly associated with CD under odds ratio (OR) of 2.319 (95% CI: 1.603, 3.485,p < 0.001) after adjustment for confounders. Ninety-nine mediator CpGs were selected from SIS, and then, seven candidate CpGs were obtained by de-sparsifying the LASSO regression. Four of these CpGs showed statistical significance, and the average causal mediation effects (ACME) were attenuated from 0.066 to 0.126. Notably, three significant mediator CpGs had absolute sensitivity parameters of 0.40, indicating that these mediation effects were robust even when the assumptions were slightly violated. Genes (BCL3 and FKBP5) harboring these four CpGs were related to CD. These findings suggest that changes in methylation are involved in the mechanism by which smoking increases risk of CD.Copyright © 2022 Wang, Xia and Su.",
+No,20220523,methods,35440009,Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach.,Clin Epigenetics,"DNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R2Methylation) towards childhood phenotypes is unknown. An estimate of R2Methylationwould provide context regarding the importance of DNA methylation explaining variance in health outcomes. We therefore estimated the variance explained by epigenome-wide cord blood methylation (R2Methylation) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n = 775) and Generation R (n = 1382).Using information from > 470,000 autosomal probes we estimated that DNA methylation at birth explains 32% (SDCV = 0.06) of gestational age variance and 5% (SDCV = 0.02) of birth weight variance. The R2Methylationestimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations.The results suggest that cord blood methylation explains a moderate degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the true R2Methylationfor these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth.© 2022. The Author(s).",
+No,20220523,methods,35501393,Multi-omics single-cell data integration and regulatory inference with graph-linked embedding.,Nat Biotechnol,"Despite the emergence of experimental methods for simultaneous measurement of multiple omics modalities in single cells, most single-cell datasets include only one modality. A major obstacle in integrating omics data from multiple modalities is that different omics layers typically have distinct feature spaces. Here, we propose a computational framework called GLUE (graph-linked unified embedding), which bridges the gap by modeling regulatory interactions across omics layers explicitly. Systematic benchmarking demonstrated that GLUE is more accurate, robust and scalable than state-of-the-art tools for heterogeneous single-cell multi-omics data. We applied GLUE to various challenging tasks, including triple-omics integration, integrative regulatory inference and multi-omics human cell atlas construction over millions of cells, where GLUE was able to correct previous annotations. GLUE features a modular design that can be flexibly extended and enhanced for new analysis tasks. The full package is available online at https://github.com/gao-lab/GLUE .© 2022. The Author(s).",
+No,20220523,prediction,35523767,Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum.,Transl Psychiatry,"Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR < 0.05), but not the ventral striatum of AUD cases. In the VS, DE genes at FDR < 0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune- and inflammation-related processes in AUD.© 2022. The Author(s).",
+No,20220523,prediction,35490552,Complex trait methylation scores in the prediction of major depressive disorder.,EBioMedicine,"DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions.Here, we calculated methylation scores (MS) at multiple p-value thresholds for lifestyle (BMI, smoking, alcohol consumption, and educational attainment) and biochemical (high-density lipoprotein (HDL) and total cholesterol) factors in Generation Scotland (GS) (N=9,502) and in a replication cohort (ALSPACadults, N=565), using CpG sites reported in previous well-powered methylome-wide association studies. We also compared their predictive accuracy for MDD to a MDD MS in an independent GS sub-sample (N=4,432).Each trait MS was significantly associated with its corresponding phenotype in GS (βrange=0.089-1.457) and in ALSPAC (βrange=0.078-2.533). Each MS was also significantly associated with MDD before and after adjustment for its corresponding phenotype in GS (βrange=0.053-0.145). After accounting for relevant lifestyle factors, MS for educational attainment (β=0.094) and alcohol consumption (MSp-value<0.01-0.5; βrange=-0.069-0.083) remained significantly associated with MDD in GS. Smoking (AUC=0.569) and educational attainment (AUC=0.585) MSs could discriminate MDD from controls better than the MDD MS (AUC=0.553) in the independent GS sub-sample. Analyses implicating MDD did not replicate across ALSPAC, although the direction of effect was consistent for all traits when adjusting for the MS corresponding phenotypes.We showed that lifestyle and biochemical MS were associated with MDD before and after adjustment for their corresponding phenotypes (pnominal<0.05), but not when smoking, alcohol consumption, and BMI were also included as covariates. MDD results did not replicate in the smaller, female-only independent ALSPAC cohort (NALSPAC=565; NGS=9,502), potentially due to demographic differences or low statistical power, but effect sizes were consistent with the direction reported in GS. DNAm scores for modifiable MDD risk factors may contribute to disease vulnerability and, in some cases, explain additional variance to their observed phenotypes.Wellcome Trust.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.",
+No,20220523,prediction,35473556,Accurate and highly interpretable prediction of gene expression from histone modifications.,BMC Bioinformatics,"Histone Mark Modifications (HMs) are crucial actors in gene regulation, as they actively remodel chromatin to modulate transcriptional activity: aberrant combinatorial patterns of HMs have been connected with several diseases, including cancer. HMs are, however, reversible modifications: understanding their role in disease would allow the design of 'epigenetic drugs' for specific, non-invasive treatments. Standard statistical techniques were not entirely successful in extracting representative features from raw HM signals over gene locations. On the other hand, deep learning approaches allow for effective automatic feature extraction, but at the expense of model interpretation.Here, we propose ShallowChrome, a novel computational pipeline to model transcriptional regulation via HMs in both an accurate and interpretable way. We attain state-of-the-art results on the binary classification of gene transcriptional states over 56 cell-types from the REMC database, largely outperforming recent deep learning approaches. We interpret our models by extracting insightful gene-specific regulative patterns, and we analyse them for the specific case of the PAX5 gene over three differentiated blood cell lines. Finally, we compare the patterns we obtained with the characteristic emission patterns of ChromHMM, and show that ShallowChrome is able to coherently rank groups of chromatin states w.r.t. their transcriptional activity.In this work we demonstrate that it is possible to model HM-modulated gene expression regulation in a highly accurate, yet interpretable way. Our feature extraction algorithm leverages on data downstream the identification of enriched regions to retrieve gene-wise, statistically significant and dynamically located features for each HM. These features are highly predictive of gene transcriptional state, and allow for accurate modeling by computationally efficient logistic regression models. These models allow a direct inspection and a rigorous interpretation, helping to formulate quantifiable hypotheses.© 2022. The Author(s).",
+No,20220523,pwas,35544531,Cardiovascular disease protein biomarkers are associated with kidney function: The Framingham Heart Study.,PLoS One,"Biomarkers common to chronic kidney disease (CKD) and cardiovascular disease (CVD) may reflect early impairments underlying both diseases.We evaluated associations of 71 CVD-related plasma proteins measured in 2,873 Framingham Heart Study (FHS) Offspring cohort participants with cross-sectional continuous eGFR and with longitudinal change in eGFR from baseline to follow-up (ΔeGFR). We also evaluated the associations of the 71 CVD proteins with the following dichotomous secondary outcomes: prevalent CKD stage ≥3 (cross-sectional), new-onset CKD stage ≥3 (longitudinal), and rapid decline in eGFR (longitudinal). Proteins significantly associated with eGFR and ΔeGFR were subsequently validated in 3,951 FHS Third Generation cohort participants and were tested using Mendelian randomization (MR) analysis to infer putatively causal relations between plasma protein biomarkers and kidney function.In cross-sectional analysis, 37 protein biomarkers were significantly associated with eGFR at FDR<0.05 in the FHS Offspring cohort and 20 of these validated in the FHS Third Generation cohort at p<0.05/37. In longitudinal analysis, 27 protein biomarkers were significantly associated with ΔeGFR at FDR<0.05 and 12 of these were validated in the FHS Third Generation cohort at p<0.05/27. Additionally, 35 protein biomarkers were significantly associated with prevalent CKD, five were significantly associated with new-onset CKD, and 17 were significantly associated with rapid decline in eGFR. MR suggested putatively causal relations of melanoma cell adhesion molecule (MCAM; -0.011±0.003 mL/min/1.73m2, p = 5.11E-5) and epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1; -0.006±0.002 mL/min/1.73m2, p = 0.0001) concentration with eGFR.Eight protein biomarkers were consistently associated with eGFR in cross-sectional and longitudinal analysis in both cohorts and may capture early kidney impairment; others were implicated in association and causal inference analyses. A subset of CVD protein biomarkers may contribute causally to the pathogenesis of kidney impairment and should be studied as targets for CKD treatment and early prevention.",
+No,20220523,somatic,35444284,Somatic genomic changes in single Alzheimer's disease neurons.,Nature,"Dementia in Alzheimer's disease progresses alongside neurodegeneration1-4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5at rates similar to those of dividing cells6,7which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells6-10. In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20220620,dnam age,35681159,Cardiovascular health and four epigenetic clocks.,Clin Epigenetics,"Cardiovascular health (CVH) was defined by the American Heart Association as an integrative idealness of seven clinical or lifestyle factors. Based on populations of European ancestry, recent studies have shown that ideal CVH is associated with a slower aging rate. The aging rate is measured by levels of epigenetic age acceleration (EAA), usually obtained from the residuals of regressing DNA methylation (DNAm) age on chronological age. However, little has been known about the association of CVH with biological aging in Asian populations.We here analyzed blood DNAm data and clinical/lifestyle factors of 2474 Taiwan Biobank (TWB) participants, to investigate the association of CVH with EAA. CVH was assessed by seven components: smoking status, physical activity, dietary habits, body mass index, total cholesterol, fasting glucose, and blood pressure levels. Four measures of EAA were applied, among which two were based on the first-generation DNAm clocks (HannumEAA and IEAA) and two were based on the second-generation clocks (PhenoEAA and GrimEAA). After excluding 276 individuals with cardiovascular diseases, we regressed EAA on the CVH score (ranging from 0 to 7, integrating the abovementioned seven components) while adjusting for sex, drinking status, and educational attainment. Our results showed that a decrease in one point in the CVH score was associated with a 0.350-year PhenoEAA (p = 4.5E-4) and a 0.499-year GrimEAA (p = 4.2E-15). By contrast, HannumEAA and IEAA were not significantly associated with the CVH score. We have obtained consistent results within each generation of epigenetic clocks.This is one of the first studies to comprehensively investigate the associations of CVH with four epigenetic clocks. Our TWB data showed that ideal CVH is associated with lower levels of EAA calculated according to the second-generation epigenetic clocks (PhenoEAA and GrimEAA). Having an ideal CVH status can lower EAA and reduce the risk of aging-related disorders.© 2022. The Author(s).",
+No,20220620,dnam age,35681206,Evaluation of short-term epigenetic age fluctuation.,Clin Epigenetics,"Considerable effort has been spent on lowering and maintaining the epigenetic age. However, the extent to which epigenetic age fluctuates under normal conditions is poorly understood. Therefore, we analyzed methylation data from monocytes and peripheral blood mononuclear cells collected from two Japanese men. The ranges of the Pan-tissue, Skin and blood, and DNAm PhenoAge epigenetic age during 3 months were ≥ 5.62, ≥ 3.04, and ≥ 8.23 years, and the maximum daily changes were 5.21, 3.20, and 6.53 years, respectively. These fluctuations were not suppressed by correcting for cell-type composition. Although the underlying biological mechanism remains unclear, there was a nonnegligible degree of age fluctuation which should inform personalized clinical applications.© 2022. The Author(s).",
+No,20220620,epigenetics,35608069,Large-scale integration of DNA methylation and gene expression array platforms identifies both <i>cis</i> and <i>trans</i> relationships.,Epigenetics,"Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE inciswere enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated withtransGE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming acisDNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented. An in-depth characterization of GE-associated CpG sites could improve predictions of the downstream functional impact of altered DNAm and inform best practices for interpreting DNAm-trait associations generated by EWAS.",
+No,20220620,epigenetics,35672318,Integrating 3D genomic and epigenomic data to enhance target gene discovery and drug repurposing in transcriptome-wide association studies.,Nat Commun,"Transcriptome-wide association studies (TWAS) are popular approaches to test for association between imputed gene expression levels and traits of interest. Here, we propose an integrative method PUMICE (Prediction Using Models Informed by Chromatin conformations and Epigenomics) to integrate 3D genomic and epigenomic data with expression quantitative trait loci (eQTL) to more accurately predict gene expressions. PUMICE helps define and prioritize regions that harbor cis-regulatory variants, which outperforms competing methods. We further describe an extension to our method PUMICE +, which jointly combines TWAS results from single- and multi-tissue models. Across 79 traits, PUMICE + identifies 22% more independent novel genes and increases median chi-square statistics values at known loci by 35% compared to the second-best method, as well as achieves the narrowest credible interval size. Lastly, we perform computational drug repurposing and confirm that PUMICE + outperforms other TWAS methods.© 2022. The Author(s).",
+No,20220620,epigenetics,35614216,Divergent transcriptional regulation of astrocyte reactivity across disorders.,Nature,"Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20220620,epigenetics,35710981,"Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease",Nat Genet,"More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability analysis reveals that methylation variation explains a larger fraction of heritability than gene expression. We present a multi-stage prioritization strategy and prioritize target genes for 87% of kidney function loci. We highlight key roles of proximal tubules and metabolism in kidney function regulation. Furthermore, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.",
+No,20220620,methods,35592546,The EWAS Catalog: a database of epigenome-wide association studies.,Wellcome Open Res,"Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p<1x10-4) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From January 7, 2022, The EWAS Catalog contained 1,737,746 associations from 2,686 EWAS. This includes 1,345,398 associations from 342 peer-reviewed publications. In addition, it also contains summary statistics for 392,348 associations from 427 EWAS, performed on data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Omnibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to query EWAS associations quickly and easily, and gain insight into the molecular underpinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog data extraction team continue to update the database monthly and we encourage any EWAS authors to upload their summary statistics to our website. Details of how to upload data can be found here: http://www.ewascatalog.org/upload. The EWAS Catalog is available at http://www.ewascatalog.org.Copyright: © 2022 Battram T et al.",
+No,20220620,prediction,35681440,Artificial Intelligence and Circulating Cell-Free DNA Methylation Profiling: Mechanism and Detection of Alzheimer's Disease.,Cells,"Despite extensive efforts, significant gaps remain in our understanding of Alzheimer's disease (AD) pathophysiology. Novel approaches using circulating cell-free DNA (cfDNA) have the potential to revolutionize our understanding of neurodegenerative disorders.We performed DNA methylation profiling of cfDNA from AD patients and compared them to cognitively normal controls. Six Artificial Intelligence (AI) platforms were utilized for the diagnosis of AD while enrichment analysis was used to elucidate the pathogenesis of AD.A total of 3684 CpGs were significantly (adj.p-value &lt; 0.05) differentially methylated in AD versus controls. All six AI algorithms achieved high predictive accuracy (AUC = 0.949-0.998) in an independent test group. As an example, Deep Learning (DL) achieved an AUC (95% CI) = 0.99 (0.95-1.0), with 94.5% sensitivity and specificity.We describe numerous epigenetically altered genes which were previously reported to be differentially expressed in the brain of AD sufferers. Genes identified by AI to be the best predictors of AD were either known to be expressed in the brain or have been previously linked to AD. We highlight enrichment in the Calcium signaling pathway, Glutamatergic synapse, Hedgehog signaling pathway, Axon guidance and Olfactory transduction in AD sufferers. To the best of our knowledge, this is the first reported genome-wide DNA methylation study using cfDNA to detect AD.",
+No,20220620,telomeres,35681050,"Genetic, parental and lifestyle factors influence telomere length.",Commun Biol,"The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.© 2022. The Author(s).",
+Yes,20220620,ewas,35703085,"DNA methylation in people with Anorexia Nervosa: Epigenome-wide patterns in actively ill, long-term remitted, and healthy-eater women.",World J Biol Psychiatry,"Objectives:Recent studies have reported altered methylation levels at disorder-relevant DNA sites in people who are ill with Anorexia Nervosa (AN) compared to findings in people with no eating disorder (ED) or in whom AN has remitted. The preceding implies state-related influences upon gene expression in people with AN. The present study further examined this notion.Methods:We measured genome-wide DNA methylation in 145 women with active AN, 49 showing stable one-year remission of AN, and 64 with no ED.Results:Comparisons revealed 205 differentially methylated sites between active and no ED groups, and 162 differentially methylated sites between active and remitted groups (Q < 0.01). Probes tended to map onto genes relevant to psychiatric, metabolic and immune functions. Notably, several of the genes identified here as being differentially methylated in people with AN (e.g.,SYNJ2, PRKAG2, STAT3,CSGALNACT1, NEGR1,NR1H3) have figured in previous studies on AN. Effects also associated illness chronicity and lower BMI with more pronounced DNA methylation alterations, and remission of AN with normalization of DNA methylation.Conclusions:Findings corroborate earlier results suggesting reversible DNA methylation alterations in AN, and point to particular genes at which epigenetic mechanisms may act to shape AN phenomenology.",
+Yes,20220620,ewas,35700439,Epigenome-wide Association Study Identified VTI1A DNA Methylation Associated with Accelerometer-assessed Physical Activity.,Med Sci Sports Exerc,"Health benefits of physical activity (PA) may be mediated by DNA methylation alterations. The purpose of the current study was to comprehensively identify CpG sites whose methylation levels were associated with accelerometer-assessed total PA in a general Japanese population.The study participants were from the baseline survey of Saga Japan Multi-institutional Collaborative Cohort. PA was objectively measured by a single-axis accelerometer for seven days. We employed a two-stage strategy. In the discovery stage, we performed a meta-analysis of two epigenome-wide association studies (EWAS) of total PA in 898 individuals (a combination of random sample [n = 507] and case-control study sample [n = 391]. Peripheral blood DNA methylation levels were measured using Infinium EPIC or HM450 arrays. In the replication stage, we subsequently examined whether CpG sites significantly associated (P < 1 × 10-5) with total PA were replicated in another sample (n = 1711), in which methylation levels were measured by pyrosequencing. A multiple linear regression was performed to determine the cross-sectional association between total PA and methylation levels with adjustment for potential confounders, including BMI. A fixed-effects model was used in the meta-analysis. Correlations between total PA-associated DNA methylation and several inflammatory markers, such as hs-CRP, were also conducted.In the meta-analysis, nine CpG sites were significantly associated with total PA (P < 1 × 10-5). Among the nine sites, one site cg07030336 (annotated to VTI1A/ZDHHC6 gene) was successfully replicated (P = 0.009).The current study showed that greater accelerometer-assessed total PA was associated with higher DNA methylation levels at cg07030336 (VTI1A/ZDHHC6) in the general population. Additionally, we found a divergent relationship between the methylation levels at cg07030336 and several inflammatory biomarkers.Copyright © 2022 by the American College of Sports Medicine.",
+Yes,20220620,ewas,35692099,DNA methylation patterns reflect individual's lifestyle independent of obesity.,Clin Transl Med,"Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects on blood DNA methylation in participants of the LIFE-Adult study, a well-characterised population-based cohort from Germany.Lifestyle scores (LS) based on diet, physical activity, smoking and alcohol intake were calculated in 4107 participants of the LIFE-Adult study. Fifty subjects with an extremely healthy lifestyle and 50 with an extremely unhealthy lifestyle (5th and 95th percentiles LS) were selected for genome-wide DNA methylation analysis in blood samples employing Illumina Infinium® Methylation EPIC BeadChip system technology.Differences in DNA methylation patterns between body mass index groups (<25 vs. >30 kg/m2) were rather marginal compared to inter-lifestyle differences (0 vs. 145 differentially methylated positions [DMPs]), which identified 4682 differentially methylated regions (DMRs; false discovery rate [FDR <5%) annotated to 4426 unique genes. A DMR annotated to the glutamine-fructose-6-phosphate transaminase 2 (GFPT2) locus showed the strongest hypomethylation (�6.9%), and one annotated to glutamate rich 1 (ERICH1) showed the strongest hypermethylation (�5.4%) in healthy compared to unhealthy lifestyle individuals. Intersection analysis showed that diet, physical activity, smoking and alcohol intake equally contributed to the observed differences, which affected, among others, pathways related to glutamatergic synapses (adj. p < .01) and axon guidance (adj. p < .05). We showed that methylation age correlates with chronological age and waist-to-hip ratio with lower DNA methylation age (DNAmAge) acceleration distances in participants with healthy lifestyles. Finally, two identified top DMPs for the alanyl aminopeptidase (ANPEP) locus also showed the strongest expression quantitative trait methylation in blood.DNA methylation patterns help discriminate individuals with a healthy versus unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.",
+Yes,20220620,ewas,35690418,Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.,Mutat Res Rev Mutat Res,"Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits.We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268).In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction.This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.",
+Yes,20220620,ewas,35681244,An epigenome-wide study of DNA methylation profiles and lung function among American Indians in the Strong Heart Study.,Clin Epigenetics,"Epigenetic modifications, including DNA methylation (DNAm), are often related to environmental exposures, and are increasingly recognized as key processes in the pathogenesis of chronic lung disease. American Indian communities have a high burden of lung disease compared to the national average. The objective of this study was to investigate the association of DNAm and lung function in the Strong Heart Study (SHS). We conducted a cross-sectional study of American Indian adults, 45-74 years of age who participated in the SHS. DNAm was measured using the Illumina Infinium Human MethylationEPIC platform at baseline (1989-1991). Lung function was measured via spirometry, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), at visit 2 (1993-1995). Airflow limitation was defined as FEV1 < 70% predicted and FEV1/FVC < 0.7, restriction was defined as FEV1/FVC > 0.7 and FVC < 80% predicted, and normal spirometry was defined as FEV1/FVC > 0.7, FEV1 > 70% predicted, FVC > 80% predicted. We used elastic-net models to select relevant CpGs for lung function and spirometry-defined lung disease. We also conducted bioinformatic analyses to evaluate the biological plausibility of the findings.Among 1677 participants, 21.2% had spirometry-defined airflow limitation and 13.6% had spirometry-defined restrictive pattern lung function. Elastic-net models selected 1118 Differentially Methylated Positions (DMPs) as predictors of airflow limitation and 1385 for restrictive pattern lung function. A total of 12 DMPs overlapped between airflow limitation and restrictive pattern. EGFR, MAPK1 and PRPF8 genes were the most connected nodes in the protein-protein interaction network. Many of the DMPs targeted genes with biological roles related to lung function such as protein kinases.We found multiple differentially methylated CpG sites associated with chronic lung disease. These signals could contribute to better understand molecular mechanisms involved in lung disease, as assessed systemically, as well as to identify patterns that could be useful for diagnostic purposes. Further experimental and longitudinal studies are needed to assess whether DNA methylation has a causal role in lung disease.© 2022. The Author(s).",
+Yes,20220620,ewas,35679866,An epigenome-wide view of osteoarthritis in primary tissues.,Am J Hum Genet,"Osteoarthritis is a complex degenerative joint disease. Here, we investigate matched genotype and methylation profiles of primary chondrocytes from macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage and from synoviocytes collected from 98 osteoarthritis-affected individuals undergoing knee replacement surgery. We perform an epigenome-wide association study of knee cartilage degeneration and report robustly replicating methylation markers, which reveal an etiologic mechanism linked to the migration of epithelial cells. Using machine learning, we derive methylation models of cartilage degeneration, which we validate with 82% accuracy in independent data. We report a genome-wide methylation quantitative trait locus (mQTL) map of articular cartilage and synovium and identify 18 disease-grade-specific mQTLs in osteoarthritis cartilage. We resolve osteoarthritis GWAS loci through causal inference and colocalization analyses and decipher the epigenetic mechanisms that mediate the effect of genotype on disease risk. Together, our findings provide enhanced insights into epigenetic mechanisms underlying osteoarthritis in primary tissues.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.",
+Yes,20220620,ewas,35672357,Large-scale placenta DNA methylation integrated analysis reveals fetal sex-specific differentially methylated CpG sites and regions.,Sci Rep,"Although male-female differences in placental structure and function have been observed, little is understood about their molecular underpinnings. Here, we present a mega-analysis of 14 publicly available placenta DNA methylation (DNAm) microarray datasets to identify individual CpGs and regions associated with fetal sex. In the discovery dataset of placentas from full term pregnancies (N = 532 samples), 5212 CpGs met genome-wide significance (p < 1E-8) and were enriched in pathways such as keratinization (FDR p-value = 7.37E-14), chemokine activity (FDR p-value = 1.56E-2), and eosinophil migration (FDR p-value = 1.83E-2). Nine differentially methylated regions were identified (fwerArea < 0.1) including a region in the promoter of ZNF300 that showed consistent differential DNAm in samples from earlier timepoints in pregnancy and appeared to be driven predominately by effects in the trophoblast cell type. We describe the largest study of fetal sex differences in placenta DNAm performed to date, revealing genes and pathways characterizing sex-specific placenta function and health outcomes later in life.© 2022. The Author(s).",
+Yes,20220620,ewas,35665255,DNA Methylation Mediates the Association Between Individual and Neighborhood Social Disadvantage and Cardiovascular Risk Factors.,Front Cardiovasc Med,"Low socioeconomic status (SES) and living in a disadvantaged neighborhood are associated with poor cardiovascular health. Multiple lines of evidence have linked DNA methylation to both cardiovascular risk factors and social disadvantage indicators. However, limited research has investigated the role of DNA methylation in mediating the associations of individual- and neighborhood-level disadvantage with multiple cardiovascular risk factors in large, multi-ethnic, population-based cohorts. We examined whether disadvantage at the individual level (childhood and adult SES) and neighborhood level (summary neighborhood SES as assessed by Census data and social environment as assessed by perceptions of aesthetic quality, safety, and social cohesion) were associated with 11 cardiovascular risk factors including measures of obesity, diabetes, lipids, and hypertension in 1,154 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). For significant associations, we conducted epigenome-wide mediation analysis to identify methylation sites mediating the relationship between individual/neighborhood disadvantage and cardiovascular risk factors using the JT-Comp method that assesses sparse mediation effects under a composite null hypothesis. In models adjusting for age, sex, race/ethnicity, smoking, medication use, and genetic principal components of ancestry, epigenetic mediation was detected for the associations of adult SES with body mass index (BMI), insulin, and high-density lipoprotein cholesterol (HDL-C), as well as for the association between neighborhood socioeconomic disadvantage and HDL-C at FDRq< 0.05. The 410 CpG mediators identified for the SES-BMI association were enriched for CpGs associated with gene expression (expression quantitative trait methylation loci, or eQTMs), and corresponding genes were enriched in antigen processing and presentation pathways. For cardiovascular risk factors other than BMI, most of the epigenetic mediators lost significance after controlling for BMI. However, 43 methylation sites showed evidence of mediating the neighborhood socioeconomic disadvantage and HDL-C association after BMI adjustment. The identified mediators were enriched for eQTMs, and corresponding genes were enriched in inflammatory and apoptotic pathways. Our findings support the hypothesis that DNA methylation acts as a mediator between individual- and neighborhood-level disadvantage and cardiovascular risk factors, and shed light on the potential underlying epigenetic pathways. Future studies are needed to fully elucidate the biological mechanisms that link social disadvantage to poor cardiovascular health.Copyright © 2022 Wang, Zhao, Ammous, Song, Du, Shang, Ratliff, Moore, Kelly, Needham, Diez Roux, Liu, Butler, Kardia, Mukherjee, Zhou and Smith.",
+Yes,20220620,ewas,35654255,Epigenome-wide DNA methylation signature of plasma zinc and their mediation roles in the association of zinc with lung cancer risk.,Environ Pollut,"Essential trace element zinc is associated with decreased lung cancer risk, but underlying mechanisms remain unclear. This study aimed to investigate role of DNA methylation in zinc-lung cancer association. We conducted a case-cohort study within prospective Dongfeng-Tongji cohort, including 359 incident lung cancer cases and a randomly selected sub-cohort of 1399 participants. Epigenome-wide association study (EWAS) was used to examine association of plasma zinc with DNA methylation in peripheral blood. For the zinc-related CpGs, their mediation effects on zinc-lung cancer association were assessed; their diagnostic performance for lung cancer was testified in the case-cohort study and further validated in another 126 pairs of lung cancer case-control study. We identified 28 CpGs associated with plasma zinc at P < 1.0 × 10-5and seven of them (cg07077080, cg01077808, cg17749033, cg15554270, cg26125625, cg10669424, and cg15409013 annotated to GSR, CALR3, SLC16A3, PHLPP2, SLC12A8, VGLL4, and ADAMTS16, respectively) were associated with incident risk of lung cancer. Moreover, the above seven CpGs were differently methylated between 126 pairs of lung cancer and adjacent normal lung tissues and had the same directions with EWAS of zinc. They could mediate a separate 7.05%�22.65% and a joint 29.42% of zinc-lung cancer association. Compared to using traditional factors, addition of methylation risk score exerted improved discriminations for lung cancer both in case-cohort study [area under the curve (AUC) = 0.818 vs. 0.738] and in case-control study (AUC = 0.816 vs. 0.646). Our results provide new insights for the biological role of DNA methylation in the inverse association of zinc with incident lung cancer.Copyright © 2022 Elsevier Ltd. All rights reserved.",
+Yes,20220620,ewas,35652342,Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study.,Circulation,"Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD.In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events.We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age.CPT1A,ABCG1, andSREBF1appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genesSARS1,SOCS3, andLINC-PINTstatistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87;P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28;P=1.22E-05).Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.",
+Yes,20220620,ewas,35650177,Epigenome-wide DNA methylation in obsessive-compulsive disorder.,Transl Psychiatry,"In adult patients with obsessive-compulsive disorder (OCD), altered DNA methylation has been discerned in several candidate genes, while DNA methylation on an epigenome-wide level has been investigated in only one Chinese study so far. Here, an epigenome-wide association study (EWAS) was performed in a sample of 76 OCD patients of European ancestry (37 women, age ± SD: 33.51 ± 10.92 years) and 76 sex- and age-matched healthy controls for the first time using the Illumina MethylationEPIC BeadChip. After quality control, nine epigenome-wide significant quantitative trait methylation sites (QTMs) and 21 suggestive hits were discerned in the final sample of 68 patients and 68 controls. The top hit (cg24159721) and four other significant QTMs (cg11894324, cg01070250, cg11330075, cg15174812) map to the region of the microRNA 12136 gene (MIR12136). Two additional significant CpG sites (cg05740793, cg20450977) are located in the flanking region of the MT-RNR2 (humanin) like 8 gene (MT-RNRL8), while two further QTMs (cg16267121, cg15890734) map to the regions of the MT-RNR2 (humanin) like 3 (MT-RNRL3) and MT-RNR2 (humanin) like 2 (MT-RNRL2) genes. Provided replication of the present findings in larger samples, the identified QTMs might provide more biological insight into the pathogenesis of OCD and thereby could in the future serve as peripheral epigenetic markers of OCD risk with the potential to inform targeted preventive and therapeutic efforts.© 2022. The Author(s).",
+Yes,20220620,ewas,35635730,The dynamics of methylation of CpG sites associated with SLE subtypes in a longitudinal cohort.,Arthritis Rheumatol,"Cross-sectional studies have revealed associations between DNA methylation and systemic lupus erythematosus (SLE) outcomes. To study the dynamics of DNA methylation, we examined participants from a SLE longitudinal cohort sampled at two time-points.One hundred and one participants from the California Lupus Epidemiology Study were studied. DNA extracted from blood at cohort enrollment and after two years was analyzed using the Illumina EPIC BeadChip. Paired t-tests were utilized to identify changes at 256 CpG sites previously associated with SLE subtypes as well as genome-wide. Mixed linear models were developed to understand the relationship between DNA methylation and disease activity, medication use and sample cell proportions, adjusting for age, sex and genetic principal components.The majority of CpGs that were previously associated with SLE subtypes remained stable over two years (185 CpGs (72.3%), t-test FDR >0.05). Compared to background genome-wide methylation, there was an enrichment of SLE subtype associated CpGs that changed over time (27.7% vs 0.34%). Changes in cell proportion were associated with changes at 67 CpGs (p<2.70E-05) and 15 CpGs had at least one significant association with use of an immunosuppressive medication.In this longitudinal cohort of SLE, we identified a subset of SLE subtype associated CpGs that were stable over time and may be useful as biomarkers of disease subtypes. Another subset of SLE subtype-associated CpGs changed at a higher proportion compared to the genome-wide methylome. Additional studies are needed to understand the etiology and impact of these methylation changes in SLE-associated CpGs.This article is protected by copyright. All rights reserved.",
+Yes,20220620,ewas,35627945,Differential Methylation Analysis of Suicidal Ideation Severity in Schizophrenia with the Illumina MethylationEPIC Array.,Healthcare (Basel),"There is a multitude of factors that makes difficult to identify those at risk for suicide, especially among schizophrenia patients. Suicide cannot be explained by genetics alone, therefore epigenetic mechanisms including DNA methylation are thought to play a role. DNA methylation could be a valuable tool in helping predict those at-risk individuals. This cross-sectional study comprised 112 subjects diagnosed with schizophrenia spectrum disorders, and were grouped according to the current suicidal ideation severity. DNA methylation across the genome was measured with the Infinium®MethylationEPIC BeadChip. We utilized the dmpFinder and bumphunter functions within the Bioconductor minfi package to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs), respectively. Following quality control, we removed one sample from the analysis and reported the most significant DMPs and DMRs associated with suicidal ideation severity. All positions and regions identified in this analysis were only found to have suggestive levels of significance at the genome-wide level. The present study was one of the first to investigate genome-wide methylation and suicidal ideation severity. While there were many strengths of our study, including investigating both differentially methylated positions and regions, further larger-scale studies are necessary to replicate, support, and validate our findings presented here.",
+Yes,20220620,ewas,35596190,The mediating effect of DNA methylation in the association between maternal sleep during pregnancy and offspring adiposity status: a prospective cohort study.,Clin Epigenetics,"Childhood overweight/obesity is a global public health concern. It is important to identify its early-life risk factors. Maternal poor sleep is common in late pregnancy, and previous studies indicated that poor sleep may influence the offspring's adiposity status. However, very few studies in humans investigated the effect of the different sleep parameters (sleep quantity, quality, and timing) on the offspring's adiposity indicators, and long-term studies are even more scarce. In addition, the underlying mechanism remains unclear. The present study therefore aimed to examine the association between the three maternal sleep dimensions in the late pregnancy and the offspring adiposity indicators and to explore the potential mediating effect of the cord blood DNA methylation in the above association.Included participants in the current study were 2211 healthy pregnant women with singleton gestation from the Shanghai Birth Cohort (SBC) and Shanghai Sleep Birth Cohort (SSBC). Maternal nighttime sleep duration, quality, and midpoint (an indicator of circadian rhythm) were assessed by the same instrument in both cohorts during late pregnancy, and the offspring's body mass index (BMI) and subcutaneous fat (SF) were measured at 2 years old. Additionally, in 231 SSBC samples, the genome-wide DNA methylation levels were measured using the Illumina Infinium Methylation EPIC BeadChip. The multivariate linear regression was used to determine the associations between the maternal sleep parameters and the offspring adiposity indicators. The epigenome-wide association study was conducted to identify the maternal sleep-related CpG sites. The mediation analysis was performed to evaluate the potential intermediate role of DNA methylation in the association between maternal sleep and offspring adiposity indicators.The mean maternal nighttime sleep duration and the sleep midpoint for combined cohorts were 9.24 ± 1.13 h and 3.02 ± 0.82, respectively, and 24.5% of pregnant women experienced poor sleep quality in late pregnancy. After adjusting for the covariates, the maternal later sleep midpoint was associated with the increased SF in offspring (Coef. = 0.62, 95% CI 0.37-0.87, p < 0.001) at 2 years old. However, no significant associations of the nighttime sleep duration or sleep quality with the offspring adiposity indicators were found. In the SSBC sample, 45 differential methylated probes (DMPs) were associated with the maternal sleep midpoint, and then, we observed 10 and 3 DMPs that were also associated with the offspring's SF and BMI at 2 years, of which cg04351668 (MARCH9) and cg12232388 significantly mediated the relationship of sleep midpoint and SF and cg12232388 and cg12225226 mediated the sleep midpoint-BMI association, respectively.Maternal later sleep timing in late pregnancy was associated with higher childhood adiposity in the offspring. Cord blood DNA methylation may play a mediation role in that relationship.© 2022. The Author(s).",
+Yes,20220620,ewas,35595947,Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking.,Eur J Epidemiol,"Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients.© 2022. The Author(s).",
+No,20220815,prediction,35064064,AHRR (cg05575921) Methylation Safely Improves Specificity of Lung Cancer Screening Eligibility Criteria: A Cohort Study,Cancer Epidemiol Biomarkers Prev.,"Background: Screening reduces lung cancer mortality, but specificities of eligibility criteria are low. We tested if leukocyte AHRR(cg05575921) methylation improves specificity of lung cancer screening eligibility criteria.
 
 Methods: A total of 9,206 and 5,370 individuals of the 1991 to 1994 and 2001 to 2003 examinations of the Copenhagen City Heart Study, Denmark, were followed for lung cancer within 5 years after examination and mortality. Screening eligibility criteria (DANTE, DLCST, ITALUNG, LUSI, NELSON, NLST, and PLCOM2012) were evaluated, and AHRR (cg05575921) methylation extent at different methylation cut points was added. The model with the lowest number of eligible individuals per 5-year lung cancer was validated within the 2001 to 2003 examination.
 
@@ -1631,517 +1631,547 @@ Results: Eligibility criteria identified risk-groups ranging from 3,182 (DANTE)
 Conclusions: Adding AHRR (cg05575921) methylation on top of current eligibility criteria for lung cancer screening improves specificity by excluding those individuals with the lowest risk.
 
 Impact: The results point toward a potential clinical use of AHRR (cg05575921) methylation, which is a cost-effective measurement compared with lung CT scanning, to provide additional predictive risk information to identify eligible smokers for lung cancer screening. See related commentary by Hung, p. 698.",
-,No,20220815,dnam age,35552703,Sperm epigenetic clock associates with pregnancy outcomes in the general population.,Hum Reprod,"Is sperm epigenetic aging (SEA) associated with probability of pregnancy among couples in the general population?We observed a 17% lower cumulative probability at 12 months for couples with male partners in the older compared to the younger SEA categories.The strong relation between chronological age and DNA methylation profiles has enabled the estimation of biological age as epigenetic 'clock' metrics in most somatic tissue. Such clocks in male germ cells are less developed and lack clinical relevance in terms of their utility to predict reproductive outcomes.This was a population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 and followed for up to 12 months.Sperm DNA methylation from 379 semen samples was assessed via a beadchip array. A state-of-the-art ensemble machine learning algorithm was employed to predict age from the sperm DNA methylation data. SEA was estimated from clocks derived from individual CpGs (SEACpG) and differentially methylated regions (SEADMR). Probability of pregnancy within 1 year was compared by SEA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates.Our SEACpG clock had the highest predictive performance with correlation between chronological and predicted age (r = 0.91). In adjusted discrete Cox models, SEACpG was negatively associated with TTP (fecundability odds ratios (FORs)=0.83; 95% CI: 0.76, 0.90; P = 1.2×10-5), indicating a longer TTP with advanced SEACpG. For subsequent birth outcomes, advanced SEACpG was associated with shorter gestational age (n = 192; -2.13 days; 95% CI: -3.67, -0.59; P = 0.007). Current smokers also displayed advanced SEACpG (P < 0.05). Finally, SEACpG showed a strong performance in an independent IVF cohort (n = 173; r = 0.83). SEADMR performance was comparable to SEACpG but with attenuated effect sizes.This prospective cohort study consisted primarily of Caucasian men and women, and thus analysis of large diverse cohorts is necessary to confirm the associations between SEA and couple pregnancy success in other races/ethnicities.These data suggest that our sperm epigenetic clocks may have utility as a novel biomarker to predict TTP among couples in the general population and underscore the importance of the male partner for reproductive success.This work was funded in part by grants the National Institute of Environmental Health Sciences, National Institutes of Health (R01 ES028298; PI: J.R.P. and P30 ES020957); Robert J. Sokol, MD Endowed Chair of Molecular Obstetrics and Gynecology (J.R.P.); and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contracts N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). S.L.M. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors declare no competing interests.N/A.© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
-,No,20220815,ewas,35852134,Genome-wide screening identifies DNA methylation sites that regulate the blood proteome.,Epigenomics,"Background:Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes.Materials & methods:Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins.Results: The authors identified 165 methylation sites associated with 138 proteins. The authors noted hotspot genomic regions that control the levels of several proteins. For example, methylation of theABOlocus impacted 37 proteins and contributed to cardiometabolic comorbidities, including the severity of SARS-CoV-2 infection. The authors made these findings publicly available as a Unix software that identifies methylation sites that cause disease and reveals the underlying proteins. The authors underlined the software application by showing that components of innate immunity contribute to systolic blood pressure.Conclusion:This study provides a catalog of DNA methylation sites that regulate the proteome, and the results are available as freeware for biological insight.",
-,No,20220815,meqtls,35710981,"Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease.",Nat Genet,"More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability analysis reveals that methylation variation explains a larger fraction of heritability than gene expression. We present a multi-stage prioritization strategy and prioritize target genes for 87% of kidney function loci. We highlight key roles of proximal tubules and metabolism in kidney function regulation. Furthermore, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20220815,methods,35879655,HIMA2: high-dimensional mediation analysis and its application in epigenome-wide DNA methylation data.,BMC Bioinformatics,"Mediation analysis plays a major role in identifying significant mediators in the pathway between environmental exposures and health outcomes. With advanced data collection technology for large-scale studies, there has been growing research interest in developing methodology for high-dimensional mediation analysis. In this paper we present HIMA2, an extension of the HIMA method (Zhang in Bioinformatics 32:3150-3154, 2016). First, the proposed HIMA2 reduces the dimension of mediators to a manageable level based on the sure independence screening (SIS) method (Fan in J R Stat Soc Ser B 70:849-911, 2008). Second, a de-biased Lasso procedure is implemented for estimating regression parameters. Third, we use a multiple-testing procedure to accurately control the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. We demonstrate its practical performance using Monte Carlo simulation studies and apply our method to identify DNA methylation markers which mediate the pathway from smoking to reduced lung function in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.© 2022. The Author(s).",
-,No,20220815,methods,35856716,High-dimension to high-dimension screening for detecting genome-wide epigenetic and noncoding RNA regulators of gene expression.,Bioinformatics,"The advancement of high-throughput technology characterizes a wide variety of epigenetic modifications and noncoding RNAs across the genome involved in disease pathogenesis via regulating gene expression. The high-dimensionality of both epigenetic/noncoding RNA and gene expression data make it challenging to identify the important regulators of genes. Conducting univariate test for each possible regulator-gene pair is subject to serious multiple comparison burden, and direct application of regularization methods to select regulator-gene pairs is computationally infeasible. Applying fast screening to reduce dimension first before regularization is more efficient and stable than applying regularization methods alone.We propose a novel screening method based on robust partial correlation to detect epigenetic and noncoding RNA regulators of gene expression over the whole genome, a problem that includes both high-dimensional predictors and high-dimensional responses. Compared to existing screening methods, our method is conceptually innovative that it reduces the dimension of both predictor and response, and screens at both node (regulators or genes) and edge (regulator-gene pairs) levels. We develop data-driven procedures to determine the conditional sets and the optimal screening threshold, and implement a fast iterative algorithm. Simulations and applications to long non-coding RNA and microRNA regulation in Kidney cancer and DNA methylation regulation in Glioblastoma Multiforme illustrate the validity and advantage of our method.The R package, related source codes and real data sets used in this paper are provided at https://github.com/kehongjie/rPCor.Supplementary data are available at Bioinformatics online.© The Author(s) (2022). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,No,20220815,methods,35822029,Adapting Blood DNA Methylation Aging Clocks for Use in Saliva Samples With Cell-type Deconvolution.,Front Aging,"DeepMAge is a deep-learning DNA methylation aging clock that measures the organismal pace of aging with the information from human epigenetic profiles. In blood samples, DeepMAge can predict chronological age within a 2.8 years error margin, but in saliva samples, its performance is drastically reduced since aging clocks are restricted by the training set domain. However, saliva is an attractive fluid for genomic studies due to its availability, compared to other tissues, including blood. In this article, we display how cell type deconvolution and elastic net can be used to expand the domain of deep aging clocks to other tissues. Using our approach, DeepMAge's error in saliva samples was reduced from 20.9 to 4.7 years with no retraining.Copyright © 2021 Galkin, Kochetov, Mamoshina and Zhavoronkov.",
-,No,20220815,prediction,35864305,Peripheral blood DNA methylation profiles predict future development of B-cell Non-Hodgkin Lymphoma.,NPJ Precis Oncol,"Lack of accurate methods for early lymphoma detection limits the ability to cure patients. Since patients with Non-Hodgkin lymphomas (NHL) who present with advanced disease have worse outcomes, accurate and sensitive methods for early detection are needed to improve patient care. We developed a DNA methylation-based prediction tool for NHL, based on blood samples collected prospectively from 278 apparently healthy patients who were followed for up to 16 years to monitor for NHL development. A predictive score was developed using machine learning methods in a robust training/validation framework. Our predictive score incorporates CpG DNA methylation at 135 genomic positions, with higher scores predicting higher risk. It was 85% and 78% accurate for identifying patients at risk of developing future NHL, in patients with high or low epigenetic mitotic clock respectively, in a validation cohort. It was also sensitive at detecting active NHL (96.3% accuracy) and healthy status (95.6% accuracy) in additional independent cohorts. Scores optimized for specific NHL subtypes showed significant but lower accuracy for predicting other subtypes. Our score incorporates hyper-methylation of Polycomb and HOX genes, which have roles in NHL development, as well as PAX5 - a master transcriptional regulator of B-cell fate. Subjects with higher risk scores showed higher regulatory T-cells, memory B-cells, but lower naïve T helper lymphocytes fractions in the blood. Future prospective studies will be required to confirm the utility of our signature for managing patients who are at high risk for developing future NHL.© 2022. The Author(s).",
-,No,20220815,prediction,35740428,Predicting High Blood Pressure Using DNA Methylome-Based Machine Learning Models.,Biomedicines,"DNA methylation modification plays a vital role in the pathophysiology of high blood pressure (BP). Herein, we applied three machine learning (ML) algorithms including deep learning (DL), support vector machine, and random forest for detecting high BP using DNA methylome data. Peripheral blood samples of 50 elderly individuals were collected three times at three visits for DNA methylome profiling. Participants who had a history of hypertension and/or current high BP measure were considered to have high BP. The whole dataset was randomly divided to conduct a nested five-group cross-validation for prediction performance. Data in each outer training set were independently normalized using a min-max scaler, reduced dimensionality using principal component analysis, then fed into three predictive algorithms. Of the three ML algorithms, DL achieved the best performance (AUPRC = 0.65, AUROC = 0.73, accuracy = 0.69, and F1-score = 0.73). To confirm the reliability of using DNA methylome as a biomarker for high BP, we constructed mixed-effects models and found that 61,694 methylation sites located in 15,523 intragenic regions and 16,754 intergenic regions were significantly associated with BP measures. Our proposed models pioneered the methodology of applying ML and DNA methylome data for early detection of high BP in clinical practices.",
-,No,20220815,prediction,35839250,Explainable deep transfer learning model for disease risk prediction using high-dimensional genomic data.,PLoS Comput Biol,"Building an accurate disease risk prediction model is an essential step in the modern quest for precision medicine. While high-dimensional genomic data provides valuable data resources for the investigations of disease risk, their huge amount of noise and complex relationships between predictors and outcomes have brought tremendous analytical challenges. Deep learning model is the state-of-the-art methods for many prediction tasks, and it is a promising framework for the analysis of genomic data. However, deep learning models generally suffer from the curse of dimensionality and the lack of biological interpretability, both of which have greatly limited their applications. In this work, we have developed a deep neural network (DNN) based prediction modeling framework. We first proposed a group-wise feature importance score for feature selection, where genes harboring genetic variants with both linear and non-linear effects are efficiently detected. We then designed an explainable transfer-learning based DNN method, which can directly incorporate information from feature selection and accurately capture complex predictive effects. The proposed DNN-framework is biologically interpretable, as it is built based on the selected predictive genes. It is also computationally efficient and can be applied to genome-wide data. Through extensive simulations and real data analyses, we have demonstrated that our proposed method can not only efficiently detect predictive features, but also accurately predict disease risk, as compared to many existing methods.",
-,No,20220815,prediction,35841107,Detecting cell-of-origin and cancer-specific methylation features of cell-free DNA from Nanopore sequencing.,Genome Biol,"The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT shallow whole-genome sequencing to detect copy number alterations (CNAs) from the circulating tumor DNA (ctDNA) of cancer patients. Here, we show that cell type and cancer-specific methylation changes can also be detected, as well as cancer-associated fragmentation signatures. This feasibility study suggests that ONT shallow WGS could be a powerful tool for liquid biopsy.© 2022. The Author(s).",
-,No,20220815,review,35794667,"Diversity in EWAS: current state, challenges, and solutions.",Genome Med,"Here, we report a lack of diversity in epigenome-wide association studies (EWAS) and DNA methylation (DNAm) data, discuss current challenges, and propose solutions for EWAS and DNAm research in diverse populations. The strategies we propose include fostering community involvement, new data generation, and cost-effective approaches such as locus-specific analysis and ancestry variable region analysis.© 2022. The Author(s).",
-,No,20220815,review,35868277,What is a cell type and how to define it?,Cell,"Cell types are the basic functional units of an organism. Cell types exhibit diverse phenotypic properties at multiple levels, making them challenging to define, categorize, and understand. This review provides an overview of the basic principles of cell types rooted in evolution and development and discusses approaches to characterize and classify cell types and investigate how they contribute to the organism's function, using the mammalian brain as a primary example. I propose a roadmap toward a conceptual framework and knowledge base of cell types that will enable a deeper understanding of the dynamic changes of cellular function under healthy and diseased conditions.Copyright © 2022 Elsevier Inc. All rights reserved.",
-,No,20220815,vntr,35609568,A phenome-wide association study identifies effects of copy-number variation of VNTRs and multicopy genes on multiple human traits.,Am J Hum Genet,"The human genome contains tens of thousands of large tandem repeats and hundreds of genes that show common and highly variable copy-number changes. Due to their large size and repetitive nature, these variable number tandem repeats (VNTRs) and multicopy genes are generally recalcitrant to standard genotyping approaches and, as a result, this class of variation is poorly characterized. However, several recent studies have demonstrated that copy-number variation of VNTRs can modify local gene expression, epigenetics, and human traits, indicating that many have a functional role. Here, using read depth from whole-genome sequencing to profile copy number, we report results of a phenome-wide association study (PheWAS) of VNTRs and multicopy genes in a discovery cohort of �35,000 samples, identifying 32 traits associated with copy number of 38 VNTRs and multicopy genes at 1% FDR. We replicated many of these signals in an independent cohort and observed that VNTRs showing trait associations were significantly enriched for expression QTLs with nearby genes, providing strong support for our results. Fine-mapping studies indicated that in the majority (�90%) of cases, the VNTRs and multicopy genes we identified represent the causal variants underlying the observed associations. Furthermore, several lie in regions where prior SNV-based GWASs have failed to identify any significant associations with these traits. Our study indicates that copy number of VNTRs and multicopy genes contributes to diverse human traits and suggests that complex structural variants potentially explain some of the so-called ""missing heritability"" of SNV-based GWASs.Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
-,Yes,20220815,ewas,35943854,Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.,Brain,"Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.",
-,Yes,20220815,ewas,35904121,Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.,Hum Mutat,"An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes which can share significant overlap amongst different conditions. In this study we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.",
-,Yes,20220815,ewas,35888152,Association between Usual Dietary Intake of Food Groups and DNA Methylation and Effect Modification by Metabotype in the KORA FF4 Cohort.,Life (Basel),"Associations between diet and DNA methylation may vary among subjects with different metabolic states, which can be captured by clustering populations in metabolically homogenous subgroups, called metabotypes. Our aim was to examine the relationship between habitual consumption of various food groups and DNA methylation as well as to test for effect modification by metabotype. A cross-sectional analysis of participants (median age 58 years) of the population-based prospective KORA FF4 study, habitual dietary intake was modeled based on repeated 24-h diet recalls and a food frequency questionnaire. DNA methylation was measured using the Infinium MethylationEPIC BeadChip providing data on &gt;850,000 sites in this epigenome-wide association study (EWAS). Three metabotype clusters were identified using four standard clinical parameters and BMI. Regression models were used to associate diet and DNA methylation, and to test for effect modification. Few significant signals were identified in the basic analysis while many significant signals were observed in models including food group-metabotype interaction terms. Most findings refer to interactions of food intake with metabotype 3, which is the metabotype with the most unfavorable metabolic profile. This research highlights the importance of the metabolic characteristics of subjects when identifying associations between diet and white blood cell DNA methylation in EWAS.",
-,Yes,20220815,ewas,35882828,DNA methylation and waist-to-hip ratio: an epigenome-wide association study in Chinese monozygotic twins.,J Endocrinol Invest,"Epigenetic signatures such as DNA methylation may be associated with specific obesity traits. We performed an epigenome-wide association study (EWAS) by combining with the waist-to-hip ratio (WHR)-discordant monozygotic (MZ) twin design in an attempt to identify genetically independent DNA methylation marks associated with abdominal obesity in Northern Han Chinese and to determine the causation underlying.A total of 60 WHR discordant MZ twin pairs were selected from the Qingdao Twin Registry, China. Generalized estimated equation (GEE) model was used to regress the methylation level of CpG sites on WHR. The Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) was used to assess the temporal relationship between methylation and WHR. Gene expression analysis was conducted to validate the results of differentially methylated analyses.EWAS identified 92 CpG sites with the level of P < 10 - 4which were annotated to 32 genes, especially CADPS2, TUSC5, ZCCHC14, CORO7, COL23A1, CACNA1C, CYP26B1, and BCAT1. ICE FALCON showed significant causality between DNA methylation of several genes and WHR (P < 0.05). In region-based analysis, 14 differentially methylated regions (DMRs) located at 15 genes (slk-corrected P < 0.05) were detected. The gene expression analysis identified the significant correlation between expression levels of 5 differentially methylated genes and WHR (P < 0.05).Our study identifies the associations between specific epigenetic variations and WHR in Northern Han Chinese. These DNA methylation signatures may have value as diagnostic biomarkers and provide novel insights into the molecular mechanisms of pathogenesis.© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).",
-,Yes,20220815,ewas,35858526,Associations between antenatal maternal asthma status and placental DNA methylation.,Placenta,"Maternal asthma in pregnancy is associated with adverse perinatal and child health outcomes; however, mechanisms are poorly understood.The PRogramming of Intergenerational Stress Mechanisms (PRISM) prospective pregnancy cohort characterized asthma history during pregnancy via questionnaires and quantified placental DNAm using the Illumina Infinium HumanMethylation450 BeadChip. We performed epigenome-wide association analyses (n = 223) to estimate associations between maternal active or inactive asthma, as compared to never asthma, and placental differentially methylated positions (DMPs) and differentially variable positions (DVPs). Models adjusted for maternal pre-pregnancy body mass index, smoking status, parity, age and education level and child sex. P-values were FDR-adjusted.One hundred and fifty-nine (71.3%) pregnant women reported no history of asthma (never asthma), 15 (6.7%) reported inactive, and 49 (22%) reported active antenatal asthma. Women predominantly self-identified as Black/Hispanic Black [88 (39.5%)] and Hispanic/non-Black [42 (18.8%)]. We identified 10 probes at FDR<0.05 and 4 probes at FDR<0.10 characterized by higher variability in maternal active asthma compared to never asthma mapping to GPX3, LHPP, PECAM1, ATAD3C, and ARHGEF4 and 2 probes characterized by lower variation mapping to CHMP4A and C5orf24. Amongst women with inactive asthma, we identified 52 probes, 41 at FDR<0.05 and an additional 11 at FDR <0.10, with higher variability compared to never asthma; BMP4, LHPP, PHYHIPL, and ZSCAN23 were associated with multiple DVPs. No associations were observed with DMPs.We observed alterations in placental DNAm in women with antenatal asthma, as compared to women without a history of asthma. Further research is needed to understand the impact on fetal development.Copyright © 2022 Elsevier Ltd. All rights reserved.",
-,Yes,20220815,ewas,35850911,Effect of menopausal hormone therapy on methylation levels in early and late postmenopausal women.,Clin Epigenetics,"Cardiovascular disease (CVD) remains the leading cause of death among postmenopausal women but standard primary prevention strategies in women are not as effective as in men. By comparison, the Early versus Late Intervention Trial with Estradiol (ELITE) study demonstrated that hormone therapy (HT) was associated with significant reduction in atherosclerosis progression in women who were within six years of menopause compared to those who were 10 or more years from menopause. These findings are consistent with other studies showing significant reductions in all-cause mortality and CVD with HT, particularly when initiated in women younger than 60 years of age or within 10 years since menopause. To explore the biological mechanisms underlying the age-related atheroprotective effects of HT, we investigated changes in methylation of blood cells of postmenopausal women who participated in ELITE.We first validated the epigenetic data generated from blood leukocytes of ELITE participants by replicating previously known associations between smoking and methylation levels at previously identified CpG sites, such as cg05575921 at the AHRR locus. An epigenome-wide association study (EWAS) evaluating changes in methylation through interactions with time-since-menopause and HT revealed two significantly associated CpG sites on chromosomes 12 (cg19552895; p = 1.1 × 10-9) and 19 (cg18515510; p = 2.4 × 10-8). Specifically, HT resulted in modest, but significant, increases in methylation levels at both CpGs but only in women who were 10 or more years since menopause and randomized to HT. Changes in carotid artery intima-media thickness (CIMT) from baseline to 36 months after HT were not significantly correlated with changes in methylation levels at either cg19552895 or cg18515510. Evaluation of other previously identified CpG sites at which methylation levels in either blood or vascular tissue were associated with atherosclerosis also did not reveal any differences in methylation as a function of HT and time-since-menopause or with changes in CIMT.We identified specific methylation differences in blood in response to HT among women who were 10 or more years since menopause. The functional consequence of these change with respect to atherosclerosis progression and protective effects of HT remains to be determined and will require additional studies.© 2022. The Author(s).",
-,Yes,20220815,ewas,35837683,Genome-wide methylation analysis of early-onset schizophrenia.,Psychiatr Genet,"Schizophrenia (SCZ) is a debilitating disease with a complex genetic cause in which age at onset may reflect genetic vulnerability. Though there has been some association between genetic polymorphisms and age of onset, there has been little exploration of the role of epigenetic processes. We sought to explore the influence of DNA methylation, a key epigenetic mechanism, and its association with the age of onset of illness.One hundred thirty-eight participants aged 18-75 years and previously diagnosed with SCZ spectrum disorders by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID DSM-5) were recruited. Venous blood was collected and genome-wide DNA methylation was quantified using the Illumina Infinium HumanMethylation450 BeadChip array. Individual CpG sites and regions of differential methylation were explored by the age of onset; covariates included age, sex, as well as white blood cell composition.Binary grouping (early vs. late onset) revealed four intergenic CpG sites on chromosome 2 that were above the expected P-value threshold, with hypermethylation of the CpG site cg10392614 most strongly associated with early-onset SCZ. The four most strongly associated CpG sites, including cg 10392614, were intergenic. Continuous analysis revealed the top CpG site to be cg11723066, which is linked to the JAM3 gene, with hypomethylation associated with earlier onset; however, results were below the expected P-value threshold.Studies on DNA methylation in the first-episode psychosis population may help further our understanding of the role of epigenetics in the age of onset of SCZ.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.",
-,Yes,20220815,ewas,35836289,Maternal-fetal stress and DNA methylation signatures in neonatal saliva: an epigenome-wide association study.,Clin Epigenetics,"Maternal stress before, during and after pregnancy has profound effects on the development and lifelong function of the infant's neurocognitive development. We hypothesized that the programming of the central nervous system (CNS), hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) induced by prenatal stress (PS) is reflected in electrophysiological and epigenetic biomarkers. In this study, we aimed to find noninvasive epigenetic biomarkers of PS in the newborn salivary DNA.A total of 728 pregnant women were screened for stress exposure using Cohen Perceived Stress Scale (PSS), 164 women were enrolled, and 114 dyads were analyzed. Prenatal Distress Questionnaire (PDQ) was also administered to assess specific pregnancy worries. Transabdominal fetal electrocardiograms (taECG) were recorded to derive coupling between maternal and fetal heart rates resulting in a 'Fetal Stress Index' (FSI). Upon delivery, we collected maternal hair strands for cortisol measurements and newborn's saliva for epigenetic analyses. DNA was extracted from saliva samples, and DNA methylation was measured using EPIC BeadChip array (850 k CpG sites). Linear regression was used to identify associations between PSS/PDQ/FSI/Cortisol and DNA methylation. We found epigenome-wide significant associations for 5 CpG with PDQ and cortisol at FDR < 5%. Three CpGs were annotated to genes (Illumina Gene annotation file): YAP1, TOMM20 and CSMD1, and two CpGs were located approximately lay at 50 kb from SSBP4 and SCAMP1. In addition, two differentiated methylation regions (DMR) related to maternal stress measures PDQ and cortisol were found: DAXX and ARL4D.Genes annotated to these CpGs were found to be involved in secretion and transportation, nuclear signaling, Hippo signaling pathways, apoptosis, intracellular trafficking and neuronal signaling. Moreover, some CpGs are annotated to genes related to autism, post-traumatic stress disorder (PTSD) and schizophrenia. However, our results should be viewed as hypothesis generating until replicated in a larger sample. Early assessment of such noninvasive PS biomarkers will allow timelier detection of babies at risk and a more effective allocation of resources for early intervention programs to improve child development. A biomarker-guided early intervention strategy is the first step in the prevention of future health problems, reducing their personal and societal impact.© 2022. The Author(s).",
-,Yes,20220815,ewas,35836279,An epigenome-wide association study of insulin resistance in African Americans.,Clin Epigenetics,"African Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylation450 BeadChip, we performed an epigenome-wide association study to identify DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men (mean age 41.6 years) from the Howard University Family Study.We identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR. One DMP (cg14013695, HOXA5) is a known locus among Mexican Americans, while the other two DMPs are novel-cg00456326 (OSR1; beta = 0.027) and cg20259981 (ST18; beta = 0.010). Although the cg00456326 DMP is novel, the OSR1 gene has previously been found associated with both insulin resistance and T2D in Europeans. The genes HOXA5 and ST18 have been implicated in biological processes relevant to insulin resistance. Differential methylation at the significant HOXA5 and OSR1 DMPs is associated with differences in gene expression in the iMETHYL database. Analysis of differentially methylated regions (DMRs) did not identify any epigenome-wide DMRs for HOMA-IR. We tested transferability of HOMA-IR associated DMPs from five previous EWAS in Mexican Americans, Indian Asians, Europeans, and European ancestry Americans. Out of the 730 previously reported HOMA-IR DMPs, 47 (6.4%) were associated with HOMA-IR in this cohort of African Americans.The findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. Two of the DMPs we identified in African Americans have not been reported in other populations, and we found low transferability of HOMA-IR DMPs reported in other populations in African Americans. More work in African-ancestry populations is needed to confirm our findings as well as functional analyses to understand how such DNA methylation alterations contribute to T2D pathology.© 2022. The Author(s).",
-,Yes,20220815,ewas,35879377,Characterization of methylation patterns associated with lifestyle factors and vitamin D supplementation in a healthy elderly cohort from Southwest Sweden.,Sci Rep,"Numerous studies have shown that lifestyle factors, such as regular physical activity and vitamin D intake, may remarkably improve overall health and mental wellbeing. This is especially important in older adults whose vitamin D deficiency occurs with a high prevalence. This study aimed to examine the influence of lifestyle and vitamin D on global DNA methylation patterns in an elderly cohort in Southwest of Sweden. We also sought to examine the methylation levels of specific genes involved in vitamin D's molecular and metabolic activated pathways. We performed a genome wide methylation analysis, using Illumina Infinium DNA Methylation EPIC 850kBeadChip array, on 277 healthy individuals from Southwest Sweden at the age of 70-95. The study participants also answered queries on lifestyle, vitamin intake, heart medication, and estimated health. Vitamin D intake did not in general affect methylation patterns, which is in concert with other studies. However, when comparing the group of individuals taking vitamin supplements, including vitamin D, with those not taking supplements, a difference in methylation in the solute carrier family 25 (SCL25A24) gene was found. This confirms a previous finding, where changes in expression of SLC25A24 were associated with vitamin D treatment in human monocytes. The combination of vitamin D intake and high physical activity increased methylation of genes linked to regulation of vitamin D receptor pathway, the Wnt pathway and general cancer processes. To our knowledge, this is the first study detecting epigenetic markers associated with the combined effects of vitamin D supplementation and high physical activity. These results deserve to be further investigated in an extended, interventional study cohort, where also the levels of 25(OH)D3can be monitored.© 2022. The Author(s).",
-,Yes,20220815,ewas,35798818,"EWAS of post-COVID-19 patients shows methylation differences in the immune-response associated gene, IFI44L, three months after COVID-19 infection.",Sci Rep,"Although substantial progress has been made in managing COVID-19, it is still difficult to predict a patient's prognosis. We explored the epigenetic signatures of COVID-19 in peripheral blood using data from an ongoing prospective observational study of COVID-19 called the Norwegian Corona Cohort Study. A series of EWASs were performed to compare the DNA methylation profiles between COVID-19 cases and controls three months post-infection. We also investigated differences associated with severity and long-COVID. Three CpGs-cg22399236, cg03607951, and cg09829636-were significantly hypomethylated (FDR < 0.05) in COVID-19 positive individuals. cg03607951 is located in IFI44L which is involved in innate response to viral infection and several systemic autoimmune diseases. cg09829636 is located in ANKRD9, a gene implicated in a wide variety of cellular processes, including the degradation of IMPDH2. The link between ANKRD9 and IMPDH2 is striking given that IMPDHs are considered therapeutic targets for COVID-19. Furthermore, gene ontology analyses revealed pathways involved in response to viruses. The lack of significant differences associated with severity and long-COVID may be real or reflect limitations in sample size. Our findings support the involvement of interferon responsive genes in the pathophysiology of COVID-19 and indicate a possible link to systemic autoimmune diseases.© 2022. The Author(s).",
-,Yes,20220815,ewas,35790973,Longitudinal associations of DNA methylation and sleep in children: a meta-analysis.,Clin Epigenetics,"Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children.We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4-13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration.We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10-8). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10-8, n = 577) and sleep onset latency (p = 8.8 × 10-9, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716-2539).DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available.© 2022. The Author(s).",
-,Yes,20220815,ewas,35771992,Recreational physical activity before and during pregnancy and placental DNA methylation - an epigenome-wide association study.,Am J Clin Nutr,"Physical activity (PA) prior to and during pregnancy may have inter-generational effects on offspring health through placental epigenetic modifications. We are unaware of epidemiological studies on longitudinal PA and placental DNA methylation (DNAm).We evaluated the association between PA before and during pregnancy and placental DNAm.Placental tissues were obtained at delivery and methylation was measured using HumanMethylation450 Beadchips for participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons among 298 participants. Using the Pregnancy PA Questionnaire, women recalled periconception PA (past 12 months) at 8-13 weeks gestation, and PA since last visit at four follow-up visits at 16-22, 24-29, 30-33, 34-37 weeks. We conducted linear regression for associations of PA at each visit with methylation controlling for false discovery rate (FDR). Top 100 CpGs were queried for enrichment of functional pathways using Ingenuity Pathway Analysis.Periconception PA was significantly associated with 1 CpG site. PA since last visit for visits 1-4 was associated with 2, 2, 8, 0 CpGs (log fold changes ranging from -0.0319 to 0.0080, after controlling for FDR). The largest change in methylation occurred at a site in TIMP2, which is known to encode a protein critical for vasodilation, placentation, and uterine expansion during pregnancy (log fold change: -0.05, 95% confidence interval: -0.06, -0.03 per metabolic equivalent of task [MET]-hours/week at 30-33 weeks). Most significantly enriched pathways include Cardiac Hypertrophy Signaling, B Cell Receptor Signaling, and Netrin Signaling. Significant CpGs and enriched pathways varied by visit.Recreational PA in the year prior and during pregnancy was associated with placental DNAm. The associated CpG sites varied based on timing of PA. If replicated, the findings may inform the mechanisms underlying the impacts of PA on placenta health. Clinical trial registration number: This study was registered at ClinicalTrials.gov (NCT00912132).© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.",
-,Yes,20220815,ewas,35764815,CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation.,Pediatr Res,"Infants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health.We contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort. Neonatal inflammation status was based on the expression of six inflammation-related proteins, assessed as (1) day-one inflammation (DOI) or (2) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 postnatal weeks). Epigenome-wide CpG methylation was assessed in 354 placental samples and 318 neonatal blood samples.Placental CpG methylation displayed the strongest association with ISSI (48 CpG sites) but was not associated with DOI. This was in contrast to CpG methylation in blood spots, which was associated with DOI (111 CpG sites) and not with ISSI (one CpG site).Placental CpG methylation was strongly associated with ISSI, a measure of inflammation previously linked to later-in-life cognitive impairment, while day-one neonatal blood methylation was associated with DOI.Neonatal inflammation increases the risk of adverse later-life outcomes, especially in infants born extremely preterm. CpG methylation in the placenta and neonatal blood spots were evaluated in relation to neonatal inflammation assessed via circulating proteins as either (i) day-one inflammation (DOI) or (ii) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 weeks). Tissue specificity was observed in epigenetic-inflammatory relationships: placental CpG methylation was associated with ISSI, neonatal blood CpG methylation was associated with DOI. Supporting the placental origins of disease framework, placental epigenetic patterns are associated with a propensity for ISSI in neonates.© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.",
-,Yes,20220815,ewas,35762681,Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study.,Epilepsia,"The aim of this study was to investigate the impact of the modified ketogenic diet on DNA methylation in adults with epilepsy.In this prospective study, we investigated the genome-wide DNA methylation in whole blood in 58 adults with epilepsy treated with the modified ketogenic for 12 weeks. Patients were recruited from the National Center for Epilepsy, Norway, from March 1, 2011 to February 28, 2017. DNA methylation was analyzed using the Illumina Infinium MethylationEPIC BeadChip array. Analysis of variance and paired t-test were used to identify differentially methylated loci after 4 and 12 weeks of dietary treatment. A false discovery rate approach with a significance threshold of <5% was used to adjust for multiple comparisons.We observed a genome-wide decrease in DNA methylation, both globally and at specific sites, after 4 and 12 weeks of dietary treatment. A substantial share of the differentially methylated positions (CpGs) were annotated to genes associated with epilepsy (n = 7), lipid metabolism (n = 8), and transcriptional regulation (n = 10). Furthermore, five of the identified genes were related to inositol phosphate metabolism, which may represent a possible mechanism by which the ketogenic diet attenuates seizures.A better understanding of the modified ketogenic diet's influence at the molecular level may be the key to unraveling the mechanisms by which the diet can ameliorate seizures and possibly to identifying novel therapeutic targets for epilepsy.© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.",
-,Yes,20220815,ewas,35734807,Sensation-seeking-related DNA methylation and the development of delinquency: A longitudinal epigenome-wide study.,Dev Psychopathol,"Heightened sensation-seeking is related to the development of delinquency. Moreover, sensation-seeking, or biological correlates of sensation-seeking, are suggested as factors linking victimization to delinquency. Here, we focused on epigenetic correlates of sensation-seeking. First, we identified DNA methylation (DNAm) patterns related to sensation-seeking. Second, we investigated the association between sensation-seeking related DNAm and the development of delinquency. Third, we examined whether victimization was related to sensation-seeking related DNAm and the development of delinquency. Participants (N= 905; 49% boys) came from the Avon Longitudinal Study of Parents and Children. DNAm was assessed at birth, age 7 and age 15-17. Sensation-seeking (self-reports) was assessed at age 11 and 14. Delinquency (self-reports) was assessed at age 17-19. Sensation-seeking epigenome-wide association study revealed that no probes reached the critical significance level. However, 20 differential methylated probes reached marginal significance. With these 20 suggestive sites, a sensation-seeking cumulative DNAm risk score was created. Results showed that this DNAm risk score at age 15-17 was related to delinquency at age 17-19. Moreover, an indirect effect of victimization to delinquency via DNAm was found. Sensation-seeking related DNAm is a potential biological correlate that can help to understand the development of delinquency, including how victimization might be associated with adolescent delinquency.",
-,Yes,20220815,ewas,35732753,Association between DNA methylation variability and self-reported exposure to heavy metals.,Sci Rep,"Individuals encounter varying environmental exposures throughout their lifetimes. Some exposures such as smoking are readily observed and have high personal recall; others are more indirect or sporadic and might only be inferred from long occupational histories or lifestyles. We evaluated the utility of using lifetime-long self-reported exposures for identifying differential methylation in an amyotrophic lateral sclerosis cases-control cohort of 855 individuals. Individuals submitted paper-based surveys on exposure and occupational histories as well as whole blood samples. Genome-wide DNA methylation levels were quantified using the Illumina Infinium Human Methylation450 array. We analyzed 15 environmental exposures using the OSCA software linear and MOA models, where we regressed exposures individually by methylation adjusted for batch effects and disease status as well as predicted scores for age, sex, cell count, and smoking status. We also regressed on the first principal components on clustered environmental exposures to detect DNA methylation changes associated with a more generalised definition of environmental exposure. Five DNA methylation probes across three environmental exposures (cadmium, mercury and metalwork) were significantly associated using the MOA models and seven through the linear models, with one additionally across a principal component representing chemical exposures. Methylome-wide significance for four of these markers was driven by extreme hyper/hypo-methylation in small numbers of individuals. The results indicate the potential for using self-reported exposure histories in detecting DNA methylation changes in response to the environment, but also highlight the confounded nature of environmental exposure in cohort studies.© 2022. The Author(s).",
-,Yes,20220815,ewas,35717949,DNA Methylation and Ischemic Stroke Risk: An Epigenome-Wide Association Study.,Thromb Haemost,"Ischemic stroke (IS) risk heritability is partly explained by genetics. Other heritable factors, such as epigenetics, could explain an unknown proportion of the IS risk. The objective of this study is to evaluate DNA methylation association with IS using epigenome-wide association studies (EWAS).�We performed a two-stage EWAS comprising 1,156 subjects. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were assessed using the Infinium 450K and EPIC BeadChip in the discovery cohort (252 IS and 43 controls). Significant DMPs were replicated in an independent cohort (618 IS and 243 controls). Stroke subtype associations were also evaluated. Differentially methylated cell-type (DMCT) was analyzed in the replicated CpG sites using EpiDISH. We additionally performed pathway enrichment analysis and causality analysis with Mendelian randomization for the replicated CpG sites.�A total of 957 CpG sites were epigenome-wide-significant (p≤ 10-7) in the discovery cohort, being CpG sites in the top signals (logFC = 0.058,p = 2.35 × 10-22; logFC = 0.035,p = 3.22 × 10-22, respectively).ZFHX3andMAP3K1were among the most significant DMRs. In addition, 697 CpG sites were replicated considering Bonferroni-correctedp-values (p < 5.22 × 10-5). All the replicated DMPs were associated with risk of cardioembolic, atherothrombotic, and undetermined stroke. The DMCT analysis demonstrated that the significant associations were driven by natural killer cells. The pathway enrichment analysis showed overrepresentation of genes belonging to certain pathways including oxidative stress.ZFHX3andMAP3K1methylation was causally associated with specific stroke-subtype risk.�Specific DNA methylation pattern is causally associated with IS risk. These results could be useful for specifically predicting stroke occurrence and could potentially be evaluated as therapeutic targets.Thieme. All rights reserved.",
-,Yes,20220815,ewas,35708509,Maternal Dietary Glycemic Index and Glycemic Load in Pregnancy and Offspring Cord Blood DNA Methylation.,Diabetes Care,"Suboptimal nutrition in pregnancy is associated with worse offspring cardiometabolic health. DNA methylation may be an underlying mechanism. We meta-analyzed epigenome-wide association studies (EWAS) of maternal dietary glycemic index and load with cord blood DNA methylation.We calculated maternal glycemic index and load from food frequency questionnaires and ran EWAS on cord blood DNA methylation in 2,003 mother-offspring pairs from three cohorts. Analyses were additionally stratified by maternal BMI categories. We looked-up the findings in EWAS of maternal glycemic traits and BMI as well as in EWAS of birth weight and child BMI. We examined associations with gene expression in child blood in the online Human Early Life Exposome eQTM catalog and in 223 adipose tissue samples.Maternal glycemic index and load were associated with cord blood DNA methylation at 41 cytosine-phosphate-guanine sites (CpGs, P < 1.17 × 10-7), mostly in mothers with overweight/obesity. We did not observe overlap with CpGs associated with maternal glycemic traits, BMI, or child birth weight or BMI. Only DNA methylation at cg24458009 and cg23347399 was associated with expression of PCED1B and PCDHG, respectively, in child blood, and DNA methylation at cg27193519 was associated with expression of TFAP4, ZNF500, PPL, and ANKS3 in child subcutaneous adipose tissue.We observed multiple associations of maternal glycemic index and load during pregnancy with cord blood DNA methylation, mostly in mothers with overweight/obesity; some of these CpGs were associated with gene expression. Additional studies are required to further explore functionality, uncover causality, and study pathways to offspring health.© 2022 by the American Diabetes Association.",
-,Yes,20220815,ewas,35749371,Effect of an antenatal diet and lifestyle intervention and maternal BMI on cord blood DNA methylation in infants of overweight and obese women: The LIMIT Randomised Controlled Trial.,PLoS One,"To investigate the effect of an antenatal diet and lifestyle intervention, and maternal pre-pregnancy overweight or obesity, on infant cord blood DNA methylation.We measured DNA methylation in 645 cord blood samples from participants in the LIMIT study (an antenatal diet and lifestyle intervention for women with early pregnancy BMI ≥25.0 kg/m2) using the Illumina 450K BeadChip array, and tested for any differential methylation related to the intervention, and to maternal early pregnancy BMI. We also analysed differential methylation in relation to selected candidate genes.No CpG sites were significantly differentially methylated in relation to either the diet and lifestyle intervention, or with maternal early pregnancy BMI. There was no significant differential methylation in any of the selected genes related to the intervention, or to maternal BMI.We found no evidence of an effect of either antenatal diet and lifestyle, or of maternal early pregnancy BMI, on cord blood DNA methylation.ACTRN12607000161426.",
-,Yes,20220815,ewas,35723298,DNA Methylation Patterns According to Fatty Liver Index and Longitudinal Changes from the Korean Genome and Epidemiology Study (KoGES).,Curr Issues Mol Biol,"The role of differentially methylated regions (DMRs) in nonalcoholic fatty liver disease (NAFLD) is unclear. This study aimed to identify the role of DMR in NAFLD development and progression using the Korean Genome and Epidemiology Study (KoGES) cohort. We used laboratory evaluations and Illumina Methylation 450 k DNA methylation microarray data from KoGES. The correlation between fatty liver index (FLI) and genomic CpG sites was analyzed in 322 subjects. Longitudinal changes over 8 years were confirmed in 33 subjects. To identify CpG sites and genes related to FLI, we obtained enrichment terms for 6765 genes. DMRs were identified for both high (n= 128) and low (n= 194) groups on the basis of FLI 30 in 142 men and 180 women. To confirm longitudinal changes in 33 subjects, the ratio of follow-up and baseline investigation values was obtained. Correlations and group comparisons were performed for the 8 year change values.PITPNM3,RXFP3, andTHRBwere hypermethylated in the increased FLI groups, whereasSLC9A2andFOXI3were hypermethylated in the decreased FLI groups. DMRs describing NAFLD were determined, and functions related to inflammation were identified. Factors related to longitudinal changes are suggested, and blood circulation-related functions appear to be important in the management of NAFLD.",
-,Yes,20220815,ewas,35768464,Methylome-wide analysis of IVF neonates that underwent embryo culture in different media revealed no significant differences.,NPJ Genom Med,"A growing number of children born are conceived through in vitro fertilisation (IVF), which has been linked to an increased risk of adverse perinatal outcomes, as well as altered growth profiles and cardiometabolic differences in the resultant individuals. Some of these outcomes have also been shown to be influenced by the use of different IVF culture media and this effect is hypothesised to be mediated epigenetically, e.g. through the methylome. As such, we profiled the umbilical cord blood methylome of IVF neonates that underwent preimplantation embryo development in two different IVF culture media (G5 or HTF), using the Infinium Human Methylation EPIC BeadChip. We found no significant methylation differences between the two groups in terms of: (i) systematic differences at CpG sites or regions, (ii) imprinted sites/genes or birth weight-associated sites, (iii) stochastic differences presenting as DNA methylation outliers or differentially variable sites, and (iv) epigenetic gestational age acceleration.© 2022. The Author(s).",
-,Yes,20220815,ewas,35769265,Epigenetic DNA Methylation Signatures Associated With the Severity of Paget's Disease of Bone.,Front Cell Dev Biol,"Background:Paget's disease of bone (PDB) is characterized by focal areas of dysregulated bone turnover resulting in increased bone loss and abnormal bone formation with variable severity. PDB has a complex etiology and both genetics and environmental factors have been implicated. A recent study has identified many differentially methylated loci in PDB compared to healthy subjects. However, associations between DNA methylation profiles and disease severity of PDB have not been investigated.Objectives:To investigate the association between DNA methylation signals and PDB severity.Methods:Using 232 well-characterized PDB subjects from the PRISM trial, a disease severity score was devised based on the clinical features of PDB. DNA methylation profiling was performed using Illumina Infinium HumanMethylation 450K array.Results:We identified 100 CpG methylation sites significantly associated with PDB severity at FDR <0.05. Additionally, methylation profiles in 11 regions showed Bonferroni-significant association with disease severity including six islands (located inVCL,TBX5,CASZ1,ULBP2,NUDT15andSQSTM1), two gene bodies (CXCR6andDENND1A), and 3 promoter regions (RPL27,LINC00301andVPS29). Moreover, FDR-significant effects from region analysis implicated genes with genetic variants previously associated with PDB severity, includingRIN3andCSF1. A multivariate predictor model featuring the top severity-associated CpG sites revealed a significant correlation (R = 0.71,p= 6.9 × 10-16) between observed and predicted PDB severity scores. On dichotomizing the severity scores into low and high severity, the model featured an area under curve (AUC) of 0.80, a sensitivity of 0.74 and a specificity of 0.68.Conclusion:We identified several CpG methylation markers that are associated with PDB severity in this pioneering study while also highlighting the novel molecular pathways associated with disease progression. Further work is warranted to affirm the suitability of our model to predict the severity of PDB in newly diagnosed patients or patients with family history of PDB.Copyright © 2022 Diboun, Wani, Ralston and Albagha.",
-,Yes,20220815,ewas,35933486,Whole blood DNA methylation analysis reveals respiratory environmental traits involved in COVID-19 severity following SARS-CoV-2 infection.,Nat Commun,"SARS-CoV-2 infection can cause an inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea, and in ~5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping. The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We find an environmental trait-related signature that discriminates mild from severe cases and regulates, among other cytokines, IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics, and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.© 2022. The Author(s).",
-,Yes,20220815,ewas,35899434,Socioeconomic changes predict genome-wide DNA methylation in childhood.,Hum Mol Genet,"Childhood socioeconomic position (SEP) is a major determinant of health and well-being across the entire life course. To effectively prevent and reduce health risks related to SEP, it is critical to better understand when and under what circumstances socioeconomic adversity shapes biological processes. DNA methylation (DNAm) is one such mechanism for how early life adversity 'gets under the skin'. In this study, we evaluated the dynamic relationship between SEP and DNAm across childhood using data from 946 mother-child pairs in the Avon Longitudinal Study of Parents and Children (ALSPAC). We assessed six SEP indicators spanning financial, occupational, and residential domains during very-early childhood (ages 0-2), early childhood (ages 3-5), and middle childhood (ages 6-7). Epigenome-wide DNAm were measured at 412956 CpGs from peripheral blood at age 7. Using an innovative two-stage structured life course modeling approach, we tested three life-course hypotheses for how SEP shapes DNAm profiles-accumulation, sensitive period, and mobility. We showed that changes in the socioeconomic environment were associated with the greatest differences in DNAm, and that middle childhood may be a potential sensitive period when socioeconomic instability is especially important in shaping DNAm. Top SEP-related DNAm CpGs were overrepresented in genes involved in pathways important for neural development, immune function, and metabolic processes. Our findings highlight the importance of socioeconomic stability during childhood and if replicated, may emphasize the need for public programs to help children and families experiencing socioeconomic instability and other forms of socioeconomic adversity.© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,Yes,20220815,ewas,35843982,Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers.,Genome Med,"There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers of the identified signals, as well as their potential functional roles.Epigenome-wide association analyses were carried out to determine visceral fat mass-associated differentially methylated positions (VF-DMPs) in SAT samples from 538 TwinsUK participants. Validation and replication were performed in 333 individuals from 3 independent cohorts. To assess functional impacts of the VF-DMPs, the association between VF and gene expression was determined at the genes annotated to the VF-DMPs and an association analysis was carried out to determine whether methylation at the VF-DMPs is associated with gene expression. Further epigenetic analyses were carried out to compare methylation levels at the VF-DMPs as the response variables and a range of different metabolic health phenotypes including android:gynoid fat ratio (AGR), lipids, blood metabolomic profiles, insulin resistance, T2D and dietary intake variables. The results from all analyses were integrated to identify signals that exhibit altered SAT function and have strong relevance to metabolic health.We identified 1181 CpG positions in 788 genes to be differentially methylated with VF (VF-DMPs) with significant enrichment in the insulin signalling pathway. Follow-up cross-omic analysis of VF-DMPs integrating genetics, gene expression, metabolomics, diet, and metabolic traits highlighted VF-DMPs located in 9 genes with strong relevance to metabolic disease mechanisms, with replication of signals in FASN, SREBF1, TAGLN2, PC and CFAP410. PC methylation showed evidence for mediating effects of diet on VF. FASN DNA methylation exhibited putative causal effects on VF that were also strongly associated with insulin resistance and methylation levels in FASN better classified insulin resistance (AUC=0.91) than BMI or VF alone.Our findings help characterise the adiposity-associated methylation signature of SAT, with insights for metabolic disease risk.© 2022. The Author(s).",
-,Yes,20220815,ewas,35837690,Prenatal Socioeconomic Disadvantage and Epigenetic Alterations at Birth Among Children Born to White British and Pakistani Mothers in the Born in Bradford Study.,Epigenetics,"Prenatal socioeconomic disadvantage (SD) has been linked to DNA methylation (DNAm) in adulthood, but whether such epigenetic alterations are present at birth remains unclear. We carried out an epigenome-wide analysis of the association between several measures of individual- and area-level prenatal SD and DNAm assessed in neonatal cord blood via the Infinium EpicBeadChip among offspring born to mothers of White British (N = 455) and Pakistani (N = 493) origin in the Born in Bradford Study. Models were adjusted for mother's age, ethnicity, and education level as well as cell-type fractions and then for maternal health behaviours and neonate characteristics, and last, stratified by mother's ethnicity. P-values were corrected for multiple testing and a permutation-based approach was used to account for small cell sizes. Among all children, housing tenure (owning versus renting) as well as father's occupation (manual versus non-manual) were each associated with DNAm of one CpG site and index of multiple deprivation (IMD) was associated with DNAm of 11 CpG sites. Among children born to White British mothers, father's occupation (student or unemployed versus non-manual) was associated with DNAm of 1 CpG site and IMD with DNAm of 3 CpG sites. Among children born to Pakistani mothers, IMD was associated with DNAm of 1 CpG site. Associations were largely unchanged after further adjustment for maternal health behaviours or neonate characteristics and remained statistically significant. Our findings suggest that individual- and area-level prenatal SD may shape alterations to the neonatal epigenome, but associations vary across ethnic groups.",
-,Yes,20220815,ewas,35717575,Investigating DNA methylation as a mediator of genetic risk in childhood acute lymphoblastic Leukemia.,Hum Mol Genet,"Genome-wide association studies have identified a growing number of single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL), yet the functional roles of most SNPs are unclear. Multiple lines of evidence suggest epigenetic mechanisms may mediate the impact of heritable genetic variation on phenotypes. Here, we investigated whether DNA methylation mediates the effect of genetic risk loci for childhood ALL. We performed an epigenome-wide association study (EWAS) including 808 childhood ALL cases and 919 controls from California-based studies using neonatal blood DNA. For differentially methylated CpG positions (DMPs), we next conducted association analysis with 23 known ALL risk SNPs followed by causal mediation analyses addressing the significant SNP-DMP pairs. DNA methylation at CpG cg01139861, in the promoter region of IKZF1, mediated the effects of the intronic IKZF1 risk SNP rs78396808, with the average causal mediation effect (ACME) explaining ~ 30% of the total effect (ACME P = 0.0031). In analyses stratified by self-reported race/ethnicity, the mediation effect was only significant in Latinos, explaining ~ 41% of the total effect of rs78396808 on ALL risk (ACME P = 0.0037). Conditional analyses confirmed the presence of at least three independent genetic risk loci for childhood ALL at IKZF1, with rs78396808 unique to non-European populations. We also demonstrated that the most significant DMP in the EWAS, CpG cg13344587 at gene ARID5B (P = 8.61x10-10), was entirely confounded by the ARID5B ALL risk SNP rs7090445. Our findings provide new insights into the functional pathways of ALL risk SNPs and the DNA methylation differences associated with risk of childhood ALL.© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,Yes,20220815,ewas,35918756,Prenatal vitamin intake in first month of pregnancy and DNA methylation in cord blood and placenta in two prospective cohorts.,Epigenetics Chromatin,"Prenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the US Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies.In placenta, prenatal vitamin intake was marginally associated with -0.52% (95% CI -1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with -0.60% (-1.08, -0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p-value < 0.01 (EARLI cord nCpGs = 4068, EARLI placenta nCpGs = 3647, MARBLES cord nCpGs = 4068, MARBLES placenta nCpGs = 9563) were consistently enriched in neuronal developmental pathways.Together, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.© 2022. The Author(s).",
-,No,20220815,imprinting,35787786,Genome-wide detection of imprinted differentially methylated regions using nanopore sequencing.,Elife,"Imprinting is a critical part of normal embryonic development in mammals, controlled by defined parent-of-origin (PofO) differentially methylated regions (DMRs) known as imprinting control regions. Direct nanopore sequencing of DNA provides a means to detect allelic methylation and to overcome the drawbacks of methylation array and short-read technologies. Here, we used publicly available nanopore sequencing data for 12 standard B-lymphocyte cell lines to acquire the genome-wide mapping of imprinted intervals in humans. Using the sequencing data, we were able to phase 95% of the human methylome and detect 94% of the previously well-characterized, imprinted DMRs. In addition, we found 42 novel imprinted DMRs (16 germline and 26 somatic), which were confirmed using whole-genome bisulfite sequencing (WGBS) data. Analysis of WGBS data in mouse (Mus musculus), rhesus monkey (Macaca mulatta), and chimpanzee (Pan troglodytes) suggested that 17 of these imprinted DMRs are conserved. Some of the novel imprinted intervals are within or close to imprinted genes without a known DMR. We also detected subtle parental methylation bias, spanning several kilobases at seven known imprinted clusters. At these blocks, hypermethylation occurs at the gene body of expressed allele(s) with mutually exclusive H3K36me3 and H3K27me3 allelic histone marks. These results expand upon our current knowledge of imprinting and the potential of nanopore sequencing to identify imprinting regions using only parent-offspring trios, as opposed to the large multi-generational pedigrees that have previously been required.© 2022, Akbari et al.",
-,No,20220815,imprinting,35786392,Genomic map of candidate human imprint control regions: the imprintome.,Epigenetics,"Imprinted genes - critical for growth, metabolism, and neuronal function - are expressed from one parental allele. Parent-of-origin-dependent CpG methylation regulates this expression at imprint control regions (ICRs). Since ICRs are established before tissue specification, these methylation marks are similar across cell types. Thus, they are attractive for investigating the developmental origins of adult diseases using accessible tissues, but remain unknown. We determined genome-wide candidate ICRs in humans by performing whole-genome bisulphite sequencing (WGBS) of DNA derived from the three germ layers and from gametes. We identified 1,488 hemi-methylated candidate ICRs, including 19 of 25 previously characterized ICRs (https://humanicr.org/). Gamete methylation approached 0% or 100% in 332 ICRs (178 paternally and 154 maternally methylated), supporting parent-of-origin-specific methylation, and 65% were in well-described CTCF-binding or DNaseI hypersensitive regions. This draft of the human imprintome will allow for the systematic determination of the role of early-acquired imprinting dysregulation in the pathogenesis of human diseases and developmental and behavioural disorders.",
-,No,20220815,mediation,35708873,"Alcohol consumption, blood DNA methylation and breast cancer: a Mendelian randomisation study.",Eur J Epidemiol,"Alcohol intake is thought to be a risk factor for breast cancer, but the causal relationship and carcinogenic mechanisms are not clear. We performed an up-to-date meta-analysis of prospective studies to assess observational association, and then conducted MR analysis to make causal inference based on the genetic predisposition to alcohol consumption (""drinks per week"") and pathological drinking behaviours (""alcohol use disorder"" and ""problematic alcohol use""), as well as genetically predicted DNA methylation at by alcohol-related CpG sites in blood. We found an observational dose-response association between alcohol intake and breast cancer incidence with an additional risk of 4% for per 10 g/day increase in alcohol consumption. Genetic predisposition to alcohol consumption (""drinks per week"") was not causally associated with breast cancer incidence at the OR of 1.01 (95% CI 0.84, 1.23), but problematic alcohol use (PAU) was linked to a higher breast cancer risk at the OR of 1.76 (95% CI 1.04, 2.99) when conditioning on alcohol consumption. Epigenetic MR analysis identified four CpG sites, cg03260624 near CDC7 gene, cg10816169 near ZNF318 gene, cg03345232 near RIN3 gene, and cg26312998 near RP11-867G23.13 gene, where genetically predicted epigenetic modifications were associated with an increased breast cancer incidence risk. Our findings re-affirmed that alcohol consumption is of high risk for breast cancer incidence even at a very low dose, and the pathogenic effect of alcohol on breast cancer could be due to pathological drinking behaviour and epigenetic modification at several CpG sites, which could be potential intervention targets for breast cancer prevention.© 2022. The Author(s).",
-,No,20220815,methods,35914392,Examining the epigenetic mechanisms of childhood adversity and sensitive periods: A gene set-based approach.,Psychoneuroendocrinology,"Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods.Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (ngenes= 15), closing (ngenes= 36), and expression (ngenes= 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences.Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction.Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications.Copyright © 2022 Elsevier Ltd. All rights reserved.",
-,No,20220815,methods,35870905,EpiVisR: exploratory data analysis and visualization in epigenome-wide association analyses.,BMC Bioinformatics,"With the widespread availability of microarray technology for epigenetic research, methods for calling differentially methylated probes or differentially methylated regions have become effective tools to analyze this type of data. Furthermore, visualization is usually employed for quality check of results and for further insights. Expert knowledge is required to leverage capabilities of these methods. To overcome this limitation and make visualization in epigenetic research available to the public, we designed EpiVisR.The EpiVisR tool allows to select and visualize combinations of traits (i.e., concentrations of chemical compounds) and differentially methylated probes/regions. It supports various modes of enriched presentation to get the most knowledge out of existing data: (1) enriched Manhattan plot and enriched volcano plot for selection of probes, (2) trait-methylation plot for visualization of selected trait values against methylation values, (3) methylation profile plot for visualization of a selected range of probes against selected trait values as well as, (4) correlation profile plot for selection and visualization of further probes that are correlated to the selected probe. EpiVisR additionally allows exporting selected data to external tools for tasks such as network analysis.The key advantage of EpiVisR is the annotation of data in the enriched plots (and tied tables) as well as linking to external data sources for further integrated data analysis. Using the EpiVisR approach will allow users to integrate data from traits with epigenetic analyses that are connected by belonging to the same individuals. Merging data from various data sources among the same cohort and visualizing them will enable users to gain more insights from existing data.© 2022. The Author(s).",
-,No,20220815,methods,35765087,Low reliability of DNA methylation across Illumina Infinium platforms in cord blood: implications for replication studies and meta-analyses of prenatal exposures.,Clin Epigenetics,"There is an increasing interest in the role of epigenetics in epidemiology, but the emerging research field faces several critical biological and technical challenges. In particular, recent studies have shown poor correlation of measured DNA methylation (DNAm) levels within and across Illumina Infinium platforms in various tissues. In this study, we have investigated concordance between 450 k and EPIC Infinium platforms in cord blood. We could not replicate our previous findings on the association of prenatal paracetamol exposure with cord blood DNAm, which prompted an investigation of cross-platform DNAm differences.This study is based on two DNAm data sets from cord blood samples selected from the Norwegian Mother, Father and Child Cohort Study (MoBa). DNAm of one data set was measured using the 450 k platform and the other data set was measured using the EPIC platform. Initial analyses of the EPIC data could not replicate any of our previous significant findings in the 450 k data on associations between prenatal paracetamol exposure and cord blood DNAm. A subset of the samples (n = 17) was included in both data sets, which enabled analyses of technical sources potentially contributing to the negative replication. Analyses of these 17 samples with repeated measurements revealed high per-sample correlations ([Formula: see text] 0.99), but low per-CpG correlations ([Formula: see text] � 0.24) between the platforms. 1.7% of the CpGs exhibited a mean DNAm difference across platforms > 0.1. Furthermore, only 26.7% of the CpGs exhibited a moderate or better cross-platform reliability (intra-class correlation coefficient ≥ 0.5).The observations of low cross-platform probe correlation and reliability corroborate previous reports in other tissues. Our study cannot determine the origin of the differences between platforms. Nevertheless, it emulates the setting in studies using data from multiple Infinium platforms, often analysed several years apart. Therefore, the findings may have important implications for future epigenome-wide association studies (EWASs), in replication, meta-analyses and longitudinal studies. Cognisance and transparency of the challenges related to cross-platform studies may enhance the interpretation, replicability and validity of EWAS results both in cord blood and other tissues, ultimately improving the clinical relevance of epigenetic epidemiology.© 2022. The Author(s).",
-,No,20220815,methods,35615339,Estimating and accounting for unobserved covariates in high-dimensional correlated data.,J Am Stat Assoc,"Many high dimensional and high-throughput biological datasets have complex sample correlation structures, which include longitudinal and multiple tissue data, as well as data with multiple treatment conditions or related individuals. These data, as well as nearly all high-throughput 'omic' data, are influenced by technical and biological factors unknown to the researcher, which, if unaccounted for, can severely obfuscate estimation of and inference on the effects of interest. We therefore developed CBCV and CorrConf: provably accurate and computationally efficient methods to choose the number of and estimate latent confounding factors present in high dimensional data with correlated or nonexchangeable residuals. We demonstrate each method's superior performance compared to other state of the art methods by analyzing simulated multi-tissue gene expression data and identifying sex-associated DNA methylation sites in a real, longitudinal twin study.",
-,No,20220815,methods,35879805,A review of deep learning applications in human genomics using next-generation sequencing data.,Hum Genomics,"Genomics is advancing towards data-driven science. Through the advent of high-throughput data generating technologies in human genomics, we are overwhelmed with the heap of genomic data. To extract knowledge and pattern out of this genomic data, artificial intelligence especially deep learning methods has been instrumental. In the current review, we address development and application of deep learning methods/models in different subarea of human genomics. We assessed over- and under-charted area of genomics by deep learning techniques. Deep learning algorithms underlying the genomic tools have been discussed briefly in later part of this review. Finally, we discussed briefly about the late application of deep learning tools in genomic. Conclusively, this review is timely for biotechnology or genomic scientists in order to guide them why, when and how to use deep learning methods to analyse human genomic data.© 2022. The Author(s).",
-,No,20220815,prediction,35892159,DNA methylation profiling improves routine diagnosis of paediatric central nervous system tumours: A prospective population-based study.,Neuropathol Appl Neurobiol,"Paediatric brain tumours are rare, and establishing a precise diagnosis can be challenging. Analysis of DNA methylation profiles has been shown to be a reliable method to classify central nervous system (CNS) tumours with high accuracy. We aimed to prospectively analyse CNS tumours diagnosed in Sweden, to assess the clinical impact of adding DNA methylation-based classification to standard paediatric brain tumour diagnostics in an unselected cohort.All CNS tumours diagnosed in children (0-18 years) during 2017-2020 were eligible for inclusion provided sufficient tumour material was available. Tumours were analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier. The initial histopathological diagnosis was compared with the DNA methylation-based classification. For incongruent results, a blinded re-evaluation was performed by an experienced neuropathologist.Two hundred forty tumours with a histopathology-based diagnosis were profiled. A high-confidence methylation score of 0.84 or more was reached in 78% of the cases. In 69%, the histopathological diagnosis was confirmed, and for some of these also refined, 6% were incongruent, and the re-evaluation favoured the methylation-based classification. In the remaining 3% of cases, the methylation class was non-contributory. The change in diagnosis would have had a direct impact on the clinical management in 5% of all patients.Integrating DNA methylation-based tumour classification into routine clinical analysis improves diagnostics and provides molecular information that is important for treatment decisions. The results from methylation profiling should be interpreted in the context of clinical and histopathological information.© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.",
-,No,20220815,prediction,35740615,"The Early Detection of Breast Cancer Using Liquid Biopsies: Model Estimates of the Benefits, Harms, and Costs.",Cancers (Basel),"Breast cancer screening is associated with harms, such as false-positives and overdiagnoses, and, thus, novel screen tests can be considered. Liquid biopsies have been proposed as a novel method for the early detection of cancer, but low cell-free DNA tumor fraction might pose a problem for the use in population screening. Using breast cancer microsimulation model MISCAN-Fadia, we estimated the outcomes of using liquid biopsies in breast cancer screening in women aged 50 to 74 in the United States. For varying combinations of test sensitivity and specificity, we quantify the impact of the use of liquid biopsies on the harms and benefits of screening, and we estimate the maximum liquid biopsy price for cost-effective implementation in breast cancer screening at a cost-effectiveness threshold of USD 50,000. We investigate under what conditions liquid biopsies could be a suitable alternative to digital mammography and compare these conditions to a CCGA substudy. Outcomes were compared to digital mammography screening, and include mortality reduction, overdiagnoses, quality-adjusted life-years (QALYs), and the maximum price of a liquid biopsy for cost-effective implementation. When liquid biopsies are unable to detect DCIS, a large proportion of overdiagnosed cases is prevented but overall breast cancer mortality reduction and quality of life are lower, and costs are higher compared to digital mammography screening. Liquid biopsies prices should be restricted to USD 187 per liquid biopsy depending on test performance. Overall, liquid biopsies that are unable to detect ductal carcinoma in situ (DCIS) need to be able to detect small, early-stage tumors, with high specificity, at low costs in order to be an alternative to digital mammography. Liquid biopsies might be more suitable as an addition to digital mammography than as an alternative.",
-,No,20220815,prediction,35859180,Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer.,Nature,"Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2-12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20220815,review,35762294,Association between alcohol consumption and DNA methylation in blood: a systematic review of observational studies.,Epigenomics,"Aim:We systematically reviewed and evaluated current literature on alcohol consumption and DNA methylation (DNAm) at the genome-wide and probe-wise level in blood of adults.Materials & methods:Five databases (PubMed, Embase, Web of Science, CINAHL and PsycInfo) were searched until 20 December 2020. Studies assessing the effect of alcohol dependence on DNAm were not eligible.Results:11 cross-sectional studies were included with 88 to 9643 participants. Overall, all studies had a risk of bias criteria unclear or unmet. Epigenome-wide association studies identified between 0 and 5458 differentially methylated positions, and 15 were observed in at least four studies.Conclusion:Potential methylation markers for alcohol consumption have been identified, but further validation in large cohorts is needed.",
-,No,20220815,ml,35758797,"An approachable, flexible and practical machine learning workshop for biologists.",Bioinformatics,"The increasing prevalence and importance of machine learning in biological research have created a need for machine learning training resources tailored towards biological researchers. However, existing resources are often inaccessible, infeasible or inappropriate for biologists because they require significant computational and mathematical knowledge, demand an unrealistic time-investment or teach skills primarily for computational researchers. We created the Machine Learning for Biologists (ML4Bio) workshop, a short, intensive workshop that empowers biological researchers to comprehend machine learning applications and pursue machine learning collaborations in their own research. The ML4Bio workshop focuses on classification and was designed around three principles: (i) emphasizing preparedness over fluency or expertise, (ii) necessitating minimal coding and mathematical background and (iii) requiring low time investment. It incorporates active learning methods and custom open-source software that allows participants to explore machine learning workflows. After multiple sessions to improve workshop design, we performed a study on three workshop sessions. Despite some confusion around identifying subtle methodological flaws in machine learning workflows, participants generally reported that the workshop met their goals, provided them with valuable skills and knowledge and greatly increased their beliefs that they could engage in research that uses machine learning. ML4Bio is an educational tool for biological researchers, and its creation and evaluation provide valuable insight into tailoring educational resources for active researchers in different domains.Workshop materials are available at https://github.com/carpentries-incubator/ml4bio-workshop and the ml4bio software is available at https://github.com/gitter-lab/ml4bio.Supplementary data are available at Bioinformatics online.© The Author(s) 2022. Published by Oxford University Press.",
-,No,20220905,circulating,36010184,Tracing the Origin of Cell-Free DNA Molecules through Tissue-Specific Epigenetic Signatures.,Diagnostics (Basel),"All cell and tissue types constantly release DNA fragments into human body fluids by various mechanisms including programmed cell death, accidental cell degradation and active extrusion. Particularly, cell-free DNA (cfDNA) in plasma or serum has been utilized for minimally invasive molecular diagnostics. Disease onset or pathological conditions that lead to increased cell death alter the contribution of different tissues to the total pool of cfDNA. Because cfDNA molecules retain cell-type specific epigenetic features, it is possible to infer tissue-of-origin from epigenetic characteristics. Recent research efforts demonstrated that analysis of, e.g., methylation patterns, nucleosome occupancy, and fragmentomics determined the cell- or tissue-of-origin of individual cfDNA molecules. This novel tissue-of origin-analysis enables to estimate the contributions of different tissues to the total cfDNA pool in body fluids and find tissues with increased cell death (pathologic condition), expanding the portfolio of liquid biopsies towards a wide range of pathologies and early diagnosis. In this review, we summarize the currently available tissue-of-origin approaches and point out the next steps towards clinical implementation.",
-,No,20220905,chromatin,35947558,Chromatin accessibility of primary human cancers ties regional mutational processes and signatures with tissues of origin.,PLoS Comput Biol,"Somatic mutations in cancer genomes are associated with DNA replication timing (RT) and chromatin accessibility (CA), however these observations are based on normal tissues and cell lines while primary cancer epigenomes remain uncharacterised. Here we use machine learning to model megabase-scale mutation burden in 2,500 whole cancer genomes and 17 cancer types via a compendium of 900 CA and RT profiles covering primary cancers, normal tissues, and cell lines. CA profiles of primary cancers, rather than those of normal tissues, are most predictive of regional mutagenesis in most cancer types. Feature prioritisation shows that the epigenomes of matching cancer types and organ systems are often the strongest predictors of regional mutation burden, highlighting disease-specific associations of mutational processes. The genomic distributions of mutational signatures are also shaped by the epigenomes of matched cancer and tissue types, with SBS5/40, carcinogenic and unknown signatures most accurately predicted by our models. In contrast, fewer associations of RT and regional mutagenesis are found. Lastly, the models highlight genomic regions with overrepresented mutations that dramatically exceed epigenome-derived expectations and show a pan-cancer convergence to genes and pathways involved in development and oncogenesis, indicating the potential of this approach for coding and non-coding driver discovery. The association of regional mutational processes with the epigenomes of primary cancers suggests that the landscape of passenger mutations is predominantly shaped by the epigenomes of cancer cells after oncogenic transformation.",
-,No,20220905,chromatin,35978191,Spatial profiling of chromatin accessibility in mouse and human tissues.,Nature,"Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context1. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping2-5, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry6and microfluidic deterministic barcoding5. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.© 2022. The Author(s).",
-,Yes,20220905,ewas,36046194,Fetal sex-specific epigenetic associations with prenatal maternal depressive symptoms.,iScience,"Prenatal maternal mental health is a global health challenge with poorly defined biological mechanisms. We used maternal blood samples collected during the second trimester from a Singaporean longitudinal birth cohort study to examine the association between inter-individual genome-wide DNA methylation and prenatal maternal depressive symptoms. We found that (1) the maternal methylome was significantly associated with prenatal maternal depressive symptomsonlyin mothers with a female fetus; and (2) this sex-dependent association was observed in a comparable, UK-based birth cohort study. Qualitative analyses showed fetal sex-specific differences in genomic features of depression-related CpGs and genes mapped from these CpGs in mothers with female fetuses implicated in a depression-associated WNT/β-catenin signaling pathway. These same genes also showed enriched expression in brain regions linked to major depressive disorder. We also found similar female-specific associations with fetal-facing placenta methylome. Our fetal sex-specific findings provide evidence for maternal-fetal interactions as a mechanism for intergenerational transmission.© 2022 The Authors.",
-,No,20220905,ewas,36039408,Epigenetic signature of exposure to maternal <i>Trypanosoma cruzi</i> infection in cord blood cells from uninfected newborns.,Epigenomics,"Aims:To assess the epigenetic effects ofin uteroexposure to maternalTrypanosoma cruziinfection.Methods:We performed an epigenome-wide association study to compare the DNA methylation patterns of umbilical cord blood cells from uninfected babies from chagasic and uninfected mothers. DNA methylation was measured using Infinium EPIC arrays.Results:We identified a differential DNA methylation signature of fetal exposure to maternalT. cruziinfection, in the absence of parasite transmission, with 12 differentially methylated sites in B cells and CD4+T cells, including eight protein-coding genes.Conclusion:These genes participate in hematopoietic cell differentiation and the immune response and may be involved in immune disorders. They also have been associated with several developmental disorders and syndromes.",
-,Yes,20220905,ewas,36036794,Associations of Heavy Metals with Activities of Daily Living Disability: An Epigenome-Wide View of DNA Methylation and Mediation Analysis.,Environ Health Perspect,"Exposure to heavy metals has been reported to be associated with multiple diseases. However, direct associations and potential mechanisms of heavy metals with physical disability remain unclear.We aimed to quantify associations of heavy metals with physical disability and further explore the potential mechanisms of DNA methylation on the genome scale.A cross-sectional study of 4,391 older adults was conducted and activities of daily living (ADL) disability were identified using a 14-item scale questionnaire including basic and instrumental activities to assess the presence of disability (yes or no) rated on a scale of dependence. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated to quantify associations between heavy metals and ADL disability prevalence using multivariate logistic regression and Bayesian kernel machine regression (BKMR) models. Whole blood-derived DNA methylation was measured using the HumanMethylationEPIC BeadChip array. An ADL disability-related epigenome-wide DNA methylation association study (EWAS) was performed among 212 sex-matched ADL disability cases and controls, and mediation analysis was further applied to explore potential mediators of DNA methylation.Each 1-standard deviation (SD) higher difference inlog10-transformed manganese, copper, arsenic, and cadmium level was significantly associated with a 14% (95% CI: 1.05, 1.24), 16% (95% CI:1.07, 1.26), 22% (95% CI:1.13, 1.33), and 15% (95% CI:1.06, 1.26) higher odds of ADL disability, which remained significant in the multiple-metal and BKMR models. A total of 85 differential DNA methylation sites were identified to be associated with ADL disability prevalence, among which methylation level at cg220000984 and cg23012519 (annotated toIRGMandPKP3) mediated 31.0% and 31.2% of manganese-associated ADL disability prevalence, cg06723863 (annotated toESRP2) mediated 32.4% of copper-associated ADL disability prevalence, cg24433124 (nearest toIER3) mediated 15.8% of arsenic-associated ADL disability prevalence, and cg07905190 and cg17485717 (annotated toFREM1andTCP11L1) mediated 21.5% and 30.5% of cadmium-associated ADL disability prevalence (allp<0.05).Our findings suggested that heavy metals contributed to higher prevalence of ADL disability and that locus-specific DNA methylation are partial mediators, providing potential biomarkers for further cellular mechanism studies. https://doi.org/10.1289/EHP10602.",
-,Yes,20220905,ewas,36029471,"Analysis of systemic epigenetic alterations in inflammatory bowel disease: defining geographical, genetic, and immune-inflammatory influences on the circulating methylome.",J Crohns Colitis,"Epigenetic alterations may provide valuable insights into gene-environment interactions play in the pathogenesis of Inflammatory Bowel Disease (IBD).Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) with covariates of age, sex, and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission.A total of 137 differentially methylated positions (DMP) were identified in IBD, including VMP1/MIR21 (p=9.11×10 -15) and RPS6KA2 (6.43×10 -13); with consistency seen across Scandinavia and UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10 -15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10 -16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10 -7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10 -4).These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
-,No,20220905,ewas,36017556,Epigenome-wide association studies of occupational exposure to benzene and formaldehyde.,Epigenetics,"relationship between certain myeloid neoplasms and exposure to benzene or formaldehyde. DNA methylation could underlie benzene- and formaldehyde-induced health outcomes, but data in exposed human populations are limited. We conducted two cross-sectional epigenome-wide association studies (EWAS), one in workers exposed to benzene and another in workers exposed to formaldehyde. Using HumanMethylation450 BeadChips, we investigated differences in blood cell DNA methylation among 50 benzene-exposed subjects and 48 controls, and among 31 formaldehyde-exposed subjects and 40 controls. We performed CpG-level and regional-level analyses. In the benzene EWAS, we found genome-wide significant alterations, i.e., FWER-controlledP-values <0.05, in the mean and variance of methylation at 22 and 318 CpG sites, respectively, and in mean methylation of a large genomic region. Pathway analysis of genes corresponding to benzene-associated differential methylation sites revealed an impact on the AMPK signalling pathway. In formaldehyde-exposed subjects compared to controls, 9 CpGs in theDUSP22gene promoter had genome-wide significant decreased methylation variability and a large region of theHOXA5promoter with 44 CpGs was hypomethylated. Our findings suggest that DNA methylation may contribute to the pathogenesis of diseases related to benzene and formaldehyde exposure. Aberrant expression and methylation ofHOXA5previously has been shown to be clinically significant in myeloid leukaemias. The tumour suppressor geneDUSP22is a potential biomarker of exposure to formaldehyde, and irregularities have been associated with multiple exposures and diseases.",
-,Yes,20220905,ewas,36012217,Experiences of Trauma and DNA Methylation Profiles among African American Mothers and Children.,Int J Mol Sci,"Potentially traumatic experiences have been associated with chronic diseases. Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed as an explanation for this association. We examined the association of experiences of trauma with epigenome-wide DNAm among African American mothers (n= 236) and their children aged 3-5 years (n= 232; N = 500), using the Life Events Checklist-5 (LEC) and Traumatic Events Screening Inventory-Parent Report Revised (TESI-PRR). We identified no DNAm sites significantly associated with potentially traumatic experience scores in mothers. One CpG site on theENOX1gene was methylome-wide-significant in children (FDR-corrected q-value = 0.05) from the TESI-PRR. This protein-coding gene is associated with mental illness, including unipolar depression, bipolar, and schizophrenia. Future research should further examine the associations between childhood trauma, DNAm, and health outcomes among this understudied and high-risk group. Findings from such longitudinal research may inform clinical and translational approaches to prevent adverse health outcomes associated with epigenetic changes.",
-,Yes,20220905,ewas,35998097,Systematic Review and Meta-analysis of Peripheral Blood DNA methylation studies in Inflammatory Bowel Disease.,J Crohns Colitis,"Over the past decade, the DNA methylome has been increasingly studied in peripheral blood of inflammatory bowel disease (IBD) patients. However, a comprehensive summary and meta-analysis of peripheral blood leukocyte (PBL) DNA methylation studies has thus far not been conducted. Here, we systematically reviewed all available literature up to February 2022 and summarized the observations by means of meta-analysis.We conducted a systematic search and critical appraisal of IBD-associated DNA methylation studies in PBL using the biomarker-based cross-sectional studies (BIOCROSS) tool. Subsequently, we performed meta-analyses on the summary statistics obtained from epigenome-wide association studies (EWAS) that included patients with Crohn's Disease (CD), ulcerative colitis (UC) and/or healthy controls (HC).Altogether, we included 15 studies for systematic review. Critical appraisal revealed large methodological and outcome heterogeneity between studies. Summary statistics were obtained from 4 studies based on a cumulative 552 samples (177 CD, 132 UC and 243 HC). Consistent differential methylation was identified for 256 differentially methylated probes (DMPs; Bonferroni-adjusted p-value ≤0.05) when comparing CD with HC and 103 when comparing UC with HC. Comparing IBD (CD + UC) with HC resulted in 224 DMPs. Importantly, several of the previously identified DMPs, such as VMP1/TMEM49/MIR21 and RPS6KA2, were consistently differentially methylated across all studies.Methodological homogenization of IBD epigenetic studies is needed to allow for easier aggregation and independent validation. Nonetheless, we were capable of confirming previous observations. Our results can serve as the basis for future IBD epigenetic biomarker research in PBL.© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.",
-,Yes,20220905,ewas,35998020,Whole-genome bisulfite sequencing analysis of circulating tumour DNA for the detection and molecular classification of cancer.,Clin Transl Med,"Cancer cell-specific variation and circulating tumour DNA (ctDNA) methylation are promising biomarkers for non-invasive cancer detection and molecular classification. Nevertheless, the applications of ctDNA to the early detection and screening of cancer remain highly challenging due to the scarcity of cancer cell-specific ctDNA, the low signal-to-noise ratio of DNA variation, and the lack of non-locus-specific DNA methylation technologies.We enrolled three cohorts of breast cancer (BC) patients from two hospitals in China (BC: n = 123; healthy controls: n = 40). We developed a ctDNA whole-genome bisulfite sequencing technology employing robust trace ctDNA capture from up to 200 μL plasma, mini-input (1 ng) library preparation, unbiased genome-wide coverage and comprehensive computational methods.A diagnostic signature comprising 15 ctDNA methylation markers exhibited high accuracy in the early (area under the curve [AUC] of 0.967) and advanced (AUC of 0.971) BC stages in multicentre patient cohorts. Furthermore, we revealed a ctDNA methylation signature that discriminates estrogen receptor status (Training set: AUC of 0.984 and Test set: AUC of 0.780). Different cancer types, including hepatocellular carcinoma and lung cancer, could also be well distinguished.Our study provides a toolset to generate unbiased whole-genome ctDNA methylomes with a minimal amount of plasma to develop highly specific and sensitive biomarkers for the early diagnosis and molecular subtyping of cancer.© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.",
-,Yes,20220905,ewas,35995800,Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology.,Nat Commun,"Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.© 2022. The Author(s).",
-,Yes,20220905,ewas,35987900,Pre-diagnostic DNA methylation in blood leucocytes in cutaneous melanoma; a nested case-control study within the Norwegian Women and Cancer cohort.,Sci Rep,"The prognosis of cutaneous melanoma depends on early detection, and good biomarkers for melanoma risk may provide a valuable tool to detect melanoma development at a pre-clinical stage. By studying the epigenetic profile in pre-diagnostic blood samples of melanoma cases and cancer free controls, we aimed to identify DNA methylation sites conferring melanoma risk. DNA methylation was measured at 775,528 CpG sites using the Illumina EPIC array in whole blood in incident melanoma cases (n = 183) and matched cancer-free controls (n = 183) in the Norwegian Women and Cancer cohort. Phenotypic information and ultraviolet radiation exposure were obtained from questionnaires. Epigenome wide association (EWAS) was analyzed in future melanoma cases and controls with conditional logistic regression, with correction for multiple testing using the false discovery rate (FDR). We extended the analysis by including a public data set on melanoma (GSE120878), and combining these different data sets using a version of covariate modulated FDR (AdaPT). The analysis on future melanoma cases and controls did not identify any genome wide significant CpG sites (0.85 ≤ padj ≤ 0.99). In the restricted AdaPT analysis, 7 CpG sites were suggestive at the FDR level of 0.15. These CpG sites may potentially be used as pre-diagnostic biomarkers of melanoma risk.© 2022. The Author(s).",
-,Yes,20220905,ewas,35982059,Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer's disease.,Nat Commun,"To better understand DNA methylation in Alzheimer's disease (AD) from both mechanistic and biomarker perspectives, we performed an epigenome-wide meta-analysis of blood DNA methylation in two large independent blood-based studies in AD, the ADNI and AIBL studies, and identified 5 CpGs, mapped to the SPIDR, CDH6 genes, and intergenic regions, that are significantly associated with AD diagnosis. A cross-tissue analysis that combined these blood DNA methylation datasets with four brain methylation datasets prioritized 97 CpGs and 10 genomic regions that are significantly associated with both AD neuropathology and AD diagnosis. An out-of-sample validation using the AddNeuroMed dataset showed the best performing logistic regression model includes age, sex, immune cell type proportions, and methylation risk score based on prioritized CpGs in cross-tissue analysis (AUC = 0.696, 95% CI: 0.616 - 0.770, P-value = 2.78 × 10-5). Our study offers new insights into epigenetics in AD and provides a valuable resource for future AD biomarker discovery.© 2022. The Author(s).",
-,Yes,20220905,ewas,35979830,Soluble CD14-associated DNA methylation sites predict mortality among men with HIV infection.,AIDS,"Elevated plasma levels of sCD14 predict all-cause mortality in people with HIV (PWH). Epigenetic regulation plays a key role in infection and inflammation. To reveal the epigenetic relationships between sCD14, immune function and disease progression among PWH, we conducted an epigenome-wide association study (EWAS) of sCD14 and investigated the relationship with mortality.DNA methylation (DNAm) levels of peripheral blood samples from PWH in the Veterans Aging Cohort Study (VACS) were measured using the Illumina Infinium Methylation 450K (n = 549) and EPIC (850K) BeadChip (n = 526). Adjusted for covariates and multiple testing, we conducted an epigenome-wide discovery, replication, and meta-analysis to identify significant associations with sCD14. We then examined and replicated the relationship between the principal epigenetic sites and survival using Cox regression models.We identified 118 DNAm sites significantly associated with sCD14 in the meta-analysis of 1075 PWH. The principal associated DNAm sites mapped to genes (e.g. STAT1, PARP9, IFITM1, MX1, and IFIT1) related to inflammation and antiviral response. Adjusting for multiple testing, 10 of 118 sCD14-associated DNAm sites significantly predicted survival time conditional on sCD14 levels.The identification of DNAm sites independently predicting survival may improve our understanding of prognosis and potential therapeutic targets among PWH.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.",
-,Yes,20220905,ewas,35977396,Intake of mother's milk by very low birth weight infants and variation in DNA methylation of genes involved in neurodevelopment at 5.5 years.,Am J Clin Nutr,"Mechanisms responsible for associations between intake of mother's milk (MM) in very low birth weight (VLBW, <1500 grams) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification.To assess whether early MM intake by VLBW infants is associated with variations in DNAm at 5.5 years, and whether these variations correlate with neurodevelopmental phenotypes.This cohort study was a 5.5-year follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether % MM (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (5.7 ± 0.2 years, n = 143; birth weight of 1008 ± 517 grams). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, magnetic resonance imaging) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV).EWAS analysis demonstrated % MM intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 (MYO15B) and cg00851389 (MT1A) at 5.5 years (P < 9E-08). Gene Set Enrichment Analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from EWAS was associated with cortical surface area and IQ at 5.5 years (P < 0.05).In-hospital % MM intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 years; some of these DNAm variations are associated with brain structure and IQ. Clinical Trial Registration: ISRCTN35317141 at isrctn.com and NCT02759809 at clinicaltrials.gov.© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.",
-,Yes,20220905,ewas,35965483,"Epigenome-wide association study analysis of calorie restriction in humans, CALERIE TM Trial analysis.",J Gerontol A Biol Sci Med Sci,"Calorie restriction (CR) increases healthy lifespan and is accompanied by slowing or reversal of aging-associated DNA methylation (DNAm) changes in animal models. In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE TM) human trial we evaluated associations of CR and changes in whole-blood DNAm.CALERIE TM randomized 220 healthy, non-obese adults in a 2:1 allocation to two years of CR or ad libitum (AL) diet. The average CR in the treatment group through 24-months of follow-up was 12%. Whole blood (baseline, 12 and 24 month) DNAm profiles were measured. Epigenome-wide association study (EWAS) analysis tested CR-induced changes from baseline to 12- and 24-months in the n=197 participants with available DNAm data.CR treatment was not associated with epigenome-wide significant (FDR<0.05) DNAm changes at the individual-CpG-site level. Secondary analysis of sets of CpG sites identified in published EWAS revealed that CR induced DNAm changes opposite to those associated with higher body mass index and cigarette smoking (p<0.003 at 12- and 24-month follow-ups). In contrast, CR altered DNAm at chronological-age associated CpG sites in the direction of older age (p<0.003 at 12- and 24-month follow-ups).Although individual CpG site DNAm changes in response to CR were not identified, analyses of sets CpGs identified in prior EWAS revealed CR-induced changes to blood DNAm. Altered CpG sets were enriched for insulin-production, glucose-tolerance, inflammation, and DNA-binding and -regulation pathways, several of which are known to be modified by CR. DNAm changes may contribute to CR effects on aging.© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.",
-,Yes,20220905,ewas,35945220,Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health.,Nat Commun,"Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.© 2022. The Author(s).",
-,Yes,20220905,ewas,35947335,DNA methylation trajectories and accelerated epigenetic aging in incident type 2 diabetes.,Geroscience,"DNA methylation (DNAm) patterns across the genome changes during aging and development of complex diseases including type 2 diabetes (T2D). Our study aimed to estimate DNAm trajectories of CpG sites associated with T2D, epigenetic age (DNAmAge), and age acceleration based on four epigenetic clocks (GrimAge, Hannum, Horvath, phenoAge) in the period 10 years prior to and up to T2D onset. In this nested case-control study within Doetinchem Cohort Study, we included 132 incident T2D cases and 132 age- and sex-matched controls. DNAm was measured in blood using the Illumina Infinium Methylation EPIC array. From 107 CpG sites associated with T2D, 10 CpG sites (9%) showed different slopes of DNAm trajectories over time (p < 0.05) and an additional 8 CpG sites (8%) showed significant differences in DNAm levels (at least 1%, p-value per time point < 0.05) at all three time points with nearly parallel trajectories between incident T2D cases and controls. In controls, age acceleration levels were negative (slower epigenetic aging), while in incident T2D cases, levels were positive, suggesting accelerated aging in the case group. We showed that DNAm levels at specific CpG sites, up to 10 years before T2D onset, are different between incident T2D cases and healthy controls and distinct patterns of clinical traits over time may have an impact on those DNAm profiles. Up to 10 years before T2D diagnosis, cases manifested accelerated epigenetic aging. Markers of biological aging including age acceleration estimates based on Horvath need further investigation to assess their utility for predicting age-related diseases including T2D.© 2022. The Author(s), under exclusive licence to American Aging Association.",
-,Yes,20220905,ewas,35879030,Methylome-wide Association Study of Patients with Recent-onset Psychosis.,Clin Psychopharmacol Neurosci,"Dysregulation of gene expression through epigenetic mechanisms may have a vital role in the pathogenesis of schizophrenia (SZ). In this study, we investigated the association of altered methylation patterns with SZ symptoms and early trauma in patients and healthy controls.The present study was conducted to identify methylation changes in CpG sites in peripheral blood associated with recent-onset (RO) psychosis using methylome-wide analysis. Lifestyle factors, such as smoking, alcohol, exercise, and diet, were controlled.We identified 2,912 differentially methylated CpG sites in patients with RO psychosis compared to controls. Most of the genes associated with the top 20 differentially methylated sites had not been reported in previous methylation studies and were involved in apoptosis, autophagy, axonal growth, neuroinflammation, protein folding, etc. The top 15 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways included the oxytocin signaling pathway, long-term depression pathway, axon guidance, endometrial cancer, long-term potentiation, mitogen-activated protein kinase signaling pathway, and glutamatergic pathway, among others. In the patient group, significant associations of novel methylated genes with early trauma and psychopathology were observed.Our results suggest an association of differential DNA methylation with the pathophysiology of psychosis and early trauma. Blood DNA methylation signatures show promise as biomarkers of future psychosis.",
-,Yes,20220905,ewas,35930640,Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes.,Sci Adv,"Trained immunity describes the capacity of innate immune cells to develop heterologous memory in response to certain exogenous exposures. This phenomenon mediates, at least in part, the beneficial off-target effects of the BCG vaccine. Using an in vitro model of trained immunity, we show that BCG exposure induces a persistent change in active histone modifications, DNA methylation, transcription, and adenosine-to-inosine RNA modification in human monocytes. By profiling DNA methylation of circulating monocytes from infants in the MIS BAIR clinical trial, we identify a BCG-associated DNA methylation signature that persisted more than 12 months after neonatal BCG vaccination. Genes associated with this epigenetic signature are involved in viral response pathways, consistent with the reported off-target protection against viral infections in neonates, adults, and the elderly. Our findings indicate that the off-target effects of BCG in infants are accompanied by epigenetic remodeling of circulating monocytes that lasts more than 1 year.",
-,No,20220905,mediation,35989709,Large-Scale Hypothesis Testing for Causal Mediation Effects with Applications in Genome-wide Epigenetic Studies.,J Am Stat Assoc,"In genome-wide epigenetic studies, it is of great scientific interest to assess whether the effect of an exposure on a clinical outcome is mediated through DNA methylations. However, statistical inference for causal mediation effects is challenged by the fact that one needs to test a large number of composite null hypotheses across the whole epigenome. Two popular tests, the Wald-type Sobel's test and the joint significant test using the traditional null distribution are underpowered and thus can miss important scientific discoveries. In this paper, we show that the null distribution of Sobel's test is not the standard normal distribution and the null distribution of the joint significant test is not uniform under the composite null of no mediation effect, especially in finite samples and under the singular point null case that the exposure has no effect on the mediator and the mediator has no effect on the outcome. Our results explain why these two tests are underpowered, and more importantly motivate us to develop a more powerful Divide-Aggregate Composite-null Test (DACT) for the composite null hypothesis of no mediation effect by leveraging epigenome-wide data. We adopted Efron's empirical null framework for assessing statistical significance of the DACT test. We showed analytically that the proposed DACT method had improved power, and could well control type I error rate. Our extensive simulation studies showed that, in finite samples, the DACT method properly controlled the type I error rate and outperformed Sobel's test and the joint significance test for detecting mediation effects. We applied the DACT method to the US Department of Veterans Affairs Normative Aging Study, an ongoing prospective cohort study which included men who were aged 21 to 80 years at entry. We identified multiple DNA methylation CpG sites that might mediate the effect of smoking on lung function with effect sizes ranging from -0.18 to -0.79 and false discovery rate controlled at level 0.05, including the CpG sites in the genes AHRR and F2RL3. Our sensitivity analysis found small residual correlations (less than 0.01) of the error terms between the outcome and mediator regressions, suggesting that our results are robust to unmeasured confounding factors.",
-,No,20220905,methods,36047742,An evaluation of the genome-wide false positive rates of common methods for identifying differentially methylated regions using illumina methylation arrays.,Epigenetics,"Differentially methylated regions (DMRs) are genomic regions with specific methylation patterns across multiple loci that are associated with a phenotype. We examined the genome-wide false positive (GFP) rates of five widely used DMR methods: comb-p, Bumphunter, DMRcate, mCSEA and coMethDMR using both Illumina HumanMethylation450 (450 K) and MethylationEPIC (EPIC) data and simulated continuous and dichotomous null phenotypes (i.e., generated independently of methylation data). coMethDMR provided well-controlled GFP rates (~5%) except when analysing skewed continuous phenotypes. DMRcate generally had well-controlled GFP rates when applied to 450 K data except for the skewed continuous phenotype and EPIC data only for the normally distributed continuous phenotype. GFP rates for mCSEA were at least 0.096 and comb-p yielded GFP rates above 0.34. Bumphunter had high GFP rates of at least 0.35 across conditions, reaching as high as 0.95. Analysis of the performance of these methods in specific regions of the genome found that regions with higher correlation across loci had higher regional false positive rates on average across methods. Based on the false positive rates, coMethDMR is the most recommended analysis method, and DMRcate had acceptable performance when analysing 450 K data. However, as both could display higher levels of FPs for skewed continuous distributions, a normalizing transformation of skewed continuous phenotypes is suggested. This study highlights the importance of genome-wide simulations when evaluating the performance of DMR-analysis methods.",
-,No,20220905,methods,36040576,Assessing Differential Variability of High-Throughput DNA Methylation Data.,Curr Environ Health Rep,"DNA methylation (DNAm) is essential to human development and plays an important role as a biomarker due to its susceptibility to environmental exposures. This article reviews the current state of statistical methods developed for differential variability analysis focusing on DNAm data.With the advent of high-throughput technologies allowing for highly reliable and cost-effective measurements of DNAm, many epigenome studies have analyzed DNAm levels to uncover biological mechanisms underlying past environmental exposures and subsequent health outcomes. These studies typically focused on detecting sites or regions which differ in their mean DNAm levels among exposure groups. However, more recent studies highlighted the importance of identifying differentially variable sites or regions as biologically relevant features. Currently, the analysis of differentially variable DNAm sites has not yet gained widespread adoption in environmental studies; yet, it is important to examine the effects of environmental exposures on inter-individual epigenetic variability. In this article, we describe six of the most widely used statistical approaches for analyzing differential variability of DNAm levels and provide a discussion of their advantages and current limitations.© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.",
-,No,20220905,methods,35948928,Identification of influential probe types in epigenetic predictions of human traits: implications for microarray design.,Clin Epigenetics,"CpG methylation levels can help to explain inter-individual differences in phenotypic traits. Few studies have explored whether identifying probe subsets based on their biological and statistical properties can maximise predictions whilst minimising array content. Variance component analyses and penalised regression (epigenetic predictors) were used to test the influence of (i) the number of probes considered, (ii) mean probe variability and (iii) methylation QTL status on the variance captured in eighteen traits by blood DNA methylation. Training and test samples comprised ≤ 4450 and ≤ 2578 unrelated individuals from Generation Scotland, respectively.As the number of probes under consideration decreased, so too did the estimates from variance components and prediction analyses. Methylation QTL status and mean probe variability did not influence variance components. However, relative effect sizes were 15% larger for epigenetic predictors based on probes with known or reported methylation QTLs compared to probes without reported methylation QTLs. Relative effect sizes were 45% larger for predictors based on probes with mean Beta-values between 10 and 90% compared to those based on hypo- or hypermethylated probes (Beta-value ≤ 10% or ≥ 90%).Arrays with fewer probes could reduce costs, leading to increased sample sizes for analyses. Our results show that reducing array content can restrict prediction metrics and careful attention must be given to the biological and distribution properties of CpG probes in array content selection.© 2022. The Author(s).",
-,No,20220905,ml,36011003,Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis.,Cancers (Basel),"Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set.",
-,No,20220905,ml,35933478,Developing machine learning algorithms for dynamic estimation of progression during active surveillance for prostate cancer.,NPJ Digit Med,"Active Surveillance (AS) for prostate cancer is a management option that continually monitors early disease and considers intervention if progression occurs. A robust method to incorporate ""live"" updates of progression risk during follow-up has hitherto been lacking. To address this, we developed a deep learning-based individualised longitudinal survival model using Dynamic-DeepHit-Lite (DDHL) that learns data-driven distribution of time-to-event outcomes. Further refining outputs, we used a reinforcement learning approach (Actor-Critic) for temporal predictive clustering (AC-TPC) to discover groups with similar time-to-event outcomes to support clinical utility. We applied these methods to data from 585 men on AS with longitudinal and comprehensive follow-up (median 4.4 years). Time-dependent C-indices and Brier scores were calculated and compared to Cox regression and landmarking methods. Both Cox and DDHL models including only baseline variables showed comparable C-indices but the DDHL model performance improved with additional follow-up data. With 3 years of data collection and 3 years follow-up the DDHL model had a C-index of 0.79 (±0.11) compared to 0.70 (±0.15) for landmarking Cox and 0.67 (±0.09) for baseline Cox only. Model calibration was good across all models tested. The AC-TPC method further discovered 4 distinct outcome-related temporal clusters with distinct progression trajectories. Those in the lowest risk cluster had negligible progression risk while those in the highest cluster had a 50% risk of progression by 5 years. In summary, we report a novel machine learning approach to inform personalised follow-up during active surveillance which improves predictive power with increasing data input over time.© 2022. The Author(s).",
-,No,20220905,ml,35785523,Interpretable Machine Learning Models to Predict the Resistance of Breast Cancer Patients to Doxorubicin from Their microRNA Profiles.,Adv Sci (Weinh),"Doxorubicin is a common treatment for breast cancer. However, not all patients respond to this drug, which sometimes causes life-threatening side effects. Accurately anticipating doxorubicin-resistant patients would therefore permit to spare them this risk while considering alternative treatments without delay. Stratifying patients based on molecular markers in their pretreatment tumors is a promising approach to advance toward this ambitious goal, but single-gene gene markers such as HER2 expression have not shown to be sufficiently predictive. The recent availability of matched doxorubicin-response and diverse molecular profiles across breast cancer patients permits now analysis at a much larger scale. 16 machine learning algorithms and 8 molecular profiles are systematically evaluated on the same cohort of patients. Only 2 of the 128 resulting models are substantially predictive, showing that they can be easily missed by a standard-scale analysis. The best model is classification and regression tree (CART) nonlinearly combining 4 selected miRNA isoforms to predict doxorubicin response (median Matthew correlation coefficient (MCC) and area under the curve (AUC) of 0.56 and 0.80, respectively). By contrast, HER2 expression is significantly less predictive (median MCC and AUC of 0.14 and 0.57, respectively). As the predictive accuracy of this CART model increases with larger training sets, its update with future data should result in even better accuracy.© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.",
-,No,20220905,ml,36010273,Big Data in Laboratory Medicine-FAIR Quality for AI?,Diagnostics (Basel),"Laboratory medicine is a digital science. Every large hospital produces a wealth of data each day-from simple numerical results from, e.g., sodium measurements to highly complex output of ""-omics"" analyses, as well as quality control results and metadata. Processing, connecting, storing, and ordering extensive parts of these individual data requires Big Data techniques. Whereas novel technologies such as artificial intelligence and machine learning have exciting application for the augmentation of laboratory medicine, the Big Data concept remains fundamental for any sophisticated data analysis in large databases. To make laboratory medicine data optimally usable for clinical and research purposes, they need to be FAIR: findable, accessible, interoperable, and reusable. This can be achieved, for example, by automated recording, connection of devices, efficient ETL (Extract, Transform, Load) processes, careful data governance, and modern data security solutions. Enriched with clinical data, laboratory medicine data allow a gain in pathophysiological insights, can improve patient care, or can be used to develop reference intervals for diagnostic purposes. Nevertheless, Big Data in laboratory medicine do not come without challenges: the growing number of analyses and data derived from them is a demanding task to be taken care of. Laboratory medicine experts are and will be needed to drive this development, take an active role in the ongoing digitalization, and provide guidance for their clinical colleagues engaging with the laboratory data in research.",
-,No,20220905,nanopore,36030244,Epigenetic tumor heterogeneity in the era of single-cell profiling with nanopore sequencing.,Clin Epigenetics,"Nanopore sequencing has brought the technology to the next generation in the science of sequencing. This is achieved through research advancing on: pore efficiency, creating mechanisms to control DNA translocation, enhancing signal-to-noise ratio, and expanding to long-read ranges. Heterogeneity regarding epigenetics would be broad as mutations in the epigenome are sensitive to cause new challenges in cancer research. Epigenetic enzymes which catalyze DNA methylation and histone modification are dysregulated in cancer cells and cause numerous heterogeneous clones to evolve. Detection of this heterogeneity in these clones plays an indispensable role in the treatment of various cancer types. With single-cell profiling, the nanopore sequencing technology could provide a simple sequence at long reads and is expected to be used soon at the bedside or doctor's office. Here, we review the advancements of nanopore sequencing and its use in the detection of epigenetic heterogeneity in cancer.© 2022. The Author(s).",
-,No,20220905,organoids,35999641,DNA methylation analysis of normal colon organoids from familial adenomatous polyposis patients reveals novel insight into colon cancer development.,Clin Epigenetics,"Familial adenomatous polyposis (FAP) is an inherited colorectal cancer (CRC) syndrome resulting from germ line mutations in the adenomatous polyposis coli (APC) gene. While FAP accounts for less than 1% of all CRC cases, loss of APC expression is seen in > 80% of non-hereditary CRCs. To better understand molecular mechanisms underlying APC-driven CRC, we performed an epigenome-wide analysis of colon organoids derived from normal-appearing colons of FAP patients versus healthy subjects to identify differentially methylated regions (DMRs) that may precede the onset of CRC.We identified 358 DMRs when comparing colon organoids of FAP patients to those of healthy subjects (FDR < 0.05, |mean beta difference| = 5%). Of these, nearly 50% of DMRs were also differentially methylated in at least one of three CRC tumor and normal adjacent tissue (NAT) cohorts (TCGA-COAD, GSE193535 and ColoCare). Moreover, 27 of the DMRs mapped to CRC genome-wide association study (GWAS) loci. We provide evidence suggesting that some of these DMRs led to significant differences in gene expression of adjacent genes using quantitative PCR. For example, we identified significantly greater expression of five genes: Kazal-type serine peptidase inhibitor domain 1 (KAZALD1, P = 0.032), F-Box and leucine-rich repeat protein 8 (FBXL8, P = 0.036), TRIM31 antisense RNA 1 (TRIM31-AS1, P = 0.036), Fas apoptotic inhibitory molecule 2 (FAIM2, P = 0.049) and (Collagen beta (1-0)galactosyltransferase 2 (COLGALT2, P = 0.049). Importantly, both FBXL8 and TRIM31-AS1 were also significantly differentially expressed in TCGA-COAD tumor versus matched NAT, supporting a role for these genes in CRC tumor development.We performed the first DNA methylome-wide analysis of normal colon organoids derived from FAP patients compared to those of healthy subjects. Our results reveal that normal colon organoids from FAP patients exhibit extensive epigenetic differences compared to those of healthy subjects that appear similar to those exhibited in CRC tumor. Our analyses therefore identify DMRs and candidate target genes that are potentially important in CRC tumor development in FAP, with potential implications for non-hereditary CRC.© 2022. The Author(s).",
-,No,20220905,mqtl,35969790,Deep learning predicts DNA methylation regulatory variants in the human brain and elucidates the genetics of psychiatric disorders.,Proc Natl Acad Sci U S A,"There is growing evidence for the role of DNA methylation (DNAm) quantitative trait loci (mQTLs) in the genetics of complex traits, including psychiatric disorders. However, due to extensive linkage disequilibrium (LD) of the genome, it is challenging to identify causal genetic variations that drive DNAm levels by population-based genetic association studies. This limits the utility of mQTLs for fine-mapping risk loci underlying psychiatric disorders identified by genome-wide association studies (GWAS). Here we present INTERACT, a deep learning model that integrates convolutional neural networks with transformer, to predict effects of genetic variations on DNAm levels at CpG sites in the human brain. We show that INTERACT-derived DNAm regulatory variants are not confounded by LD, are concentrated in regulatory genomic regions in the human brain, and are convergent with mQTL evidence from genetic association analysis. We further demonstrate that predicted DNAm regulatory variants are enriched for heritability of brain-related traits and improve polygenic risk prediction for schizophrenia across diverse ancestry samples. Finally, we applied predicted DNAm regulatory variants for fine-mapping schizophrenia GWAS risk loci to identify potential novel risk genes. Our study shows the power of a deep learning approach to identify functional regulatory variants that may elucidate the genetic basis of complex traits.",
-,No,20220905,prediction,36008412,Methylation risk scores are associated with a collection of phenotypes within electronic health record systems.,NPJ Genom Med,"Inference of clinical phenotypes is a fundamental task in precision medicine, and has therefore been heavily investigated in recent years in the context of electronic health records (EHR) using a large arsenal of machine learning techniques, as well as in the context of genetics using polygenic risk scores (PRS). In this work, we considered the epigenetic analog of PRS, methylation risk scores (MRS), a linear combination of methylation states. We measured methylation across a large cohort (n = 831) of diverse samples in the UCLA Health biobank, for which both genetic and complete EHR data are available. We constructed MRS for 607 phenotypes spanning diagnoses, clinical lab tests, and medication prescriptions. When added to a baseline set of predictive features, MRS significantly improved the imputation of 139 outcomes, whereas the PRS improved only 22 (median improvement for methylation 10.74%, 141.52%, and 15.46% in medications, labs, and diagnosis codes, respectively, whereas genotypes only improved the labs at a median increase of 18.42%). We added significant MRS to state-of-the-art EHR imputation methods that leverage the entire set of medical records, and found that including MRS as a medical feature in the algorithm significantly improves EHR imputation in 37% of lab tests examined (median R2increase 47.6%). Finally, we replicated several MRS in multiple external studies of methylation (minimum p-value of 2.72 × 10-7) and replicated 22 of 30 tested MRS internally in two separate cohorts of different ethnicity. Our publicly available results and weights show promise for methylation risk scores as clinical and scientific tools.© 2022. The Author(s).",
-,No,20220905,prediction,36013215,The False Dawn of Polygenic Risk Scores for Human Disease Prediction.,J Pers Med,"Polygenic risk scores (PRSs) are being constructed for many diseases and are presented today as a promising avenue in the field of human genetics. These scores aim at predicting the risk of developing a disease by leveraging the many genome-wide association studies (GWAS) conducted during the two last decades. Important investments are being made to improve score estimates by increasing GWAS sample sizes, by developing more sophisticated methods, and by proposing different corrections for potential biases. PRSs have entered the market with direct-to-consumer companies proposing to compute them from saliva samples and even recently to help parents select the healthiest embryos. In this paper, we recall how PRSs arose and question the credit they are given by revisiting underlying assumptions in light of the history of human genetics and by comparing them with estimated breeding values (EBVs) used for selection in livestock.",
-,No,20220905,prediction,35858592,Genetic and environmental variation impact transferability of polygenic risk scores.,Cell Rep Med,"Even when polygenic risk scores (PRSs) are trained in African ancestral populations, Kamiza and colleagues showed that genetic and environmental variation within sub-Saharan African populations impacts prediction performance, highlighting the challenges of clinical implementation of PRSs for risk assessment.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.",
-,No,20220905,prediction,36034882,Redefining Age-Based Screening and Diagnostic Guidelines: An Opportunity for Biological Aging Clocks in Clinical Medicine?,Lancet Healthy Longev,NA,
-,No,20220905,prediction,35966405,Interpreting Neural Networks for Biological Sequences by Learning Stochastic Masks.,Nat Mach Intell,"Sequence-based neural networks can learn to make accurate predictions from large biological datasets, but model interpretation remains challenging. Many existing feature attribution methods are optimized for continuous rather than discrete input patterns and assess individual feature importance in isolation, making them ill-suited for interpreting non-linear interactions in molecular sequences. Building on work in computer vision and natural language processing, we developed an approach based on deep learning - Scrambler networks - wherein the most salient sequence positions are identified with learned input masks. Scramblers learn to predict Position-Specific Scoring Matrices (PSSMs) where unimportant nucleotides or residues are scrambled by raising their entropy. We apply Scramblers to interpret the effects of genetic variants, uncover non-linear interactions between cis-regulatory elements, explain binding specificity for protein-protein interactions, and identify structural determinants ofde novodesigned proteins. We show that Scramblers enable efficient attribution across large datasets and result in high-quality explanations, often outperforming state-of-the-art methods.",
-,No,20220905,prediction,35945544,A benchmark study of deep learning-based multi-omics data fusion methods for cancer.,Genome Biol,"A fused method using a combination of multi-omics data enables a comprehensive study of complex biological processes and highlights the interrelationship of relevant biomolecules and their functions. Driven by high-throughput sequencing technologies, several promising deep learning methods have been proposed for fusing multi-omics data generated from a large number of samples.In this study, 16 representative deep learning methods are comprehensively evaluated on simulated, single-cell, and cancer multi-omics datasets. For each of the datasets, two tasks are designed: classification and clustering. The classification performance is evaluated by using three benchmarking metrics including accuracy, F1 macro, and F1 weighted. Meanwhile, the clustering performance is evaluated by using four benchmarking metrics including the Jaccard index (JI), C-index, silhouette score, and Davies Bouldin score. For the cancer multi-omics datasets, the methods' strength in capturing the association of multi-omics dimensionality reduction results with survival and clinical annotations is further evaluated. The benchmarking results indicate that moGAT achieves the best classification performance. Meanwhile, efmmdVAE, efVAE, and lfmmdVAE show the most promising performance across all complementary contexts in clustering tasks.Our benchmarking results not only provide a reference for biomedical researchers to choose appropriate deep learning-based multi-omics data fusion methods, but also suggest the future directions for the development of more effective multi-omics data fusion methods. The deep learning frameworks are available at https://github.com/zhenglinyi/DL-mo .© 2022. The Author(s).",
-,No,20220905,proteome,35839778,Pan-cancer proteomic map of 949 human cell lines.,Cancer Cell,"The proteome provides unique insights into disease biology beyond the genome and transcriptome. A lack of large proteomic datasets has restricted the identification of new cancer biomarkers. Here, proteomes of 949 cancer cell lines across 28 tissue types are analyzed by mass spectrometry. Deploying a workflow to quantify 8,498 proteins, these data capture evidence of cell-type and post-transcriptional modifications. Integrating multi-omics, drug response, and CRISPR-Cas9 gene essentiality screens with a deep learning-based pipeline reveals thousands of protein biomarkers of cancer vulnerabilities that are not significant at the transcript level. The power of the proteome to predict drug response is very similar to that of the transcriptome. Further, random downsampling to only 1,500 proteins has limited impact on predictive power, consistent with protein networks being highly connected and co-regulated. This pan-cancer proteomic map (ProCan-DepMapSanger) is a comprehensive resource available at https://cellmodelpassports.sanger.ac.uk.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.",
-,No,20220905,transposons,36008480,Mammalian genome innovation through transposon domestication.,Nat Cell Biol,"Since the discovery of transposons, their sheer abundance in host genomes has puzzled many. While historically viewed as largely harmless 'parasitic' DNAs during evolution, transposons are not a mere record of ancient genome invasion. Instead, nearly every element of transposon biology has been integrated into host biology. Here we review how host genome sequences introduced by transposon activities provide raw material for genome innovation and document the distinct evolutionary path of each species.© 2022. Springer Nature Limited.",
-,No,20220905,validation,35959851,Fine-mapping and replication of EWAS loci harboring putative epigenetic alterations associated with AD neuropathology in a large collection of human brain tissue samples.,Alzheimers Dement,"Our previous epigenome-wide association study (EWAS) of Alzheimer's disease (AD) in human brain identified 71 CpGs associated with AD pathology. However, due to low coverage of the Illumina platform, many important CpGs might have been missed.In a large collection of human brain tissue samples (N = 864), we fine-mapped previous EWAS loci by targeted bisulfite sequencing and examined their associations with AD neuropathology. DNA methylation was also linked to gene expression of the same brain cortex.Our targeted sequencing captured 130 CpGs (�1.2 kb), 93 of which are novel. Of the 130 CpGs, 57 sites (only 17 included in previous EWAS) and 12 gene regions (e.g., ANK1, BIN1, RHBDF2, SPG7, PODXL) were significantly associated with amyloid load. DNA methylation in some regions was associated with expression of nearby genes.Targeted methylation sequencing can validate previous EWAS loci and discover novel CpGs associated with AD pathology.© 2022 the Alzheimer's Association.",
-,No,20221003,dnam age,36064845,A new cognitive clock matching phenotypic and epigenetic ages.,Transl Psychiatry,"Cognitive abilities decline with age, constituting a major manifestation of aging. The quantitative biomarkers of this process, as well as the correspondence to different biological clocks, remain largely an open problem. In this paper we employ the following cognitive tests: 1. differentiation of shades (campimetry); 2. evaluation of the arithmetic correctness and 3. detection of reversed letters and identify the most significant age-related cognitive indices. Based on their subsets we construct a machine learning-based Cognitive Clock that predicts chronological age with a mean absolute error of 8.62 years. Remarkably, epigenetic and phenotypic ages are predicted by Cognitive Clock with an even better accuracy. We also demonstrate the presence of correlations between cognitive, phenotypic and epigenetic age accelerations that suggests a deep connection between cognitive performance and aging status of an individual.© 2022. The Author(s).",
-,No,20221003,epigenetics,36064783,Two-layer design protects genes from mutations in their enhancers,Nature,,
-,No,20221003,epigenetics,35951677,Nested epistasis enhancer networks for robust genome regulation,Science,"Mammalian genomes have multiple enhancers spanning an ultralong distance (>megabases) to modulate important genes, but it is unclear how these enhancers coordinate to achieve this task. We combine multiplexed CRISPRi screening with machine learning to define quantitative enhancer-enhancer interactions. We find that the ultralong distance enhancer network has a nested multilayer architecture that confers functional robustness of gene expression. Experimental characterization reveals that enhancer epistasis is maintained by three-dimensional chromosomal interactions and BRD4 condensation. Machine learning prediction of synergistic enhancers provides an effective strategy to identify noncoding variant pairs associated with pathogenic genes in diseases beyond genome-wide association studies analysis. Our work unveils nested epistasis enhancer networks, which can better explain enhancer functions within cells and in diseases.",
-,Yes,20221003,ewas,36170668,Longitudinal Association of DNA Methylation with Type 2 Diabetes and Glycemic Traits: A 5-year Cross-Lagged Twin Study.,Diabetes,"Previous cross-sectional Epigenome-Wide Association Studies (EWASs) in adults have reported hundreds of 5'-cytosine-phosphate-guanine-3' (CpG) sites associated with type 2 diabetes mellitus (T2DM) and glycemic traits. However, the results from EWASs have been inconsistent, and longitudinal observations of these associations are scarce. Twin studies provide a valuable tool for epigenetic studies, as they are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and EMBASE for EWASs, and 214, 33, and 117 candidate CpG sites were selected for T2DM, HbA1c and fasting blood glucose (FBG). Based on 1,070 twins from the Chinese National Twin Registry, 67, 17 and 16 CpG sites from previous studies were validated for T2DM, HbA1c and FBG. Longitudinal review and blood sampling for phenotypic information and DNAm were conducted twice in 2013 and 2018 on 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. 11 significant paths from T2DM to subsequent DNAm and 15 paths from DNAm to subsequent T2DM were detected, suggesting both directions of associations. For glycemic traits, we detected 17 cross-lagged associations from baseline glycemic traits to subsequent DNAm, and none was from the other cross-lagged direction, indicating CpG sites may be the consequences, not the causes, of glycemic traits. Finally, a longitudinal mediation analysis was performed, and the potential role of DNAm of cg19693031, cg00574958 and cg04816311 in mediating the effect of glycemic traits on T2DM was detected.© 2022 by the American Diabetes Association.",
-,Yes,20221003,ewas,36148884,Prenatal lead (Pb) exposure is associated with differential placental DNA methylation and hydroxymethylation in a human population.,Epigenetics,"Prenatal lead (Pb) exposure is associated with adverse developmental outcomes and to epigenetic alterations such as DNA methylation and hydroxymethylation in animal models and in newborn blood. Given the importance of the placenta in foetal development, we sought to examine how prenatal Pb exposure was associated with differential placental DNA methylation and hydroxymethylation and to identify affected biological pathways linked to developmental outcomes. Maternal (n = 167) and infant (n = 172) toenail and placenta (n = 115) samples for prenatal Pb exposure were obtained from participants in a US birth cohort, and methylation and hydroxymethylation data were quantified using the Illumina Infinium MethylationEPIC BeadChip. An epigenome-wide association study was applied to identify differential methylation and hydroxymethylation associated with Pb exposure. Biological functions of the Pb-associated genes were determined by overrepresentation analysis through ConsensusPathDB. Prenatal Pb quantified from maternal toenail, infant toenail, and placenta was associated with 480, 27, and 2 differentially methylated sites (q < 0.05), respectively, with both increases and decreases associated with exposure. Alternatively, we identified 2, 1, and 14 differentially hydroxymethylated site(s) associated with maternal toenail, infant toenail, and placental Pb, respectively, with most showing increases in hydroxymethylation with exposure. Significantly overrepresented pathways amongst genes associated with differential methylation and hydroxymethylation (q < 0.10) included mechanisms pertaining to nervous system and organ development, calcium transport and regulation, and signalling activities. Our results suggest that both methylation and hydroxymethylation in the placenta can be variable based on Pb exposure and that the pathways impacted could affect placental function.",
-,Yes,20221003,ewas,36142605,Identification of <i>NHLRC1</i> as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS).,Int J Mol Sci,"Changes in DNA methylation identified by epigenome-wide association studies (EWAS) have been recently linked to increased lung cancer risk. However, the cellular effects of these differentially methylated positions (DMPs) are often unclear. Therefore, we investigated top differentially methylated positions identified from an EWAS study. This included a putative regulatory region ofNHLRC1. Hypomethylation of this gene was recently linked with decreased survival rates in lung cancer patients. HumanMethylation450 BeadChip array (450K) analysis was performed on 66 lung cancer case-control pairs from the European Prospective Investigation into Cancer and Nutrition Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs identified in these pre-diagnostic blood samples were then investigated for differential DNA methylation in lung tumor versus adjacent normal lung tissue from The Cancer Genome Atlas (TCGA) and replicated in two independent lung tumor versus adjacent normal tissue replication sets with MassARRAY. The EPIC HD top hypermethylated DMP cg06646708 was found to be a hypomethylated region in multiple data sets of lung tumor versus adjacent normal tissue. Hypomethylation within this region caused increased mRNA transcription of the closest geneNHLRC1in lung tumors. In functional assays, we demonstrate attenuated proliferation, viability, migration, and invasion uponNHLRC1knock-down in lung cancer cells. Furthermore, diminished AKT phosphorylation at serine 473 causing expression of pro-apoptotic AKT-repressed genes was detected in these knock-down experiments. In conclusion, this study demonstrates the powerful potential for discovery of novel functional mechanisms in oncogenesis based on EWAS DNA methylation data.NHLRC1holds promise as a new prognostic biomarker for lung cancer survival and prognosis, as well as a target for novel treatment strategies in lung cancer patients.",
-,Yes,20221003,ewas,36109771,Distinct sex-specific DNA methylation differences in Alzheimer's disease.,Alzheimers Res Ther,"Sex is increasingly recognized as a significant factor contributing to the biological and clinical heterogeneity in AD. There is also growing evidence for the prominent role of DNA methylation (DNAm) in Alzheimer's disease (AD).We studied sex-specific DNA methylation differences in the blood samples of AD subjects compared to cognitively normal subjects, by performing sex-specific meta-analyses of two large blood-based epigenome-wide association studies (ADNI and AIBL), which included DNA methylation data for a total of 1284 whole blood samples (632 females and 652 males). Within each dataset, we used two complementary analytical strategies, a sex-stratified analysis that examined methylation to AD associations in male and female samples separately, and a methylation-by-sex interaction analysis that compared the magnitude of these associations between different sexes. After adjusting for age, estimated immune cell type proportions, batch effects, and correcting for inflation, the inverse-variance fixed-effects meta-analysis model was used to identify the most consistent DNAm differences across datasets. In addition, we also evaluated the performance of the sex-specific methylation-based risk prediction models for AD diagnosis using an independent external dataset.In the sex-stratified analysis, we identified 2 CpGs, mapped to the PRRC2A and RPS8 genes, significantly associated with AD in females at a 5% false discovery rate, and an additional 25 significant CpGs (21 in females, 4 in males) at P-value < 1×10-5. In methylation-by-sex interaction analysis, we identified 5 significant CpGs at P-value < 10-5. Out-of-sample validations using the AddNeuroMed dataset showed in females, the best logistic prediction model included age, estimated immune cell-type proportions, and methylation risk scores (MRS) computed from 9 of the 23 CpGs identified in AD vs. CN analysis that are also available in AddNeuroMed dataset (AUC = 0.74, 95% CI: 0.65-0.83). In males, the best logistic prediction model included only age and MRS computed from 2 of the 5 CpGs identified in methylation-by-sex interaction analysis that are also available in the AddNeuroMed dataset (AUC = 0.70, 95% CI: 0.56-0.82).Overall, our results show that the DNA methylation differences in AD are largely distinct between males and females. Our best-performing sex-specific methylation-based prediction model in females performed better than that for males and additionally included estimated cell-type proportions. The significant discriminatory classification of AD samples with our methylation-based prediction models demonstrates that sex-specific DNA methylation could be a predictive biomarker for AD. As sex is a strong factor underlying phenotypic variability in AD, the results of our study are particularly relevant for a better understanding of the epigenetic architecture that underlie AD and for promoting precision medicine in AD.© 2022. The Author(s).",
-,Yes,20221003,ewas,36091392,The shared mother-child epigenetic signature of neglect is related to maternal adverse events.,Front Physiol,"Studies of DNA methylation have revealed the biological mechanisms by which life adversity confers risk for later physical and mental health problems. What remains unknown is the ""biologically embedding"" of maternal adverse experiences resulting in maladaptive parenting and whether these epigenetic effects are transmitted to the next generation. This study focuses on neglectful mothering indexed by a severe disregard for the basic and psychological needs of the child. Using the Illumina Human Methylation EPIC BeadChip in saliva samples, we identified genes with differentially methylated regions (DMRs) in those mothers with (n= 51), versus those without (n= 87), neglectful behavior that present similar DMRs patterns in their children being neglected versus non-neglected (n= 40 vs. 75). Mothers reported the emotional intensity of adverse life events. After covariate adjustment and multiple testing corrections, we identified 69 DMRs in the mother epigenome and 42 DMRs in the child epigenome that were simultaneously above the α = 0.01 threshold. The common set of nine DMRs contained genes related to childhood adversity, neonatal and infant diabetes, child neurobehavioral development and other health problems such as obesity, hypertension, cancer, posttraumatic stress, and the Alzheimer's disease; four of the genes were associated with maternal life adversity. Identifying a shared epigenetic signature of neglect linked to maternal life adversity is an essential step in breaking the intergenerational transmission of one of the most common forms of childhood maltreatment.Copyright © 2022 León, Herrero Roldán, Rodrigo, López Rodríguez, Fisher, Mitchell and Lage-Castellanos.",
-,Yes,20221003,ewas,36127421,DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival.,Nat Commun,"Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.© 2022. The Author(s).",
-,No,20221003,ml,36064595,Big data in basic and translational cancer research.,Nat Rev Cancer,"Historically, the primary focus of cancer research has been molecular and clinical studies of a few essential pathways and genes. Recent years have seen the rapid accumulation of large-scale cancer omics data catalysed by breakthroughs in high-throughput technologies. This fast data growth has given rise to an evolving concept of 'big data' in cancer, whose analysis demands large computational resources and can potentially bring novel insights into essential questions. Indeed, the combination of big data, bioinformatics and artificial intelligence has led to notable advances in our basic understanding of cancer biology and to translational advancements. Further advances will require a concerted effort among data scientists, clinicians, biologists and policymakers. Here, we review the current state of the art and future challenges for harnessing big data to advance cancer research and treatment.© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
-,No,20221003,ml,36155971,A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis.,PLoS Comput Biol,"Previous studies for cancer biomarker discovery based on pre-diagnostic blood DNA methylation (DNAm) profiles, either ignore the explicit modeling of the Time To Diagnosis (TTD), or provide inconsistent results. This lack of consistency is likely due to the limitations of standard EWAS approaches, that model the effect of DNAm at CpG sites on TTD independently. In this work, we aim to identify blood DNAm profiles associated with TTD, with the aim to improve the reliability of the results, as well as their biological meaningfulness. We argue that a global approach to estimate CpG sites effect profile should capture the complex (potentially non-linear) relationships interplaying between sites. To prove our concept, we develop a new Deep Learning-based approach assessing the relevance of individual CpG Islands (i.e., assigning a weight to each site) in determining TTD while modeling their combined effect in a survival analysis scenario. The algorithm combines a tailored sampling procedure with DNAm sites agglomeration, deep non-linear survival modeling and SHapley Additive exPlanations (SHAP) values estimation to aid robustness of the derived effects profile. The proposed approach deals with the common complexities arising from epidemiological studies, such as small sample size, noise, and low signal-to-noise ratio of blood-derived DNAm. We apply our approach to a prospective case-control study on breast cancer nested in the EPIC Italy cohort and we perform weighted gene-set enrichment analyses to demonstrate the biological meaningfulness of the obtained results. We compared the results of Deep Survival EWAS with those of a traditional EWAS approach, demonstrating that our method performs better than the standard approach in identifying biologically relevant pathways.",
-,No,20221003,prediction,36153611,Liquid biopsies based on DNA methylation as biomarkers for the detection and prognosis of lung cancer.,Clin Epigenetics,"Lung cancer (LC) is the main cause of cancer-related mortality. Most LC patients are diagnosed in an advanced stage when the symptoms are obvious, and the prognosis is quite poor. Although low-dose computed tomography (LDCT) is a routine clinical examination for early detection of LC, the false-positive rate is over 90%. As one of the intensely studied epigenetic modifications, DNA methylation plays a key role in various diseases, including cancer and other diseases. Hypermethylation in tumor suppressor genes or hypomethylation in oncogenes is an important event in tumorigenesis. Remarkably, DNA methylation usually occurs in the very early stage of malignant tumors. Thus, DNA methylation analysis may provide some useful information about the early detection of LC. In recent years, liquid biopsy has developed rapidly. Liquid biopsy can detect and monitor both primary and metastatic malignant tumors and can reflect tumor heterogeneity. Moreover, it is a minimally invasive procedure, and it causes less pain for patients. This review summarized various liquid biopsies based on DNA methylation for LC. At first, we briefly discussed some emerging technologies for DNA methylation analysis. Subsequently, we outlined cell-free DNA (cfDNA), sputum, bronchoalveolar lavage fluid, bronchial aspirates, and bronchial washings DNA methylation-based liquid biopsy for the early detection of LC. Finally, the prognostic value of DNA methylation in cfDNA and sputum and the diagnostic value of other DNA methylation-based liquid biopsies for LC were also analyzed.© 2022. The Author(s).",
-,No,20221003,prediction,36068634,Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies.,Breast Cancer Res,"DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer.Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage.None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics.We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.© 2022. The Author(s).",
-,No,20221003,prediction,36138228,Ten challenges for clinical translation in psychiatric genetics.,Nat Genet,"Genome-wide association studies have identified hundreds of robust genetic associations underlying psychiatric disorders and provided important biological insights into disease onset and progression. There is optimism that genetic findings will pave the way to precision psychiatry by facilitating the development of more effective treatments and the identification of groups of patients that these treatments should be targeted toward. However, there are several challenges that must be addressed before genetic findings can be translated into the clinic. In this Perspective, we highlight ten challenges for the field of psychiatric genetics, focused on the robust and generalizable detection of genetic risk factors, improved definition and assessment of psychopathology and achieving better clinical indicators. We discuss recent advancements in the field that will improve the explanatory and predictive power of genetic data and ultimately contribute to improving the management and treatment of patients with a psychiatric disorder.© 2022. Springer Nature America, Inc.",
-,No,20221003,single-cell rna-seq,36050550,Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data.,Nat Genet,"Single-cell RNA sequencing (scRNA-seq) provides unique insights into the pathology and cellular origin of disease. We introduce single-cell disease relevance score (scDRS), an approach that links scRNA-seq with polygenic disease risk at single-cell resolution, independent of annotated cell types. scDRS identifies cells exhibiting excess expression across disease-associated genes implicated by genome-wide association studies (GWASs). We applied scDRS to 74 diseases/traits and 1.3 million single-cell gene-expression profiles across 31 tissues/organs. Cell-type-level results broadly recapitulated known cell-type-disease associations. Individual-cell-level results identified subpopulations of disease-associated cells not captured by existing cell-type labels, including T cell subpopulations associated with inflammatory bowel disease, partially characterized by their effector-like states; neuron subpopulations associated with schizophrenia, partially characterized by their spatial locations; and hepatocyte subpopulations associated with triglyceride levels, partially characterized by their higher ploidy levels. Genes whose expression was correlated with the scDRS score across cells (reflecting coexpression with GWAS disease-associated genes) were strongly enriched for gold-standard drug target and Mendelian disease genes.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20221003,twas,36073148,The placenta epigenome-brain axis: placental epigenomic and transcriptomic responses that preprogram cognitive impairment.,Epigenomics,"Aim:The placenta-brain axis reflects a developmental linkage where disrupted placental function is associated with impaired neurodevelopment later in life. Placental gene expression and the expression of epigenetic modifiers such as miRNAs may be tied to these impairments and are understudied.Materials & methods:The expression levels of mRNAs (n = 37,268) and their targeting miRNAs (n = 2083) were assessed within placentas collected from the ELGAN study cohort (n = 386). The ELGAN adolescents were assessed for neurocognitive function at age 10 and the association with placental mRNA/miRNAs was determined.Results:Placental mRNAs related to inflammatory and apoptotic processes are under miRNA control and associated with cognitive impairment at age 10.Conclusion:Findings highlight key placenta epigenome-brain relationships that support the developmental origins of health and disease hypothesis.",
-,Yes,20221024,ewas,36246163,Stress Overload and DNA Methylation in African American Women in the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study.,Epigenet Insights,"Experiencing psychosocial stress is associated with poor health outcomes such as hypertension and obesity, which are risk factors for developing cardiovascular disease. African American women experience disproportionate risk for cardiovascular disease including exposure to high levels of psychosocial stress. We hypothesized that psychosocial stress, such as perceived stress overload, may influence epigenetic marks, specifically DNA methylation (DNAm), that contribute to increased risk for cardiovascular disease in African American women.We conducted an epigenome-wide study evaluating the relationship of psychosocial stress and DNAm among African American mothers from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN) cohort. Linear mixed effects models were used to explore the epigenome-wide associations with the Stress Overload Scale (SOS), which examines self-reported past-week stress, event load and personal vulnerability.In total, n = 228 participants were included in our analysis. After adjusting for known epigenetic confounders, we did not identify any DNAm sites associated with maternal report of stress measured by SOS after controlling for multiple comparisons. Several of the top differentially methylated CpG sites related to SOS score (P< 1 × 10-5), mapped to genes of unknown significance for hypertension or heart disease, namely,PXDNLandC22orf42.This study provides foundational knowledge for future studies examining epigenetic associations with stress and other psychosocial measures in African Americans, a key area for growth in epigenetics. Future studies including larger sample sizes and replication data are warranted.© The Author(s) 2022.",
-,Yes,20221024,ewas,36243740,Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans.,Clin Epigenetics,"Ethnic differences in non-communicable disease risk have been described between individuals of South Asian and European ethnicity that are only partially explained by genetics and other known risk factors. DNA methylation is one underexplored mechanism that may explain differences in disease risk. Currently, there is little knowledge of how DNA methylation varies between South Asian and European ethnicities. This study characterised differences in blood DNA methylation between individuals of self-reported European and South Asian ethnicity from two UK-based cohorts: Southall and Brent Revisited and Born in Bradford. DNA methylation differences between ethnicities were widespread throughout the genome (n = 16,433 CpG sites, 3.4% sites tested). Specifically, 76% of associations were attributable to ethnic differences in cell composition with fewer effects attributable to smoking and genetic variation. Ethnicity-associated CpG sites were enriched for EWAS Catalog phenotypes including metabolites. This work highlights the need to consider ethnic diversity in epigenetic research.© 2022. The Author(s).",
-,Yes,20221024,ewas,36243213,Mediation by DNA methylation on the association of BMI and serum uric acid in Chinese monozygotic twins.,Gene,"Obesity is an established risk factor for hyperuricemia, but the mechanisms are only partially understood. We examined whether BMI-related DNA methylation (DNAm) variation would mediate the association of BMI with serum uric acid (SUA). We first conducted an epigenome-wide association analysis (EWAS) in 64 monozygotic twin pairs to detect BMI-related DNAm variation and then evaluated the mediated effect of DNAm using mediation analysis. Ontology enrichments analysis was performed for CpGs using GREAT tool. The genes where the candidate CpG mediators mapped were validated using gene expression data. BMI was positively associated with log10transformed SUA level (β = 0.01, P < 0.001). The association between BMI and DNAm of 138 CpGs reached P < 1 × 10-4level. Twenty BMI-related differentially methylated regions within MAP2K2, POU4F2, AGAP2, MRGPRE, ADM5, and NKX1-1 were found. Of the 138 CpGs, 4 within VENTX (involved in cellular responses to stress pathway), SMOC2 (enable calcium ion binding), and FSCN2 (a member of fascin protein family) mediated the association between BMI and SUA, with a mediating effect of 0.002-μmol/L lower log10transformed SUA levels and a proportion of 18.89 %-24.92 % negative mediating effect. BMI × DNAm interactions on SUA were observed for 2 CpGs within VENTX. The gene expression level of VENTX was also negatively associated with SUA level. BMI-related DNAm variation may partially mediate the association of BMI with SUA.Copyright © 2022 Elsevier B.V. All rights reserved.",
-,No,20221024,methods,36242584,A systematic assessment of cell type deconvolution algorithms for DNA methylation data.,Brief Bioinform,"We performed systematic assessment of computational deconvolution methods that play an important role in the estimation of cell type proportions from bulk methylation data. The proposed framework methylDeConv (available as an R package) integrates several deconvolution methods for methylation profiles (Illumina HumanMethylation450 and MethylationEPIC arrays) and offers different cell-type-specific CpG selection to construct the extended reference library which incorporates the main immune cell subsets, epithelial cells and cell-free DNAs. We compared the performance of different deconvolution algorithms via simulations and benchmark datasets and further investigated the associations of the estimated cell type proportions to cancer therapy in breast cancer and subtypes in melanoma methylation case studies. Our results indicated that the deconvolution based on the extended reference library is critical to obtain accurate estimates of cell proportions in non-blood tissues.© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,Yes,20221024,ewas,36241462,"Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study.",Biol Psychiatry,"Negative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.To identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10-8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.Our findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.Copyright © 2022. Published by Elsevier Inc.",
-,No,20221024,methods,36239035,The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip.,Epigenetics,"DNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilizing precious or limited DNA sources. We used a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. We found that data are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; and that low DNA input is associated with a reduction in power to detect EWAS associations, requiring larger sample sizes. We conclude that DNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken.",
-,Yes,20221024,ewas,36217170,Fetal exposure to phthalates and bisphenols and DNA methylation at birth: the Generation R Study.,Clin Epigenetics,"Phthalates and bisphenols are non-persistent endocrine disrupting chemicals that are ubiquitously present in our environment and may have long-lasting health effects following fetal exposure. A potential mechanism underlying these exposure-outcome relationships is differential DNA methylation. Our objective was to examine the associations of maternal phthalate and bisphenol concentrations during pregnancy with DNA methylation in cord blood using a chemical mixtures approach.This study was embedded in a prospective birth cohort study in the Netherlands and included 306 participants. We measured urine phthalates and bisphenols concentrations in the first, second and third trimester. Cord blood DNA methylation in their children was processed using the Illumina Infinium HumanMethylation450 BeadChip using an epigenome-wide association approach. Using quantile g-computation, we examined the association of increasing all mixture components by one quartile with cord blood DNA methylation.We did not find evidence for statistically significant associations of a maternal mixture of phthalates and bisphenols during any of the trimesters of pregnancy with DNA methylation in cord blood (all p values > 4.01 * 10-8). However, we identified one suggestive association (p value < 1.0 * 10-6) of the first trimester maternal mixture of phthalates and bisphenols and three suggestive associations of the second trimester maternal mixture of phthalates and bisphenols with DNA methylation in cord blood.Although we did not identify genome-wide significant results, we identified some suggestive associations of exposure to a maternal mixture of phthalates and bisphenols in the first and second trimester with DNA methylation in cord blood that need further exploration in larger study samples.© 2022. The Author(s).",
-,Yes,20221024,ewas,36206092,"At age 9, the methylome of assisted reproductive technology children that underwent embryo culture in different media is not significantly different on a genome-wide scale.",Hum Reprod,"Can we detect DNA methylation differences between ART children that underwent embryo culture in different media?We identified no significant differences in site-specific or regional DNA methylation between the different culture medium groups.Embryo culture in G3 or K-SICM medium leads to differences in embryonic, neonatal and childhood outcomes, including growth and weight. The methylome may mediate this association as the period of in vitro culture of ART treatments coincides with epigenetic reprogramming.This study was conducted as a follow-up to a previous culture medium comparison study in which couples were pseudo-randomized to embryo culture in G3 or K-SICM medium. Of the resultant singletons, 120 (n = 65 G3, n = 55 K-SICM), were recruited at age 9.The ART children provided a saliva sample from which the methylome was analysed using the Infinium MethylationEPIC array. After quality and context filtering, 106 (n = 57 G3, n = 49 K-SICM) samples and 659 708 sites were retained for the analyses. Differential methylation analyses were conducted using mixed effects linear models corrected for age, sex, sample plate and cell composition. These were applied to all cytosine-guanine dinucleotide (CpG) sites, various genomic regions (genes, promoters, CpG Islands (CGIs)) and as a targeted analysis of imprinted genes and birth weight-associated CpG sites. Differential variance was assessed using the improved epigenetic variable outliers for risk prediction analysis (iEVORA) algorithm and methylation outliers were identified using a previously defined threshold (upper or lower quartile plus or minus three times the interquartile range, respectively).After correcting for multiple testing, we did not identify any significantly differentially methylated CpG sites, genes, promoters or CGIs between G3 and K-SICM children despite a lenient corrected P-value threshold of 0.1. Targeted analyses of (sites within) imprinted genes and birth weight-associated sites also did not identify any significant differences. The number of DNA methylation outliers per sample was comparable between the culture medium groups. iEVORA identified 101 differentially variable CpG sites of which 94 were more variable in the G3 group.Gene Expression Omnibus (GEO) GSE196432.To detect significant methylation differences with a magnitude of <10% between the groups many more participants would be necessary; however, the clinical relevance of such small differences is unclear.The results of this study are reassuring, suggesting that if there is an effect of the culture medium on DNA methylation (and methylation-mediated diseases risk), it does not differ between the two media investigated here. The findings concur with other methylome studies of ART neonates and children that underwent embryo culture in different media, which also found no significant methylome differences.Study funded by March of Dimes (6-FY13-153), EVA (Erfelijkheid Voortplanting & Aanleg) specialty programme (grant no. KP111513) of Maastricht University Medical Centre (MUMC+) and the Horizon 2020 innovation (ERIN) (grant no. EU952516) of the European Commission. The authors do not report any conflicts of interest relevant to this study.Dutch Trial register-NL4083.© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.",
-,Yes,20221024,ewas,36201768,Epigenome-wide analysis of DNA methylation and optimism in women and men.,Psychosom Med,"Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized DNAm would differ among older individuals who are more versus less optimistic.Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities (N = 3,816) and men (only white, N = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the inabldividual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the number of independent degrees of freedom approach: effective degrees of freedom correction using the number of principal components (PCs), explaining>95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathways analyses using the Ingenuity Pathway Analysis software.We found essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm~optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, neurodevelopmental and neurodegenerative disorders.Our findings provide new insights into possible mechanisms underlying optimism and health.Copyright © 2022 by the American Psychosomatic Society.",
-,Yes,20221024,ewas,36196007,Maternal Periconceptional Folic Acid Supplementation and DNA Methylation Patterns in Adolescent Offspring.,J Nutr,"Folate, including the folic acid form, is a key component of the one-carbon metabolic pathway used for DNA methylation. Changes in DNA methylation patterns during critical development periods are associated with disease outcomes and are associated with changes in nutritional status in pregnancy. The long-term impact of periconceptional folic acid supplementation on DNA methylation patterns is unknown.To determine the long-term impact of periconceptional folic acid supplementation on DNA methylation patterns, we examined the association of the recommended dosage (400 μg/d) and time period (periconceptional before pregnancy through first trimester) of folic acid supplementation with the DNA methylation patterns in the offspring at age 14-17 y compared with offspring with no supplementation.Two geographic sites in China from the 1993-1995 Community Intervention Program of folic acid supplementation were selected for the follow-up study. DNA methylation at 402,730 CpG sites was assessed using saliva samples from 89 mothers and 179 adolescents (89 male). The mean age at saliva collection was 40 y among mothers (range: 35-54 y) and 15 y among adolescents (range: 14-17 y). Epigenome-wide analyses were conducted to assess the interactions of periconceptional folic acid exposure, the 5,10-methylenetetrahydrofolate reductase (MTHFR)-C677T genotype, and epigenome-wide DNA methylation controlling for offspring sex, geographic region, and background cell composition in the saliva.In the primary outcome, no significant differences were observed in epigenome-wide methylation patterns between adolescents exposed and those non-exposed to maternal periconceptional folic acid supplementation after adjustment for potential confounders [false discovery rate (FDR) P values < 0.05]. The MTHFR-C677T genotype did not modify this lack of association (FDR P values < 0.05).Overall, there were no differences in DNA methylation between adolescents who were exposed during the critical developmental window and those not exposed to the recommended periconceptional/first-trimester dosage of folic acid.Published by Oxford University Press on behalf of the American Society for Nutrition 2022.",
-,Yes,20221024,ewas,36180927,Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study.,Clin Epigenetics,"The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke.We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10-06) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH.The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 × 10-08) and in MERTK (p value = 1.56 × 10-07). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 × 10-06and p value = 1.3 × 10-02, respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = - 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = - 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells.DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation.© 2022. The Author(s).",
-,Yes,20221024,ewas,36179964,"Genome-wide DNA methylation analysis of middle-aged and elderly monozygotic twins with age-related hearing loss in Qingdao, China.",Gene,"To explore the differences in DNA methylation associated with age-related hearing loss in a study of 57 twin pairs from China.Monozygotic twins were identified through the Qingdao Twin Registration system. The median age of participants was > 50 years. Their hearing thresholds were measured using a multilevel pure-tone audiometry assessment. The pure-tone audiometry was calculated at low frequencies (0.5, 1.0, and 2.0 kHz), speech frequencies (0.5, 1.0, 2.0, and 4.0 kHz), and high frequencies (4.0 and 8 kHz). The CpG sites were tested using a linear mixed-effects model, and the function of the cis-regulatory regions and ontological enrichments were predicted using the online Genomic Regions Enrichment of Annotations Tool. The differentially methylated regions were identified using a comb-p python library approach.In each of the PTA categories (low-, speech-, high-frequency), age-related hearing loss was detected in 25.9%, 19.3%, and 52.8% of participants. In the low-, speech- and high-frequency categories we identified 18, 42, and 12 individual CpG sites and 6, 11, and 6 differentially methylated regions. The CpG site located near DUSP4 had the strongest association with low- and speech-frequency, while the strongest association with high-frequency was near C21orf58. We identified associations of ALG10 with high-frequency hearing, C3 and LCK with low- and speech-frequency hearing, and GBX2 with low-frequency hearing. Top pathways that may be related to hearing, such as the Notch signaling pathway, were also identified.Our study is the first of its kind to identify these genes and their associated with DNA methylation may play essential roles in the hearing process. The results of our epigenome-wide association study on twins clarify the complex mechanisms underlying age-related hearing loss.Copyright © 2022 Elsevier B.V. All rights reserved.",
-,No,20221024,epigenetics,36179666,Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes.,Cell,"Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.",
-,No,20221024,methods,36179079,mHapTk: A comprehensive toolkit for the analysis of DNA methylation haplotypes.,Bioinformatics,"Bisulfite sequencing (BS-seq) remains the gold standard technique to detect DNA methylation profiles at single-nucleotide resolution. The DNA methylation status of CpG sites on the same fragment represents a discrete methylation haplotype (mHap). The mHap-level metrics were demonstrated to be promising cancer biomarkers and explain more gene expression variation than average methylation. However, most existing tools focus on average methylation and neglect mHap patterns. Here, we present mhapTk, a comprehensive python toolkit for the analysis of DNA methylation haplotypes. It calculates eight mHap-level summary statistics in predefined regions or across individual CpG in a genome-wide manner. It identifies methylation haplotype blocks (MHBs), in which methylations of pairwise CpGs is tightly correlated. Furthermore, mHap patterns can be visualized with the built-in functions in mHapTk or external tools such as IGV and deepTools.https://jiantaoshi.github.io/mhaptk/index.html.Supplementary data are available at Bioinformatics online.© The Author(s) (2022). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,Yes,20221024,ewas,36178055,Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls.,Am J Clin Nutr,"Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relationship by food sources versus folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known.We evaluated the relationship between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study.Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n = 189) and controls (n = 205) in the California Childhood Leukemia Study (CCLS) from 1995-2008 was compared to periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term.Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n = 394). The top differentially methylated region at the promoter region of DUSP22 demonstrated DNA hypermethylation in ALL cases but not controls in response to total and food folate intake. We further identified eight interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and education level.We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.",
-,No,20221024,methods,36175791,Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics.,Nat Genet,"Genome-wide association studies provide a powerful means of identifying loci and genes contributing to disease, but in many cases, the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. In the present study, we introduce sc-linker, a framework for integrating single-cell RNA-sequencing, epigenomic SNP-to-gene maps and genome-wide association study summary statistics to infer the underlying cell types and processes by which genetic variants influence disease. The inferred disease enrichments recapitulated known biology and highlighted notable cell-disease relationships, including γ-aminobutyric acid-ergic neurons in major depressive disorder, a disease-dependent M-cell program in ulcerative colitis and a disease-specific complement cascade process in multiple sclerosis. In autoimmune disease, both healthy and disease-dependent immune cell-type programs were associated, whereas only disease-dependent epithelial cell programs were prominent, suggesting a role in disease response rather than initiation. Our framework provides a powerful approach for identifying the cell types and cellular processes by which genetic variants influence disease.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20221024,prediction,36175966,A blood DNA methylation biomarker for predicting short-term risk of cardiovascular events.,Clin Epigenetics,"Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposure to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predicts diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-the-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-the-art DNAm risk scores for cardiovascular diseases, the 'next-generation' epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2.Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent data sets from Europe and the USA. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant).We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of prediction models based on DNAm surrogates and discuss methodological aspects for further improvements. Finally, our results encourage testing this approach for other NCD diseases by training and developing DNAm surrogates for disease-specific risk factors and exposures.© 2022. The Author(s).",
-,No,20221024,methods,36265006,Deep mendelian randomization: Investigating the causal knowledge of genomic deep learning models,PLoS Comput Biol,"Multi-task deep learning (DL) models can accurately predict diverse genomic marks from sequence, but whether these models learn the causal relationships between genomic marks is unknown. Here, we describe Deep Mendelian Randomization (DeepMR), a method for estimating causal relationships between genomic marks learned by genomic DL models. By combining Mendelian randomization with in silico mutagenesis, DeepMR obtains local (locus specific) and global estimates of (an assumed) linear causal relationship between marks. In a simulation designed to test recovery of pairwise causal relations between transcription factors (TFs), DeepMR gives accurate and unbiased estimates of the 'true' global causal effect, but its coverage decays in the presence of sequence-dependent confounding. We then apply DeepMR to examine the global relationships learned by a state-of-the-art DL model, BPNet, between TFs involved in reprogramming. DeepMR's causal effect estimates validate previously hypothesized relationships between TFs and suggest new relationships for future investigation.",
-,No,20221114,dnam age,36346848,In utero exposure to the Great Depression is reflected in late-life epigenetic aging signatures.,Proc Natl Acad Sci U S A,"Research on maternal-fetal epigenetic programming argues that adverse exposures to the intrauterine environment can have long-term effects on adult morbidity and mortality. However, causal research on epigenetic programming in humans at a population level is rare and is often unable to separate intrauterine effects from conditions in the postnatal period that may continue to impact child development. In this study, we used a quasi-natural experiment that leverages state-year variation in economic shocks during the Great Depression to examine the causal effect of environmental exposures in early life on late-life accelerated epigenetic aging for 832 participants in the US Health and Retirement Study (HRS). HRS is the first population-representative study to collect epigenome-wide DNA methylation data that has the sample size and geographic variation necessary to exploit quasi-random variation in state environments, which expands possibilities for causal research in epigenetics. Our findings suggest that exposure to changing economic conditions in the 1930s had lasting impacts on next-generation epigenetic aging signatures that were developed to predict mortality risk (GrimAge) and physiological decline (DunedinPoAm). We show that these effects are localized to the in utero period specifically as opposed to the preconception, postnatal, childhood, or early adolescent periods. After evaluating endogenous shifts in mortality and fertility related to Depression-era birth cohorts, we conclude that these effects likely represent lower bound estimates of the true impacts of the economic shock on long-term epigenetic aging.",
-,No,20221114,dnam age,36304118,A set of common buccal CpGs that predict epigenetic age and associate with lifespan-regulating genes.,iScience,"Epigenetic aging clocks are computational models that use DNA methylation sites to predict age. Since cheek swabs are non-invasive and painless, collecting DNA from buccal tissue is highly desirable. Here, we review 11 existing clocks that have been applied to buccal tissue. Two of these were exclusively trained on adults and, while moderately accurate, have not been used to capture health-relevant differences in epigenetic age. Using 130 common CpGs utilized by two or more existing buccal clocks, we generate a proof-of-concept predictor in an adult methylomic dataset. In addition to accurately estimating age (r = 0.95 and mean absolute error = 3.88 years), this clock predicted that Down syndrome subjects were significantly older relative to controls. A literature and database review of CpG-associated genes identified numerous genes (e.g.,CLOCK,ELOVL2, andVGF) and molecules (e.g., alpha-linolenic acid, glycine, and spermidine) reported to influence lifespan and/or age-related disease in model organisms.© 2022 The Author(s).",
-,No,20221114,dnam age,36294002,Do Loneliness and Per Capita Income Combine to Increase the Pace of Biological Aging for Black Adults across Late Middle Age?,Int J Environ Res Public Health,"In a sample of 685 late middle-aged Black adults (M age at 2019 = 57.17 years), we examined the effects of loneliness and per capita income on accelerated aging using a newly developed DNA-methylation based index: the DunedinPACE. First, using linear, mixed effects regression in a growth curve framework, we found that change in DunedinPACE was dependent on age, with a linear model best fitting the data (b = 0.004,p&lt; 0.001), indicating that average pace of change increased among older participants. A quadratic effect was also tested, but was non-significant. Beyond the effect of age, both change in loneliness (b = 0.009,p&lt; 0.05) and change in per capita income (b = -0.016,p&lt; 0.001) were significantly associated with change in DunedinPACE across an 11-year period, accounting for significant between person variability observed in the unconditional model. Including non-self-report indices of smoking and alcohol use did not reduce the association of loneliness or per capita income with DunedinPACE. However, change in smoking was strongly associated with change in DunedinPACE such that those reducing their smoking aged less rapidly than those continuing to smoke. In addition, both loneliness and per capita income were associated with DunedinPACE after controlling for variation in cell-types.",
-,No,20221114,dnam age,36292773,Epigenetic and Proteomic Biomarkers of Elevated Alcohol Use Predict Epigenetic Aging and Cell-Type variation Better Than Self-Report.,Genes (Basel),"Excessive alcohol consumption (EAC) has a generally accepted effect on morbidity and mortality, outcomes thought to be reflected in measures of epigenetic aging (EA). As the association of self-reported EAC with EA has not been consistent with these expectations, underscoring the need for readily employable non-self-report tools for accurately assessing and monitoring the contribution of EAC to accelerated EA, newly developed alcohol consumption DNA methylation indices, such as the Alcohol T Score (ATS) and Methyl DetectR (MDR), may be helpful. To test that hypothesis, we used these new indices along with the carbohydrate deficient transferrin (CDT), concurrent as well as past self-reports of EAC, and well-established measures of cigarette smoking to examine the relationship of EAC to both accelerated EA and immune cell counts in a cohort of 437 young Black American adults. We found that MDR, CDT, and ATS were intercorrelated, even after controlling for gender and cotinine effects. Correlations between EA and self-reported EAC were low or non-significant, replicating prior research, whereas correlations with non-self-report indices were significant and more substantial. Comparing non-self-report indices showed that the ATS predicted more than four times as much variance in EA, CDT4 cells and B-cells as for both the MDR and CDT, and better predicted indices of accelerated EA. We conclude that each of the non-self-report indices have differing predictive capacities with respect to key alcohol-related health outcomes, and that the ATS may be particularly useful for clinicians seeking to understand and prevent accelerated EA. The results also underscore the likelihood of substantial underestimates of problematic use when self-report is used and a reduction in correlations with EA and variance in cell-types.",
-,No,20221114,dnam age,36289503,Marijuana use and DNA methylation-based biological age in young adults.,Clin Epigenetics,"Marijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana's effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation.A random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with available whole blood at examination years (Y) 15 and Y20 underwent epigenomic profiling. Four EAA estimates (intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration, PhenoAge acceleration, and GrimAge acceleration) were calculated from DNA methylation levels measured at Y15 and Y20. Ever use and cumulative marijuana-years were calculated from the baseline visit to Y15 and Y20, and recent marijuana use (both any and number of days of use in the last 30 days) were calculated at Y15 and Y20. Ever use of marijuana and each additional marijuana-year were associated with a 6-month (P < 0.001) and a 2.5-month (P < 0.001) higher average in GrimAge acceleration (GAA) using generalized estimating equations, respectively. Recent use and each additional day of recent use were associated with a 20-month (P < 0.001) and a 1-month (P < 0.001) higher GAA, respectively. A statistical interaction between marijuana-years and alcohol consumption on GAA was observed (P = 0.011), with nondrinkers exhibiting a higher GAA (β = 0.21 [95% CI 0.05, 0.36], P = 0.008) compared to heavy drinkers (β = 0.05 [95% CI - 0.09, 0.18], P = 0.500) per each additional marijuana-year. No associations were observed for the remaining EAA estimates.These findings suggest cumulative and recent marijuana use are associated with age-related epigenetic changes that are related to lifespan. These observed associations may be modified by alcohol consumption. Given the increase in use and legalization, these findings provide novel insight on the effect of marijuana use on the aging process as captured through blood DNA methylation.© 2022. The Author(s).",
-,No,20221114,dnam age,36227464,Maternal Adversity and Epigenetic Age Acceleration Predict Heightened Emotional Reactivity in Offspring: Implications for Intergenerational Transmission of Risk.,Res Child Adolesc Psychopathol,"Black American women are disproportionately exposed to adversities that may have an intergenerational impact on mental health. The present study examined whether maternal exposure to adversity and epigenetic age acceleration (EAA; a biomarker of stress exposure) predicts the socioemotional health of her offspring. During pregnancy, 180 Black American women self-reported experiences of childhood adversity and marginalization-related adversity (i.e., racial discrimination and gendered racial stress) and provided a blood sample for epigenetic assessment. At a three-year follow-up visit, women reported their offspring's emotional reactivity (an early indicator of psychopathology) via the CBCL/1.5-5. After adjusting for maternal education and offspring sex, results indicated that greater maternal experiences of childhood trauma (β = 0.21, SE(β) = 0.01; p = 0.01) and racial discrimination (β = 0.14, SE(β) = 0.07; p = 0.049) predicted greater offspring emotional reactivity, as did maternal EAA (β = 0.17, SE(β) = 0.09, p = 0.046). Our findings suggest that maternal EAA could serve as an early biomarker for intergenerational risk conferred by maternal adversity, and that 'maternal adversity' must be defined more broadly to include social marginalization, particularly for Black Americans.© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20221114,ewas,36345830,Association Between DNA Methylation and Blood Pressure: A 5-Year Longitudinal Twin Study.,Hypertension,"Previous EWASs (Epigenome-Wide Association Studies) have reported hundreds of blood pressure (BP) associated 5'-cytosine-phosphate-guanine-3' (CpG) sites. However, their results were inconsistent. Longitudinal observations on the temporal relationship between DNA methylation and BP are lacking.A candidate CpG site association study for BP was conducted on 1072 twins in the Chinese National Twin Registry. PubMed and EMBASE were searched for candidate CpG sites. Cross-lagged models were used to assess the temporal relationship between BP and DNA methylation in 308 twins who completed 2 surveys in 2013 and 2018. Then, the significant cross-lagged associations were validated by adopting the Inference About Causation From Examination of Familial Confounding approach. Finally, to evaluate the cumulative effects of DNA methylation on the progression of hypertension, we established methylation risk scores based on BP-associated CpG sites and performed Markov multistate models.16 and 20 CpG sites were validated to be associated with systolic BP and diastolic BP, respectively. In the cross-lagged analysis, we detected that methylation of 2 CpG sites could predict subsequent systolic BP, and systolic BP predicted methylation at another 3 CpG sites. For diastolic BP, methylation at 3 CpG sites had significant cross-lagged effects for predicting diastolic BP levels, while the prediction from the opposite direction was observed at one site. Among these, 3 associations were validated in the Inference About Causation From Examination of Familial Confounding analysis. Using the Markov multistate model, we observed that methylation risk scores were associated with the development of hypertension.Our findings suggest the significance of DNA methylation in the development of hypertension.",
-,Yes,20221114,ewas,36344488,Epigenome-wide DNA methylation analysis of whole blood cells derived from patients with GAD and OCD in the Chinese Han population.,Transl Psychiatry,"Generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD) had high comorbidity and affected more than 44 million people around the world leading to a huge burden on health and economy. Here, we conducted an epigenome-wide DNA methylation study employing 93 patients with GAD, 65 patients with OCD, and 302 health controls, to explore epigenetic alterations associated with the onset and differences of GAD and OCD. We identified multiple differentially methylated positions (DMPs) and regions (DMRs): three DMP genes included RIOK3 (cg21515243, p = 8.00 × 10-10), DNASE2 (cg09379601, p = 1.10 × 10-9), and PSMB4 (cg01334186, p = 3.70 × 10-7) and two DMR genes USP6NL (p = 4.50 × 10-4) and CPLX1 (p = 6.95 × 10-4) were associated with the onset of GAD and OCD; three DMPs genes included LDLRAP1 (cg21400344, p = 4.40 × 10-12), ACIN1 (cg23712970, p = 2.98×10-11), and SCRT1 (cg25472897, p = 5.60 × 10-11) and three DMR genes WDR19 (p = 3.39 × 10-3), SYCP1 (p = 6.41 × 10-3), and FAM172A (p = 5.74 × 10-3) were associated with the differences between GAD and OCD. Investigation of epigenetic age and chronological age revealed a different epigenetic development trajectory of GAD and OCD. Conclusively, our findings which yielded robust models may aid in distinguishing patients from healthy controls (AUC = 0.90-0.99) or classifying patients with GAD and OCD (AUC = 0.89-0.99), and may power the precision medicine for them.© 2022. The Author(s).",
-,Yes,20221114,ewas,36326208,Meta-analysis of DNA methylation datasets shows aberrant DNA methylation of thyroid development or function genes in Down syndrome.,Thyroid,"In Down syndrome (DS) there is a high occurrence of congenital hypothyroidism (CH) and subclinical hypothyroidism (SH) early in life. The etiology of CH and early SH in DS remains unclear. Previous research has shown genome-wide transcriptional and epigenetic alterations in DS. Thus, we hypothesized that CH and early SH could be caused by epigenetically driven transcriptional downregulation of thyroid-related genes, through promoter region hypermethylation.We extracted whole blood DNA methylation (DNAm) profiles of DS and non-DS individuals from four independent Illumina array-based datasets (252 DS individuals and 519 non-DS individuals). The data were divided in a discovery and validation dataset. Epigenome-wide association analysis was performed using a linear regression model, after which we filtered for thyroid-related genes.In the discovery dataset, we identified significant associations for DS in 18 thyroid-related genes. 21 of 30 significant differentially methylated positions (DMPs) were also significant in the validation dataset. A meta-analysis of the discovery and validation datasets detected 31 DMPs, including 29 promoter-associated CpGs with identical direction of effect across the datasets, and two differentially methylated regions (DMRs). 27 DMPs were hypomethylated and promoter-associated. The mean methylation difference of hypomethylated thyroid-related DMPs decreased with age.Contrary to our hypothesis of generalized hypermethylation of promoter regions of thyroid-related genes - indicative of epigenetic silencing of promoters and subsequent transcriptional downregulation, causing the biochemical thyroid abnormalities in DS -, we found an enrichment of hypomethylated DMPs annotated to promoter regions of these genes. This suggests that CH and early SH in DS are not caused by differential methylation of thyroid-related genes. Considering epigenetic regulation is dynamic, we hypothesize the observed thyroid-related gene DNAm changes could be a rescue phenomenon in an attempt to ameliorate the thyroid phenotype, through epigenetic upregulation of thyroid-related genes. This hypothesis is supported by the finding of decreasing methylation difference of thyroid-related genes with age. The prevalence of early SH declines with age, so hypothetically, epigenetic upregulation of thyroid-related genes also diminishes. While this study provides interesting insights, the exact origin of CH and early SH in DS remains unknown.",
-,Yes,20221114,ewas,36325427,Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients.,Brain Behav Immun Health,"Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS<5). For PD patients with a history of clinical depression compared to those without, we found no differences in immune cell composition. However, a history of clinical depression among patients was associated with differentially methylated CpGs. Epigenome-wide association analysis (EWAS) revealed 35 CpGs associated at an FDR≤0.05 (569 CpGs at FDR≤0.10, 1718 CpGs at FDR≤0.15). Gene set enrichment analysis implicated immune system pathways, including immunoregulatory interactions between lymphoid and non-lymphoid cells (p-adj = 0.003) and cytokine-cytokine receptor interaction (p-adj = 0.004). Based on functional genomics, 25 (71%) of the FDR≤0.05 CpGs were associated with genetic variation at 45 different methylation quantitative trait loci (meQTL). Twenty-six of the meQTLs were also expression QTLs (eQTLs) associated with the abundance of 53 transcripts in blood and 22 transcripts in brain (substantia nigra, putamen basal ganglia, or frontal cortex). Notably, cg15199181 was strongly related to rs823114 (SNP-CpG p-value = 3.27E-310), a SNP identified in a PD meta-GWAS and related to differential expression ofPM20D1,RAB29,SLC41A1, andNUCKS1. The entire set of genes detected through functional genomics was most strongly overrepresented for interferon-gamma-mediated signaling pathway (enrichment ratio = 18.8, FDR = 4.4e-03) and T cell receptor signaling pathway (enrichment ratio = 13.2, FDR = 4.4e-03). Overall, the current study provides evidence of immune system involvement in depression among Parkinson's patients.© 2022 The Authors.",
-,Yes,20221114,ewas,36319817,Meta-analysis of epigenome-wide association studies of major depressive disorder.,Sci Rep,"Epigenetic mechanisms have been hypothesized to play a role in the etiology of major depressive disorder (MDD). In this study, we performed a meta-analysis between two case-control MDD cohorts to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in MDD. Using samples from two Cohorts (a total of 298 MDD cases and 63 controls with repeated samples, on average ~ 1.8 samples/subject), we performed an EWAS meta-analysis. Multiple cytosine-phosphate-guanine sites annotated to TNNT3 were associated with MDD reaching study-wide significance, including cg08337959 (p = 2.3 × 10-11). Among DMPs with association p values less than 0.0001, pathways from REACTOME such as Ras activation upon Ca2+influx through the NMDA receptor (p = 0.0001, p-adjusted = 0.05) and long-term potentiation (p = 0.0002, p-adjusted = 0.05) were enriched in this study. A total of 127 DMRs with Sidak-corrected p value < 0.05 were identified from the meta-analysis, including DMRs annotated to TNNT3 (chr11: 1948933 to 1949130 [6 probes], Sidak corrected P value = 4.32 × 10-41), S100A13 (chr1: 153599479 to 153600972 [22 probes], Sidak corrected P value = 5.32 × 10-18), NRXN1 (chr2: 50201413 to 50201505 [4 probes], Sidak corrected P value = 1.19 × 10-11), IL17RA (chr22: 17564750 to 17565149, Sidak corrected P value = 9.31 × 10-8), and NPFFR2 (chr4: 72897565 to 72898212, Sidak corrected P value = 8.19 × 10-7). Using 2 Cohorts of depression case-control samples, we identified DMPs and DMRs associated with MDD. The molecular pathways implicated by these data include mechanisms involved in neuronal synaptic plasticity, calcium signaling, and inflammation, consistent with reports from previous genetic and protein biomarker studies indicating that these mechanisms are involved in the neurobiology of depression.© 2022. The Author(s).",
-,Yes,20221114,ewas,36303554,Epigenome-wide association study of biomarkers of liver function identifies albumin-associated DNA methylation sites among male veterans with HIV.,Front Genet,"Background: Liver disease (LD) is an important cause of morbidity and mortality for people with HIV (PWH). The molecular factors linked with LD in PWH are varied and incompletely characterized. We performed an epigenome-wide association study (EWAS) to identify associations between DNA methylation (DNAm) and biomarkers of liver function-aspartate transaminase, alanine transaminase, albumin, total bilirubin, platelet count, FIB-4 score, and APRI score-in male United States veterans with HIV.Methods:Blood samples and clinical data were obtained from 960 HIV-infected male PWH from the Veterans Aging Cohort Study. DNAm was assessed using the Illumina 450K or the EPIC 850K array in two mutually exclusive subsets. We performed a meta-analysis for each DNAm site measured by either platform. We also examined the associations between four measures of DNAm age acceleration (AA) and liver biomarkers.Results:Nine DNAm sites were positively associated with serum albumin in the meta-analysis of the EPIC and 450K EWAS after correcting for multiple testing. Four DNAm sites (cg16936953, cg18942579, cg01409343, and cg12054453), annotated within theTMEM49and four of the remaining five sites (cg18181703, cg03546163, cg20995564, and cg23966214) annotated toSOCS3,FKBP5,ZEB2, andSAMD14genes, respectively. The DNAm site, cg12992827, was not annotated to any known coding sequence. No significant associations were detected for the other six liver biomarkers. Higher PhenoAA was significantly associated with lower level of serum albumin (β= -0.007,p-value = 8.6 × 10-4, CI: -0.011116, -0.002884).Conclusion:We identified epigenetic associations of both individual DNAm sites and DNAm AA with liver function through serum albumin in men with HIV. Further replication analyses in independent cohorts are warranted to confirm the epigenetic mechanisms underlying liver function and LD in PWH.Copyright © 2022 Titanji, Lee, Wang, Chen, Hui, Lo Re III, So-Armah, Justice, Xu, Freiberg, Gwinn, Marconi and Sun.",
-,No,20221114,ewas,36292679,Profiling Genome-Wide DNA Methylation in Children with Autism Spectrum Disorder and in Children with Fragile X Syndrome.,Genes (Basel),"Autism spectrum disorder (ASD) is an early onset, developmental disorder whose genetic cause is heterogeneous and complex. In total, 70% of ASD cases are due to an unknown etiology. Among the monogenic causes of ASD, fragile X syndrome (FXS) accounts for 2-4% of ASD cases, and 60% of individuals with FXS present with ASD. Epigenetic changes, specifically DNA methylation, which modulates gene expression levels, play a significant role in the pathogenesis of both disorders. Thus, in this study, using the Human Methylation EPIC Bead Chip, we examined the global DNA methylation profiles of biological samples derived from 57 age-matched male participants (2-6 years old), including 23 subjects with ASD, 23 subjects with FXS with ASD (FXSA) and 11 typical developing (TD) children. After controlling for technical variation and white blood cell composition, using the conservatory threshold of the false discovery rate (FDR ≤ 0.05), in the three comparison groups, TD vs. AD, TD vs. FXSA and ASD vs. FXSA, we identified 156, 79 and 3100 differentially methylated sites (DMS), and 14, 13 and 263 differential methylation regions (DMRs). Interestingly, several genes differentially methylated among the three groups were among those listed in the SFARI Gene database, including thePAK2,GTF2IandFOXP1genes important for brain development. Further, enrichment analyses identified pathways involved in several functions, including synaptic plasticity. Our preliminary study identified a significant role of altered DNA methylation in the pathology of ASD and FXS, suggesting that the characterization of a DNA methylation signature may help to unravel the pathogenicity of FXS and ASD and may help the development of an improved diagnostic classification of children with ASD and FXSA. In addition, it may pave the way for developing therapeutic interventions that could reverse the altered methylome profile in children with neurodevelopmental disorders.",
-,Yes,20221114,ewas,36292585,Differentially Methylated DNA Regions and Left Ventricular Hypertrophy in African Americans: A HyperGEN Study.,Genes (Basel),"Left ventricular (LV) hypertrophy (LVH) is an independent risk factor for cardiovascular disease, and African Americans experience a disparate high risk of LVH. Genetic studies have identified potential candidate genes and variants related to the condition. Epigenetic modifications may continue to help unravel disease mechanisms. We used methylation and echocardiography data from 636 African Americans selected from the Hypertension Genetic Epidemiology Network (HyperGEN) to identify differentially methylated regions (DMRs) associated with LVH. DNA extracted from whole blood was assayed on Illumina Methyl450 arrays. We fit linear mixed models to examine associations between co-methylated regions and LV traits, and we then conducted single CpG analyses within significant DMRs. We identified associations between DMRs and ejection fraction (<i>XKR6</i>), LV internal diastolic dimension (<i>TRAK1</i>), LV mass index (<i>GSE1</i>, <i>RPS15 A</i>, <i>PSMD7</i>), and relative wall thickness (<i>DNHD1</i>). In single CpG analysis, CpG sites annotated to <i>TRAK1</i> and <i>DNHD1</i> were significant. These CpGs were not associated with LV traits in replication cohorts but the direction of effect for <i>DNHD1</i> was consistent across cohorts. Of note, <i>DNHD1</i>, <i>GSE1</i>, and <i>PSMD7</i> may contribute to cardiac structural function. Future studies should evaluate relationships between regional DNA methylation patterns and the development of LVH.",
-,Yes,20221114,ewas,36274151,Temporal associations between leukocytes DNA methylation and blood lipids: a longitudinal study.,Clin Epigenetics,"The associations between blood lipids and DNA methylation have been investigated in epigenome-wide association studies mainly among European ancestry populations. Several studies have explored the direction of the association using cross-sectional data, while evidence of longitudinal data is still lacking.We tested the associations between peripheral blood leukocytes DNA methylation and four lipid measures from Illumina 450 K or EPIC arrays in 1084 participants from the Chinese National Twin Registry and replicated the result in 988 participants from the China Kadoorie Biobank. A total of 23 associations of 19 CpG sites were identified, with 4 CpG sites located in or adjacent to 3 genes (TMEM49, SNX5/SNORD17 and CCDC7) being novel. Among the validated associations, we conducted a cross-lagged analysis to explore the temporal sequence and found temporal associations of methylation levels of 2 CpG sites with triglyceride and 2 CpG sites with high-density lipoprotein-cholesterol (HDL-C) in all twins. In addition, methylation levels of cg11024682 located in SREBF1 at baseline were temporally associated with triglyceride at follow-up in only monozygotic twins. We then performed a mediation analysis with the longitudinal data and the result showed that the association between body mass index and HDL-C was partially mediated by the methylation level of cg06500161 (ABCG1), with a mediation proportion of 10.1%.Our study indicated that the DNA methylation levels of ABCG1, AKAP1 and SREBF1 may be involved in lipid metabolism and provided evidence for elucidating the regulatory mechanism of lipid homeostasis.© 2022. The Author(s).",
-,Yes,20221114,ewas,36266660,Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition.,BMC Med,"Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development.Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy.At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure-but not pulsatile pressure-and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia.This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy.© 2022. The Author(s).",
-,Yes,20221114,ewas,36253871,Local CpG density affects the trajectory and variance of age-associated DNA methylation changes.,Genome Biol,"DNA methylation is an epigenetic mark associated with the repression of gene promoters. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Altered rates of aging inferred from these clocks are observed in human disease. However, the molecular mechanisms underpinning age-associated DNA methylation changes remain unknown. Local DNA sequence can program steady-state DNA methylation levels, but how it influences age-associated methylation changes is unknown.We analyze longitudinal human DNA methylation trajectories at 345,895 CpGs from 600 individuals aged between 67 and 80 to understand the factors responsible for age-associated epigenetic changes at individual CpGs. We show that changes in methylation with age occur at 182,760 loci largely independently of variation in cell type proportions. These changes are especially apparent at 8322 low CpG density loci. Using SNP data from the same individuals, we demonstrate that methylation trajectories are affected by local sequence polymorphisms at 1487 low CpG density loci. More generally, we find that low CpG density regions are particularly prone to change and do so variably between individuals in people aged over 65. This differs from the behavior of these regions in younger individuals where they predominantly lose methylation.Our results, which we reproduce in two independent groups of individuals, demonstrate that local DNA sequence influences age-associated DNA methylation changes in humans in vivo. We suggest that this occurs because interactions between CpGs reinforce maintenance of methylation patterns in CpG dense regions.© 2022. The Author(s).",
-,Yes,20221114,ewas,36329530,Whole blood methylome-derived features to discriminate endocrine hypertension.,Clin Epigenetics,"Arterial hypertension represents a worldwide health burden and a major risk factor for cardiovascular morbidity and mortality. Hypertension can be primary (primary hypertension, PHT), or secondary to endocrine disorders (endocrine hypertension, EHT), such as Cushing's syndrome (CS), primary aldosteronism (PA), and pheochromocytoma/paraganglioma (PPGL). Diagnosis of EHT is currently based on hormone assays. Efficient detection remains challenging, but is crucial to properly orientate patients for diagnostic confirmation and specific treatment. More accurate biomarkers would help in the diagnostic pathway. We hypothesized that each type of endocrine hypertension could be associated with a specific blood DNA methylation signature, which could be used for disease discrimination. To identify such markers, we aimed at exploring the methylome profiles in a cohort of 255 patients with hypertension, either PHT (n = 42) or EHT (n = 213), and at identifying specific discriminating signatures using machine learning approaches.Unsupervised classification of samples showed discrimination of PHT from EHT. CS patients clustered separately from all other patients, whereas PA and PPGL showed an overall overlap. Global methylation was decreased in the CS group compared to PHT. Supervised comparison with PHT identified differentially methylated CpG sites for each type of endocrine hypertension, showing a diffuse genomic location. Among the most differentially methylated genes, FKBP5 was identified in the CS group. Using four different machine learning methods-Lasso (Least Absolute Shrinkage and Selection Operator), Logistic Regression, Random Forest, and Support Vector Machine-predictive models for each type of endocrine hypertension were built on training cohorts (80% of samples for each hypertension type) and estimated on validation cohorts (20% of samples for each hypertension type). Balanced accuracies ranged from 0.55 to 0.74 for predicting EHT, 0.85 to 0.95 for predicting CS, 0.66 to 0.88 for predicting PA, and 0.70 to 0.83 for predicting PPGL.The blood DNA methylome can discriminate endocrine hypertension, with methylation signatures for each type of endocrine disorder.© 2022. The Author(s).",
-,No,20221114,meqtl,36342317,Identification of novel meQTLs strongly associated with rheumatoid arthritis by large-scale epigenome-wide analysis.,FEBS Open Bio,"Rheumatoid arthritis (RA) is highly heritable, and previous studies have suggested that genetic variation may affect susceptibility to RA by altering epigenetic modifications (e.g., DNA methylation). Here, we examined how genetic variation influences DNA methylation (DNAm) in RA by integrating individual genetic variation and DNAm data. Epigenome-wide meQTL (methylation quantitative trait loci) analysis was performed on 354 RA patients and 335 controls, scanning 30,101,744 relationships between 62 SNPs and 485,512 DNA methylation sites. Two regulatory relationship pairs (FDR<0.05) showed very strong associations with RA risk. One was rs10796216-cg00475509, and the DNAm decreased by 0.0168 per addition of allele rs10796216-A. The other was rs6546473-cg13358873, for which a 0.0365 reduction of DNAm at cg13358873 was observed for each addition of allele rs6546473-A, and lower DNAm was found to be significantly associated with RA risk (P = 2.0407e-28). Moreover, both pairs of meQTL showed a strong regulatory relationship only in RA samples, so they can be subsequently considered as risk markers for RA. In conclusion, our integrated analysis of genetic and epigenetic variation suggests that genetic variation may affect the risk of RA by regulating DNA methylation levels. Alterations of DNAm at cg00475509 and cg13358873 loci conferred by rs10796216-A and rs6546473-A allele may suggest a potential risk for RA. Our results deepen our understanding of the genetic and epigenetic mechanisms of RA and provide novel associations that can be further investigated in future studies.This article is protected by copyright. All rights reserved.",
-,No,20221114,methods,36335502,Phasing DNA Methylation.,Methods Mol Biol,"Haplotyping enables the study of allele-specific events. Heterozygous variants, primarily single nucleotide variants (SNVs), enable the assignment of the paternal and maternal origin of the chromosomes and are widely employed to phase sequencing reads to their haplotype of origin. Certain long-read technologies enable the detection of both the DNA sequence and DNA modifications. These long reads and their inherent methylation information are suitable for genome-wide haplotyping and allele-specific DNA methylation analysis. Here, we describe the workflow to phase reads and DNA methylation using nanopore sequencing.© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.",
-,No,20221114,methods,36282535,A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis.,Hum Mol Genet,"Multiple sclerosis (MS) is a complex dysimmune disorder of the central nervous system. Genome-wide association studies (GWAS) have identified 233 genetic variations associated with MS at the genome-wide significant level. Epigenetic studies have pinpointed differentially methylated CpG sites in MS patients. However, the interplay between genetic risk factors and epigenetic regulation remains elusive. Here, we employed a network model to integrate GWAS summary statistics of 14 802 MS cases and 26 703 controls with DNA methylation profiles from 140 MS cases and 139 controls and the human interactome. We identified differentially methylated genes by aggregating additive effects of differentially methylated CpG sites within promoter regions. We reconstructed a gene regulatory network (GRN) using literature-curated transcription factor knowledge. Colocalization of the MS GWAS and methylation quantitative trait loci (mQTL) was performed to assess the GRN. The resultant MS-associated GRN highlighted several single nucleotide polymorphisms (SNPs) with GWAS-mQTL colocalization: rs6032663, rs6065926, and rs2024568 of CD40 locus, rs9913597 of STAT3 locus, and rs887864 and rs741175 of CIITA locus. Moreover, synergistic mQTL and eQTL signals were identified in CD40, suggesting gene expression alteration was likely induced by epigenetic changes. Web-based Cell-type Specific Enrichment Analysis of Genes (WebCSEA) indicated that the GRN was enriched in T follicular helper cells (p-value = 0.0016). Drug target enrichment analysis of annotations from the Therapeutic Target Database (TTD) revealed the GRN was also enriched with drug target genes (p-value = 3.89 × 10-4), revealing repurposable candidates for MS treatment. These candidates included vorinostat (HDAC1 inhibitor) and sivelestat (ELANE inhibitor), which warrant further investigation.© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,No,20221114,methods,36280888,Significant variation in the performance of DNA methylation predictors across data preprocessing and normalization strategies.,Genome Biol,"DNA methylation (DNAm)-based predictors hold great promise to serve as clinical tools for health interventions and disease management. While these algorithms often have high prediction accuracy, the consistency of their performance remains to be determined. We therefore conduct a systematic evaluation across 101 different DNAm data preprocessing and normalization strategies and assess how each analytical strategy affects the consistency of 41 DNAm-based predictors.Our analyses are conducted in a large EPIC DNAm array dataset from the Jackson Heart Study (N = 2053) that included 146 pairs of technical replicate samples. By estimating the average absolute agreement between replicate pairs, we show that 32 out of 41 predictors (78%) demonstrate excellent consistency when appropriate data processing and normalization steps are implemented. Across all pairs of predictors, we find a moderate correlation in performance across analytical strategies (mean rho = 0.40, SD = 0.27), highlighting significant heterogeneity in performance across algorithms. Successful or unsuccessful removal of technical variation furthermore significantly impacts downstream phenotypic association analysis, such as all-cause mortality risk associations.We show that DNAm-based algorithms are sensitive to technical variation. The right choice of data processing strategy is important to achieve reproducible estimates and improve prediction accuracy in downstream phenotypic association analyses. For each of the 41 DNAm predictors, we report its degree of consistency and provide the best performing analytical strategy as a guideline for the research community. As DNAm-based predictors become more and more widely used, our work helps improve their performance and standardize their implementation.© 2022. The Author(s).",
-,No,20221114,methods,36277076,A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking.,Nat Aging,"Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectoriesin vivoandin vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking,in vitrostudies, and clinical trials of aging interventions.",
-,No,20221114,methods,36319638,Unsupervised learning of aging principles from longitudinal data.,Nat Commun,"Age is the leading risk factor for prevalent diseases and death. However, the relation between age-related physiological changes and lifespan is poorly understood. We combined analytical and machine learning tools to describe the aging process in large sets of longitudinal measurements. Assuming that aging results from a dynamic instability of the organism state, we designed a deep artificial neural network, including auto-encoder and auto-regression (AR) components. The AR model tied the dynamics of physiological state with the stochastic evolution of a single variable, the ""dynamic frailty indicator"" (dFI). In a subset of blood tests from the Mouse Phenome Database, dFI increased exponentially and predicted the remaining lifespan. The observation of the limiting dFI was consistent with the late-life mortality deceleration. dFI changed along with hallmarks of aging, including frailty index, molecular markers of inflammation, senescent cell accumulation, and responded to life-shortening (high-fat diet) and life-extending (rapamycin) treatments.© 2022. The Author(s).",
-,No,20221114,ml,36335101,Learning the histone codes with large genomic windows and three-dimensional chromatin interactions using transformer.,Nat Commun,"The quantitative characterization of the transcriptional control by histone modifications has been challenged by many computational studies, but most of them only focus on narrow and linear genomic regions around promoters, leaving a room for improvement. We present Chromoformer, a transformer-based, three-dimensional chromatin conformation-aware deep learning architecture that achieves the state-of-the-art performance in the quantitative deciphering of the histone codes in gene regulation. The core essence of Chromoformer architecture lies in the three variants of attention operation, each specialized to model individual hierarchy of transcriptional regulation involving from core promoters to distal elements in contact with promoters through three-dimensional chromatin interactions. In-depth interpretation of Chromoformer reveals that it adaptively utilizes the long-range dependencies between histone modifications associated with transcription initiation and elongation. We also show that the quantitative kinetics of transcription factories and Polycomb group bodies can be captured by Chromoformer. Together, our study highlights the great advantage of attention-based deep modeling of complex interactions in epigenomes.© 2022. The Author(s).",
-,No,20221114,prediction,36329159,"Precision gynecologic oncology: circulating cell free DNA epigenomic analysis, artificial intelligence and the accurate detection of ovarian cancer.",Sci Rep,"Ovarian cancer (OC) is the most lethal gynecologic cancer due primarily to its asymptomatic nature and late stage at diagnosis. The development of non-invasive markers is an urgent priority. We report the accurate detection of epithelial OC using Artificial Intelligence (AI) and genome-wide epigenetic analysis of circulating cell free tumor DNA (cfTDNA). In a prospective study, we performed genome-wide DNA methylation profiling of cytosine (CpG) markers. Both conventional logistic regression and six AI platforms were used for OC detection. Further, we performed Gene Set Enrichment Analysis (GSEA) analysis to elucidate the molecular pathogenesis of OC. A total of 179,238 CpGs were significantly differentially methylated (FDR p-value < 0.05) genome-wide in OC. High OC diagnostic accuracies were achieved. Conventional logistic regression achieved an area under the ROC curve (AUC) [95% CI] 0.99 [± 0.1] with 95% sensitivity and 100% specificity. Multiple AI platforms each achieved high diagnostic accuracies (AUC = 0.99-1.00). For example, for Deep Learning (DL)/AI AUC = 1.00, sensitivity = 100% and 88% specificity. In terms of OC pathogenesis: GSEA analysis identified 'Adipogenesis' and 'retinoblastoma gene in cancer' as the top perturbed molecular pathway in OC. This finding of epigenomic dysregulation of molecular pathways that have been previously linked to cancer adds biological plausibility to our results.© 2022. The Author(s).",
-,No,20221114,prediction,36305646,DNA methylation biomarkers for noninvasive detection of triple-negative breast cancer using liquid biopsy.,Int J Cancer,"Noninvasive detection of aberrant DNA methylation could provide invaluable biomarkers for earlier detection of triple-negative breast cancer (TNBC) which could help clinicians with easier and more efficient treatment options. We evaluated genome-wide DNA methylation data derived from TNBC and normal breast tissues, peripheral blood of TNBC cases and controls and reference samples of sorted blood and mammary cells. Differentially methylated regions (DMRs) between TNBC and normal breast tissues were stringently selected, verified and externally validated. A machine-learning algorithm was applied to select the top DMRs, which then were evaluated on plasma-derived circulating cell-free DNA (cfDNA) samples of TNBC patients and healthy controls. We identified 23 DMRs accounting for the methylation profile of blood cells and reference mammary cells and then selected six top DMRs for cfDNA analysis. We quantified un-/methylated copies of these DMRs by droplet digital PCR analysis in a plasma test set from TNBC patients and healthy controls and confirmed our findings obtained on tissues. Differential cfDNA methylation was confirmed in an independent validation set of plasma samples. A methylation score combining signatures of the top three DMRs overlapping with the SPAG6, LINC10606 and TBCD/ZNF750 genes had the best capability to discriminate TNBC patients from controls (AUC = 0.78 in the test set and AUC = 0.74 in validation set). Our findings demonstrate the usefulness of cfDNA-based methylation signatures as noninvasive liquid biopsy markers for the diagnosis of TNBC.© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",
-,No,20221114,prediction,36274755,Hierarchical Ridge Regression for Incorporating Prior Information in Genomic Studies.,J Data Sci,"There is a great deal of prior knowledge about gene function and regulation in the form of annotations or prior results that, if directly integrated into individual prognostic or diagnostic studies, could improve predictive performance. For example, in a study to develop a predictive model for cancer survival based on gene expression, effect sizes from previous studies or the grouping of genes based on pathways constitute such prior knowledge. However, this external information is typically only used post-analysis to aid in the interpretation of any findings. We propose a new hierarchical two-level ridge regression model that can integrate external information in the form of ""meta features"" to predict an outcome. We show that the model can be fit efficiently using cyclic coordinate descent by recasting the problem as a single-level regression model. In a simulation-based evaluation we show that the proposed method outperforms standard ridge regression and competing methods that integrate prior information, in terms of prediction performance when the meta features are informative on the mean of the features, and that there is no loss in performance when the meta features are uninformative. We demonstrate our approach with applications to the prediction of chronological age based on methylation features and breast cancer mortality based on gene expression features.",
-,No,20221114,prediction,36261477,A machine learning approach utilizing DNA methylation as an accurate classifier of COVID-19 disease severity.,Sci Rep,"Since the onset of the COVID-19 pandemic, increasing cases with variable outcomes continue globally because of variants and despite vaccines and therapies. There is a need to identify at-risk individuals early that would benefit from timely medical interventions. DNA methylation provides an opportunity to identify an epigenetic signature of individuals at increased risk. We utilized machine learning to identify DNA methylation signatures of COVID-19 disease from data available through NCBI Gene Expression Omnibus. A training cohort of 460 individuals (164 COVID-19-infected and 296 non-infected) and an external validation dataset of 128 individuals (102 COVID-19-infected and 26 non-COVID-associated pneumonia) were reanalyzed. Data was processed using ChAMP and beta values were logit transformed. The JADBio AutoML platform was leveraged to identify a methylation signature associated with severe COVID-19 disease. We identified a random forest classification model from 4 unique methylation sites with the power to discern individuals with severe COVID-19 disease. The average area under the curve of receiver operator characteristic (AUC-ROC) of the model was 0.933 and the average area under the precision-recall curve (AUC-PRC) was 0.965. When applied to our external validation, this model produced an AUC-ROC of 0.898 and an AUC-PRC of 0.864. These results further our understanding of the utility of DNA methylation in COVID-19 disease pathology and serve as a platform to inform future COVID-19 related studies.© 2022. The Author(s).",
-,No,20221114,prediction,36309516,The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors.,Nat Commun,"Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples.© 2022. The Author(s).",
-,No,20221114,prediction,36281400,5-Hydroxymethylcytosines in circulating cell-free DNA reveal a diagnostic biomarker for glioma.,Heliyon,"Gliomas typically have unfavorable prognosis, due to late detection and interventions. However, effective biomarkers for early glioma diagnosis based on 5-hydroxymethylcytosines (5 hm C) in circulating cell-free DNA (cfDNA) are not currently available. 5 hm C profiles in GSE132118 set were subjected for establishment of diagnostic model using the LASSO (least absolute shrinkage and selection operator) algorithm. The 5 hm C-based models demonstrated great potency in differentiating healthy subjects from gliomas, with area under the curves (AUCs) > 0.91 in the training and validation sets. Moreover, the indicator performed well in combination with clinicopathological characteristics to differentiate glioblastomas (GBMs) from lower grade glioma (LGGs). Enrichment analysis on 5 hm C profiles displayed great correlation with glioma pathophysiology. The 5 hm C-derived biomarker might act as an effective and non-invasive measure in glioma screening.© 2022 The Authors.",
-,No,20221114,pwas,36253349,Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke.,Nat Commun,"Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10-4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.© 2022. The Author(s).",
-,No,20221114,pwas,36273219,Plasma proteome profiling identifies changes associated to AD but not to FTD.,Acta Neuropathol Commun,"Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process.Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis.Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified.We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.© 2022. The Author(s).",
-,No,20221114,reference,36330950,LncBook 2.0: integrating human long non-coding RNAs with multi-omics annotations.,Nucleic Acids Res,"LncBook, a comprehensive resource of human long non-coding RNAs (lncRNAs), has been used in a wide range of lncRNA studies across various biological contexts. Here, we present LncBook 2.0 (https://ngdc.cncb.ac.cn/lncbook), with significant updates and enhancements as follows: (i) incorporation of 119 722 new transcripts, 9632 new genes, and gene structure update of 21 305 lncRNAs; (ii) characterization of conservation features of human lncRNA genes across 40 vertebrates; (iii) integration of lncRNA-encoded small proteins; (iv) enrichment of expression and DNA methylation profiles with more biological contexts and (v) identification of lncRNA-protein interactions and improved prediction of lncRNA-miRNA interactions. Collectively, LncBook 2.0 accommodates a high-quality collection of 95 243 lncRNA genes and 323 950 transcripts and incorporates their abundant annotations at different omics levels, thereby enabling users to decipher functional significance of lncRNAs in different biological contexts.© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.",
-,No,20221114,reference,36320053,A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples.,Clin Epigenetics,"Epigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal swabs, and saliva as surrogates. To aid the functional interpretation of EWAS findings in such settings, there is a need to assess the correlation of DNAm variability across tissues in the same individuals. In this study, we performed a correlation analysis between DNAm data of a total of n = 120 matched post-mortem buccal and prefrontal cortex samples. We identified nearly 25,000 (3% of approximately 730,000) cytosine-phosphate-guanine (CpG) sites showing significant (false discovery rate q < 0.05) correlations between buccal and PFC samples. Correlated CpG sites showed a preponderance to being located in promoter regions and showed a significant enrichment of being determined by genetic factors, i.e. methylation quantitative trait loci (mQTL), based on buccal and dorsolateral prefrontal cortex mQTL databases. Our novel buccal-brain DNAm correlation map will provide a valuable resource for future EWAS using buccal samples for studying DNAm effects on phenotypes relating to the brain. All correlation results are made freely available to the public online.© 2022. The Author(s).",
-,No,20221114,reference,36270064,"Genome-wide DNA methylation analysis of post-operative delirium with brain, blood, saliva, and buccal samples from neurosurgery patients.",J Psychiatr Res,"No previous study demonstrates the difference in the genome-wide DNA methylation status of post-operative delirium (POD) using human brain tissue obtained from neurosurgery and multiple peripheral tissues such as blood, saliva, and buccal samples from the same individuals. We aimed to identify epigenetic marks of DNA methylation in the brain and peripheral tissues to elucidate the potential pathophysiological mechanism of POD.The four tissue types (brain, blood, saliva, buccal) of DNA samples from up to 40 patients, including 11 POD cases, were analyzed using Illumina EPIC array. DNAm differences between patients with and without POD were examined. We also conducted enrichment analysis based on the top DNAm signals.The most different CpG site between control and POD was found at cg16526133 near the ADAMTS9 gene from the brain tissue(p = 8.66E-08). However, there are no CpG sites to reach the genome-wide significant level. The enrichment analysis based on the 1000 top hit CpG site (p < 0.05) on the four tissues showed several intriguing pathways. In the brain, there are pathways including ""positive regulation of glial cell differentiation"". Blood samples showed also pathways related to immune function. Besides, both saliva and the buccal sample showed pathways related to circadian rhythm, although these findings were not FDR significant.Enrichment analysis found several intriguing pathways related to potential delirium pathophysiology. Present data may further support the role of epigenetics, especially DNA methylation, in the molecular mechanisms of delirium pathogenesis.Copyright © 2022 Elsevier Ltd. All rights reserved.",
-,No,20221114,reference,36229504,Assessment of variability in the plasma 7k SomaScan proteomics assay.,Sci Rep,"SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current version, the 7k SomaScan assay v4.1 is capable of measuring 7288 human proteins. In this work, we present an extensive technical assessment of this platform based on a study of 2050 samples across 22 plates. Included in the study design were inter-plate technical duplicates from 102 human subjects, which allowed us to characterize different normalization procedures, evaluate assay variability by multiple analytical approaches, present signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments on this wide range of technical aspects, we aim for this work to serve as a valuable resource for the growing community of SomaScan users.© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
-,No,20221114,epigenetics,36163261,Single-cell multi-omics profiling links dynamic DNA methylation to cell fate decisions during mouse early organogenesis,Genome Biol,"Background: Perturbation of DNA methyltransferases (DNMTs) and of the active DNA demethylation pathway via ten-eleven translocation (TET) methylcytosine dioxygenases results in severe developmental defects and embryonic lethality. Dynamic control of DNA methylation is therefore vital for embryogenesis, yet the underlying mechanisms remain poorly understood.
+No,20220815,dnam age,35552703,Sperm epigenetic clock associates with pregnancy outcomes in the general population.,Hum Reprod,"Is sperm epigenetic aging (SEA) associated with probability of pregnancy among couples in the general population?We observed a 17% lower cumulative probability at 12 months for couples with male partners in the older compared to the younger SEA categories.The strong relation between chronological age and DNA methylation profiles has enabled the estimation of biological age as epigenetic 'clock' metrics in most somatic tissue. Such clocks in male germ cells are less developed and lack clinical relevance in terms of their utility to predict reproductive outcomes.This was a population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 and followed for up to 12 months.Sperm DNA methylation from 379 semen samples was assessed via a beadchip array. A state-of-the-art ensemble machine learning algorithm was employed to predict age from the sperm DNA methylation data. SEA was estimated from clocks derived from individual CpGs (SEACpG) and differentially methylated regions (SEADMR). Probability of pregnancy within 1 year was compared by SEA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates.Our SEACpG clock had the highest predictive performance with correlation between chronological and predicted age (r = 0.91). In adjusted discrete Cox models, SEACpG was negatively associated with TTP (fecundability odds ratios (FORs)=0.83; 95% CI: 0.76, 0.90; P = 1.2×10-5), indicating a longer TTP with advanced SEACpG. For subsequent birth outcomes, advanced SEACpG was associated with shorter gestational age (n = 192; -2.13 days; 95% CI: -3.67, -0.59; P = 0.007). Current smokers also displayed advanced SEACpG (P < 0.05). Finally, SEACpG showed a strong performance in an independent IVF cohort (n = 173; r = 0.83). SEADMR performance was comparable to SEACpG but with attenuated effect sizes.This prospective cohort study consisted primarily of Caucasian men and women, and thus analysis of large diverse cohorts is necessary to confirm the associations between SEA and couple pregnancy success in other races/ethnicities.These data suggest that our sperm epigenetic clocks may have utility as a novel biomarker to predict TTP among couples in the general population and underscore the importance of the male partner for reproductive success.This work was funded in part by grants the National Institute of Environmental Health Sciences, National Institutes of Health (R01 ES028298; PI: J.R.P. and P30 ES020957); Robert J. Sokol, MD Endowed Chair of Molecular Obstetrics and Gynecology (J.R.P.); and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contracts N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). S.L.M. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors declare no competing interests.N/A.© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
+No,20220815,ewas,35852134,Genome-wide screening identifies DNA methylation sites that regulate the blood proteome.,Epigenomics,"Background:Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes.Materials & methods:Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins.Results: The authors identified 165 methylation sites associated with 138 proteins. The authors noted hotspot genomic regions that control the levels of several proteins. For example, methylation of theABOlocus impacted 37 proteins and contributed to cardiometabolic comorbidities, including the severity of SARS-CoV-2 infection. The authors made these findings publicly available as a Unix software that identifies methylation sites that cause disease and reveals the underlying proteins. The authors underlined the software application by showing that components of innate immunity contribute to systolic blood pressure.Conclusion:This study provides a catalog of DNA methylation sites that regulate the proteome, and the results are available as freeware for biological insight.",
+No,20220815,meqtls,35710981,"Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease.",Nat Genet,"More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability analysis reveals that methylation variation explains a larger fraction of heritability than gene expression. We present a multi-stage prioritization strategy and prioritize target genes for 87% of kidney function loci. We highlight key roles of proximal tubules and metabolism in kidney function regulation. Furthermore, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20220815,methods,35879655,HIMA2: high-dimensional mediation analysis and its application in epigenome-wide DNA methylation data.,BMC Bioinformatics,"Mediation analysis plays a major role in identifying significant mediators in the pathway between environmental exposures and health outcomes. With advanced data collection technology for large-scale studies, there has been growing research interest in developing methodology for high-dimensional mediation analysis. In this paper we present HIMA2, an extension of the HIMA method (Zhang in Bioinformatics 32:3150-3154, 2016). First, the proposed HIMA2 reduces the dimension of mediators to a manageable level based on the sure independence screening (SIS) method (Fan in J R Stat Soc Ser B 70:849-911, 2008). Second, a de-biased Lasso procedure is implemented for estimating regression parameters. Third, we use a multiple-testing procedure to accurately control the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. We demonstrate its practical performance using Monte Carlo simulation studies and apply our method to identify DNA methylation markers which mediate the pathway from smoking to reduced lung function in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.© 2022. The Author(s).",
+No,20220815,methods,35856716,High-dimension to high-dimension screening for detecting genome-wide epigenetic and noncoding RNA regulators of gene expression.,Bioinformatics,"The advancement of high-throughput technology characterizes a wide variety of epigenetic modifications and noncoding RNAs across the genome involved in disease pathogenesis via regulating gene expression. The high-dimensionality of both epigenetic/noncoding RNA and gene expression data make it challenging to identify the important regulators of genes. Conducting univariate test for each possible regulator-gene pair is subject to serious multiple comparison burden, and direct application of regularization methods to select regulator-gene pairs is computationally infeasible. Applying fast screening to reduce dimension first before regularization is more efficient and stable than applying regularization methods alone.We propose a novel screening method based on robust partial correlation to detect epigenetic and noncoding RNA regulators of gene expression over the whole genome, a problem that includes both high-dimensional predictors and high-dimensional responses. Compared to existing screening methods, our method is conceptually innovative that it reduces the dimension of both predictor and response, and screens at both node (regulators or genes) and edge (regulator-gene pairs) levels. We develop data-driven procedures to determine the conditional sets and the optimal screening threshold, and implement a fast iterative algorithm. Simulations and applications to long non-coding RNA and microRNA regulation in Kidney cancer and DNA methylation regulation in Glioblastoma Multiforme illustrate the validity and advantage of our method.The R package, related source codes and real data sets used in this paper are provided at https://github.com/kehongjie/rPCor.Supplementary data are available at Bioinformatics online.© The Author(s) (2022). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+No,20220815,methods,35822029,Adapting Blood DNA Methylation Aging Clocks for Use in Saliva Samples With Cell-type Deconvolution.,Front Aging,"DeepMAge is a deep-learning DNA methylation aging clock that measures the organismal pace of aging with the information from human epigenetic profiles. In blood samples, DeepMAge can predict chronological age within a 2.8 years error margin, but in saliva samples, its performance is drastically reduced since aging clocks are restricted by the training set domain. However, saliva is an attractive fluid for genomic studies due to its availability, compared to other tissues, including blood. In this article, we display how cell type deconvolution and elastic net can be used to expand the domain of deep aging clocks to other tissues. Using our approach, DeepMAge's error in saliva samples was reduced from 20.9 to 4.7 years with no retraining.Copyright © 2021 Galkin, Kochetov, Mamoshina and Zhavoronkov.",
+No,20220815,prediction,35864305,Peripheral blood DNA methylation profiles predict future development of B-cell Non-Hodgkin Lymphoma.,NPJ Precis Oncol,"Lack of accurate methods for early lymphoma detection limits the ability to cure patients. Since patients with Non-Hodgkin lymphomas (NHL) who present with advanced disease have worse outcomes, accurate and sensitive methods for early detection are needed to improve patient care. We developed a DNA methylation-based prediction tool for NHL, based on blood samples collected prospectively from 278 apparently healthy patients who were followed for up to 16 years to monitor for NHL development. A predictive score was developed using machine learning methods in a robust training/validation framework. Our predictive score incorporates CpG DNA methylation at 135 genomic positions, with higher scores predicting higher risk. It was 85% and 78% accurate for identifying patients at risk of developing future NHL, in patients with high or low epigenetic mitotic clock respectively, in a validation cohort. It was also sensitive at detecting active NHL (96.3% accuracy) and healthy status (95.6% accuracy) in additional independent cohorts. Scores optimized for specific NHL subtypes showed significant but lower accuracy for predicting other subtypes. Our score incorporates hyper-methylation of Polycomb and HOX genes, which have roles in NHL development, as well as PAX5 - a master transcriptional regulator of B-cell fate. Subjects with higher risk scores showed higher regulatory T-cells, memory B-cells, but lower naïve T helper lymphocytes fractions in the blood. Future prospective studies will be required to confirm the utility of our signature for managing patients who are at high risk for developing future NHL.© 2022. The Author(s).",
+No,20220815,prediction,35740428,Predicting High Blood Pressure Using DNA Methylome-Based Machine Learning Models.,Biomedicines,"DNA methylation modification plays a vital role in the pathophysiology of high blood pressure (BP). Herein, we applied three machine learning (ML) algorithms including deep learning (DL), support vector machine, and random forest for detecting high BP using DNA methylome data. Peripheral blood samples of 50 elderly individuals were collected three times at three visits for DNA methylome profiling. Participants who had a history of hypertension and/or current high BP measure were considered to have high BP. The whole dataset was randomly divided to conduct a nested five-group cross-validation for prediction performance. Data in each outer training set were independently normalized using a min-max scaler, reduced dimensionality using principal component analysis, then fed into three predictive algorithms. Of the three ML algorithms, DL achieved the best performance (AUPRC = 0.65, AUROC = 0.73, accuracy = 0.69, and F1-score = 0.73). To confirm the reliability of using DNA methylome as a biomarker for high BP, we constructed mixed-effects models and found that 61,694 methylation sites located in 15,523 intragenic regions and 16,754 intergenic regions were significantly associated with BP measures. Our proposed models pioneered the methodology of applying ML and DNA methylome data for early detection of high BP in clinical practices.",
+No,20220815,prediction,35839250,Explainable deep transfer learning model for disease risk prediction using high-dimensional genomic data.,PLoS Comput Biol,"Building an accurate disease risk prediction model is an essential step in the modern quest for precision medicine. While high-dimensional genomic data provides valuable data resources for the investigations of disease risk, their huge amount of noise and complex relationships between predictors and outcomes have brought tremendous analytical challenges. Deep learning model is the state-of-the-art methods for many prediction tasks, and it is a promising framework for the analysis of genomic data. However, deep learning models generally suffer from the curse of dimensionality and the lack of biological interpretability, both of which have greatly limited their applications. In this work, we have developed a deep neural network (DNN) based prediction modeling framework. We first proposed a group-wise feature importance score for feature selection, where genes harboring genetic variants with both linear and non-linear effects are efficiently detected. We then designed an explainable transfer-learning based DNN method, which can directly incorporate information from feature selection and accurately capture complex predictive effects. The proposed DNN-framework is biologically interpretable, as it is built based on the selected predictive genes. It is also computationally efficient and can be applied to genome-wide data. Through extensive simulations and real data analyses, we have demonstrated that our proposed method can not only efficiently detect predictive features, but also accurately predict disease risk, as compared to many existing methods.",
+No,20220815,prediction,35841107,Detecting cell-of-origin and cancer-specific methylation features of cell-free DNA from Nanopore sequencing.,Genome Biol,"The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT shallow whole-genome sequencing to detect copy number alterations (CNAs) from the circulating tumor DNA (ctDNA) of cancer patients. Here, we show that cell type and cancer-specific methylation changes can also be detected, as well as cancer-associated fragmentation signatures. This feasibility study suggests that ONT shallow WGS could be a powerful tool for liquid biopsy.© 2022. The Author(s).",
+No,20220815,review,35794667,"Diversity in EWAS: current state, challenges, and solutions.",Genome Med,"Here, we report a lack of diversity in epigenome-wide association studies (EWAS) and DNA methylation (DNAm) data, discuss current challenges, and propose solutions for EWAS and DNAm research in diverse populations. The strategies we propose include fostering community involvement, new data generation, and cost-effective approaches such as locus-specific analysis and ancestry variable region analysis.© 2022. The Author(s).",
+No,20220815,review,35868277,What is a cell type and how to define it?,Cell,"Cell types are the basic functional units of an organism. Cell types exhibit diverse phenotypic properties at multiple levels, making them challenging to define, categorize, and understand. This review provides an overview of the basic principles of cell types rooted in evolution and development and discusses approaches to characterize and classify cell types and investigate how they contribute to the organism's function, using the mammalian brain as a primary example. I propose a roadmap toward a conceptual framework and knowledge base of cell types that will enable a deeper understanding of the dynamic changes of cellular function under healthy and diseased conditions.Copyright © 2022 Elsevier Inc. All rights reserved.",
+No,20220815,vntr,35609568,A phenome-wide association study identifies effects of copy-number variation of VNTRs and multicopy genes on multiple human traits.,Am J Hum Genet,"The human genome contains tens of thousands of large tandem repeats and hundreds of genes that show common and highly variable copy-number changes. Due to their large size and repetitive nature, these variable number tandem repeats (VNTRs) and multicopy genes are generally recalcitrant to standard genotyping approaches and, as a result, this class of variation is poorly characterized. However, several recent studies have demonstrated that copy-number variation of VNTRs can modify local gene expression, epigenetics, and human traits, indicating that many have a functional role. Here, using read depth from whole-genome sequencing to profile copy number, we report results of a phenome-wide association study (PheWAS) of VNTRs and multicopy genes in a discovery cohort of �35,000 samples, identifying 32 traits associated with copy number of 38 VNTRs and multicopy genes at 1% FDR. We replicated many of these signals in an independent cohort and observed that VNTRs showing trait associations were significantly enriched for expression QTLs with nearby genes, providing strong support for our results. Fine-mapping studies indicated that in the majority (�90%) of cases, the VNTRs and multicopy genes we identified represent the causal variants underlying the observed associations. Furthermore, several lie in regions where prior SNV-based GWASs have failed to identify any significant associations with these traits. Our study indicates that copy number of VNTRs and multicopy genes contributes to diverse human traits and suggests that complex structural variants potentially explain some of the so-called ""missing heritability"" of SNV-based GWASs.Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
+Yes,20220815,ewas,35943854,Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.,Brain,"Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.",
+Yes,20220815,ewas,35904121,Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.,Hum Mutat,"An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes which can share significant overlap amongst different conditions. In this study we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.",
+Yes,20220815,ewas,35888152,Association between Usual Dietary Intake of Food Groups and DNA Methylation and Effect Modification by Metabotype in the KORA FF4 Cohort.,Life (Basel),"Associations between diet and DNA methylation may vary among subjects with different metabolic states, which can be captured by clustering populations in metabolically homogenous subgroups, called metabotypes. Our aim was to examine the relationship between habitual consumption of various food groups and DNA methylation as well as to test for effect modification by metabotype. A cross-sectional analysis of participants (median age 58 years) of the population-based prospective KORA FF4 study, habitual dietary intake was modeled based on repeated 24-h diet recalls and a food frequency questionnaire. DNA methylation was measured using the Infinium MethylationEPIC BeadChip providing data on &gt;850,000 sites in this epigenome-wide association study (EWAS). Three metabotype clusters were identified using four standard clinical parameters and BMI. Regression models were used to associate diet and DNA methylation, and to test for effect modification. Few significant signals were identified in the basic analysis while many significant signals were observed in models including food group-metabotype interaction terms. Most findings refer to interactions of food intake with metabotype 3, which is the metabotype with the most unfavorable metabolic profile. This research highlights the importance of the metabolic characteristics of subjects when identifying associations between diet and white blood cell DNA methylation in EWAS.",
+Yes,20220815,ewas,35882828,DNA methylation and waist-to-hip ratio: an epigenome-wide association study in Chinese monozygotic twins.,J Endocrinol Invest,"Epigenetic signatures such as DNA methylation may be associated with specific obesity traits. We performed an epigenome-wide association study (EWAS) by combining with the waist-to-hip ratio (WHR)-discordant monozygotic (MZ) twin design in an attempt to identify genetically independent DNA methylation marks associated with abdominal obesity in Northern Han Chinese and to determine the causation underlying.A total of 60 WHR discordant MZ twin pairs were selected from the Qingdao Twin Registry, China. Generalized estimated equation (GEE) model was used to regress the methylation level of CpG sites on WHR. The Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) was used to assess the temporal relationship between methylation and WHR. Gene expression analysis was conducted to validate the results of differentially methylated analyses.EWAS identified 92 CpG sites with the level of P < 10 - 4which were annotated to 32 genes, especially CADPS2, TUSC5, ZCCHC14, CORO7, COL23A1, CACNA1C, CYP26B1, and BCAT1. ICE FALCON showed significant causality between DNA methylation of several genes and WHR (P < 0.05). In region-based analysis, 14 differentially methylated regions (DMRs) located at 15 genes (slk-corrected P < 0.05) were detected. The gene expression analysis identified the significant correlation between expression levels of 5 differentially methylated genes and WHR (P < 0.05).Our study identifies the associations between specific epigenetic variations and WHR in Northern Han Chinese. These DNA methylation signatures may have value as diagnostic biomarkers and provide novel insights into the molecular mechanisms of pathogenesis.© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).",
+Yes,20220815,ewas,35858526,Associations between antenatal maternal asthma status and placental DNA methylation.,Placenta,"Maternal asthma in pregnancy is associated with adverse perinatal and child health outcomes; however, mechanisms are poorly understood.The PRogramming of Intergenerational Stress Mechanisms (PRISM) prospective pregnancy cohort characterized asthma history during pregnancy via questionnaires and quantified placental DNAm using the Illumina Infinium HumanMethylation450 BeadChip. We performed epigenome-wide association analyses (n = 223) to estimate associations between maternal active or inactive asthma, as compared to never asthma, and placental differentially methylated positions (DMPs) and differentially variable positions (DVPs). Models adjusted for maternal pre-pregnancy body mass index, smoking status, parity, age and education level and child sex. P-values were FDR-adjusted.One hundred and fifty-nine (71.3%) pregnant women reported no history of asthma (never asthma), 15 (6.7%) reported inactive, and 49 (22%) reported active antenatal asthma. Women predominantly self-identified as Black/Hispanic Black [88 (39.5%)] and Hispanic/non-Black [42 (18.8%)]. We identified 10 probes at FDR<0.05 and 4 probes at FDR<0.10 characterized by higher variability in maternal active asthma compared to never asthma mapping to GPX3, LHPP, PECAM1, ATAD3C, and ARHGEF4 and 2 probes characterized by lower variation mapping to CHMP4A and C5orf24. Amongst women with inactive asthma, we identified 52 probes, 41 at FDR<0.05 and an additional 11 at FDR <0.10, with higher variability compared to never asthma; BMP4, LHPP, PHYHIPL, and ZSCAN23 were associated with multiple DVPs. No associations were observed with DMPs.We observed alterations in placental DNAm in women with antenatal asthma, as compared to women without a history of asthma. Further research is needed to understand the impact on fetal development.Copyright © 2022 Elsevier Ltd. All rights reserved.",
+Yes,20220815,ewas,35850911,Effect of menopausal hormone therapy on methylation levels in early and late postmenopausal women.,Clin Epigenetics,"Cardiovascular disease (CVD) remains the leading cause of death among postmenopausal women but standard primary prevention strategies in women are not as effective as in men. By comparison, the Early versus Late Intervention Trial with Estradiol (ELITE) study demonstrated that hormone therapy (HT) was associated with significant reduction in atherosclerosis progression in women who were within six years of menopause compared to those who were 10 or more years from menopause. These findings are consistent with other studies showing significant reductions in all-cause mortality and CVD with HT, particularly when initiated in women younger than 60 years of age or within 10 years since menopause. To explore the biological mechanisms underlying the age-related atheroprotective effects of HT, we investigated changes in methylation of blood cells of postmenopausal women who participated in ELITE.We first validated the epigenetic data generated from blood leukocytes of ELITE participants by replicating previously known associations between smoking and methylation levels at previously identified CpG sites, such as cg05575921 at the AHRR locus. An epigenome-wide association study (EWAS) evaluating changes in methylation through interactions with time-since-menopause and HT revealed two significantly associated CpG sites on chromosomes 12 (cg19552895; p = 1.1 × 10-9) and 19 (cg18515510; p = 2.4 × 10-8). Specifically, HT resulted in modest, but significant, increases in methylation levels at both CpGs but only in women who were 10 or more years since menopause and randomized to HT. Changes in carotid artery intima-media thickness (CIMT) from baseline to 36 months after HT were not significantly correlated with changes in methylation levels at either cg19552895 or cg18515510. Evaluation of other previously identified CpG sites at which methylation levels in either blood or vascular tissue were associated with atherosclerosis also did not reveal any differences in methylation as a function of HT and time-since-menopause or with changes in CIMT.We identified specific methylation differences in blood in response to HT among women who were 10 or more years since menopause. The functional consequence of these change with respect to atherosclerosis progression and protective effects of HT remains to be determined and will require additional studies.© 2022. The Author(s).",
+Yes,20220815,ewas,35837683,Genome-wide methylation analysis of early-onset schizophrenia.,Psychiatr Genet,"Schizophrenia (SCZ) is a debilitating disease with a complex genetic cause in which age at onset may reflect genetic vulnerability. Though there has been some association between genetic polymorphisms and age of onset, there has been little exploration of the role of epigenetic processes. We sought to explore the influence of DNA methylation, a key epigenetic mechanism, and its association with the age of onset of illness.One hundred thirty-eight participants aged 18-75 years and previously diagnosed with SCZ spectrum disorders by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID DSM-5) were recruited. Venous blood was collected and genome-wide DNA methylation was quantified using the Illumina Infinium HumanMethylation450 BeadChip array. Individual CpG sites and regions of differential methylation were explored by the age of onset; covariates included age, sex, as well as white blood cell composition.Binary grouping (early vs. late onset) revealed four intergenic CpG sites on chromosome 2 that were above the expected P-value threshold, with hypermethylation of the CpG site cg10392614 most strongly associated with early-onset SCZ. The four most strongly associated CpG sites, including cg 10392614, were intergenic. Continuous analysis revealed the top CpG site to be cg11723066, which is linked to the JAM3 gene, with hypomethylation associated with earlier onset; however, results were below the expected P-value threshold.Studies on DNA methylation in the first-episode psychosis population may help further our understanding of the role of epigenetics in the age of onset of SCZ.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.",
+Yes,20220815,ewas,35836289,Maternal-fetal stress and DNA methylation signatures in neonatal saliva: an epigenome-wide association study.,Clin Epigenetics,"Maternal stress before, during and after pregnancy has profound effects on the development and lifelong function of the infant's neurocognitive development. We hypothesized that the programming of the central nervous system (CNS), hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) induced by prenatal stress (PS) is reflected in electrophysiological and epigenetic biomarkers. In this study, we aimed to find noninvasive epigenetic biomarkers of PS in the newborn salivary DNA.A total of 728 pregnant women were screened for stress exposure using Cohen Perceived Stress Scale (PSS), 164 women were enrolled, and 114 dyads were analyzed. Prenatal Distress Questionnaire (PDQ) was also administered to assess specific pregnancy worries. Transabdominal fetal electrocardiograms (taECG) were recorded to derive coupling between maternal and fetal heart rates resulting in a 'Fetal Stress Index' (FSI). Upon delivery, we collected maternal hair strands for cortisol measurements and newborn's saliva for epigenetic analyses. DNA was extracted from saliva samples, and DNA methylation was measured using EPIC BeadChip array (850 k CpG sites). Linear regression was used to identify associations between PSS/PDQ/FSI/Cortisol and DNA methylation. We found epigenome-wide significant associations for 5 CpG with PDQ and cortisol at FDR < 5%. Three CpGs were annotated to genes (Illumina Gene annotation file): YAP1, TOMM20 and CSMD1, and two CpGs were located approximately lay at 50 kb from SSBP4 and SCAMP1. In addition, two differentiated methylation regions (DMR) related to maternal stress measures PDQ and cortisol were found: DAXX and ARL4D.Genes annotated to these CpGs were found to be involved in secretion and transportation, nuclear signaling, Hippo signaling pathways, apoptosis, intracellular trafficking and neuronal signaling. Moreover, some CpGs are annotated to genes related to autism, post-traumatic stress disorder (PTSD) and schizophrenia. However, our results should be viewed as hypothesis generating until replicated in a larger sample. Early assessment of such noninvasive PS biomarkers will allow timelier detection of babies at risk and a more effective allocation of resources for early intervention programs to improve child development. A biomarker-guided early intervention strategy is the first step in the prevention of future health problems, reducing their personal and societal impact.© 2022. The Author(s).",
+Yes,20220815,ewas,35836279,An epigenome-wide association study of insulin resistance in African Americans.,Clin Epigenetics,"African Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylation450 BeadChip, we performed an epigenome-wide association study to identify DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men (mean age 41.6 years) from the Howard University Family Study.We identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR. One DMP (cg14013695, HOXA5) is a known locus among Mexican Americans, while the other two DMPs are novel-cg00456326 (OSR1; beta = 0.027) and cg20259981 (ST18; beta = 0.010). Although the cg00456326 DMP is novel, the OSR1 gene has previously been found associated with both insulin resistance and T2D in Europeans. The genes HOXA5 and ST18 have been implicated in biological processes relevant to insulin resistance. Differential methylation at the significant HOXA5 and OSR1 DMPs is associated with differences in gene expression in the iMETHYL database. Analysis of differentially methylated regions (DMRs) did not identify any epigenome-wide DMRs for HOMA-IR. We tested transferability of HOMA-IR associated DMPs from five previous EWAS in Mexican Americans, Indian Asians, Europeans, and European ancestry Americans. Out of the 730 previously reported HOMA-IR DMPs, 47 (6.4%) were associated with HOMA-IR in this cohort of African Americans.The findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. Two of the DMPs we identified in African Americans have not been reported in other populations, and we found low transferability of HOMA-IR DMPs reported in other populations in African Americans. More work in African-ancestry populations is needed to confirm our findings as well as functional analyses to understand how such DNA methylation alterations contribute to T2D pathology.© 2022. The Author(s).",
+Yes,20220815,ewas,35879377,Characterization of methylation patterns associated with lifestyle factors and vitamin D supplementation in a healthy elderly cohort from Southwest Sweden.,Sci Rep,"Numerous studies have shown that lifestyle factors, such as regular physical activity and vitamin D intake, may remarkably improve overall health and mental wellbeing. This is especially important in older adults whose vitamin D deficiency occurs with a high prevalence. This study aimed to examine the influence of lifestyle and vitamin D on global DNA methylation patterns in an elderly cohort in Southwest of Sweden. We also sought to examine the methylation levels of specific genes involved in vitamin D's molecular and metabolic activated pathways. We performed a genome wide methylation analysis, using Illumina Infinium DNA Methylation EPIC 850kBeadChip array, on 277 healthy individuals from Southwest Sweden at the age of 70-95. The study participants also answered queries on lifestyle, vitamin intake, heart medication, and estimated health. Vitamin D intake did not in general affect methylation patterns, which is in concert with other studies. However, when comparing the group of individuals taking vitamin supplements, including vitamin D, with those not taking supplements, a difference in methylation in the solute carrier family 25 (SCL25A24) gene was found. This confirms a previous finding, where changes in expression of SLC25A24 were associated with vitamin D treatment in human monocytes. The combination of vitamin D intake and high physical activity increased methylation of genes linked to regulation of vitamin D receptor pathway, the Wnt pathway and general cancer processes. To our knowledge, this is the first study detecting epigenetic markers associated with the combined effects of vitamin D supplementation and high physical activity. These results deserve to be further investigated in an extended, interventional study cohort, where also the levels of 25(OH)D3can be monitored.© 2022. The Author(s).",
+Yes,20220815,ewas,35798818,"EWAS of post-COVID-19 patients shows methylation differences in the immune-response associated gene, IFI44L, three months after COVID-19 infection.",Sci Rep,"Although substantial progress has been made in managing COVID-19, it is still difficult to predict a patient's prognosis. We explored the epigenetic signatures of COVID-19 in peripheral blood using data from an ongoing prospective observational study of COVID-19 called the Norwegian Corona Cohort Study. A series of EWASs were performed to compare the DNA methylation profiles between COVID-19 cases and controls three months post-infection. We also investigated differences associated with severity and long-COVID. Three CpGs-cg22399236, cg03607951, and cg09829636-were significantly hypomethylated (FDR < 0.05) in COVID-19 positive individuals. cg03607951 is located in IFI44L which is involved in innate response to viral infection and several systemic autoimmune diseases. cg09829636 is located in ANKRD9, a gene implicated in a wide variety of cellular processes, including the degradation of IMPDH2. The link between ANKRD9 and IMPDH2 is striking given that IMPDHs are considered therapeutic targets for COVID-19. Furthermore, gene ontology analyses revealed pathways involved in response to viruses. The lack of significant differences associated with severity and long-COVID may be real or reflect limitations in sample size. Our findings support the involvement of interferon responsive genes in the pathophysiology of COVID-19 and indicate a possible link to systemic autoimmune diseases.© 2022. The Author(s).",
+Yes,20220815,ewas,35790973,Longitudinal associations of DNA methylation and sleep in children: a meta-analysis.,Clin Epigenetics,"Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children.We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4-13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration.We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10-8). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10-8, n = 577) and sleep onset latency (p = 8.8 × 10-9, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716-2539).DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available.© 2022. The Author(s).",
+Yes,20220815,ewas,35771992,Recreational physical activity before and during pregnancy and placental DNA methylation - an epigenome-wide association study.,Am J Clin Nutr,"Physical activity (PA) prior to and during pregnancy may have inter-generational effects on offspring health through placental epigenetic modifications. We are unaware of epidemiological studies on longitudinal PA and placental DNA methylation (DNAm).We evaluated the association between PA before and during pregnancy and placental DNAm.Placental tissues were obtained at delivery and methylation was measured using HumanMethylation450 Beadchips for participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons among 298 participants. Using the Pregnancy PA Questionnaire, women recalled periconception PA (past 12 months) at 8-13 weeks gestation, and PA since last visit at four follow-up visits at 16-22, 24-29, 30-33, 34-37 weeks. We conducted linear regression for associations of PA at each visit with methylation controlling for false discovery rate (FDR). Top 100 CpGs were queried for enrichment of functional pathways using Ingenuity Pathway Analysis.Periconception PA was significantly associated with 1 CpG site. PA since last visit for visits 1-4 was associated with 2, 2, 8, 0 CpGs (log fold changes ranging from -0.0319 to 0.0080, after controlling for FDR). The largest change in methylation occurred at a site in TIMP2, which is known to encode a protein critical for vasodilation, placentation, and uterine expansion during pregnancy (log fold change: -0.05, 95% confidence interval: -0.06, -0.03 per metabolic equivalent of task [MET]-hours/week at 30-33 weeks). Most significantly enriched pathways include Cardiac Hypertrophy Signaling, B Cell Receptor Signaling, and Netrin Signaling. Significant CpGs and enriched pathways varied by visit.Recreational PA in the year prior and during pregnancy was associated with placental DNAm. The associated CpG sites varied based on timing of PA. If replicated, the findings may inform the mechanisms underlying the impacts of PA on placenta health. Clinical trial registration number: This study was registered at ClinicalTrials.gov (NCT00912132).© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.",
+Yes,20220815,ewas,35764815,CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation.,Pediatr Res,"Infants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health.We contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort. Neonatal inflammation status was based on the expression of six inflammation-related proteins, assessed as (1) day-one inflammation (DOI) or (2) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 postnatal weeks). Epigenome-wide CpG methylation was assessed in 354 placental samples and 318 neonatal blood samples.Placental CpG methylation displayed the strongest association with ISSI (48 CpG sites) but was not associated with DOI. This was in contrast to CpG methylation in blood spots, which was associated with DOI (111 CpG sites) and not with ISSI (one CpG site).Placental CpG methylation was strongly associated with ISSI, a measure of inflammation previously linked to later-in-life cognitive impairment, while day-one neonatal blood methylation was associated with DOI.Neonatal inflammation increases the risk of adverse later-life outcomes, especially in infants born extremely preterm. CpG methylation in the placenta and neonatal blood spots were evaluated in relation to neonatal inflammation assessed via circulating proteins as either (i) day-one inflammation (DOI) or (ii) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 weeks). Tissue specificity was observed in epigenetic-inflammatory relationships: placental CpG methylation was associated with ISSI, neonatal blood CpG methylation was associated with DOI. Supporting the placental origins of disease framework, placental epigenetic patterns are associated with a propensity for ISSI in neonates.© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.",
+Yes,20220815,ewas,35762681,Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study.,Epilepsia,"The aim of this study was to investigate the impact of the modified ketogenic diet on DNA methylation in adults with epilepsy.In this prospective study, we investigated the genome-wide DNA methylation in whole blood in 58 adults with epilepsy treated with the modified ketogenic for 12 weeks. Patients were recruited from the National Center for Epilepsy, Norway, from March 1, 2011 to February 28, 2017. DNA methylation was analyzed using the Illumina Infinium MethylationEPIC BeadChip array. Analysis of variance and paired t-test were used to identify differentially methylated loci after 4 and 12 weeks of dietary treatment. A false discovery rate approach with a significance threshold of <5% was used to adjust for multiple comparisons.We observed a genome-wide decrease in DNA methylation, both globally and at specific sites, after 4 and 12 weeks of dietary treatment. A substantial share of the differentially methylated positions (CpGs) were annotated to genes associated with epilepsy (n = 7), lipid metabolism (n = 8), and transcriptional regulation (n = 10). Furthermore, five of the identified genes were related to inositol phosphate metabolism, which may represent a possible mechanism by which the ketogenic diet attenuates seizures.A better understanding of the modified ketogenic diet's influence at the molecular level may be the key to unraveling the mechanisms by which the diet can ameliorate seizures and possibly to identifying novel therapeutic targets for epilepsy.© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.",
+Yes,20220815,ewas,35734807,Sensation-seeking-related DNA methylation and the development of delinquency: A longitudinal epigenome-wide study.,Dev Psychopathol,"Heightened sensation-seeking is related to the development of delinquency. Moreover, sensation-seeking, or biological correlates of sensation-seeking, are suggested as factors linking victimization to delinquency. Here, we focused on epigenetic correlates of sensation-seeking. First, we identified DNA methylation (DNAm) patterns related to sensation-seeking. Second, we investigated the association between sensation-seeking related DNAm and the development of delinquency. Third, we examined whether victimization was related to sensation-seeking related DNAm and the development of delinquency. Participants (N= 905; 49% boys) came from the Avon Longitudinal Study of Parents and Children. DNAm was assessed at birth, age 7 and age 15-17. Sensation-seeking (self-reports) was assessed at age 11 and 14. Delinquency (self-reports) was assessed at age 17-19. Sensation-seeking epigenome-wide association study revealed that no probes reached the critical significance level. However, 20 differential methylated probes reached marginal significance. With these 20 suggestive sites, a sensation-seeking cumulative DNAm risk score was created. Results showed that this DNAm risk score at age 15-17 was related to delinquency at age 17-19. Moreover, an indirect effect of victimization to delinquency via DNAm was found. Sensation-seeking related DNAm is a potential biological correlate that can help to understand the development of delinquency, including how victimization might be associated with adolescent delinquency.",
+Yes,20220815,ewas,35732753,Association between DNA methylation variability and self-reported exposure to heavy metals.,Sci Rep,"Individuals encounter varying environmental exposures throughout their lifetimes. Some exposures such as smoking are readily observed and have high personal recall; others are more indirect or sporadic and might only be inferred from long occupational histories or lifestyles. We evaluated the utility of using lifetime-long self-reported exposures for identifying differential methylation in an amyotrophic lateral sclerosis cases-control cohort of 855 individuals. Individuals submitted paper-based surveys on exposure and occupational histories as well as whole blood samples. Genome-wide DNA methylation levels were quantified using the Illumina Infinium Human Methylation450 array. We analyzed 15 environmental exposures using the OSCA software linear and MOA models, where we regressed exposures individually by methylation adjusted for batch effects and disease status as well as predicted scores for age, sex, cell count, and smoking status. We also regressed on the first principal components on clustered environmental exposures to detect DNA methylation changes associated with a more generalised definition of environmental exposure. Five DNA methylation probes across three environmental exposures (cadmium, mercury and metalwork) were significantly associated using the MOA models and seven through the linear models, with one additionally across a principal component representing chemical exposures. Methylome-wide significance for four of these markers was driven by extreme hyper/hypo-methylation in small numbers of individuals. The results indicate the potential for using self-reported exposure histories in detecting DNA methylation changes in response to the environment, but also highlight the confounded nature of environmental exposure in cohort studies.© 2022. The Author(s).",
+Yes,20220815,ewas,35717949,DNA Methylation and Ischemic Stroke Risk: An Epigenome-Wide Association Study.,Thromb Haemost,"Ischemic stroke (IS) risk heritability is partly explained by genetics. Other heritable factors, such as epigenetics, could explain an unknown proportion of the IS risk. The objective of this study is to evaluate DNA methylation association with IS using epigenome-wide association studies (EWAS).�We performed a two-stage EWAS comprising 1,156 subjects. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were assessed using the Infinium 450K and EPIC BeadChip in the discovery cohort (252 IS and 43 controls). Significant DMPs were replicated in an independent cohort (618 IS and 243 controls). Stroke subtype associations were also evaluated. Differentially methylated cell-type (DMCT) was analyzed in the replicated CpG sites using EpiDISH. We additionally performed pathway enrichment analysis and causality analysis with Mendelian randomization for the replicated CpG sites.�A total of 957 CpG sites were epigenome-wide-significant (p≤ 10-7) in the discovery cohort, being CpG sites in the top signals (logFC = 0.058,p = 2.35 × 10-22; logFC = 0.035,p = 3.22 × 10-22, respectively).ZFHX3andMAP3K1were among the most significant DMRs. In addition, 697 CpG sites were replicated considering Bonferroni-correctedp-values (p < 5.22 × 10-5). All the replicated DMPs were associated with risk of cardioembolic, atherothrombotic, and undetermined stroke. The DMCT analysis demonstrated that the significant associations were driven by natural killer cells. The pathway enrichment analysis showed overrepresentation of genes belonging to certain pathways including oxidative stress.ZFHX3andMAP3K1methylation was causally associated with specific stroke-subtype risk.�Specific DNA methylation pattern is causally associated with IS risk. These results could be useful for specifically predicting stroke occurrence and could potentially be evaluated as therapeutic targets.Thieme. All rights reserved.",
+Yes,20220815,ewas,35708509,Maternal Dietary Glycemic Index and Glycemic Load in Pregnancy and Offspring Cord Blood DNA Methylation.,Diabetes Care,"Suboptimal nutrition in pregnancy is associated with worse offspring cardiometabolic health. DNA methylation may be an underlying mechanism. We meta-analyzed epigenome-wide association studies (EWAS) of maternal dietary glycemic index and load with cord blood DNA methylation.We calculated maternal glycemic index and load from food frequency questionnaires and ran EWAS on cord blood DNA methylation in 2,003 mother-offspring pairs from three cohorts. Analyses were additionally stratified by maternal BMI categories. We looked-up the findings in EWAS of maternal glycemic traits and BMI as well as in EWAS of birth weight and child BMI. We examined associations with gene expression in child blood in the online Human Early Life Exposome eQTM catalog and in 223 adipose tissue samples.Maternal glycemic index and load were associated with cord blood DNA methylation at 41 cytosine-phosphate-guanine sites (CpGs, P < 1.17 × 10-7), mostly in mothers with overweight/obesity. We did not observe overlap with CpGs associated with maternal glycemic traits, BMI, or child birth weight or BMI. Only DNA methylation at cg24458009 and cg23347399 was associated with expression of PCED1B and PCDHG, respectively, in child blood, and DNA methylation at cg27193519 was associated with expression of TFAP4, ZNF500, PPL, and ANKS3 in child subcutaneous adipose tissue.We observed multiple associations of maternal glycemic index and load during pregnancy with cord blood DNA methylation, mostly in mothers with overweight/obesity; some of these CpGs were associated with gene expression. Additional studies are required to further explore functionality, uncover causality, and study pathways to offspring health.© 2022 by the American Diabetes Association.",
+Yes,20220815,ewas,35749371,Effect of an antenatal diet and lifestyle intervention and maternal BMI on cord blood DNA methylation in infants of overweight and obese women: The LIMIT Randomised Controlled Trial.,PLoS One,"To investigate the effect of an antenatal diet and lifestyle intervention, and maternal pre-pregnancy overweight or obesity, on infant cord blood DNA methylation.We measured DNA methylation in 645 cord blood samples from participants in the LIMIT study (an antenatal diet and lifestyle intervention for women with early pregnancy BMI ≥25.0 kg/m2) using the Illumina 450K BeadChip array, and tested for any differential methylation related to the intervention, and to maternal early pregnancy BMI. We also analysed differential methylation in relation to selected candidate genes.No CpG sites were significantly differentially methylated in relation to either the diet and lifestyle intervention, or with maternal early pregnancy BMI. There was no significant differential methylation in any of the selected genes related to the intervention, or to maternal BMI.We found no evidence of an effect of either antenatal diet and lifestyle, or of maternal early pregnancy BMI, on cord blood DNA methylation.ACTRN12607000161426.",
+Yes,20220815,ewas,35723298,DNA Methylation Patterns According to Fatty Liver Index and Longitudinal Changes from the Korean Genome and Epidemiology Study (KoGES).,Curr Issues Mol Biol,"The role of differentially methylated regions (DMRs) in nonalcoholic fatty liver disease (NAFLD) is unclear. This study aimed to identify the role of DMR in NAFLD development and progression using the Korean Genome and Epidemiology Study (KoGES) cohort. We used laboratory evaluations and Illumina Methylation 450 k DNA methylation microarray data from KoGES. The correlation between fatty liver index (FLI) and genomic CpG sites was analyzed in 322 subjects. Longitudinal changes over 8 years were confirmed in 33 subjects. To identify CpG sites and genes related to FLI, we obtained enrichment terms for 6765 genes. DMRs were identified for both high (n= 128) and low (n= 194) groups on the basis of FLI 30 in 142 men and 180 women. To confirm longitudinal changes in 33 subjects, the ratio of follow-up and baseline investigation values was obtained. Correlations and group comparisons were performed for the 8 year change values.PITPNM3,RXFP3, andTHRBwere hypermethylated in the increased FLI groups, whereasSLC9A2andFOXI3were hypermethylated in the decreased FLI groups. DMRs describing NAFLD were determined, and functions related to inflammation were identified. Factors related to longitudinal changes are suggested, and blood circulation-related functions appear to be important in the management of NAFLD.",
+Yes,20220815,ewas,35768464,Methylome-wide analysis of IVF neonates that underwent embryo culture in different media revealed no significant differences.,NPJ Genom Med,"A growing number of children born are conceived through in vitro fertilisation (IVF), which has been linked to an increased risk of adverse perinatal outcomes, as well as altered growth profiles and cardiometabolic differences in the resultant individuals. Some of these outcomes have also been shown to be influenced by the use of different IVF culture media and this effect is hypothesised to be mediated epigenetically, e.g. through the methylome. As such, we profiled the umbilical cord blood methylome of IVF neonates that underwent preimplantation embryo development in two different IVF culture media (G5 or HTF), using the Infinium Human Methylation EPIC BeadChip. We found no significant methylation differences between the two groups in terms of: (i) systematic differences at CpG sites or regions, (ii) imprinted sites/genes or birth weight-associated sites, (iii) stochastic differences presenting as DNA methylation outliers or differentially variable sites, and (iv) epigenetic gestational age acceleration.© 2022. The Author(s).",
+Yes,20220815,ewas,35769265,Epigenetic DNA Methylation Signatures Associated With the Severity of Paget's Disease of Bone.,Front Cell Dev Biol,"Background:Paget's disease of bone (PDB) is characterized by focal areas of dysregulated bone turnover resulting in increased bone loss and abnormal bone formation with variable severity. PDB has a complex etiology and both genetics and environmental factors have been implicated. A recent study has identified many differentially methylated loci in PDB compared to healthy subjects. However, associations between DNA methylation profiles and disease severity of PDB have not been investigated.Objectives:To investigate the association between DNA methylation signals and PDB severity.Methods:Using 232 well-characterized PDB subjects from the PRISM trial, a disease severity score was devised based on the clinical features of PDB. DNA methylation profiling was performed using Illumina Infinium HumanMethylation 450K array.Results:We identified 100 CpG methylation sites significantly associated with PDB severity at FDR <0.05. Additionally, methylation profiles in 11 regions showed Bonferroni-significant association with disease severity including six islands (located inVCL,TBX5,CASZ1,ULBP2,NUDT15andSQSTM1), two gene bodies (CXCR6andDENND1A), and 3 promoter regions (RPL27,LINC00301andVPS29). Moreover, FDR-significant effects from region analysis implicated genes with genetic variants previously associated with PDB severity, includingRIN3andCSF1. A multivariate predictor model featuring the top severity-associated CpG sites revealed a significant correlation (R = 0.71,p= 6.9 × 10-16) between observed and predicted PDB severity scores. On dichotomizing the severity scores into low and high severity, the model featured an area under curve (AUC) of 0.80, a sensitivity of 0.74 and a specificity of 0.68.Conclusion:We identified several CpG methylation markers that are associated with PDB severity in this pioneering study while also highlighting the novel molecular pathways associated with disease progression. Further work is warranted to affirm the suitability of our model to predict the severity of PDB in newly diagnosed patients or patients with family history of PDB.Copyright © 2022 Diboun, Wani, Ralston and Albagha.",
+Yes,20220815,ewas,35933486,Whole blood DNA methylation analysis reveals respiratory environmental traits involved in COVID-19 severity following SARS-CoV-2 infection.,Nat Commun,"SARS-CoV-2 infection can cause an inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea, and in ~5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping. The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We find an environmental trait-related signature that discriminates mild from severe cases and regulates, among other cytokines, IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics, and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.© 2022. The Author(s).",
+Yes,20220815,ewas,35899434,Socioeconomic changes predict genome-wide DNA methylation in childhood.,Hum Mol Genet,"Childhood socioeconomic position (SEP) is a major determinant of health and well-being across the entire life course. To effectively prevent and reduce health risks related to SEP, it is critical to better understand when and under what circumstances socioeconomic adversity shapes biological processes. DNA methylation (DNAm) is one such mechanism for how early life adversity 'gets under the skin'. In this study, we evaluated the dynamic relationship between SEP and DNAm across childhood using data from 946 mother-child pairs in the Avon Longitudinal Study of Parents and Children (ALSPAC). We assessed six SEP indicators spanning financial, occupational, and residential domains during very-early childhood (ages 0-2), early childhood (ages 3-5), and middle childhood (ages 6-7). Epigenome-wide DNAm were measured at 412956 CpGs from peripheral blood at age 7. Using an innovative two-stage structured life course modeling approach, we tested three life-course hypotheses for how SEP shapes DNAm profiles-accumulation, sensitive period, and mobility. We showed that changes in the socioeconomic environment were associated with the greatest differences in DNAm, and that middle childhood may be a potential sensitive period when socioeconomic instability is especially important in shaping DNAm. Top SEP-related DNAm CpGs were overrepresented in genes involved in pathways important for neural development, immune function, and metabolic processes. Our findings highlight the importance of socioeconomic stability during childhood and if replicated, may emphasize the need for public programs to help children and families experiencing socioeconomic instability and other forms of socioeconomic adversity.© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+Yes,20220815,ewas,35843982,Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers.,Genome Med,"There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers of the identified signals, as well as their potential functional roles.Epigenome-wide association analyses were carried out to determine visceral fat mass-associated differentially methylated positions (VF-DMPs) in SAT samples from 538 TwinsUK participants. Validation and replication were performed in 333 individuals from 3 independent cohorts. To assess functional impacts of the VF-DMPs, the association between VF and gene expression was determined at the genes annotated to the VF-DMPs and an association analysis was carried out to determine whether methylation at the VF-DMPs is associated with gene expression. Further epigenetic analyses were carried out to compare methylation levels at the VF-DMPs as the response variables and a range of different metabolic health phenotypes including android:gynoid fat ratio (AGR), lipids, blood metabolomic profiles, insulin resistance, T2D and dietary intake variables. The results from all analyses were integrated to identify signals that exhibit altered SAT function and have strong relevance to metabolic health.We identified 1181 CpG positions in 788 genes to be differentially methylated with VF (VF-DMPs) with significant enrichment in the insulin signalling pathway. Follow-up cross-omic analysis of VF-DMPs integrating genetics, gene expression, metabolomics, diet, and metabolic traits highlighted VF-DMPs located in 9 genes with strong relevance to metabolic disease mechanisms, with replication of signals in FASN, SREBF1, TAGLN2, PC and CFAP410. PC methylation showed evidence for mediating effects of diet on VF. FASN DNA methylation exhibited putative causal effects on VF that were also strongly associated with insulin resistance and methylation levels in FASN better classified insulin resistance (AUC=0.91) than BMI or VF alone.Our findings help characterise the adiposity-associated methylation signature of SAT, with insights for metabolic disease risk.© 2022. The Author(s).",
+Yes,20220815,ewas,35837690,Prenatal Socioeconomic Disadvantage and Epigenetic Alterations at Birth Among Children Born to White British and Pakistani Mothers in the Born in Bradford Study.,Epigenetics,"Prenatal socioeconomic disadvantage (SD) has been linked to DNA methylation (DNAm) in adulthood, but whether such epigenetic alterations are present at birth remains unclear. We carried out an epigenome-wide analysis of the association between several measures of individual- and area-level prenatal SD and DNAm assessed in neonatal cord blood via the Infinium EpicBeadChip among offspring born to mothers of White British (N = 455) and Pakistani (N = 493) origin in the Born in Bradford Study. Models were adjusted for mother's age, ethnicity, and education level as well as cell-type fractions and then for maternal health behaviours and neonate characteristics, and last, stratified by mother's ethnicity. P-values were corrected for multiple testing and a permutation-based approach was used to account for small cell sizes. Among all children, housing tenure (owning versus renting) as well as father's occupation (manual versus non-manual) were each associated with DNAm of one CpG site and index of multiple deprivation (IMD) was associated with DNAm of 11 CpG sites. Among children born to White British mothers, father's occupation (student or unemployed versus non-manual) was associated with DNAm of 1 CpG site and IMD with DNAm of 3 CpG sites. Among children born to Pakistani mothers, IMD was associated with DNAm of 1 CpG site. Associations were largely unchanged after further adjustment for maternal health behaviours or neonate characteristics and remained statistically significant. Our findings suggest that individual- and area-level prenatal SD may shape alterations to the neonatal epigenome, but associations vary across ethnic groups.",
+Yes,20220815,ewas,35717575,Investigating DNA methylation as a mediator of genetic risk in childhood acute lymphoblastic Leukemia.,Hum Mol Genet,"Genome-wide association studies have identified a growing number of single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL), yet the functional roles of most SNPs are unclear. Multiple lines of evidence suggest epigenetic mechanisms may mediate the impact of heritable genetic variation on phenotypes. Here, we investigated whether DNA methylation mediates the effect of genetic risk loci for childhood ALL. We performed an epigenome-wide association study (EWAS) including 808 childhood ALL cases and 919 controls from California-based studies using neonatal blood DNA. For differentially methylated CpG positions (DMPs), we next conducted association analysis with 23 known ALL risk SNPs followed by causal mediation analyses addressing the significant SNP-DMP pairs. DNA methylation at CpG cg01139861, in the promoter region of IKZF1, mediated the effects of the intronic IKZF1 risk SNP rs78396808, with the average causal mediation effect (ACME) explaining ~ 30% of the total effect (ACME P = 0.0031). In analyses stratified by self-reported race/ethnicity, the mediation effect was only significant in Latinos, explaining ~ 41% of the total effect of rs78396808 on ALL risk (ACME P = 0.0037). Conditional analyses confirmed the presence of at least three independent genetic risk loci for childhood ALL at IKZF1, with rs78396808 unique to non-European populations. We also demonstrated that the most significant DMP in the EWAS, CpG cg13344587 at gene ARID5B (P = 8.61x10-10), was entirely confounded by the ARID5B ALL risk SNP rs7090445. Our findings provide new insights into the functional pathways of ALL risk SNPs and the DNA methylation differences associated with risk of childhood ALL.© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+Yes,20220815,ewas,35918756,Prenatal vitamin intake in first month of pregnancy and DNA methylation in cord blood and placenta in two prospective cohorts.,Epigenetics Chromatin,"Prenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the US Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies.In placenta, prenatal vitamin intake was marginally associated with -0.52% (95% CI -1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with -0.60% (-1.08, -0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p-value < 0.01 (EARLI cord nCpGs = 4068, EARLI placenta nCpGs = 3647, MARBLES cord nCpGs = 4068, MARBLES placenta nCpGs = 9563) were consistently enriched in neuronal developmental pathways.Together, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.© 2022. The Author(s).",
+No,20220815,imprinting,35787786,Genome-wide detection of imprinted differentially methylated regions using nanopore sequencing.,Elife,"Imprinting is a critical part of normal embryonic development in mammals, controlled by defined parent-of-origin (PofO) differentially methylated regions (DMRs) known as imprinting control regions. Direct nanopore sequencing of DNA provides a means to detect allelic methylation and to overcome the drawbacks of methylation array and short-read technologies. Here, we used publicly available nanopore sequencing data for 12 standard B-lymphocyte cell lines to acquire the genome-wide mapping of imprinted intervals in humans. Using the sequencing data, we were able to phase 95% of the human methylome and detect 94% of the previously well-characterized, imprinted DMRs. In addition, we found 42 novel imprinted DMRs (16 germline and 26 somatic), which were confirmed using whole-genome bisulfite sequencing (WGBS) data. Analysis of WGBS data in mouse (Mus musculus), rhesus monkey (Macaca mulatta), and chimpanzee (Pan troglodytes) suggested that 17 of these imprinted DMRs are conserved. Some of the novel imprinted intervals are within or close to imprinted genes without a known DMR. We also detected subtle parental methylation bias, spanning several kilobases at seven known imprinted clusters. At these blocks, hypermethylation occurs at the gene body of expressed allele(s) with mutually exclusive H3K36me3 and H3K27me3 allelic histone marks. These results expand upon our current knowledge of imprinting and the potential of nanopore sequencing to identify imprinting regions using only parent-offspring trios, as opposed to the large multi-generational pedigrees that have previously been required.© 2022, Akbari et al.",
+No,20220815,imprinting,35786392,Genomic map of candidate human imprint control regions: the imprintome.,Epigenetics,"Imprinted genes - critical for growth, metabolism, and neuronal function - are expressed from one parental allele. Parent-of-origin-dependent CpG methylation regulates this expression at imprint control regions (ICRs). Since ICRs are established before tissue specification, these methylation marks are similar across cell types. Thus, they are attractive for investigating the developmental origins of adult diseases using accessible tissues, but remain unknown. We determined genome-wide candidate ICRs in humans by performing whole-genome bisulphite sequencing (WGBS) of DNA derived from the three germ layers and from gametes. We identified 1,488 hemi-methylated candidate ICRs, including 19 of 25 previously characterized ICRs (https://humanicr.org/). Gamete methylation approached 0% or 100% in 332 ICRs (178 paternally and 154 maternally methylated), supporting parent-of-origin-specific methylation, and 65% were in well-described CTCF-binding or DNaseI hypersensitive regions. This draft of the human imprintome will allow for the systematic determination of the role of early-acquired imprinting dysregulation in the pathogenesis of human diseases and developmental and behavioural disorders.",
+No,20220815,mediation,35708873,"Alcohol consumption, blood DNA methylation and breast cancer: a Mendelian randomisation study.",Eur J Epidemiol,"Alcohol intake is thought to be a risk factor for breast cancer, but the causal relationship and carcinogenic mechanisms are not clear. We performed an up-to-date meta-analysis of prospective studies to assess observational association, and then conducted MR analysis to make causal inference based on the genetic predisposition to alcohol consumption (""drinks per week"") and pathological drinking behaviours (""alcohol use disorder"" and ""problematic alcohol use""), as well as genetically predicted DNA methylation at by alcohol-related CpG sites in blood. We found an observational dose-response association between alcohol intake and breast cancer incidence with an additional risk of 4% for per 10 g/day increase in alcohol consumption. Genetic predisposition to alcohol consumption (""drinks per week"") was not causally associated with breast cancer incidence at the OR of 1.01 (95% CI 0.84, 1.23), but problematic alcohol use (PAU) was linked to a higher breast cancer risk at the OR of 1.76 (95% CI 1.04, 2.99) when conditioning on alcohol consumption. Epigenetic MR analysis identified four CpG sites, cg03260624 near CDC7 gene, cg10816169 near ZNF318 gene, cg03345232 near RIN3 gene, and cg26312998 near RP11-867G23.13 gene, where genetically predicted epigenetic modifications were associated with an increased breast cancer incidence risk. Our findings re-affirmed that alcohol consumption is of high risk for breast cancer incidence even at a very low dose, and the pathogenic effect of alcohol on breast cancer could be due to pathological drinking behaviour and epigenetic modification at several CpG sites, which could be potential intervention targets for breast cancer prevention.© 2022. The Author(s).",
+No,20220815,methods,35914392,Examining the epigenetic mechanisms of childhood adversity and sensitive periods: A gene set-based approach.,Psychoneuroendocrinology,"Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods.Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (ngenes= 15), closing (ngenes= 36), and expression (ngenes= 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences.Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction.Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications.Copyright © 2022 Elsevier Ltd. All rights reserved.",
+No,20220815,methods,35870905,EpiVisR: exploratory data analysis and visualization in epigenome-wide association analyses.,BMC Bioinformatics,"With the widespread availability of microarray technology for epigenetic research, methods for calling differentially methylated probes or differentially methylated regions have become effective tools to analyze this type of data. Furthermore, visualization is usually employed for quality check of results and for further insights. Expert knowledge is required to leverage capabilities of these methods. To overcome this limitation and make visualization in epigenetic research available to the public, we designed EpiVisR.The EpiVisR tool allows to select and visualize combinations of traits (i.e., concentrations of chemical compounds) and differentially methylated probes/regions. It supports various modes of enriched presentation to get the most knowledge out of existing data: (1) enriched Manhattan plot and enriched volcano plot for selection of probes, (2) trait-methylation plot for visualization of selected trait values against methylation values, (3) methylation profile plot for visualization of a selected range of probes against selected trait values as well as, (4) correlation profile plot for selection and visualization of further probes that are correlated to the selected probe. EpiVisR additionally allows exporting selected data to external tools for tasks such as network analysis.The key advantage of EpiVisR is the annotation of data in the enriched plots (and tied tables) as well as linking to external data sources for further integrated data analysis. Using the EpiVisR approach will allow users to integrate data from traits with epigenetic analyses that are connected by belonging to the same individuals. Merging data from various data sources among the same cohort and visualizing them will enable users to gain more insights from existing data.© 2022. The Author(s).",
+No,20220815,methods,35765087,Low reliability of DNA methylation across Illumina Infinium platforms in cord blood: implications for replication studies and meta-analyses of prenatal exposures.,Clin Epigenetics,"There is an increasing interest in the role of epigenetics in epidemiology, but the emerging research field faces several critical biological and technical challenges. In particular, recent studies have shown poor correlation of measured DNA methylation (DNAm) levels within and across Illumina Infinium platforms in various tissues. In this study, we have investigated concordance between 450 k and EPIC Infinium platforms in cord blood. We could not replicate our previous findings on the association of prenatal paracetamol exposure with cord blood DNAm, which prompted an investigation of cross-platform DNAm differences.This study is based on two DNAm data sets from cord blood samples selected from the Norwegian Mother, Father and Child Cohort Study (MoBa). DNAm of one data set was measured using the 450 k platform and the other data set was measured using the EPIC platform. Initial analyses of the EPIC data could not replicate any of our previous significant findings in the 450 k data on associations between prenatal paracetamol exposure and cord blood DNAm. A subset of the samples (n = 17) was included in both data sets, which enabled analyses of technical sources potentially contributing to the negative replication. Analyses of these 17 samples with repeated measurements revealed high per-sample correlations ([Formula: see text] 0.99), but low per-CpG correlations ([Formula: see text] � 0.24) between the platforms. 1.7% of the CpGs exhibited a mean DNAm difference across platforms > 0.1. Furthermore, only 26.7% of the CpGs exhibited a moderate or better cross-platform reliability (intra-class correlation coefficient ≥ 0.5).The observations of low cross-platform probe correlation and reliability corroborate previous reports in other tissues. Our study cannot determine the origin of the differences between platforms. Nevertheless, it emulates the setting in studies using data from multiple Infinium platforms, often analysed several years apart. Therefore, the findings may have important implications for future epigenome-wide association studies (EWASs), in replication, meta-analyses and longitudinal studies. Cognisance and transparency of the challenges related to cross-platform studies may enhance the interpretation, replicability and validity of EWAS results both in cord blood and other tissues, ultimately improving the clinical relevance of epigenetic epidemiology.© 2022. The Author(s).",
+No,20220815,methods,35615339,Estimating and accounting for unobserved covariates in high-dimensional correlated data.,J Am Stat Assoc,"Many high dimensional and high-throughput biological datasets have complex sample correlation structures, which include longitudinal and multiple tissue data, as well as data with multiple treatment conditions or related individuals. These data, as well as nearly all high-throughput 'omic' data, are influenced by technical and biological factors unknown to the researcher, which, if unaccounted for, can severely obfuscate estimation of and inference on the effects of interest. We therefore developed CBCV and CorrConf: provably accurate and computationally efficient methods to choose the number of and estimate latent confounding factors present in high dimensional data with correlated or nonexchangeable residuals. We demonstrate each method's superior performance compared to other state of the art methods by analyzing simulated multi-tissue gene expression data and identifying sex-associated DNA methylation sites in a real, longitudinal twin study.",
+No,20220815,methods,35879805,A review of deep learning applications in human genomics using next-generation sequencing data.,Hum Genomics,"Genomics is advancing towards data-driven science. Through the advent of high-throughput data generating technologies in human genomics, we are overwhelmed with the heap of genomic data. To extract knowledge and pattern out of this genomic data, artificial intelligence especially deep learning methods has been instrumental. In the current review, we address development and application of deep learning methods/models in different subarea of human genomics. We assessed over- and under-charted area of genomics by deep learning techniques. Deep learning algorithms underlying the genomic tools have been discussed briefly in later part of this review. Finally, we discussed briefly about the late application of deep learning tools in genomic. Conclusively, this review is timely for biotechnology or genomic scientists in order to guide them why, when and how to use deep learning methods to analyse human genomic data.© 2022. The Author(s).",
+No,20220815,prediction,35892159,DNA methylation profiling improves routine diagnosis of paediatric central nervous system tumours: A prospective population-based study.,Neuropathol Appl Neurobiol,"Paediatric brain tumours are rare, and establishing a precise diagnosis can be challenging. Analysis of DNA methylation profiles has been shown to be a reliable method to classify central nervous system (CNS) tumours with high accuracy. We aimed to prospectively analyse CNS tumours diagnosed in Sweden, to assess the clinical impact of adding DNA methylation-based classification to standard paediatric brain tumour diagnostics in an unselected cohort.All CNS tumours diagnosed in children (0-18 years) during 2017-2020 were eligible for inclusion provided sufficient tumour material was available. Tumours were analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier. The initial histopathological diagnosis was compared with the DNA methylation-based classification. For incongruent results, a blinded re-evaluation was performed by an experienced neuropathologist.Two hundred forty tumours with a histopathology-based diagnosis were profiled. A high-confidence methylation score of 0.84 or more was reached in 78% of the cases. In 69%, the histopathological diagnosis was confirmed, and for some of these also refined, 6% were incongruent, and the re-evaluation favoured the methylation-based classification. In the remaining 3% of cases, the methylation class was non-contributory. The change in diagnosis would have had a direct impact on the clinical management in 5% of all patients.Integrating DNA methylation-based tumour classification into routine clinical analysis improves diagnostics and provides molecular information that is important for treatment decisions. The results from methylation profiling should be interpreted in the context of clinical and histopathological information.© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.",
+No,20220815,prediction,35740615,"The Early Detection of Breast Cancer Using Liquid Biopsies: Model Estimates of the Benefits, Harms, and Costs.",Cancers (Basel),"Breast cancer screening is associated with harms, such as false-positives and overdiagnoses, and, thus, novel screen tests can be considered. Liquid biopsies have been proposed as a novel method for the early detection of cancer, but low cell-free DNA tumor fraction might pose a problem for the use in population screening. Using breast cancer microsimulation model MISCAN-Fadia, we estimated the outcomes of using liquid biopsies in breast cancer screening in women aged 50 to 74 in the United States. For varying combinations of test sensitivity and specificity, we quantify the impact of the use of liquid biopsies on the harms and benefits of screening, and we estimate the maximum liquid biopsy price for cost-effective implementation in breast cancer screening at a cost-effectiveness threshold of USD 50,000. We investigate under what conditions liquid biopsies could be a suitable alternative to digital mammography and compare these conditions to a CCGA substudy. Outcomes were compared to digital mammography screening, and include mortality reduction, overdiagnoses, quality-adjusted life-years (QALYs), and the maximum price of a liquid biopsy for cost-effective implementation. When liquid biopsies are unable to detect DCIS, a large proportion of overdiagnosed cases is prevented but overall breast cancer mortality reduction and quality of life are lower, and costs are higher compared to digital mammography screening. Liquid biopsies prices should be restricted to USD 187 per liquid biopsy depending on test performance. Overall, liquid biopsies that are unable to detect ductal carcinoma in situ (DCIS) need to be able to detect small, early-stage tumors, with high specificity, at low costs in order to be an alternative to digital mammography. Liquid biopsies might be more suitable as an addition to digital mammography than as an alternative.",
+No,20220815,prediction,35859180,Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer.,Nature,"Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2-12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20220815,review,35762294,Association between alcohol consumption and DNA methylation in blood: a systematic review of observational studies.,Epigenomics,"Aim:We systematically reviewed and evaluated current literature on alcohol consumption and DNA methylation (DNAm) at the genome-wide and probe-wise level in blood of adults.Materials & methods:Five databases (PubMed, Embase, Web of Science, CINAHL and PsycInfo) were searched until 20 December 2020. Studies assessing the effect of alcohol dependence on DNAm were not eligible.Results:11 cross-sectional studies were included with 88 to 9643 participants. Overall, all studies had a risk of bias criteria unclear or unmet. Epigenome-wide association studies identified between 0 and 5458 differentially methylated positions, and 15 were observed in at least four studies.Conclusion:Potential methylation markers for alcohol consumption have been identified, but further validation in large cohorts is needed.",
+No,20220815,ml,35758797,"An approachable, flexible and practical machine learning workshop for biologists.",Bioinformatics,"The increasing prevalence and importance of machine learning in biological research have created a need for machine learning training resources tailored towards biological researchers. However, existing resources are often inaccessible, infeasible or inappropriate for biologists because they require significant computational and mathematical knowledge, demand an unrealistic time-investment or teach skills primarily for computational researchers. We created the Machine Learning for Biologists (ML4Bio) workshop, a short, intensive workshop that empowers biological researchers to comprehend machine learning applications and pursue machine learning collaborations in their own research. The ML4Bio workshop focuses on classification and was designed around three principles: (i) emphasizing preparedness over fluency or expertise, (ii) necessitating minimal coding and mathematical background and (iii) requiring low time investment. It incorporates active learning methods and custom open-source software that allows participants to explore machine learning workflows. After multiple sessions to improve workshop design, we performed a study on three workshop sessions. Despite some confusion around identifying subtle methodological flaws in machine learning workflows, participants generally reported that the workshop met their goals, provided them with valuable skills and knowledge and greatly increased their beliefs that they could engage in research that uses machine learning. ML4Bio is an educational tool for biological researchers, and its creation and evaluation provide valuable insight into tailoring educational resources for active researchers in different domains.Workshop materials are available at https://github.com/carpentries-incubator/ml4bio-workshop and the ml4bio software is available at https://github.com/gitter-lab/ml4bio.Supplementary data are available at Bioinformatics online.© The Author(s) 2022. Published by Oxford University Press.",
+No,20220905,circulating,36010184,Tracing the Origin of Cell-Free DNA Molecules through Tissue-Specific Epigenetic Signatures.,Diagnostics (Basel),"All cell and tissue types constantly release DNA fragments into human body fluids by various mechanisms including programmed cell death, accidental cell degradation and active extrusion. Particularly, cell-free DNA (cfDNA) in plasma or serum has been utilized for minimally invasive molecular diagnostics. Disease onset or pathological conditions that lead to increased cell death alter the contribution of different tissues to the total pool of cfDNA. Because cfDNA molecules retain cell-type specific epigenetic features, it is possible to infer tissue-of-origin from epigenetic characteristics. Recent research efforts demonstrated that analysis of, e.g., methylation patterns, nucleosome occupancy, and fragmentomics determined the cell- or tissue-of-origin of individual cfDNA molecules. This novel tissue-of origin-analysis enables to estimate the contributions of different tissues to the total cfDNA pool in body fluids and find tissues with increased cell death (pathologic condition), expanding the portfolio of liquid biopsies towards a wide range of pathologies and early diagnosis. In this review, we summarize the currently available tissue-of-origin approaches and point out the next steps towards clinical implementation.",
+No,20220905,chromatin,35947558,Chromatin accessibility of primary human cancers ties regional mutational processes and signatures with tissues of origin.,PLoS Comput Biol,"Somatic mutations in cancer genomes are associated with DNA replication timing (RT) and chromatin accessibility (CA), however these observations are based on normal tissues and cell lines while primary cancer epigenomes remain uncharacterised. Here we use machine learning to model megabase-scale mutation burden in 2,500 whole cancer genomes and 17 cancer types via a compendium of 900 CA and RT profiles covering primary cancers, normal tissues, and cell lines. CA profiles of primary cancers, rather than those of normal tissues, are most predictive of regional mutagenesis in most cancer types. Feature prioritisation shows that the epigenomes of matching cancer types and organ systems are often the strongest predictors of regional mutation burden, highlighting disease-specific associations of mutational processes. The genomic distributions of mutational signatures are also shaped by the epigenomes of matched cancer and tissue types, with SBS5/40, carcinogenic and unknown signatures most accurately predicted by our models. In contrast, fewer associations of RT and regional mutagenesis are found. Lastly, the models highlight genomic regions with overrepresented mutations that dramatically exceed epigenome-derived expectations and show a pan-cancer convergence to genes and pathways involved in development and oncogenesis, indicating the potential of this approach for coding and non-coding driver discovery. The association of regional mutational processes with the epigenomes of primary cancers suggests that the landscape of passenger mutations is predominantly shaped by the epigenomes of cancer cells after oncogenic transformation.",
+No,20220905,chromatin,35978191,Spatial profiling of chromatin accessibility in mouse and human tissues.,Nature,"Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context1. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping2-5, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry6and microfluidic deterministic barcoding5. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.© 2022. The Author(s).",
+Yes,20220905,ewas,36046194,Fetal sex-specific epigenetic associations with prenatal maternal depressive symptoms.,iScience,"Prenatal maternal mental health is a global health challenge with poorly defined biological mechanisms. We used maternal blood samples collected during the second trimester from a Singaporean longitudinal birth cohort study to examine the association between inter-individual genome-wide DNA methylation and prenatal maternal depressive symptoms. We found that (1) the maternal methylome was significantly associated with prenatal maternal depressive symptomsonlyin mothers with a female fetus; and (2) this sex-dependent association was observed in a comparable, UK-based birth cohort study. Qualitative analyses showed fetal sex-specific differences in genomic features of depression-related CpGs and genes mapped from these CpGs in mothers with female fetuses implicated in a depression-associated WNT/β-catenin signaling pathway. These same genes also showed enriched expression in brain regions linked to major depressive disorder. We also found similar female-specific associations with fetal-facing placenta methylome. Our fetal sex-specific findings provide evidence for maternal-fetal interactions as a mechanism for intergenerational transmission.© 2022 The Authors.",
+No,20220905,ewas,36039408,Epigenetic signature of exposure to maternal <i>Trypanosoma cruzi</i> infection in cord blood cells from uninfected newborns.,Epigenomics,"Aims:To assess the epigenetic effects ofin uteroexposure to maternalTrypanosoma cruziinfection.Methods:We performed an epigenome-wide association study to compare the DNA methylation patterns of umbilical cord blood cells from uninfected babies from chagasic and uninfected mothers. DNA methylation was measured using Infinium EPIC arrays.Results:We identified a differential DNA methylation signature of fetal exposure to maternalT. cruziinfection, in the absence of parasite transmission, with 12 differentially methylated sites in B cells and CD4+T cells, including eight protein-coding genes.Conclusion:These genes participate in hematopoietic cell differentiation and the immune response and may be involved in immune disorders. They also have been associated with several developmental disorders and syndromes.",
+Yes,20220905,ewas,36036794,Associations of Heavy Metals with Activities of Daily Living Disability: An Epigenome-Wide View of DNA Methylation and Mediation Analysis.,Environ Health Perspect,"Exposure to heavy metals has been reported to be associated with multiple diseases. However, direct associations and potential mechanisms of heavy metals with physical disability remain unclear.We aimed to quantify associations of heavy metals with physical disability and further explore the potential mechanisms of DNA methylation on the genome scale.A cross-sectional study of 4,391 older adults was conducted and activities of daily living (ADL) disability were identified using a 14-item scale questionnaire including basic and instrumental activities to assess the presence of disability (yes or no) rated on a scale of dependence. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated to quantify associations between heavy metals and ADL disability prevalence using multivariate logistic regression and Bayesian kernel machine regression (BKMR) models. Whole blood-derived DNA methylation was measured using the HumanMethylationEPIC BeadChip array. An ADL disability-related epigenome-wide DNA methylation association study (EWAS) was performed among 212 sex-matched ADL disability cases and controls, and mediation analysis was further applied to explore potential mediators of DNA methylation.Each 1-standard deviation (SD) higher difference inlog10-transformed manganese, copper, arsenic, and cadmium level was significantly associated with a 14% (95% CI: 1.05, 1.24), 16% (95% CI:1.07, 1.26), 22% (95% CI:1.13, 1.33), and 15% (95% CI:1.06, 1.26) higher odds of ADL disability, which remained significant in the multiple-metal and BKMR models. A total of 85 differential DNA methylation sites were identified to be associated with ADL disability prevalence, among which methylation level at cg220000984 and cg23012519 (annotated toIRGMandPKP3) mediated 31.0% and 31.2% of manganese-associated ADL disability prevalence, cg06723863 (annotated toESRP2) mediated 32.4% of copper-associated ADL disability prevalence, cg24433124 (nearest toIER3) mediated 15.8% of arsenic-associated ADL disability prevalence, and cg07905190 and cg17485717 (annotated toFREM1andTCP11L1) mediated 21.5% and 30.5% of cadmium-associated ADL disability prevalence (allp<0.05).Our findings suggested that heavy metals contributed to higher prevalence of ADL disability and that locus-specific DNA methylation are partial mediators, providing potential biomarkers for further cellular mechanism studies. https://doi.org/10.1289/EHP10602.",
+Yes,20220905,ewas,36029471,"Analysis of systemic epigenetic alterations in inflammatory bowel disease: defining geographical, genetic, and immune-inflammatory influences on the circulating methylome.",J Crohns Colitis,"Epigenetic alterations may provide valuable insights into gene-environment interactions play in the pathogenesis of Inflammatory Bowel Disease (IBD).Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) with covariates of age, sex, and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission.A total of 137 differentially methylated positions (DMP) were identified in IBD, including VMP1/MIR21 (p=9.11×10 -15) and RPS6KA2 (6.43×10 -13); with consistency seen across Scandinavia and UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10 -15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10 -16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10 -7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10 -4).These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
+No,20220905,ewas,36017556,Epigenome-wide association studies of occupational exposure to benzene and formaldehyde.,Epigenetics,"relationship between certain myeloid neoplasms and exposure to benzene or formaldehyde. DNA methylation could underlie benzene- and formaldehyde-induced health outcomes, but data in exposed human populations are limited. We conducted two cross-sectional epigenome-wide association studies (EWAS), one in workers exposed to benzene and another in workers exposed to formaldehyde. Using HumanMethylation450 BeadChips, we investigated differences in blood cell DNA methylation among 50 benzene-exposed subjects and 48 controls, and among 31 formaldehyde-exposed subjects and 40 controls. We performed CpG-level and regional-level analyses. In the benzene EWAS, we found genome-wide significant alterations, i.e., FWER-controlledP-values <0.05, in the mean and variance of methylation at 22 and 318 CpG sites, respectively, and in mean methylation of a large genomic region. Pathway analysis of genes corresponding to benzene-associated differential methylation sites revealed an impact on the AMPK signalling pathway. In formaldehyde-exposed subjects compared to controls, 9 CpGs in theDUSP22gene promoter had genome-wide significant decreased methylation variability and a large region of theHOXA5promoter with 44 CpGs was hypomethylated. Our findings suggest that DNA methylation may contribute to the pathogenesis of diseases related to benzene and formaldehyde exposure. Aberrant expression and methylation ofHOXA5previously has been shown to be clinically significant in myeloid leukaemias. The tumour suppressor geneDUSP22is a potential biomarker of exposure to formaldehyde, and irregularities have been associated with multiple exposures and diseases.",
+Yes,20220905,ewas,36012217,Experiences of Trauma and DNA Methylation Profiles among African American Mothers and Children.,Int J Mol Sci,"Potentially traumatic experiences have been associated with chronic diseases. Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed as an explanation for this association. We examined the association of experiences of trauma with epigenome-wide DNAm among African American mothers (n= 236) and their children aged 3-5 years (n= 232; N = 500), using the Life Events Checklist-5 (LEC) and Traumatic Events Screening Inventory-Parent Report Revised (TESI-PRR). We identified no DNAm sites significantly associated with potentially traumatic experience scores in mothers. One CpG site on theENOX1gene was methylome-wide-significant in children (FDR-corrected q-value = 0.05) from the TESI-PRR. This protein-coding gene is associated with mental illness, including unipolar depression, bipolar, and schizophrenia. Future research should further examine the associations between childhood trauma, DNAm, and health outcomes among this understudied and high-risk group. Findings from such longitudinal research may inform clinical and translational approaches to prevent adverse health outcomes associated with epigenetic changes.",
+Yes,20220905,ewas,35998097,Systematic Review and Meta-analysis of Peripheral Blood DNA methylation studies in Inflammatory Bowel Disease.,J Crohns Colitis,"Over the past decade, the DNA methylome has been increasingly studied in peripheral blood of inflammatory bowel disease (IBD) patients. However, a comprehensive summary and meta-analysis of peripheral blood leukocyte (PBL) DNA methylation studies has thus far not been conducted. Here, we systematically reviewed all available literature up to February 2022 and summarized the observations by means of meta-analysis.We conducted a systematic search and critical appraisal of IBD-associated DNA methylation studies in PBL using the biomarker-based cross-sectional studies (BIOCROSS) tool. Subsequently, we performed meta-analyses on the summary statistics obtained from epigenome-wide association studies (EWAS) that included patients with Crohn's Disease (CD), ulcerative colitis (UC) and/or healthy controls (HC).Altogether, we included 15 studies for systematic review. Critical appraisal revealed large methodological and outcome heterogeneity between studies. Summary statistics were obtained from 4 studies based on a cumulative 552 samples (177 CD, 132 UC and 243 HC). Consistent differential methylation was identified for 256 differentially methylated probes (DMPs; Bonferroni-adjusted p-value ≤0.05) when comparing CD with HC and 103 when comparing UC with HC. Comparing IBD (CD + UC) with HC resulted in 224 DMPs. Importantly, several of the previously identified DMPs, such as VMP1/TMEM49/MIR21 and RPS6KA2, were consistently differentially methylated across all studies.Methodological homogenization of IBD epigenetic studies is needed to allow for easier aggregation and independent validation. Nonetheless, we were capable of confirming previous observations. Our results can serve as the basis for future IBD epigenetic biomarker research in PBL.© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.",
+Yes,20220905,ewas,35998020,Whole-genome bisulfite sequencing analysis of circulating tumour DNA for the detection and molecular classification of cancer.,Clin Transl Med,"Cancer cell-specific variation and circulating tumour DNA (ctDNA) methylation are promising biomarkers for non-invasive cancer detection and molecular classification. Nevertheless, the applications of ctDNA to the early detection and screening of cancer remain highly challenging due to the scarcity of cancer cell-specific ctDNA, the low signal-to-noise ratio of DNA variation, and the lack of non-locus-specific DNA methylation technologies.We enrolled three cohorts of breast cancer (BC) patients from two hospitals in China (BC: n = 123; healthy controls: n = 40). We developed a ctDNA whole-genome bisulfite sequencing technology employing robust trace ctDNA capture from up to 200 μL plasma, mini-input (1 ng) library preparation, unbiased genome-wide coverage and comprehensive computational methods.A diagnostic signature comprising 15 ctDNA methylation markers exhibited high accuracy in the early (area under the curve [AUC] of 0.967) and advanced (AUC of 0.971) BC stages in multicentre patient cohorts. Furthermore, we revealed a ctDNA methylation signature that discriminates estrogen receptor status (Training set: AUC of 0.984 and Test set: AUC of 0.780). Different cancer types, including hepatocellular carcinoma and lung cancer, could also be well distinguished.Our study provides a toolset to generate unbiased whole-genome ctDNA methylomes with a minimal amount of plasma to develop highly specific and sensitive biomarkers for the early diagnosis and molecular subtyping of cancer.© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.",
+Yes,20220905,ewas,35995800,Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology.,Nat Commun,"Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.© 2022. The Author(s).",
+Yes,20220905,ewas,35987900,Pre-diagnostic DNA methylation in blood leucocytes in cutaneous melanoma; a nested case-control study within the Norwegian Women and Cancer cohort.,Sci Rep,"The prognosis of cutaneous melanoma depends on early detection, and good biomarkers for melanoma risk may provide a valuable tool to detect melanoma development at a pre-clinical stage. By studying the epigenetic profile in pre-diagnostic blood samples of melanoma cases and cancer free controls, we aimed to identify DNA methylation sites conferring melanoma risk. DNA methylation was measured at 775,528 CpG sites using the Illumina EPIC array in whole blood in incident melanoma cases (n = 183) and matched cancer-free controls (n = 183) in the Norwegian Women and Cancer cohort. Phenotypic information and ultraviolet radiation exposure were obtained from questionnaires. Epigenome wide association (EWAS) was analyzed in future melanoma cases and controls with conditional logistic regression, with correction for multiple testing using the false discovery rate (FDR). We extended the analysis by including a public data set on melanoma (GSE120878), and combining these different data sets using a version of covariate modulated FDR (AdaPT). The analysis on future melanoma cases and controls did not identify any genome wide significant CpG sites (0.85 ≤ padj ≤ 0.99). In the restricted AdaPT analysis, 7 CpG sites were suggestive at the FDR level of 0.15. These CpG sites may potentially be used as pre-diagnostic biomarkers of melanoma risk.© 2022. The Author(s).",
+Yes,20220905,ewas,35982059,Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer's disease.,Nat Commun,"To better understand DNA methylation in Alzheimer's disease (AD) from both mechanistic and biomarker perspectives, we performed an epigenome-wide meta-analysis of blood DNA methylation in two large independent blood-based studies in AD, the ADNI and AIBL studies, and identified 5 CpGs, mapped to the SPIDR, CDH6 genes, and intergenic regions, that are significantly associated with AD diagnosis. A cross-tissue analysis that combined these blood DNA methylation datasets with four brain methylation datasets prioritized 97 CpGs and 10 genomic regions that are significantly associated with both AD neuropathology and AD diagnosis. An out-of-sample validation using the AddNeuroMed dataset showed the best performing logistic regression model includes age, sex, immune cell type proportions, and methylation risk score based on prioritized CpGs in cross-tissue analysis (AUC = 0.696, 95% CI: 0.616 - 0.770, P-value = 2.78 × 10-5). Our study offers new insights into epigenetics in AD and provides a valuable resource for future AD biomarker discovery.© 2022. The Author(s).",
+Yes,20220905,ewas,35979830,Soluble CD14-associated DNA methylation sites predict mortality among men with HIV infection.,AIDS,"Elevated plasma levels of sCD14 predict all-cause mortality in people with HIV (PWH). Epigenetic regulation plays a key role in infection and inflammation. To reveal the epigenetic relationships between sCD14, immune function and disease progression among PWH, we conducted an epigenome-wide association study (EWAS) of sCD14 and investigated the relationship with mortality.DNA methylation (DNAm) levels of peripheral blood samples from PWH in the Veterans Aging Cohort Study (VACS) were measured using the Illumina Infinium Methylation 450K (n = 549) and EPIC (850K) BeadChip (n = 526). Adjusted for covariates and multiple testing, we conducted an epigenome-wide discovery, replication, and meta-analysis to identify significant associations with sCD14. We then examined and replicated the relationship between the principal epigenetic sites and survival using Cox regression models.We identified 118 DNAm sites significantly associated with sCD14 in the meta-analysis of 1075 PWH. The principal associated DNAm sites mapped to genes (e.g. STAT1, PARP9, IFITM1, MX1, and IFIT1) related to inflammation and antiviral response. Adjusting for multiple testing, 10 of 118 sCD14-associated DNAm sites significantly predicted survival time conditional on sCD14 levels.The identification of DNAm sites independently predicting survival may improve our understanding of prognosis and potential therapeutic targets among PWH.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.",
+Yes,20220905,ewas,35977396,Intake of mother's milk by very low birth weight infants and variation in DNA methylation of genes involved in neurodevelopment at 5.5 years.,Am J Clin Nutr,"Mechanisms responsible for associations between intake of mother's milk (MM) in very low birth weight (VLBW, <1500 grams) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification.To assess whether early MM intake by VLBW infants is associated with variations in DNAm at 5.5 years, and whether these variations correlate with neurodevelopmental phenotypes.This cohort study was a 5.5-year follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether % MM (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (5.7 ± 0.2 years, n = 143; birth weight of 1008 ± 517 grams). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, magnetic resonance imaging) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV).EWAS analysis demonstrated % MM intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 (MYO15B) and cg00851389 (MT1A) at 5.5 years (P < 9E-08). Gene Set Enrichment Analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from EWAS was associated with cortical surface area and IQ at 5.5 years (P < 0.05).In-hospital % MM intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 years; some of these DNAm variations are associated with brain structure and IQ. Clinical Trial Registration: ISRCTN35317141 at isrctn.com and NCT02759809 at clinicaltrials.gov.© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.",
+Yes,20220905,ewas,35965483,"Epigenome-wide association study analysis of calorie restriction in humans, CALERIE TM Trial analysis.",J Gerontol A Biol Sci Med Sci,"Calorie restriction (CR) increases healthy lifespan and is accompanied by slowing or reversal of aging-associated DNA methylation (DNAm) changes in animal models. In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE TM) human trial we evaluated associations of CR and changes in whole-blood DNAm.CALERIE TM randomized 220 healthy, non-obese adults in a 2:1 allocation to two years of CR or ad libitum (AL) diet. The average CR in the treatment group through 24-months of follow-up was 12%. Whole blood (baseline, 12 and 24 month) DNAm profiles were measured. Epigenome-wide association study (EWAS) analysis tested CR-induced changes from baseline to 12- and 24-months in the n=197 participants with available DNAm data.CR treatment was not associated with epigenome-wide significant (FDR<0.05) DNAm changes at the individual-CpG-site level. Secondary analysis of sets of CpG sites identified in published EWAS revealed that CR induced DNAm changes opposite to those associated with higher body mass index and cigarette smoking (p<0.003 at 12- and 24-month follow-ups). In contrast, CR altered DNAm at chronological-age associated CpG sites in the direction of older age (p<0.003 at 12- and 24-month follow-ups).Although individual CpG site DNAm changes in response to CR were not identified, analyses of sets CpGs identified in prior EWAS revealed CR-induced changes to blood DNAm. Altered CpG sets were enriched for insulin-production, glucose-tolerance, inflammation, and DNA-binding and -regulation pathways, several of which are known to be modified by CR. DNAm changes may contribute to CR effects on aging.© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.",
+Yes,20220905,ewas,35945220,Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health.,Nat Commun,"Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.© 2022. The Author(s).",
+Yes,20220905,ewas,35947335,DNA methylation trajectories and accelerated epigenetic aging in incident type 2 diabetes.,Geroscience,"DNA methylation (DNAm) patterns across the genome changes during aging and development of complex diseases including type 2 diabetes (T2D). Our study aimed to estimate DNAm trajectories of CpG sites associated with T2D, epigenetic age (DNAmAge), and age acceleration based on four epigenetic clocks (GrimAge, Hannum, Horvath, phenoAge) in the period 10 years prior to and up to T2D onset. In this nested case-control study within Doetinchem Cohort Study, we included 132 incident T2D cases and 132 age- and sex-matched controls. DNAm was measured in blood using the Illumina Infinium Methylation EPIC array. From 107 CpG sites associated with T2D, 10 CpG sites (9%) showed different slopes of DNAm trajectories over time (p < 0.05) and an additional 8 CpG sites (8%) showed significant differences in DNAm levels (at least 1%, p-value per time point < 0.05) at all three time points with nearly parallel trajectories between incident T2D cases and controls. In controls, age acceleration levels were negative (slower epigenetic aging), while in incident T2D cases, levels were positive, suggesting accelerated aging in the case group. We showed that DNAm levels at specific CpG sites, up to 10 years before T2D onset, are different between incident T2D cases and healthy controls and distinct patterns of clinical traits over time may have an impact on those DNAm profiles. Up to 10 years before T2D diagnosis, cases manifested accelerated epigenetic aging. Markers of biological aging including age acceleration estimates based on Horvath need further investigation to assess their utility for predicting age-related diseases including T2D.© 2022. The Author(s), under exclusive licence to American Aging Association.",
+Yes,20220905,ewas,35879030,Methylome-wide Association Study of Patients with Recent-onset Psychosis.,Clin Psychopharmacol Neurosci,"Dysregulation of gene expression through epigenetic mechanisms may have a vital role in the pathogenesis of schizophrenia (SZ). In this study, we investigated the association of altered methylation patterns with SZ symptoms and early trauma in patients and healthy controls.The present study was conducted to identify methylation changes in CpG sites in peripheral blood associated with recent-onset (RO) psychosis using methylome-wide analysis. Lifestyle factors, such as smoking, alcohol, exercise, and diet, were controlled.We identified 2,912 differentially methylated CpG sites in patients with RO psychosis compared to controls. Most of the genes associated with the top 20 differentially methylated sites had not been reported in previous methylation studies and were involved in apoptosis, autophagy, axonal growth, neuroinflammation, protein folding, etc. The top 15 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways included the oxytocin signaling pathway, long-term depression pathway, axon guidance, endometrial cancer, long-term potentiation, mitogen-activated protein kinase signaling pathway, and glutamatergic pathway, among others. In the patient group, significant associations of novel methylated genes with early trauma and psychopathology were observed.Our results suggest an association of differential DNA methylation with the pathophysiology of psychosis and early trauma. Blood DNA methylation signatures show promise as biomarkers of future psychosis.",
+Yes,20220905,ewas,35930640,Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes.,Sci Adv,"Trained immunity describes the capacity of innate immune cells to develop heterologous memory in response to certain exogenous exposures. This phenomenon mediates, at least in part, the beneficial off-target effects of the BCG vaccine. Using an in vitro model of trained immunity, we show that BCG exposure induces a persistent change in active histone modifications, DNA methylation, transcription, and adenosine-to-inosine RNA modification in human monocytes. By profiling DNA methylation of circulating monocytes from infants in the MIS BAIR clinical trial, we identify a BCG-associated DNA methylation signature that persisted more than 12 months after neonatal BCG vaccination. Genes associated with this epigenetic signature are involved in viral response pathways, consistent with the reported off-target protection against viral infections in neonates, adults, and the elderly. Our findings indicate that the off-target effects of BCG in infants are accompanied by epigenetic remodeling of circulating monocytes that lasts more than 1 year.",
+No,20220905,mediation,35989709,Large-Scale Hypothesis Testing for Causal Mediation Effects with Applications in Genome-wide Epigenetic Studies.,J Am Stat Assoc,"In genome-wide epigenetic studies, it is of great scientific interest to assess whether the effect of an exposure on a clinical outcome is mediated through DNA methylations. However, statistical inference for causal mediation effects is challenged by the fact that one needs to test a large number of composite null hypotheses across the whole epigenome. Two popular tests, the Wald-type Sobel's test and the joint significant test using the traditional null distribution are underpowered and thus can miss important scientific discoveries. In this paper, we show that the null distribution of Sobel's test is not the standard normal distribution and the null distribution of the joint significant test is not uniform under the composite null of no mediation effect, especially in finite samples and under the singular point null case that the exposure has no effect on the mediator and the mediator has no effect on the outcome. Our results explain why these two tests are underpowered, and more importantly motivate us to develop a more powerful Divide-Aggregate Composite-null Test (DACT) for the composite null hypothesis of no mediation effect by leveraging epigenome-wide data. We adopted Efron's empirical null framework for assessing statistical significance of the DACT test. We showed analytically that the proposed DACT method had improved power, and could well control type I error rate. Our extensive simulation studies showed that, in finite samples, the DACT method properly controlled the type I error rate and outperformed Sobel's test and the joint significance test for detecting mediation effects. We applied the DACT method to the US Department of Veterans Affairs Normative Aging Study, an ongoing prospective cohort study which included men who were aged 21 to 80 years at entry. We identified multiple DNA methylation CpG sites that might mediate the effect of smoking on lung function with effect sizes ranging from -0.18 to -0.79 and false discovery rate controlled at level 0.05, including the CpG sites in the genes AHRR and F2RL3. Our sensitivity analysis found small residual correlations (less than 0.01) of the error terms between the outcome and mediator regressions, suggesting that our results are robust to unmeasured confounding factors.",
+No,20220905,methods,36047742,An evaluation of the genome-wide false positive rates of common methods for identifying differentially methylated regions using illumina methylation arrays.,Epigenetics,"Differentially methylated regions (DMRs) are genomic regions with specific methylation patterns across multiple loci that are associated with a phenotype. We examined the genome-wide false positive (GFP) rates of five widely used DMR methods: comb-p, Bumphunter, DMRcate, mCSEA and coMethDMR using both Illumina HumanMethylation450 (450 K) and MethylationEPIC (EPIC) data and simulated continuous and dichotomous null phenotypes (i.e., generated independently of methylation data). coMethDMR provided well-controlled GFP rates (~5%) except when analysing skewed continuous phenotypes. DMRcate generally had well-controlled GFP rates when applied to 450 K data except for the skewed continuous phenotype and EPIC data only for the normally distributed continuous phenotype. GFP rates for mCSEA were at least 0.096 and comb-p yielded GFP rates above 0.34. Bumphunter had high GFP rates of at least 0.35 across conditions, reaching as high as 0.95. Analysis of the performance of these methods in specific regions of the genome found that regions with higher correlation across loci had higher regional false positive rates on average across methods. Based on the false positive rates, coMethDMR is the most recommended analysis method, and DMRcate had acceptable performance when analysing 450 K data. However, as both could display higher levels of FPs for skewed continuous distributions, a normalizing transformation of skewed continuous phenotypes is suggested. This study highlights the importance of genome-wide simulations when evaluating the performance of DMR-analysis methods.",
+No,20220905,methods,36040576,Assessing Differential Variability of High-Throughput DNA Methylation Data.,Curr Environ Health Rep,"DNA methylation (DNAm) is essential to human development and plays an important role as a biomarker due to its susceptibility to environmental exposures. This article reviews the current state of statistical methods developed for differential variability analysis focusing on DNAm data.With the advent of high-throughput technologies allowing for highly reliable and cost-effective measurements of DNAm, many epigenome studies have analyzed DNAm levels to uncover biological mechanisms underlying past environmental exposures and subsequent health outcomes. These studies typically focused on detecting sites or regions which differ in their mean DNAm levels among exposure groups. However, more recent studies highlighted the importance of identifying differentially variable sites or regions as biologically relevant features. Currently, the analysis of differentially variable DNAm sites has not yet gained widespread adoption in environmental studies; yet, it is important to examine the effects of environmental exposures on inter-individual epigenetic variability. In this article, we describe six of the most widely used statistical approaches for analyzing differential variability of DNAm levels and provide a discussion of their advantages and current limitations.© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.",
+No,20220905,methods,35948928,Identification of influential probe types in epigenetic predictions of human traits: implications for microarray design.,Clin Epigenetics,"CpG methylation levels can help to explain inter-individual differences in phenotypic traits. Few studies have explored whether identifying probe subsets based on their biological and statistical properties can maximise predictions whilst minimising array content. Variance component analyses and penalised regression (epigenetic predictors) were used to test the influence of (i) the number of probes considered, (ii) mean probe variability and (iii) methylation QTL status on the variance captured in eighteen traits by blood DNA methylation. Training and test samples comprised ≤ 4450 and ≤ 2578 unrelated individuals from Generation Scotland, respectively.As the number of probes under consideration decreased, so too did the estimates from variance components and prediction analyses. Methylation QTL status and mean probe variability did not influence variance components. However, relative effect sizes were 15% larger for epigenetic predictors based on probes with known or reported methylation QTLs compared to probes without reported methylation QTLs. Relative effect sizes were 45% larger for predictors based on probes with mean Beta-values between 10 and 90% compared to those based on hypo- or hypermethylated probes (Beta-value ≤ 10% or ≥ 90%).Arrays with fewer probes could reduce costs, leading to increased sample sizes for analyses. Our results show that reducing array content can restrict prediction metrics and careful attention must be given to the biological and distribution properties of CpG probes in array content selection.© 2022. The Author(s).",
+No,20220905,ml,36011003,Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis.,Cancers (Basel),"Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set.",
+No,20220905,ml,35933478,Developing machine learning algorithms for dynamic estimation of progression during active surveillance for prostate cancer.,NPJ Digit Med,"Active Surveillance (AS) for prostate cancer is a management option that continually monitors early disease and considers intervention if progression occurs. A robust method to incorporate ""live"" updates of progression risk during follow-up has hitherto been lacking. To address this, we developed a deep learning-based individualised longitudinal survival model using Dynamic-DeepHit-Lite (DDHL) that learns data-driven distribution of time-to-event outcomes. Further refining outputs, we used a reinforcement learning approach (Actor-Critic) for temporal predictive clustering (AC-TPC) to discover groups with similar time-to-event outcomes to support clinical utility. We applied these methods to data from 585 men on AS with longitudinal and comprehensive follow-up (median 4.4 years). Time-dependent C-indices and Brier scores were calculated and compared to Cox regression and landmarking methods. Both Cox and DDHL models including only baseline variables showed comparable C-indices but the DDHL model performance improved with additional follow-up data. With 3 years of data collection and 3 years follow-up the DDHL model had a C-index of 0.79 (±0.11) compared to 0.70 (±0.15) for landmarking Cox and 0.67 (±0.09) for baseline Cox only. Model calibration was good across all models tested. The AC-TPC method further discovered 4 distinct outcome-related temporal clusters with distinct progression trajectories. Those in the lowest risk cluster had negligible progression risk while those in the highest cluster had a 50% risk of progression by 5 years. In summary, we report a novel machine learning approach to inform personalised follow-up during active surveillance which improves predictive power with increasing data input over time.© 2022. The Author(s).",
+No,20220905,ml,35785523,Interpretable Machine Learning Models to Predict the Resistance of Breast Cancer Patients to Doxorubicin from Their microRNA Profiles.,Adv Sci (Weinh),"Doxorubicin is a common treatment for breast cancer. However, not all patients respond to this drug, which sometimes causes life-threatening side effects. Accurately anticipating doxorubicin-resistant patients would therefore permit to spare them this risk while considering alternative treatments without delay. Stratifying patients based on molecular markers in their pretreatment tumors is a promising approach to advance toward this ambitious goal, but single-gene gene markers such as HER2 expression have not shown to be sufficiently predictive. The recent availability of matched doxorubicin-response and diverse molecular profiles across breast cancer patients permits now analysis at a much larger scale. 16 machine learning algorithms and 8 molecular profiles are systematically evaluated on the same cohort of patients. Only 2 of the 128 resulting models are substantially predictive, showing that they can be easily missed by a standard-scale analysis. The best model is classification and regression tree (CART) nonlinearly combining 4 selected miRNA isoforms to predict doxorubicin response (median Matthew correlation coefficient (MCC) and area under the curve (AUC) of 0.56 and 0.80, respectively). By contrast, HER2 expression is significantly less predictive (median MCC and AUC of 0.14 and 0.57, respectively). As the predictive accuracy of this CART model increases with larger training sets, its update with future data should result in even better accuracy.© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.",
+No,20220905,ml,36010273,Big Data in Laboratory Medicine-FAIR Quality for AI?,Diagnostics (Basel),"Laboratory medicine is a digital science. Every large hospital produces a wealth of data each day-from simple numerical results from, e.g., sodium measurements to highly complex output of ""-omics"" analyses, as well as quality control results and metadata. Processing, connecting, storing, and ordering extensive parts of these individual data requires Big Data techniques. Whereas novel technologies such as artificial intelligence and machine learning have exciting application for the augmentation of laboratory medicine, the Big Data concept remains fundamental for any sophisticated data analysis in large databases. To make laboratory medicine data optimally usable for clinical and research purposes, they need to be FAIR: findable, accessible, interoperable, and reusable. This can be achieved, for example, by automated recording, connection of devices, efficient ETL (Extract, Transform, Load) processes, careful data governance, and modern data security solutions. Enriched with clinical data, laboratory medicine data allow a gain in pathophysiological insights, can improve patient care, or can be used to develop reference intervals for diagnostic purposes. Nevertheless, Big Data in laboratory medicine do not come without challenges: the growing number of analyses and data derived from them is a demanding task to be taken care of. Laboratory medicine experts are and will be needed to drive this development, take an active role in the ongoing digitalization, and provide guidance for their clinical colleagues engaging with the laboratory data in research.",
+No,20220905,nanopore,36030244,Epigenetic tumor heterogeneity in the era of single-cell profiling with nanopore sequencing.,Clin Epigenetics,"Nanopore sequencing has brought the technology to the next generation in the science of sequencing. This is achieved through research advancing on: pore efficiency, creating mechanisms to control DNA translocation, enhancing signal-to-noise ratio, and expanding to long-read ranges. Heterogeneity regarding epigenetics would be broad as mutations in the epigenome are sensitive to cause new challenges in cancer research. Epigenetic enzymes which catalyze DNA methylation and histone modification are dysregulated in cancer cells and cause numerous heterogeneous clones to evolve. Detection of this heterogeneity in these clones plays an indispensable role in the treatment of various cancer types. With single-cell profiling, the nanopore sequencing technology could provide a simple sequence at long reads and is expected to be used soon at the bedside or doctor's office. Here, we review the advancements of nanopore sequencing and its use in the detection of epigenetic heterogeneity in cancer.© 2022. The Author(s).",
+No,20220905,organoids,35999641,DNA methylation analysis of normal colon organoids from familial adenomatous polyposis patients reveals novel insight into colon cancer development.,Clin Epigenetics,"Familial adenomatous polyposis (FAP) is an inherited colorectal cancer (CRC) syndrome resulting from germ line mutations in the adenomatous polyposis coli (APC) gene. While FAP accounts for less than 1% of all CRC cases, loss of APC expression is seen in > 80% of non-hereditary CRCs. To better understand molecular mechanisms underlying APC-driven CRC, we performed an epigenome-wide analysis of colon organoids derived from normal-appearing colons of FAP patients versus healthy subjects to identify differentially methylated regions (DMRs) that may precede the onset of CRC.We identified 358 DMRs when comparing colon organoids of FAP patients to those of healthy subjects (FDR < 0.05, |mean beta difference| = 5%). Of these, nearly 50% of DMRs were also differentially methylated in at least one of three CRC tumor and normal adjacent tissue (NAT) cohorts (TCGA-COAD, GSE193535 and ColoCare). Moreover, 27 of the DMRs mapped to CRC genome-wide association study (GWAS) loci. We provide evidence suggesting that some of these DMRs led to significant differences in gene expression of adjacent genes using quantitative PCR. For example, we identified significantly greater expression of five genes: Kazal-type serine peptidase inhibitor domain 1 (KAZALD1, P = 0.032), F-Box and leucine-rich repeat protein 8 (FBXL8, P = 0.036), TRIM31 antisense RNA 1 (TRIM31-AS1, P = 0.036), Fas apoptotic inhibitory molecule 2 (FAIM2, P = 0.049) and (Collagen beta (1-0)galactosyltransferase 2 (COLGALT2, P = 0.049). Importantly, both FBXL8 and TRIM31-AS1 were also significantly differentially expressed in TCGA-COAD tumor versus matched NAT, supporting a role for these genes in CRC tumor development.We performed the first DNA methylome-wide analysis of normal colon organoids derived from FAP patients compared to those of healthy subjects. Our results reveal that normal colon organoids from FAP patients exhibit extensive epigenetic differences compared to those of healthy subjects that appear similar to those exhibited in CRC tumor. Our analyses therefore identify DMRs and candidate target genes that are potentially important in CRC tumor development in FAP, with potential implications for non-hereditary CRC.© 2022. The Author(s).",
+No,20220905,mqtl,35969790,Deep learning predicts DNA methylation regulatory variants in the human brain and elucidates the genetics of psychiatric disorders.,Proc Natl Acad Sci U S A,"There is growing evidence for the role of DNA methylation (DNAm) quantitative trait loci (mQTLs) in the genetics of complex traits, including psychiatric disorders. However, due to extensive linkage disequilibrium (LD) of the genome, it is challenging to identify causal genetic variations that drive DNAm levels by population-based genetic association studies. This limits the utility of mQTLs for fine-mapping risk loci underlying psychiatric disorders identified by genome-wide association studies (GWAS). Here we present INTERACT, a deep learning model that integrates convolutional neural networks with transformer, to predict effects of genetic variations on DNAm levels at CpG sites in the human brain. We show that INTERACT-derived DNAm regulatory variants are not confounded by LD, are concentrated in regulatory genomic regions in the human brain, and are convergent with mQTL evidence from genetic association analysis. We further demonstrate that predicted DNAm regulatory variants are enriched for heritability of brain-related traits and improve polygenic risk prediction for schizophrenia across diverse ancestry samples. Finally, we applied predicted DNAm regulatory variants for fine-mapping schizophrenia GWAS risk loci to identify potential novel risk genes. Our study shows the power of a deep learning approach to identify functional regulatory variants that may elucidate the genetic basis of complex traits.",
+No,20220905,prediction,36008412,Methylation risk scores are associated with a collection of phenotypes within electronic health record systems.,NPJ Genom Med,"Inference of clinical phenotypes is a fundamental task in precision medicine, and has therefore been heavily investigated in recent years in the context of electronic health records (EHR) using a large arsenal of machine learning techniques, as well as in the context of genetics using polygenic risk scores (PRS). In this work, we considered the epigenetic analog of PRS, methylation risk scores (MRS), a linear combination of methylation states. We measured methylation across a large cohort (n = 831) of diverse samples in the UCLA Health biobank, for which both genetic and complete EHR data are available. We constructed MRS for 607 phenotypes spanning diagnoses, clinical lab tests, and medication prescriptions. When added to a baseline set of predictive features, MRS significantly improved the imputation of 139 outcomes, whereas the PRS improved only 22 (median improvement for methylation 10.74%, 141.52%, and 15.46% in medications, labs, and diagnosis codes, respectively, whereas genotypes only improved the labs at a median increase of 18.42%). We added significant MRS to state-of-the-art EHR imputation methods that leverage the entire set of medical records, and found that including MRS as a medical feature in the algorithm significantly improves EHR imputation in 37% of lab tests examined (median R2increase 47.6%). Finally, we replicated several MRS in multiple external studies of methylation (minimum p-value of 2.72 × 10-7) and replicated 22 of 30 tested MRS internally in two separate cohorts of different ethnicity. Our publicly available results and weights show promise for methylation risk scores as clinical and scientific tools.© 2022. The Author(s).",
+No,20220905,prediction,36013215,The False Dawn of Polygenic Risk Scores for Human Disease Prediction.,J Pers Med,"Polygenic risk scores (PRSs) are being constructed for many diseases and are presented today as a promising avenue in the field of human genetics. These scores aim at predicting the risk of developing a disease by leveraging the many genome-wide association studies (GWAS) conducted during the two last decades. Important investments are being made to improve score estimates by increasing GWAS sample sizes, by developing more sophisticated methods, and by proposing different corrections for potential biases. PRSs have entered the market with direct-to-consumer companies proposing to compute them from saliva samples and even recently to help parents select the healthiest embryos. In this paper, we recall how PRSs arose and question the credit they are given by revisiting underlying assumptions in light of the history of human genetics and by comparing them with estimated breeding values (EBVs) used for selection in livestock.",
+No,20220905,prediction,35858592,Genetic and environmental variation impact transferability of polygenic risk scores.,Cell Rep Med,"Even when polygenic risk scores (PRSs) are trained in African ancestral populations, Kamiza and colleagues showed that genetic and environmental variation within sub-Saharan African populations impacts prediction performance, highlighting the challenges of clinical implementation of PRSs for risk assessment.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.",
+No,20220905,prediction,36034882,Redefining Age-Based Screening and Diagnostic Guidelines: An Opportunity for Biological Aging Clocks in Clinical Medicine?,Lancet Healthy Longev,NA,
+No,20220905,prediction,35966405,Interpreting Neural Networks for Biological Sequences by Learning Stochastic Masks.,Nat Mach Intell,"Sequence-based neural networks can learn to make accurate predictions from large biological datasets, but model interpretation remains challenging. Many existing feature attribution methods are optimized for continuous rather than discrete input patterns and assess individual feature importance in isolation, making them ill-suited for interpreting non-linear interactions in molecular sequences. Building on work in computer vision and natural language processing, we developed an approach based on deep learning - Scrambler networks - wherein the most salient sequence positions are identified with learned input masks. Scramblers learn to predict Position-Specific Scoring Matrices (PSSMs) where unimportant nucleotides or residues are scrambled by raising their entropy. We apply Scramblers to interpret the effects of genetic variants, uncover non-linear interactions between cis-regulatory elements, explain binding specificity for protein-protein interactions, and identify structural determinants ofde novodesigned proteins. We show that Scramblers enable efficient attribution across large datasets and result in high-quality explanations, often outperforming state-of-the-art methods.",
+No,20220905,prediction,35945544,A benchmark study of deep learning-based multi-omics data fusion methods for cancer.,Genome Biol,"A fused method using a combination of multi-omics data enables a comprehensive study of complex biological processes and highlights the interrelationship of relevant biomolecules and their functions. Driven by high-throughput sequencing technologies, several promising deep learning methods have been proposed for fusing multi-omics data generated from a large number of samples.In this study, 16 representative deep learning methods are comprehensively evaluated on simulated, single-cell, and cancer multi-omics datasets. For each of the datasets, two tasks are designed: classification and clustering. The classification performance is evaluated by using three benchmarking metrics including accuracy, F1 macro, and F1 weighted. Meanwhile, the clustering performance is evaluated by using four benchmarking metrics including the Jaccard index (JI), C-index, silhouette score, and Davies Bouldin score. For the cancer multi-omics datasets, the methods' strength in capturing the association of multi-omics dimensionality reduction results with survival and clinical annotations is further evaluated. The benchmarking results indicate that moGAT achieves the best classification performance. Meanwhile, efmmdVAE, efVAE, and lfmmdVAE show the most promising performance across all complementary contexts in clustering tasks.Our benchmarking results not only provide a reference for biomedical researchers to choose appropriate deep learning-based multi-omics data fusion methods, but also suggest the future directions for the development of more effective multi-omics data fusion methods. The deep learning frameworks are available at https://github.com/zhenglinyi/DL-mo .© 2022. The Author(s).",
+No,20220905,proteome,35839778,Pan-cancer proteomic map of 949 human cell lines.,Cancer Cell,"The proteome provides unique insights into disease biology beyond the genome and transcriptome. A lack of large proteomic datasets has restricted the identification of new cancer biomarkers. Here, proteomes of 949 cancer cell lines across 28 tissue types are analyzed by mass spectrometry. Deploying a workflow to quantify 8,498 proteins, these data capture evidence of cell-type and post-transcriptional modifications. Integrating multi-omics, drug response, and CRISPR-Cas9 gene essentiality screens with a deep learning-based pipeline reveals thousands of protein biomarkers of cancer vulnerabilities that are not significant at the transcript level. The power of the proteome to predict drug response is very similar to that of the transcriptome. Further, random downsampling to only 1,500 proteins has limited impact on predictive power, consistent with protein networks being highly connected and co-regulated. This pan-cancer proteomic map (ProCan-DepMapSanger) is a comprehensive resource available at https://cellmodelpassports.sanger.ac.uk.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.",
+No,20220905,transposons,36008480,Mammalian genome innovation through transposon domestication.,Nat Cell Biol,"Since the discovery of transposons, their sheer abundance in host genomes has puzzled many. While historically viewed as largely harmless 'parasitic' DNAs during evolution, transposons are not a mere record of ancient genome invasion. Instead, nearly every element of transposon biology has been integrated into host biology. Here we review how host genome sequences introduced by transposon activities provide raw material for genome innovation and document the distinct evolutionary path of each species.© 2022. Springer Nature Limited.",
+No,20220905,validation,35959851,Fine-mapping and replication of EWAS loci harboring putative epigenetic alterations associated with AD neuropathology in a large collection of human brain tissue samples.,Alzheimers Dement,"Our previous epigenome-wide association study (EWAS) of Alzheimer's disease (AD) in human brain identified 71 CpGs associated with AD pathology. However, due to low coverage of the Illumina platform, many important CpGs might have been missed.In a large collection of human brain tissue samples (N = 864), we fine-mapped previous EWAS loci by targeted bisulfite sequencing and examined their associations with AD neuropathology. DNA methylation was also linked to gene expression of the same brain cortex.Our targeted sequencing captured 130 CpGs (�1.2 kb), 93 of which are novel. Of the 130 CpGs, 57 sites (only 17 included in previous EWAS) and 12 gene regions (e.g., ANK1, BIN1, RHBDF2, SPG7, PODXL) were significantly associated with amyloid load. DNA methylation in some regions was associated with expression of nearby genes.Targeted methylation sequencing can validate previous EWAS loci and discover novel CpGs associated with AD pathology.© 2022 the Alzheimer's Association.",
+No,20221003,dnam age,36064845,A new cognitive clock matching phenotypic and epigenetic ages.,Transl Psychiatry,"Cognitive abilities decline with age, constituting a major manifestation of aging. The quantitative biomarkers of this process, as well as the correspondence to different biological clocks, remain largely an open problem. In this paper we employ the following cognitive tests: 1. differentiation of shades (campimetry); 2. evaluation of the arithmetic correctness and 3. detection of reversed letters and identify the most significant age-related cognitive indices. Based on their subsets we construct a machine learning-based Cognitive Clock that predicts chronological age with a mean absolute error of 8.62 years. Remarkably, epigenetic and phenotypic ages are predicted by Cognitive Clock with an even better accuracy. We also demonstrate the presence of correlations between cognitive, phenotypic and epigenetic age accelerations that suggests a deep connection between cognitive performance and aging status of an individual.© 2022. The Author(s).",
+No,20221003,epigenetics,36064783,Two-layer design protects genes from mutations in their enhancers,Nature,,
+No,20221003,epigenetics,35951677,Nested epistasis enhancer networks for robust genome regulation,Science,"Mammalian genomes have multiple enhancers spanning an ultralong distance (>megabases) to modulate important genes, but it is unclear how these enhancers coordinate to achieve this task. We combine multiplexed CRISPRi screening with machine learning to define quantitative enhancer-enhancer interactions. We find that the ultralong distance enhancer network has a nested multilayer architecture that confers functional robustness of gene expression. Experimental characterization reveals that enhancer epistasis is maintained by three-dimensional chromosomal interactions and BRD4 condensation. Machine learning prediction of synergistic enhancers provides an effective strategy to identify noncoding variant pairs associated with pathogenic genes in diseases beyond genome-wide association studies analysis. Our work unveils nested epistasis enhancer networks, which can better explain enhancer functions within cells and in diseases.",
+Yes,20221003,ewas,36170668,Longitudinal Association of DNA Methylation with Type 2 Diabetes and Glycemic Traits: A 5-year Cross-Lagged Twin Study.,Diabetes,"Previous cross-sectional Epigenome-Wide Association Studies (EWASs) in adults have reported hundreds of 5'-cytosine-phosphate-guanine-3' (CpG) sites associated with type 2 diabetes mellitus (T2DM) and glycemic traits. However, the results from EWASs have been inconsistent, and longitudinal observations of these associations are scarce. Twin studies provide a valuable tool for epigenetic studies, as they are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and EMBASE for EWASs, and 214, 33, and 117 candidate CpG sites were selected for T2DM, HbA1c and fasting blood glucose (FBG). Based on 1,070 twins from the Chinese National Twin Registry, 67, 17 and 16 CpG sites from previous studies were validated for T2DM, HbA1c and FBG. Longitudinal review and blood sampling for phenotypic information and DNAm were conducted twice in 2013 and 2018 on 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. 11 significant paths from T2DM to subsequent DNAm and 15 paths from DNAm to subsequent T2DM were detected, suggesting both directions of associations. For glycemic traits, we detected 17 cross-lagged associations from baseline glycemic traits to subsequent DNAm, and none was from the other cross-lagged direction, indicating CpG sites may be the consequences, not the causes, of glycemic traits. Finally, a longitudinal mediation analysis was performed, and the potential role of DNAm of cg19693031, cg00574958 and cg04816311 in mediating the effect of glycemic traits on T2DM was detected.© 2022 by the American Diabetes Association.",
+Yes,20221003,ewas,36148884,Prenatal lead (Pb) exposure is associated with differential placental DNA methylation and hydroxymethylation in a human population.,Epigenetics,"Prenatal lead (Pb) exposure is associated with adverse developmental outcomes and to epigenetic alterations such as DNA methylation and hydroxymethylation in animal models and in newborn blood. Given the importance of the placenta in foetal development, we sought to examine how prenatal Pb exposure was associated with differential placental DNA methylation and hydroxymethylation and to identify affected biological pathways linked to developmental outcomes. Maternal (n = 167) and infant (n = 172) toenail and placenta (n = 115) samples for prenatal Pb exposure were obtained from participants in a US birth cohort, and methylation and hydroxymethylation data were quantified using the Illumina Infinium MethylationEPIC BeadChip. An epigenome-wide association study was applied to identify differential methylation and hydroxymethylation associated with Pb exposure. Biological functions of the Pb-associated genes were determined by overrepresentation analysis through ConsensusPathDB. Prenatal Pb quantified from maternal toenail, infant toenail, and placenta was associated with 480, 27, and 2 differentially methylated sites (q < 0.05), respectively, with both increases and decreases associated with exposure. Alternatively, we identified 2, 1, and 14 differentially hydroxymethylated site(s) associated with maternal toenail, infant toenail, and placental Pb, respectively, with most showing increases in hydroxymethylation with exposure. Significantly overrepresented pathways amongst genes associated with differential methylation and hydroxymethylation (q < 0.10) included mechanisms pertaining to nervous system and organ development, calcium transport and regulation, and signalling activities. Our results suggest that both methylation and hydroxymethylation in the placenta can be variable based on Pb exposure and that the pathways impacted could affect placental function.",
+Yes,20221003,ewas,36142605,Identification of <i>NHLRC1</i> as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS).,Int J Mol Sci,"Changes in DNA methylation identified by epigenome-wide association studies (EWAS) have been recently linked to increased lung cancer risk. However, the cellular effects of these differentially methylated positions (DMPs) are often unclear. Therefore, we investigated top differentially methylated positions identified from an EWAS study. This included a putative regulatory region ofNHLRC1. Hypomethylation of this gene was recently linked with decreased survival rates in lung cancer patients. HumanMethylation450 BeadChip array (450K) analysis was performed on 66 lung cancer case-control pairs from the European Prospective Investigation into Cancer and Nutrition Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs identified in these pre-diagnostic blood samples were then investigated for differential DNA methylation in lung tumor versus adjacent normal lung tissue from The Cancer Genome Atlas (TCGA) and replicated in two independent lung tumor versus adjacent normal tissue replication sets with MassARRAY. The EPIC HD top hypermethylated DMP cg06646708 was found to be a hypomethylated region in multiple data sets of lung tumor versus adjacent normal tissue. Hypomethylation within this region caused increased mRNA transcription of the closest geneNHLRC1in lung tumors. In functional assays, we demonstrate attenuated proliferation, viability, migration, and invasion uponNHLRC1knock-down in lung cancer cells. Furthermore, diminished AKT phosphorylation at serine 473 causing expression of pro-apoptotic AKT-repressed genes was detected in these knock-down experiments. In conclusion, this study demonstrates the powerful potential for discovery of novel functional mechanisms in oncogenesis based on EWAS DNA methylation data.NHLRC1holds promise as a new prognostic biomarker for lung cancer survival and prognosis, as well as a target for novel treatment strategies in lung cancer patients.",
+Yes,20221003,ewas,36109771,Distinct sex-specific DNA methylation differences in Alzheimer's disease.,Alzheimers Res Ther,"Sex is increasingly recognized as a significant factor contributing to the biological and clinical heterogeneity in AD. There is also growing evidence for the prominent role of DNA methylation (DNAm) in Alzheimer's disease (AD).We studied sex-specific DNA methylation differences in the blood samples of AD subjects compared to cognitively normal subjects, by performing sex-specific meta-analyses of two large blood-based epigenome-wide association studies (ADNI and AIBL), which included DNA methylation data for a total of 1284 whole blood samples (632 females and 652 males). Within each dataset, we used two complementary analytical strategies, a sex-stratified analysis that examined methylation to AD associations in male and female samples separately, and a methylation-by-sex interaction analysis that compared the magnitude of these associations between different sexes. After adjusting for age, estimated immune cell type proportions, batch effects, and correcting for inflation, the inverse-variance fixed-effects meta-analysis model was used to identify the most consistent DNAm differences across datasets. In addition, we also evaluated the performance of the sex-specific methylation-based risk prediction models for AD diagnosis using an independent external dataset.In the sex-stratified analysis, we identified 2 CpGs, mapped to the PRRC2A and RPS8 genes, significantly associated with AD in females at a 5% false discovery rate, and an additional 25 significant CpGs (21 in females, 4 in males) at P-value < 1×10-5. In methylation-by-sex interaction analysis, we identified 5 significant CpGs at P-value < 10-5. Out-of-sample validations using the AddNeuroMed dataset showed in females, the best logistic prediction model included age, estimated immune cell-type proportions, and methylation risk scores (MRS) computed from 9 of the 23 CpGs identified in AD vs. CN analysis that are also available in AddNeuroMed dataset (AUC = 0.74, 95% CI: 0.65-0.83). In males, the best logistic prediction model included only age and MRS computed from 2 of the 5 CpGs identified in methylation-by-sex interaction analysis that are also available in the AddNeuroMed dataset (AUC = 0.70, 95% CI: 0.56-0.82).Overall, our results show that the DNA methylation differences in AD are largely distinct between males and females. Our best-performing sex-specific methylation-based prediction model in females performed better than that for males and additionally included estimated cell-type proportions. The significant discriminatory classification of AD samples with our methylation-based prediction models demonstrates that sex-specific DNA methylation could be a predictive biomarker for AD. As sex is a strong factor underlying phenotypic variability in AD, the results of our study are particularly relevant for a better understanding of the epigenetic architecture that underlie AD and for promoting precision medicine in AD.© 2022. The Author(s).",
+Yes,20221003,ewas,36091392,The shared mother-child epigenetic signature of neglect is related to maternal adverse events.,Front Physiol,"Studies of DNA methylation have revealed the biological mechanisms by which life adversity confers risk for later physical and mental health problems. What remains unknown is the ""biologically embedding"" of maternal adverse experiences resulting in maladaptive parenting and whether these epigenetic effects are transmitted to the next generation. This study focuses on neglectful mothering indexed by a severe disregard for the basic and psychological needs of the child. Using the Illumina Human Methylation EPIC BeadChip in saliva samples, we identified genes with differentially methylated regions (DMRs) in those mothers with (n= 51), versus those without (n= 87), neglectful behavior that present similar DMRs patterns in their children being neglected versus non-neglected (n= 40 vs. 75). Mothers reported the emotional intensity of adverse life events. After covariate adjustment and multiple testing corrections, we identified 69 DMRs in the mother epigenome and 42 DMRs in the child epigenome that were simultaneously above the α = 0.01 threshold. The common set of nine DMRs contained genes related to childhood adversity, neonatal and infant diabetes, child neurobehavioral development and other health problems such as obesity, hypertension, cancer, posttraumatic stress, and the Alzheimer's disease; four of the genes were associated with maternal life adversity. Identifying a shared epigenetic signature of neglect linked to maternal life adversity is an essential step in breaking the intergenerational transmission of one of the most common forms of childhood maltreatment.Copyright © 2022 León, Herrero Roldán, Rodrigo, López Rodríguez, Fisher, Mitchell and Lage-Castellanos.",
+Yes,20221003,ewas,36127421,DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival.,Nat Commun,"Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.© 2022. The Author(s).",
+No,20221003,ml,36064595,Big data in basic and translational cancer research.,Nat Rev Cancer,"Historically, the primary focus of cancer research has been molecular and clinical studies of a few essential pathways and genes. Recent years have seen the rapid accumulation of large-scale cancer omics data catalysed by breakthroughs in high-throughput technologies. This fast data growth has given rise to an evolving concept of 'big data' in cancer, whose analysis demands large computational resources and can potentially bring novel insights into essential questions. Indeed, the combination of big data, bioinformatics and artificial intelligence has led to notable advances in our basic understanding of cancer biology and to translational advancements. Further advances will require a concerted effort among data scientists, clinicians, biologists and policymakers. Here, we review the current state of the art and future challenges for harnessing big data to advance cancer research and treatment.© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
+No,20221003,ml,36155971,A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis.,PLoS Comput Biol,"Previous studies for cancer biomarker discovery based on pre-diagnostic blood DNA methylation (DNAm) profiles, either ignore the explicit modeling of the Time To Diagnosis (TTD), or provide inconsistent results. This lack of consistency is likely due to the limitations of standard EWAS approaches, that model the effect of DNAm at CpG sites on TTD independently. In this work, we aim to identify blood DNAm profiles associated with TTD, with the aim to improve the reliability of the results, as well as their biological meaningfulness. We argue that a global approach to estimate CpG sites effect profile should capture the complex (potentially non-linear) relationships interplaying between sites. To prove our concept, we develop a new Deep Learning-based approach assessing the relevance of individual CpG Islands (i.e., assigning a weight to each site) in determining TTD while modeling their combined effect in a survival analysis scenario. The algorithm combines a tailored sampling procedure with DNAm sites agglomeration, deep non-linear survival modeling and SHapley Additive exPlanations (SHAP) values estimation to aid robustness of the derived effects profile. The proposed approach deals with the common complexities arising from epidemiological studies, such as small sample size, noise, and low signal-to-noise ratio of blood-derived DNAm. We apply our approach to a prospective case-control study on breast cancer nested in the EPIC Italy cohort and we perform weighted gene-set enrichment analyses to demonstrate the biological meaningfulness of the obtained results. We compared the results of Deep Survival EWAS with those of a traditional EWAS approach, demonstrating that our method performs better than the standard approach in identifying biologically relevant pathways.",
+No,20221003,prediction,36153611,Liquid biopsies based on DNA methylation as biomarkers for the detection and prognosis of lung cancer.,Clin Epigenetics,"Lung cancer (LC) is the main cause of cancer-related mortality. Most LC patients are diagnosed in an advanced stage when the symptoms are obvious, and the prognosis is quite poor. Although low-dose computed tomography (LDCT) is a routine clinical examination for early detection of LC, the false-positive rate is over 90%. As one of the intensely studied epigenetic modifications, DNA methylation plays a key role in various diseases, including cancer and other diseases. Hypermethylation in tumor suppressor genes or hypomethylation in oncogenes is an important event in tumorigenesis. Remarkably, DNA methylation usually occurs in the very early stage of malignant tumors. Thus, DNA methylation analysis may provide some useful information about the early detection of LC. In recent years, liquid biopsy has developed rapidly. Liquid biopsy can detect and monitor both primary and metastatic malignant tumors and can reflect tumor heterogeneity. Moreover, it is a minimally invasive procedure, and it causes less pain for patients. This review summarized various liquid biopsies based on DNA methylation for LC. At first, we briefly discussed some emerging technologies for DNA methylation analysis. Subsequently, we outlined cell-free DNA (cfDNA), sputum, bronchoalveolar lavage fluid, bronchial aspirates, and bronchial washings DNA methylation-based liquid biopsy for the early detection of LC. Finally, the prognostic value of DNA methylation in cfDNA and sputum and the diagnostic value of other DNA methylation-based liquid biopsies for LC were also analyzed.© 2022. The Author(s).",
+No,20221003,prediction,36068634,Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies.,Breast Cancer Res,"DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer.Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage.None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics.We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.© 2022. The Author(s).",
+No,20221003,prediction,36138228,Ten challenges for clinical translation in psychiatric genetics.,Nat Genet,"Genome-wide association studies have identified hundreds of robust genetic associations underlying psychiatric disorders and provided important biological insights into disease onset and progression. There is optimism that genetic findings will pave the way to precision psychiatry by facilitating the development of more effective treatments and the identification of groups of patients that these treatments should be targeted toward. However, there are several challenges that must be addressed before genetic findings can be translated into the clinic. In this Perspective, we highlight ten challenges for the field of psychiatric genetics, focused on the robust and generalizable detection of genetic risk factors, improved definition and assessment of psychopathology and achieving better clinical indicators. We discuss recent advancements in the field that will improve the explanatory and predictive power of genetic data and ultimately contribute to improving the management and treatment of patients with a psychiatric disorder.© 2022. Springer Nature America, Inc.",
+No,20221003,single-cell rna-seq,36050550,Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data.,Nat Genet,"Single-cell RNA sequencing (scRNA-seq) provides unique insights into the pathology and cellular origin of disease. We introduce single-cell disease relevance score (scDRS), an approach that links scRNA-seq with polygenic disease risk at single-cell resolution, independent of annotated cell types. scDRS identifies cells exhibiting excess expression across disease-associated genes implicated by genome-wide association studies (GWASs). We applied scDRS to 74 diseases/traits and 1.3 million single-cell gene-expression profiles across 31 tissues/organs. Cell-type-level results broadly recapitulated known cell-type-disease associations. Individual-cell-level results identified subpopulations of disease-associated cells not captured by existing cell-type labels, including T cell subpopulations associated with inflammatory bowel disease, partially characterized by their effector-like states; neuron subpopulations associated with schizophrenia, partially characterized by their spatial locations; and hepatocyte subpopulations associated with triglyceride levels, partially characterized by their higher ploidy levels. Genes whose expression was correlated with the scDRS score across cells (reflecting coexpression with GWAS disease-associated genes) were strongly enriched for gold-standard drug target and Mendelian disease genes.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20221003,twas,36073148,The placenta epigenome-brain axis: placental epigenomic and transcriptomic responses that preprogram cognitive impairment.,Epigenomics,"Aim:The placenta-brain axis reflects a developmental linkage where disrupted placental function is associated with impaired neurodevelopment later in life. Placental gene expression and the expression of epigenetic modifiers such as miRNAs may be tied to these impairments and are understudied.Materials & methods:The expression levels of mRNAs (n = 37,268) and their targeting miRNAs (n = 2083) were assessed within placentas collected from the ELGAN study cohort (n = 386). The ELGAN adolescents were assessed for neurocognitive function at age 10 and the association with placental mRNA/miRNAs was determined.Results:Placental mRNAs related to inflammatory and apoptotic processes are under miRNA control and associated with cognitive impairment at age 10.Conclusion:Findings highlight key placenta epigenome-brain relationships that support the developmental origins of health and disease hypothesis.",
+Yes,20221024,ewas,36246163,Stress Overload and DNA Methylation in African American Women in the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study.,Epigenet Insights,"Experiencing psychosocial stress is associated with poor health outcomes such as hypertension and obesity, which are risk factors for developing cardiovascular disease. African American women experience disproportionate risk for cardiovascular disease including exposure to high levels of psychosocial stress. We hypothesized that psychosocial stress, such as perceived stress overload, may influence epigenetic marks, specifically DNA methylation (DNAm), that contribute to increased risk for cardiovascular disease in African American women.We conducted an epigenome-wide study evaluating the relationship of psychosocial stress and DNAm among African American mothers from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN) cohort. Linear mixed effects models were used to explore the epigenome-wide associations with the Stress Overload Scale (SOS), which examines self-reported past-week stress, event load and personal vulnerability.In total, n = 228 participants were included in our analysis. After adjusting for known epigenetic confounders, we did not identify any DNAm sites associated with maternal report of stress measured by SOS after controlling for multiple comparisons. Several of the top differentially methylated CpG sites related to SOS score (P< 1 × 10-5), mapped to genes of unknown significance for hypertension or heart disease, namely,PXDNLandC22orf42.This study provides foundational knowledge for future studies examining epigenetic associations with stress and other psychosocial measures in African Americans, a key area for growth in epigenetics. Future studies including larger sample sizes and replication data are warranted.© The Author(s) 2022.",
+Yes,20221024,ewas,36243740,Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans.,Clin Epigenetics,"Ethnic differences in non-communicable disease risk have been described between individuals of South Asian and European ethnicity that are only partially explained by genetics and other known risk factors. DNA methylation is one underexplored mechanism that may explain differences in disease risk. Currently, there is little knowledge of how DNA methylation varies between South Asian and European ethnicities. This study characterised differences in blood DNA methylation between individuals of self-reported European and South Asian ethnicity from two UK-based cohorts: Southall and Brent Revisited and Born in Bradford. DNA methylation differences between ethnicities were widespread throughout the genome (n = 16,433 CpG sites, 3.4% sites tested). Specifically, 76% of associations were attributable to ethnic differences in cell composition with fewer effects attributable to smoking and genetic variation. Ethnicity-associated CpG sites were enriched for EWAS Catalog phenotypes including metabolites. This work highlights the need to consider ethnic diversity in epigenetic research.© 2022. The Author(s).",
+Yes,20221024,ewas,36243213,Mediation by DNA methylation on the association of BMI and serum uric acid in Chinese monozygotic twins.,Gene,"Obesity is an established risk factor for hyperuricemia, but the mechanisms are only partially understood. We examined whether BMI-related DNA methylation (DNAm) variation would mediate the association of BMI with serum uric acid (SUA). We first conducted an epigenome-wide association analysis (EWAS) in 64 monozygotic twin pairs to detect BMI-related DNAm variation and then evaluated the mediated effect of DNAm using mediation analysis. Ontology enrichments analysis was performed for CpGs using GREAT tool. The genes where the candidate CpG mediators mapped were validated using gene expression data. BMI was positively associated with log10transformed SUA level (β = 0.01, P < 0.001). The association between BMI and DNAm of 138 CpGs reached P < 1 × 10-4level. Twenty BMI-related differentially methylated regions within MAP2K2, POU4F2, AGAP2, MRGPRE, ADM5, and NKX1-1 were found. Of the 138 CpGs, 4 within VENTX (involved in cellular responses to stress pathway), SMOC2 (enable calcium ion binding), and FSCN2 (a member of fascin protein family) mediated the association between BMI and SUA, with a mediating effect of 0.002-μmol/L lower log10transformed SUA levels and a proportion of 18.89 %-24.92 % negative mediating effect. BMI × DNAm interactions on SUA were observed for 2 CpGs within VENTX. The gene expression level of VENTX was also negatively associated with SUA level. BMI-related DNAm variation may partially mediate the association of BMI with SUA.Copyright © 2022 Elsevier B.V. All rights reserved.",
+No,20221024,methods,36242584,A systematic assessment of cell type deconvolution algorithms for DNA methylation data.,Brief Bioinform,"We performed systematic assessment of computational deconvolution methods that play an important role in the estimation of cell type proportions from bulk methylation data. The proposed framework methylDeConv (available as an R package) integrates several deconvolution methods for methylation profiles (Illumina HumanMethylation450 and MethylationEPIC arrays) and offers different cell-type-specific CpG selection to construct the extended reference library which incorporates the main immune cell subsets, epithelial cells and cell-free DNAs. We compared the performance of different deconvolution algorithms via simulations and benchmark datasets and further investigated the associations of the estimated cell type proportions to cancer therapy in breast cancer and subtypes in melanoma methylation case studies. Our results indicated that the deconvolution based on the extended reference library is critical to obtain accurate estimates of cell proportions in non-blood tissues.© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+Yes,20221024,ewas,36241462,"Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study.",Biol Psychiatry,"Negative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.To identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10-8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.Our findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.Copyright © 2022. Published by Elsevier Inc.",
+No,20221024,methods,36239035,The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip.,Epigenetics,"DNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilizing precious or limited DNA sources. We used a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. We found that data are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; and that low DNA input is associated with a reduction in power to detect EWAS associations, requiring larger sample sizes. We conclude that DNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken.",
+Yes,20221024,ewas,36217170,Fetal exposure to phthalates and bisphenols and DNA methylation at birth: the Generation R Study.,Clin Epigenetics,"Phthalates and bisphenols are non-persistent endocrine disrupting chemicals that are ubiquitously present in our environment and may have long-lasting health effects following fetal exposure. A potential mechanism underlying these exposure-outcome relationships is differential DNA methylation. Our objective was to examine the associations of maternal phthalate and bisphenol concentrations during pregnancy with DNA methylation in cord blood using a chemical mixtures approach.This study was embedded in a prospective birth cohort study in the Netherlands and included 306 participants. We measured urine phthalates and bisphenols concentrations in the first, second and third trimester. Cord blood DNA methylation in their children was processed using the Illumina Infinium HumanMethylation450 BeadChip using an epigenome-wide association approach. Using quantile g-computation, we examined the association of increasing all mixture components by one quartile with cord blood DNA methylation.We did not find evidence for statistically significant associations of a maternal mixture of phthalates and bisphenols during any of the trimesters of pregnancy with DNA methylation in cord blood (all p values > 4.01 * 10-8). However, we identified one suggestive association (p value < 1.0 * 10-6) of the first trimester maternal mixture of phthalates and bisphenols and three suggestive associations of the second trimester maternal mixture of phthalates and bisphenols with DNA methylation in cord blood.Although we did not identify genome-wide significant results, we identified some suggestive associations of exposure to a maternal mixture of phthalates and bisphenols in the first and second trimester with DNA methylation in cord blood that need further exploration in larger study samples.© 2022. The Author(s).",
+Yes,20221024,ewas,36206092,"At age 9, the methylome of assisted reproductive technology children that underwent embryo culture in different media is not significantly different on a genome-wide scale.",Hum Reprod,"Can we detect DNA methylation differences between ART children that underwent embryo culture in different media?We identified no significant differences in site-specific or regional DNA methylation between the different culture medium groups.Embryo culture in G3 or K-SICM medium leads to differences in embryonic, neonatal and childhood outcomes, including growth and weight. The methylome may mediate this association as the period of in vitro culture of ART treatments coincides with epigenetic reprogramming.This study was conducted as a follow-up to a previous culture medium comparison study in which couples were pseudo-randomized to embryo culture in G3 or K-SICM medium. Of the resultant singletons, 120 (n = 65 G3, n = 55 K-SICM), were recruited at age 9.The ART children provided a saliva sample from which the methylome was analysed using the Infinium MethylationEPIC array. After quality and context filtering, 106 (n = 57 G3, n = 49 K-SICM) samples and 659 708 sites were retained for the analyses. Differential methylation analyses were conducted using mixed effects linear models corrected for age, sex, sample plate and cell composition. These were applied to all cytosine-guanine dinucleotide (CpG) sites, various genomic regions (genes, promoters, CpG Islands (CGIs)) and as a targeted analysis of imprinted genes and birth weight-associated CpG sites. Differential variance was assessed using the improved epigenetic variable outliers for risk prediction analysis (iEVORA) algorithm and methylation outliers were identified using a previously defined threshold (upper or lower quartile plus or minus three times the interquartile range, respectively).After correcting for multiple testing, we did not identify any significantly differentially methylated CpG sites, genes, promoters or CGIs between G3 and K-SICM children despite a lenient corrected P-value threshold of 0.1. Targeted analyses of (sites within) imprinted genes and birth weight-associated sites also did not identify any significant differences. The number of DNA methylation outliers per sample was comparable between the culture medium groups. iEVORA identified 101 differentially variable CpG sites of which 94 were more variable in the G3 group.Gene Expression Omnibus (GEO) GSE196432.To detect significant methylation differences with a magnitude of <10% between the groups many more participants would be necessary; however, the clinical relevance of such small differences is unclear.The results of this study are reassuring, suggesting that if there is an effect of the culture medium on DNA methylation (and methylation-mediated diseases risk), it does not differ between the two media investigated here. The findings concur with other methylome studies of ART neonates and children that underwent embryo culture in different media, which also found no significant methylome differences.Study funded by March of Dimes (6-FY13-153), EVA (Erfelijkheid Voortplanting & Aanleg) specialty programme (grant no. KP111513) of Maastricht University Medical Centre (MUMC+) and the Horizon 2020 innovation (ERIN) (grant no. EU952516) of the European Commission. The authors do not report any conflicts of interest relevant to this study.Dutch Trial register-NL4083.© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.",
+Yes,20221024,ewas,36201768,Epigenome-wide analysis of DNA methylation and optimism in women and men.,Psychosom Med,"Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized DNAm would differ among older individuals who are more versus less optimistic.Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities (N = 3,816) and men (only white, N = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the inabldividual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the number of independent degrees of freedom approach: effective degrees of freedom correction using the number of principal components (PCs), explaining>95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathways analyses using the Ingenuity Pathway Analysis software.We found essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm~optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, neurodevelopmental and neurodegenerative disorders.Our findings provide new insights into possible mechanisms underlying optimism and health.Copyright © 2022 by the American Psychosomatic Society.",
+Yes,20221024,ewas,36196007,Maternal Periconceptional Folic Acid Supplementation and DNA Methylation Patterns in Adolescent Offspring.,J Nutr,"Folate, including the folic acid form, is a key component of the one-carbon metabolic pathway used for DNA methylation. Changes in DNA methylation patterns during critical development periods are associated with disease outcomes and are associated with changes in nutritional status in pregnancy. The long-term impact of periconceptional folic acid supplementation on DNA methylation patterns is unknown.To determine the long-term impact of periconceptional folic acid supplementation on DNA methylation patterns, we examined the association of the recommended dosage (400 μg/d) and time period (periconceptional before pregnancy through first trimester) of folic acid supplementation with the DNA methylation patterns in the offspring at age 14-17 y compared with offspring with no supplementation.Two geographic sites in China from the 1993-1995 Community Intervention Program of folic acid supplementation were selected for the follow-up study. DNA methylation at 402,730 CpG sites was assessed using saliva samples from 89 mothers and 179 adolescents (89 male). The mean age at saliva collection was 40 y among mothers (range: 35-54 y) and 15 y among adolescents (range: 14-17 y). Epigenome-wide analyses were conducted to assess the interactions of periconceptional folic acid exposure, the 5,10-methylenetetrahydrofolate reductase (MTHFR)-C677T genotype, and epigenome-wide DNA methylation controlling for offspring sex, geographic region, and background cell composition in the saliva.In the primary outcome, no significant differences were observed in epigenome-wide methylation patterns between adolescents exposed and those non-exposed to maternal periconceptional folic acid supplementation after adjustment for potential confounders [false discovery rate (FDR) P values < 0.05]. The MTHFR-C677T genotype did not modify this lack of association (FDR P values < 0.05).Overall, there were no differences in DNA methylation between adolescents who were exposed during the critical developmental window and those not exposed to the recommended periconceptional/first-trimester dosage of folic acid.Published by Oxford University Press on behalf of the American Society for Nutrition 2022.",
+Yes,20221024,ewas,36180927,Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study.,Clin Epigenetics,"The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke.We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10-06) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH.The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 × 10-08) and in MERTK (p value = 1.56 × 10-07). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 × 10-06and p value = 1.3 × 10-02, respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = - 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = - 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells.DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation.© 2022. The Author(s).",
+Yes,20221024,ewas,36179964,"Genome-wide DNA methylation analysis of middle-aged and elderly monozygotic twins with age-related hearing loss in Qingdao, China.",Gene,"To explore the differences in DNA methylation associated with age-related hearing loss in a study of 57 twin pairs from China.Monozygotic twins were identified through the Qingdao Twin Registration system. The median age of participants was > 50 years. Their hearing thresholds were measured using a multilevel pure-tone audiometry assessment. The pure-tone audiometry was calculated at low frequencies (0.5, 1.0, and 2.0 kHz), speech frequencies (0.5, 1.0, 2.0, and 4.0 kHz), and high frequencies (4.0 and 8 kHz). The CpG sites were tested using a linear mixed-effects model, and the function of the cis-regulatory regions and ontological enrichments were predicted using the online Genomic Regions Enrichment of Annotations Tool. The differentially methylated regions were identified using a comb-p python library approach.In each of the PTA categories (low-, speech-, high-frequency), age-related hearing loss was detected in 25.9%, 19.3%, and 52.8% of participants. In the low-, speech- and high-frequency categories we identified 18, 42, and 12 individual CpG sites and 6, 11, and 6 differentially methylated regions. The CpG site located near DUSP4 had the strongest association with low- and speech-frequency, while the strongest association with high-frequency was near C21orf58. We identified associations of ALG10 with high-frequency hearing, C3 and LCK with low- and speech-frequency hearing, and GBX2 with low-frequency hearing. Top pathways that may be related to hearing, such as the Notch signaling pathway, were also identified.Our study is the first of its kind to identify these genes and their associated with DNA methylation may play essential roles in the hearing process. The results of our epigenome-wide association study on twins clarify the complex mechanisms underlying age-related hearing loss.Copyright © 2022 Elsevier B.V. All rights reserved.",
+No,20221024,epigenetics,36179666,Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes.,Cell,"Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.",
+No,20221024,methods,36179079,mHapTk: A comprehensive toolkit for the analysis of DNA methylation haplotypes.,Bioinformatics,"Bisulfite sequencing (BS-seq) remains the gold standard technique to detect DNA methylation profiles at single-nucleotide resolution. The DNA methylation status of CpG sites on the same fragment represents a discrete methylation haplotype (mHap). The mHap-level metrics were demonstrated to be promising cancer biomarkers and explain more gene expression variation than average methylation. However, most existing tools focus on average methylation and neglect mHap patterns. Here, we present mhapTk, a comprehensive python toolkit for the analysis of DNA methylation haplotypes. It calculates eight mHap-level summary statistics in predefined regions or across individual CpG in a genome-wide manner. It identifies methylation haplotype blocks (MHBs), in which methylations of pairwise CpGs is tightly correlated. Furthermore, mHap patterns can be visualized with the built-in functions in mHapTk or external tools such as IGV and deepTools.https://jiantaoshi.github.io/mhaptk/index.html.Supplementary data are available at Bioinformatics online.© The Author(s) (2022). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+Yes,20221024,ewas,36178055,Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls.,Am J Clin Nutr,"Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relationship by food sources versus folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known.We evaluated the relationship between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study.Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n = 189) and controls (n = 205) in the California Childhood Leukemia Study (CCLS) from 1995-2008 was compared to periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term.Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n = 394). The top differentially methylated region at the promoter region of DUSP22 demonstrated DNA hypermethylation in ALL cases but not controls in response to total and food folate intake. We further identified eight interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and education level.We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.",
+No,20221024,methods,36175791,Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics.,Nat Genet,"Genome-wide association studies provide a powerful means of identifying loci and genes contributing to disease, but in many cases, the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. In the present study, we introduce sc-linker, a framework for integrating single-cell RNA-sequencing, epigenomic SNP-to-gene maps and genome-wide association study summary statistics to infer the underlying cell types and processes by which genetic variants influence disease. The inferred disease enrichments recapitulated known biology and highlighted notable cell-disease relationships, including γ-aminobutyric acid-ergic neurons in major depressive disorder, a disease-dependent M-cell program in ulcerative colitis and a disease-specific complement cascade process in multiple sclerosis. In autoimmune disease, both healthy and disease-dependent immune cell-type programs were associated, whereas only disease-dependent epithelial cell programs were prominent, suggesting a role in disease response rather than initiation. Our framework provides a powerful approach for identifying the cell types and cellular processes by which genetic variants influence disease.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20221024,prediction,36175966,A blood DNA methylation biomarker for predicting short-term risk of cardiovascular events.,Clin Epigenetics,"Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposure to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predicts diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-the-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-the-art DNAm risk scores for cardiovascular diseases, the 'next-generation' epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2.Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent data sets from Europe and the USA. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant).We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of prediction models based on DNAm surrogates and discuss methodological aspects for further improvements. Finally, our results encourage testing this approach for other NCD diseases by training and developing DNAm surrogates for disease-specific risk factors and exposures.© 2022. The Author(s).",
+No,20221024,methods,36265006,Deep mendelian randomization: Investigating the causal knowledge of genomic deep learning models,PLoS Comput Biol,"Multi-task deep learning (DL) models can accurately predict diverse genomic marks from sequence, but whether these models learn the causal relationships between genomic marks is unknown. Here, we describe Deep Mendelian Randomization (DeepMR), a method for estimating causal relationships between genomic marks learned by genomic DL models. By combining Mendelian randomization with in silico mutagenesis, DeepMR obtains local (locus specific) and global estimates of (an assumed) linear causal relationship between marks. In a simulation designed to test recovery of pairwise causal relations between transcription factors (TFs), DeepMR gives accurate and unbiased estimates of the 'true' global causal effect, but its coverage decays in the presence of sequence-dependent confounding. We then apply DeepMR to examine the global relationships learned by a state-of-the-art DL model, BPNet, between TFs involved in reprogramming. DeepMR's causal effect estimates validate previously hypothesized relationships between TFs and suggest new relationships for future investigation.",
+No,20221114,dnam age,36346848,In utero exposure to the Great Depression is reflected in late-life epigenetic aging signatures.,Proc Natl Acad Sci U S A,"Research on maternal-fetal epigenetic programming argues that adverse exposures to the intrauterine environment can have long-term effects on adult morbidity and mortality. However, causal research on epigenetic programming in humans at a population level is rare and is often unable to separate intrauterine effects from conditions in the postnatal period that may continue to impact child development. In this study, we used a quasi-natural experiment that leverages state-year variation in economic shocks during the Great Depression to examine the causal effect of environmental exposures in early life on late-life accelerated epigenetic aging for 832 participants in the US Health and Retirement Study (HRS). HRS is the first population-representative study to collect epigenome-wide DNA methylation data that has the sample size and geographic variation necessary to exploit quasi-random variation in state environments, which expands possibilities for causal research in epigenetics. Our findings suggest that exposure to changing economic conditions in the 1930s had lasting impacts on next-generation epigenetic aging signatures that were developed to predict mortality risk (GrimAge) and physiological decline (DunedinPoAm). We show that these effects are localized to the in utero period specifically as opposed to the preconception, postnatal, childhood, or early adolescent periods. After evaluating endogenous shifts in mortality and fertility related to Depression-era birth cohorts, we conclude that these effects likely represent lower bound estimates of the true impacts of the economic shock on long-term epigenetic aging.",
+No,20221114,dnam age,36304118,A set of common buccal CpGs that predict epigenetic age and associate with lifespan-regulating genes.,iScience,"Epigenetic aging clocks are computational models that use DNA methylation sites to predict age. Since cheek swabs are non-invasive and painless, collecting DNA from buccal tissue is highly desirable. Here, we review 11 existing clocks that have been applied to buccal tissue. Two of these were exclusively trained on adults and, while moderately accurate, have not been used to capture health-relevant differences in epigenetic age. Using 130 common CpGs utilized by two or more existing buccal clocks, we generate a proof-of-concept predictor in an adult methylomic dataset. In addition to accurately estimating age (r = 0.95 and mean absolute error = 3.88 years), this clock predicted that Down syndrome subjects were significantly older relative to controls. A literature and database review of CpG-associated genes identified numerous genes (e.g.,CLOCK,ELOVL2, andVGF) and molecules (e.g., alpha-linolenic acid, glycine, and spermidine) reported to influence lifespan and/or age-related disease in model organisms.© 2022 The Author(s).",
+No,20221114,dnam age,36294002,Do Loneliness and Per Capita Income Combine to Increase the Pace of Biological Aging for Black Adults across Late Middle Age?,Int J Environ Res Public Health,"In a sample of 685 late middle-aged Black adults (M age at 2019 = 57.17 years), we examined the effects of loneliness and per capita income on accelerated aging using a newly developed DNA-methylation based index: the DunedinPACE. First, using linear, mixed effects regression in a growth curve framework, we found that change in DunedinPACE was dependent on age, with a linear model best fitting the data (b = 0.004,p&lt; 0.001), indicating that average pace of change increased among older participants. A quadratic effect was also tested, but was non-significant. Beyond the effect of age, both change in loneliness (b = 0.009,p&lt; 0.05) and change in per capita income (b = -0.016,p&lt; 0.001) were significantly associated with change in DunedinPACE across an 11-year period, accounting for significant between person variability observed in the unconditional model. Including non-self-report indices of smoking and alcohol use did not reduce the association of loneliness or per capita income with DunedinPACE. However, change in smoking was strongly associated with change in DunedinPACE such that those reducing their smoking aged less rapidly than those continuing to smoke. In addition, both loneliness and per capita income were associated with DunedinPACE after controlling for variation in cell-types.",
+No,20221114,dnam age,36292773,Epigenetic and Proteomic Biomarkers of Elevated Alcohol Use Predict Epigenetic Aging and Cell-Type variation Better Than Self-Report.,Genes (Basel),"Excessive alcohol consumption (EAC) has a generally accepted effect on morbidity and mortality, outcomes thought to be reflected in measures of epigenetic aging (EA). As the association of self-reported EAC with EA has not been consistent with these expectations, underscoring the need for readily employable non-self-report tools for accurately assessing and monitoring the contribution of EAC to accelerated EA, newly developed alcohol consumption DNA methylation indices, such as the Alcohol T Score (ATS) and Methyl DetectR (MDR), may be helpful. To test that hypothesis, we used these new indices along with the carbohydrate deficient transferrin (CDT), concurrent as well as past self-reports of EAC, and well-established measures of cigarette smoking to examine the relationship of EAC to both accelerated EA and immune cell counts in a cohort of 437 young Black American adults. We found that MDR, CDT, and ATS were intercorrelated, even after controlling for gender and cotinine effects. Correlations between EA and self-reported EAC were low or non-significant, replicating prior research, whereas correlations with non-self-report indices were significant and more substantial. Comparing non-self-report indices showed that the ATS predicted more than four times as much variance in EA, CDT4 cells and B-cells as for both the MDR and CDT, and better predicted indices of accelerated EA. We conclude that each of the non-self-report indices have differing predictive capacities with respect to key alcohol-related health outcomes, and that the ATS may be particularly useful for clinicians seeking to understand and prevent accelerated EA. The results also underscore the likelihood of substantial underestimates of problematic use when self-report is used and a reduction in correlations with EA and variance in cell-types.",
+No,20221114,dnam age,36289503,Marijuana use and DNA methylation-based biological age in young adults.,Clin Epigenetics,"Marijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana's effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation.A random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with available whole blood at examination years (Y) 15 and Y20 underwent epigenomic profiling. Four EAA estimates (intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration, PhenoAge acceleration, and GrimAge acceleration) were calculated from DNA methylation levels measured at Y15 and Y20. Ever use and cumulative marijuana-years were calculated from the baseline visit to Y15 and Y20, and recent marijuana use (both any and number of days of use in the last 30 days) were calculated at Y15 and Y20. Ever use of marijuana and each additional marijuana-year were associated with a 6-month (P < 0.001) and a 2.5-month (P < 0.001) higher average in GrimAge acceleration (GAA) using generalized estimating equations, respectively. Recent use and each additional day of recent use were associated with a 20-month (P < 0.001) and a 1-month (P < 0.001) higher GAA, respectively. A statistical interaction between marijuana-years and alcohol consumption on GAA was observed (P = 0.011), with nondrinkers exhibiting a higher GAA (β = 0.21 [95% CI 0.05, 0.36], P = 0.008) compared to heavy drinkers (β = 0.05 [95% CI - 0.09, 0.18], P = 0.500) per each additional marijuana-year. No associations were observed for the remaining EAA estimates.These findings suggest cumulative and recent marijuana use are associated with age-related epigenetic changes that are related to lifespan. These observed associations may be modified by alcohol consumption. Given the increase in use and legalization, these findings provide novel insight on the effect of marijuana use on the aging process as captured through blood DNA methylation.© 2022. The Author(s).",
+No,20221114,dnam age,36227464,Maternal Adversity and Epigenetic Age Acceleration Predict Heightened Emotional Reactivity in Offspring: Implications for Intergenerational Transmission of Risk.,Res Child Adolesc Psychopathol,"Black American women are disproportionately exposed to adversities that may have an intergenerational impact on mental health. The present study examined whether maternal exposure to adversity and epigenetic age acceleration (EAA; a biomarker of stress exposure) predicts the socioemotional health of her offspring. During pregnancy, 180 Black American women self-reported experiences of childhood adversity and marginalization-related adversity (i.e., racial discrimination and gendered racial stress) and provided a blood sample for epigenetic assessment. At a three-year follow-up visit, women reported their offspring's emotional reactivity (an early indicator of psychopathology) via the CBCL/1.5-5. After adjusting for maternal education and offspring sex, results indicated that greater maternal experiences of childhood trauma (β = 0.21, SE(β) = 0.01; p = 0.01) and racial discrimination (β = 0.14, SE(β) = 0.07; p = 0.049) predicted greater offspring emotional reactivity, as did maternal EAA (β = 0.17, SE(β) = 0.09, p = 0.046). Our findings suggest that maternal EAA could serve as an early biomarker for intergenerational risk conferred by maternal adversity, and that 'maternal adversity' must be defined more broadly to include social marginalization, particularly for Black Americans.© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20221114,ewas,36345830,Association Between DNA Methylation and Blood Pressure: A 5-Year Longitudinal Twin Study.,Hypertension,"Previous EWASs (Epigenome-Wide Association Studies) have reported hundreds of blood pressure (BP) associated 5'-cytosine-phosphate-guanine-3' (CpG) sites. However, their results were inconsistent. Longitudinal observations on the temporal relationship between DNA methylation and BP are lacking.A candidate CpG site association study for BP was conducted on 1072 twins in the Chinese National Twin Registry. PubMed and EMBASE were searched for candidate CpG sites. Cross-lagged models were used to assess the temporal relationship between BP and DNA methylation in 308 twins who completed 2 surveys in 2013 and 2018. Then, the significant cross-lagged associations were validated by adopting the Inference About Causation From Examination of Familial Confounding approach. Finally, to evaluate the cumulative effects of DNA methylation on the progression of hypertension, we established methylation risk scores based on BP-associated CpG sites and performed Markov multistate models.16 and 20 CpG sites were validated to be associated with systolic BP and diastolic BP, respectively. In the cross-lagged analysis, we detected that methylation of 2 CpG sites could predict subsequent systolic BP, and systolic BP predicted methylation at another 3 CpG sites. For diastolic BP, methylation at 3 CpG sites had significant cross-lagged effects for predicting diastolic BP levels, while the prediction from the opposite direction was observed at one site. Among these, 3 associations were validated in the Inference About Causation From Examination of Familial Confounding analysis. Using the Markov multistate model, we observed that methylation risk scores were associated with the development of hypertension.Our findings suggest the significance of DNA methylation in the development of hypertension.",
+Yes,20221114,ewas,36344488,Epigenome-wide DNA methylation analysis of whole blood cells derived from patients with GAD and OCD in the Chinese Han population.,Transl Psychiatry,"Generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD) had high comorbidity and affected more than 44 million people around the world leading to a huge burden on health and economy. Here, we conducted an epigenome-wide DNA methylation study employing 93 patients with GAD, 65 patients with OCD, and 302 health controls, to explore epigenetic alterations associated with the onset and differences of GAD and OCD. We identified multiple differentially methylated positions (DMPs) and regions (DMRs): three DMP genes included RIOK3 (cg21515243, p = 8.00 × 10-10), DNASE2 (cg09379601, p = 1.10 × 10-9), and PSMB4 (cg01334186, p = 3.70 × 10-7) and two DMR genes USP6NL (p = 4.50 × 10-4) and CPLX1 (p = 6.95 × 10-4) were associated with the onset of GAD and OCD; three DMPs genes included LDLRAP1 (cg21400344, p = 4.40 × 10-12), ACIN1 (cg23712970, p = 2.98×10-11), and SCRT1 (cg25472897, p = 5.60 × 10-11) and three DMR genes WDR19 (p = 3.39 × 10-3), SYCP1 (p = 6.41 × 10-3), and FAM172A (p = 5.74 × 10-3) were associated with the differences between GAD and OCD. Investigation of epigenetic age and chronological age revealed a different epigenetic development trajectory of GAD and OCD. Conclusively, our findings which yielded robust models may aid in distinguishing patients from healthy controls (AUC = 0.90-0.99) or classifying patients with GAD and OCD (AUC = 0.89-0.99), and may power the precision medicine for them.© 2022. The Author(s).",
+Yes,20221114,ewas,36326208,Meta-analysis of DNA methylation datasets shows aberrant DNA methylation of thyroid development or function genes in Down syndrome.,Thyroid,"In Down syndrome (DS) there is a high occurrence of congenital hypothyroidism (CH) and subclinical hypothyroidism (SH) early in life. The etiology of CH and early SH in DS remains unclear. Previous research has shown genome-wide transcriptional and epigenetic alterations in DS. Thus, we hypothesized that CH and early SH could be caused by epigenetically driven transcriptional downregulation of thyroid-related genes, through promoter region hypermethylation.We extracted whole blood DNA methylation (DNAm) profiles of DS and non-DS individuals from four independent Illumina array-based datasets (252 DS individuals and 519 non-DS individuals). The data were divided in a discovery and validation dataset. Epigenome-wide association analysis was performed using a linear regression model, after which we filtered for thyroid-related genes.In the discovery dataset, we identified significant associations for DS in 18 thyroid-related genes. 21 of 30 significant differentially methylated positions (DMPs) were also significant in the validation dataset. A meta-analysis of the discovery and validation datasets detected 31 DMPs, including 29 promoter-associated CpGs with identical direction of effect across the datasets, and two differentially methylated regions (DMRs). 27 DMPs were hypomethylated and promoter-associated. The mean methylation difference of hypomethylated thyroid-related DMPs decreased with age.Contrary to our hypothesis of generalized hypermethylation of promoter regions of thyroid-related genes - indicative of epigenetic silencing of promoters and subsequent transcriptional downregulation, causing the biochemical thyroid abnormalities in DS -, we found an enrichment of hypomethylated DMPs annotated to promoter regions of these genes. This suggests that CH and early SH in DS are not caused by differential methylation of thyroid-related genes. Considering epigenetic regulation is dynamic, we hypothesize the observed thyroid-related gene DNAm changes could be a rescue phenomenon in an attempt to ameliorate the thyroid phenotype, through epigenetic upregulation of thyroid-related genes. This hypothesis is supported by the finding of decreasing methylation difference of thyroid-related genes with age. The prevalence of early SH declines with age, so hypothetically, epigenetic upregulation of thyroid-related genes also diminishes. While this study provides interesting insights, the exact origin of CH and early SH in DS remains unknown.",
+Yes,20221114,ewas,36325427,Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients.,Brain Behav Immun Health,"Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS<5). For PD patients with a history of clinical depression compared to those without, we found no differences in immune cell composition. However, a history of clinical depression among patients was associated with differentially methylated CpGs. Epigenome-wide association analysis (EWAS) revealed 35 CpGs associated at an FDR≤0.05 (569 CpGs at FDR≤0.10, 1718 CpGs at FDR≤0.15). Gene set enrichment analysis implicated immune system pathways, including immunoregulatory interactions between lymphoid and non-lymphoid cells (p-adj = 0.003) and cytokine-cytokine receptor interaction (p-adj = 0.004). Based on functional genomics, 25 (71%) of the FDR≤0.05 CpGs were associated with genetic variation at 45 different methylation quantitative trait loci (meQTL). Twenty-six of the meQTLs were also expression QTLs (eQTLs) associated with the abundance of 53 transcripts in blood and 22 transcripts in brain (substantia nigra, putamen basal ganglia, or frontal cortex). Notably, cg15199181 was strongly related to rs823114 (SNP-CpG p-value = 3.27E-310), a SNP identified in a PD meta-GWAS and related to differential expression ofPM20D1,RAB29,SLC41A1, andNUCKS1. The entire set of genes detected through functional genomics was most strongly overrepresented for interferon-gamma-mediated signaling pathway (enrichment ratio = 18.8, FDR = 4.4e-03) and T cell receptor signaling pathway (enrichment ratio = 13.2, FDR = 4.4e-03). Overall, the current study provides evidence of immune system involvement in depression among Parkinson's patients.© 2022 The Authors.",
+Yes,20221114,ewas,36319817,Meta-analysis of epigenome-wide association studies of major depressive disorder.,Sci Rep,"Epigenetic mechanisms have been hypothesized to play a role in the etiology of major depressive disorder (MDD). In this study, we performed a meta-analysis between two case-control MDD cohorts to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in MDD. Using samples from two Cohorts (a total of 298 MDD cases and 63 controls with repeated samples, on average ~ 1.8 samples/subject), we performed an EWAS meta-analysis. Multiple cytosine-phosphate-guanine sites annotated to TNNT3 were associated with MDD reaching study-wide significance, including cg08337959 (p = 2.3 × 10-11). Among DMPs with association p values less than 0.0001, pathways from REACTOME such as Ras activation upon Ca2+influx through the NMDA receptor (p = 0.0001, p-adjusted = 0.05) and long-term potentiation (p = 0.0002, p-adjusted = 0.05) were enriched in this study. A total of 127 DMRs with Sidak-corrected p value < 0.05 were identified from the meta-analysis, including DMRs annotated to TNNT3 (chr11: 1948933 to 1949130 [6 probes], Sidak corrected P value = 4.32 × 10-41), S100A13 (chr1: 153599479 to 153600972 [22 probes], Sidak corrected P value = 5.32 × 10-18), NRXN1 (chr2: 50201413 to 50201505 [4 probes], Sidak corrected P value = 1.19 × 10-11), IL17RA (chr22: 17564750 to 17565149, Sidak corrected P value = 9.31 × 10-8), and NPFFR2 (chr4: 72897565 to 72898212, Sidak corrected P value = 8.19 × 10-7). Using 2 Cohorts of depression case-control samples, we identified DMPs and DMRs associated with MDD. The molecular pathways implicated by these data include mechanisms involved in neuronal synaptic plasticity, calcium signaling, and inflammation, consistent with reports from previous genetic and protein biomarker studies indicating that these mechanisms are involved in the neurobiology of depression.© 2022. The Author(s).",
+Yes,20221114,ewas,36303554,Epigenome-wide association study of biomarkers of liver function identifies albumin-associated DNA methylation sites among male veterans with HIV.,Front Genet,"Background: Liver disease (LD) is an important cause of morbidity and mortality for people with HIV (PWH). The molecular factors linked with LD in PWH are varied and incompletely characterized. We performed an epigenome-wide association study (EWAS) to identify associations between DNA methylation (DNAm) and biomarkers of liver function-aspartate transaminase, alanine transaminase, albumin, total bilirubin, platelet count, FIB-4 score, and APRI score-in male United States veterans with HIV.Methods:Blood samples and clinical data were obtained from 960 HIV-infected male PWH from the Veterans Aging Cohort Study. DNAm was assessed using the Illumina 450K or the EPIC 850K array in two mutually exclusive subsets. We performed a meta-analysis for each DNAm site measured by either platform. We also examined the associations between four measures of DNAm age acceleration (AA) and liver biomarkers.Results:Nine DNAm sites were positively associated with serum albumin in the meta-analysis of the EPIC and 450K EWAS after correcting for multiple testing. Four DNAm sites (cg16936953, cg18942579, cg01409343, and cg12054453), annotated within theTMEM49and four of the remaining five sites (cg18181703, cg03546163, cg20995564, and cg23966214) annotated toSOCS3,FKBP5,ZEB2, andSAMD14genes, respectively. The DNAm site, cg12992827, was not annotated to any known coding sequence. No significant associations were detected for the other six liver biomarkers. Higher PhenoAA was significantly associated with lower level of serum albumin (β= -0.007,p-value = 8.6 × 10-4, CI: -0.011116, -0.002884).Conclusion:We identified epigenetic associations of both individual DNAm sites and DNAm AA with liver function through serum albumin in men with HIV. Further replication analyses in independent cohorts are warranted to confirm the epigenetic mechanisms underlying liver function and LD in PWH.Copyright © 2022 Titanji, Lee, Wang, Chen, Hui, Lo Re III, So-Armah, Justice, Xu, Freiberg, Gwinn, Marconi and Sun.",
+No,20221114,ewas,36292679,Profiling Genome-Wide DNA Methylation in Children with Autism Spectrum Disorder and in Children with Fragile X Syndrome.,Genes (Basel),"Autism spectrum disorder (ASD) is an early onset, developmental disorder whose genetic cause is heterogeneous and complex. In total, 70% of ASD cases are due to an unknown etiology. Among the monogenic causes of ASD, fragile X syndrome (FXS) accounts for 2-4% of ASD cases, and 60% of individuals with FXS present with ASD. Epigenetic changes, specifically DNA methylation, which modulates gene expression levels, play a significant role in the pathogenesis of both disorders. Thus, in this study, using the Human Methylation EPIC Bead Chip, we examined the global DNA methylation profiles of biological samples derived from 57 age-matched male participants (2-6 years old), including 23 subjects with ASD, 23 subjects with FXS with ASD (FXSA) and 11 typical developing (TD) children. After controlling for technical variation and white blood cell composition, using the conservatory threshold of the false discovery rate (FDR ≤ 0.05), in the three comparison groups, TD vs. AD, TD vs. FXSA and ASD vs. FXSA, we identified 156, 79 and 3100 differentially methylated sites (DMS), and 14, 13 and 263 differential methylation regions (DMRs). Interestingly, several genes differentially methylated among the three groups were among those listed in the SFARI Gene database, including thePAK2,GTF2IandFOXP1genes important for brain development. Further, enrichment analyses identified pathways involved in several functions, including synaptic plasticity. Our preliminary study identified a significant role of altered DNA methylation in the pathology of ASD and FXS, suggesting that the characterization of a DNA methylation signature may help to unravel the pathogenicity of FXS and ASD and may help the development of an improved diagnostic classification of children with ASD and FXSA. In addition, it may pave the way for developing therapeutic interventions that could reverse the altered methylome profile in children with neurodevelopmental disorders.",
+Yes,20221114,ewas,36292585,Differentially Methylated DNA Regions and Left Ventricular Hypertrophy in African Americans: A HyperGEN Study.,Genes (Basel),"Left ventricular (LV) hypertrophy (LVH) is an independent risk factor for cardiovascular disease, and African Americans experience a disparate high risk of LVH. Genetic studies have identified potential candidate genes and variants related to the condition. Epigenetic modifications may continue to help unravel disease mechanisms. We used methylation and echocardiography data from 636 African Americans selected from the Hypertension Genetic Epidemiology Network (HyperGEN) to identify differentially methylated regions (DMRs) associated with LVH. DNA extracted from whole blood was assayed on Illumina Methyl450 arrays. We fit linear mixed models to examine associations between co-methylated regions and LV traits, and we then conducted single CpG analyses within significant DMRs. We identified associations between DMRs and ejection fraction (<i>XKR6</i>), LV internal diastolic dimension (<i>TRAK1</i>), LV mass index (<i>GSE1</i>, <i>RPS15 A</i>, <i>PSMD7</i>), and relative wall thickness (<i>DNHD1</i>). In single CpG analysis, CpG sites annotated to <i>TRAK1</i> and <i>DNHD1</i> were significant. These CpGs were not associated with LV traits in replication cohorts but the direction of effect for <i>DNHD1</i> was consistent across cohorts. Of note, <i>DNHD1</i>, <i>GSE1</i>, and <i>PSMD7</i> may contribute to cardiac structural function. Future studies should evaluate relationships between regional DNA methylation patterns and the development of LVH.",
+Yes,20221114,ewas,36274151,Temporal associations between leukocytes DNA methylation and blood lipids: a longitudinal study.,Clin Epigenetics,"The associations between blood lipids and DNA methylation have been investigated in epigenome-wide association studies mainly among European ancestry populations. Several studies have explored the direction of the association using cross-sectional data, while evidence of longitudinal data is still lacking.We tested the associations between peripheral blood leukocytes DNA methylation and four lipid measures from Illumina 450 K or EPIC arrays in 1084 participants from the Chinese National Twin Registry and replicated the result in 988 participants from the China Kadoorie Biobank. A total of 23 associations of 19 CpG sites were identified, with 4 CpG sites located in or adjacent to 3 genes (TMEM49, SNX5/SNORD17 and CCDC7) being novel. Among the validated associations, we conducted a cross-lagged analysis to explore the temporal sequence and found temporal associations of methylation levels of 2 CpG sites with triglyceride and 2 CpG sites with high-density lipoprotein-cholesterol (HDL-C) in all twins. In addition, methylation levels of cg11024682 located in SREBF1 at baseline were temporally associated with triglyceride at follow-up in only monozygotic twins. We then performed a mediation analysis with the longitudinal data and the result showed that the association between body mass index and HDL-C was partially mediated by the methylation level of cg06500161 (ABCG1), with a mediation proportion of 10.1%.Our study indicated that the DNA methylation levels of ABCG1, AKAP1 and SREBF1 may be involved in lipid metabolism and provided evidence for elucidating the regulatory mechanism of lipid homeostasis.© 2022. The Author(s).",
+Yes,20221114,ewas,36266660,Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition.,BMC Med,"Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development.Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy.At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure-but not pulsatile pressure-and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia.This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy.© 2022. The Author(s).",
+Yes,20221114,ewas,36253871,Local CpG density affects the trajectory and variance of age-associated DNA methylation changes.,Genome Biol,"DNA methylation is an epigenetic mark associated with the repression of gene promoters. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Altered rates of aging inferred from these clocks are observed in human disease. However, the molecular mechanisms underpinning age-associated DNA methylation changes remain unknown. Local DNA sequence can program steady-state DNA methylation levels, but how it influences age-associated methylation changes is unknown.We analyze longitudinal human DNA methylation trajectories at 345,895 CpGs from 600 individuals aged between 67 and 80 to understand the factors responsible for age-associated epigenetic changes at individual CpGs. We show that changes in methylation with age occur at 182,760 loci largely independently of variation in cell type proportions. These changes are especially apparent at 8322 low CpG density loci. Using SNP data from the same individuals, we demonstrate that methylation trajectories are affected by local sequence polymorphisms at 1487 low CpG density loci. More generally, we find that low CpG density regions are particularly prone to change and do so variably between individuals in people aged over 65. This differs from the behavior of these regions in younger individuals where they predominantly lose methylation.Our results, which we reproduce in two independent groups of individuals, demonstrate that local DNA sequence influences age-associated DNA methylation changes in humans in vivo. We suggest that this occurs because interactions between CpGs reinforce maintenance of methylation patterns in CpG dense regions.© 2022. The Author(s).",
+Yes,20221114,ewas,36329530,Whole blood methylome-derived features to discriminate endocrine hypertension.,Clin Epigenetics,"Arterial hypertension represents a worldwide health burden and a major risk factor for cardiovascular morbidity and mortality. Hypertension can be primary (primary hypertension, PHT), or secondary to endocrine disorders (endocrine hypertension, EHT), such as Cushing's syndrome (CS), primary aldosteronism (PA), and pheochromocytoma/paraganglioma (PPGL). Diagnosis of EHT is currently based on hormone assays. Efficient detection remains challenging, but is crucial to properly orientate patients for diagnostic confirmation and specific treatment. More accurate biomarkers would help in the diagnostic pathway. We hypothesized that each type of endocrine hypertension could be associated with a specific blood DNA methylation signature, which could be used for disease discrimination. To identify such markers, we aimed at exploring the methylome profiles in a cohort of 255 patients with hypertension, either PHT (n = 42) or EHT (n = 213), and at identifying specific discriminating signatures using machine learning approaches.Unsupervised classification of samples showed discrimination of PHT from EHT. CS patients clustered separately from all other patients, whereas PA and PPGL showed an overall overlap. Global methylation was decreased in the CS group compared to PHT. Supervised comparison with PHT identified differentially methylated CpG sites for each type of endocrine hypertension, showing a diffuse genomic location. Among the most differentially methylated genes, FKBP5 was identified in the CS group. Using four different machine learning methods-Lasso (Least Absolute Shrinkage and Selection Operator), Logistic Regression, Random Forest, and Support Vector Machine-predictive models for each type of endocrine hypertension were built on training cohorts (80% of samples for each hypertension type) and estimated on validation cohorts (20% of samples for each hypertension type). Balanced accuracies ranged from 0.55 to 0.74 for predicting EHT, 0.85 to 0.95 for predicting CS, 0.66 to 0.88 for predicting PA, and 0.70 to 0.83 for predicting PPGL.The blood DNA methylome can discriminate endocrine hypertension, with methylation signatures for each type of endocrine disorder.© 2022. The Author(s).",
+No,20221114,meqtl,36342317,Identification of novel meQTLs strongly associated with rheumatoid arthritis by large-scale epigenome-wide analysis.,FEBS Open Bio,"Rheumatoid arthritis (RA) is highly heritable, and previous studies have suggested that genetic variation may affect susceptibility to RA by altering epigenetic modifications (e.g., DNA methylation). Here, we examined how genetic variation influences DNA methylation (DNAm) in RA by integrating individual genetic variation and DNAm data. Epigenome-wide meQTL (methylation quantitative trait loci) analysis was performed on 354 RA patients and 335 controls, scanning 30,101,744 relationships between 62 SNPs and 485,512 DNA methylation sites. Two regulatory relationship pairs (FDR<0.05) showed very strong associations with RA risk. One was rs10796216-cg00475509, and the DNAm decreased by 0.0168 per addition of allele rs10796216-A. The other was rs6546473-cg13358873, for which a 0.0365 reduction of DNAm at cg13358873 was observed for each addition of allele rs6546473-A, and lower DNAm was found to be significantly associated with RA risk (P = 2.0407e-28). Moreover, both pairs of meQTL showed a strong regulatory relationship only in RA samples, so they can be subsequently considered as risk markers for RA. In conclusion, our integrated analysis of genetic and epigenetic variation suggests that genetic variation may affect the risk of RA by regulating DNA methylation levels. Alterations of DNAm at cg00475509 and cg13358873 loci conferred by rs10796216-A and rs6546473-A allele may suggest a potential risk for RA. Our results deepen our understanding of the genetic and epigenetic mechanisms of RA and provide novel associations that can be further investigated in future studies.This article is protected by copyright. All rights reserved.",
+No,20221114,methods,36335502,Phasing DNA Methylation.,Methods Mol Biol,"Haplotyping enables the study of allele-specific events. Heterozygous variants, primarily single nucleotide variants (SNVs), enable the assignment of the paternal and maternal origin of the chromosomes and are widely employed to phase sequencing reads to their haplotype of origin. Certain long-read technologies enable the detection of both the DNA sequence and DNA modifications. These long reads and their inherent methylation information are suitable for genome-wide haplotyping and allele-specific DNA methylation analysis. Here, we describe the workflow to phase reads and DNA methylation using nanopore sequencing.© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.",
+No,20221114,methods,36282535,A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis.,Hum Mol Genet,"Multiple sclerosis (MS) is a complex dysimmune disorder of the central nervous system. Genome-wide association studies (GWAS) have identified 233 genetic variations associated with MS at the genome-wide significant level. Epigenetic studies have pinpointed differentially methylated CpG sites in MS patients. However, the interplay between genetic risk factors and epigenetic regulation remains elusive. Here, we employed a network model to integrate GWAS summary statistics of 14 802 MS cases and 26 703 controls with DNA methylation profiles from 140 MS cases and 139 controls and the human interactome. We identified differentially methylated genes by aggregating additive effects of differentially methylated CpG sites within promoter regions. We reconstructed a gene regulatory network (GRN) using literature-curated transcription factor knowledge. Colocalization of the MS GWAS and methylation quantitative trait loci (mQTL) was performed to assess the GRN. The resultant MS-associated GRN highlighted several single nucleotide polymorphisms (SNPs) with GWAS-mQTL colocalization: rs6032663, rs6065926, and rs2024568 of CD40 locus, rs9913597 of STAT3 locus, and rs887864 and rs741175 of CIITA locus. Moreover, synergistic mQTL and eQTL signals were identified in CD40, suggesting gene expression alteration was likely induced by epigenetic changes. Web-based Cell-type Specific Enrichment Analysis of Genes (WebCSEA) indicated that the GRN was enriched in T follicular helper cells (p-value = 0.0016). Drug target enrichment analysis of annotations from the Therapeutic Target Database (TTD) revealed the GRN was also enriched with drug target genes (p-value = 3.89 × 10-4), revealing repurposable candidates for MS treatment. These candidates included vorinostat (HDAC1 inhibitor) and sivelestat (ELANE inhibitor), which warrant further investigation.© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+No,20221114,methods,36280888,Significant variation in the performance of DNA methylation predictors across data preprocessing and normalization strategies.,Genome Biol,"DNA methylation (DNAm)-based predictors hold great promise to serve as clinical tools for health interventions and disease management. While these algorithms often have high prediction accuracy, the consistency of their performance remains to be determined. We therefore conduct a systematic evaluation across 101 different DNAm data preprocessing and normalization strategies and assess how each analytical strategy affects the consistency of 41 DNAm-based predictors.Our analyses are conducted in a large EPIC DNAm array dataset from the Jackson Heart Study (N = 2053) that included 146 pairs of technical replicate samples. By estimating the average absolute agreement between replicate pairs, we show that 32 out of 41 predictors (78%) demonstrate excellent consistency when appropriate data processing and normalization steps are implemented. Across all pairs of predictors, we find a moderate correlation in performance across analytical strategies (mean rho = 0.40, SD = 0.27), highlighting significant heterogeneity in performance across algorithms. Successful or unsuccessful removal of technical variation furthermore significantly impacts downstream phenotypic association analysis, such as all-cause mortality risk associations.We show that DNAm-based algorithms are sensitive to technical variation. The right choice of data processing strategy is important to achieve reproducible estimates and improve prediction accuracy in downstream phenotypic association analyses. For each of the 41 DNAm predictors, we report its degree of consistency and provide the best performing analytical strategy as a guideline for the research community. As DNAm-based predictors become more and more widely used, our work helps improve their performance and standardize their implementation.© 2022. The Author(s).",
+No,20221114,methods,36277076,A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking.,Nat Aging,"Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectoriesin vivoandin vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking,in vitrostudies, and clinical trials of aging interventions.",
+No,20221114,methods,36319638,Unsupervised learning of aging principles from longitudinal data.,Nat Commun,"Age is the leading risk factor for prevalent diseases and death. However, the relation between age-related physiological changes and lifespan is poorly understood. We combined analytical and machine learning tools to describe the aging process in large sets of longitudinal measurements. Assuming that aging results from a dynamic instability of the organism state, we designed a deep artificial neural network, including auto-encoder and auto-regression (AR) components. The AR model tied the dynamics of physiological state with the stochastic evolution of a single variable, the ""dynamic frailty indicator"" (dFI). In a subset of blood tests from the Mouse Phenome Database, dFI increased exponentially and predicted the remaining lifespan. The observation of the limiting dFI was consistent with the late-life mortality deceleration. dFI changed along with hallmarks of aging, including frailty index, molecular markers of inflammation, senescent cell accumulation, and responded to life-shortening (high-fat diet) and life-extending (rapamycin) treatments.© 2022. The Author(s).",
+No,20221114,ml,36335101,Learning the histone codes with large genomic windows and three-dimensional chromatin interactions using transformer.,Nat Commun,"The quantitative characterization of the transcriptional control by histone modifications has been challenged by many computational studies, but most of them only focus on narrow and linear genomic regions around promoters, leaving a room for improvement. We present Chromoformer, a transformer-based, three-dimensional chromatin conformation-aware deep learning architecture that achieves the state-of-the-art performance in the quantitative deciphering of the histone codes in gene regulation. The core essence of Chromoformer architecture lies in the three variants of attention operation, each specialized to model individual hierarchy of transcriptional regulation involving from core promoters to distal elements in contact with promoters through three-dimensional chromatin interactions. In-depth interpretation of Chromoformer reveals that it adaptively utilizes the long-range dependencies between histone modifications associated with transcription initiation and elongation. We also show that the quantitative kinetics of transcription factories and Polycomb group bodies can be captured by Chromoformer. Together, our study highlights the great advantage of attention-based deep modeling of complex interactions in epigenomes.© 2022. The Author(s).",
+No,20221114,prediction,36329159,"Precision gynecologic oncology: circulating cell free DNA epigenomic analysis, artificial intelligence and the accurate detection of ovarian cancer.",Sci Rep,"Ovarian cancer (OC) is the most lethal gynecologic cancer due primarily to its asymptomatic nature and late stage at diagnosis. The development of non-invasive markers is an urgent priority. We report the accurate detection of epithelial OC using Artificial Intelligence (AI) and genome-wide epigenetic analysis of circulating cell free tumor DNA (cfTDNA). In a prospective study, we performed genome-wide DNA methylation profiling of cytosine (CpG) markers. Both conventional logistic regression and six AI platforms were used for OC detection. Further, we performed Gene Set Enrichment Analysis (GSEA) analysis to elucidate the molecular pathogenesis of OC. A total of 179,238 CpGs were significantly differentially methylated (FDR p-value < 0.05) genome-wide in OC. High OC diagnostic accuracies were achieved. Conventional logistic regression achieved an area under the ROC curve (AUC) [95% CI] 0.99 [± 0.1] with 95% sensitivity and 100% specificity. Multiple AI platforms each achieved high diagnostic accuracies (AUC = 0.99-1.00). For example, for Deep Learning (DL)/AI AUC = 1.00, sensitivity = 100% and 88% specificity. In terms of OC pathogenesis: GSEA analysis identified 'Adipogenesis' and 'retinoblastoma gene in cancer' as the top perturbed molecular pathway in OC. This finding of epigenomic dysregulation of molecular pathways that have been previously linked to cancer adds biological plausibility to our results.© 2022. The Author(s).",
+No,20221114,prediction,36305646,DNA methylation biomarkers for noninvasive detection of triple-negative breast cancer using liquid biopsy.,Int J Cancer,"Noninvasive detection of aberrant DNA methylation could provide invaluable biomarkers for earlier detection of triple-negative breast cancer (TNBC) which could help clinicians with easier and more efficient treatment options. We evaluated genome-wide DNA methylation data derived from TNBC and normal breast tissues, peripheral blood of TNBC cases and controls and reference samples of sorted blood and mammary cells. Differentially methylated regions (DMRs) between TNBC and normal breast tissues were stringently selected, verified and externally validated. A machine-learning algorithm was applied to select the top DMRs, which then were evaluated on plasma-derived circulating cell-free DNA (cfDNA) samples of TNBC patients and healthy controls. We identified 23 DMRs accounting for the methylation profile of blood cells and reference mammary cells and then selected six top DMRs for cfDNA analysis. We quantified un-/methylated copies of these DMRs by droplet digital PCR analysis in a plasma test set from TNBC patients and healthy controls and confirmed our findings obtained on tissues. Differential cfDNA methylation was confirmed in an independent validation set of plasma samples. A methylation score combining signatures of the top three DMRs overlapping with the SPAG6, LINC10606 and TBCD/ZNF750 genes had the best capability to discriminate TNBC patients from controls (AUC = 0.78 in the test set and AUC = 0.74 in validation set). Our findings demonstrate the usefulness of cfDNA-based methylation signatures as noninvasive liquid biopsy markers for the diagnosis of TNBC.© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",
+No,20221114,prediction,36274755,Hierarchical Ridge Regression for Incorporating Prior Information in Genomic Studies.,J Data Sci,"There is a great deal of prior knowledge about gene function and regulation in the form of annotations or prior results that, if directly integrated into individual prognostic or diagnostic studies, could improve predictive performance. For example, in a study to develop a predictive model for cancer survival based on gene expression, effect sizes from previous studies or the grouping of genes based on pathways constitute such prior knowledge. However, this external information is typically only used post-analysis to aid in the interpretation of any findings. We propose a new hierarchical two-level ridge regression model that can integrate external information in the form of ""meta features"" to predict an outcome. We show that the model can be fit efficiently using cyclic coordinate descent by recasting the problem as a single-level regression model. In a simulation-based evaluation we show that the proposed method outperforms standard ridge regression and competing methods that integrate prior information, in terms of prediction performance when the meta features are informative on the mean of the features, and that there is no loss in performance when the meta features are uninformative. We demonstrate our approach with applications to the prediction of chronological age based on methylation features and breast cancer mortality based on gene expression features.",
+No,20221114,prediction,36261477,A machine learning approach utilizing DNA methylation as an accurate classifier of COVID-19 disease severity.,Sci Rep,"Since the onset of the COVID-19 pandemic, increasing cases with variable outcomes continue globally because of variants and despite vaccines and therapies. There is a need to identify at-risk individuals early that would benefit from timely medical interventions. DNA methylation provides an opportunity to identify an epigenetic signature of individuals at increased risk. We utilized machine learning to identify DNA methylation signatures of COVID-19 disease from data available through NCBI Gene Expression Omnibus. A training cohort of 460 individuals (164 COVID-19-infected and 296 non-infected) and an external validation dataset of 128 individuals (102 COVID-19-infected and 26 non-COVID-associated pneumonia) were reanalyzed. Data was processed using ChAMP and beta values were logit transformed. The JADBio AutoML platform was leveraged to identify a methylation signature associated with severe COVID-19 disease. We identified a random forest classification model from 4 unique methylation sites with the power to discern individuals with severe COVID-19 disease. The average area under the curve of receiver operator characteristic (AUC-ROC) of the model was 0.933 and the average area under the precision-recall curve (AUC-PRC) was 0.965. When applied to our external validation, this model produced an AUC-ROC of 0.898 and an AUC-PRC of 0.864. These results further our understanding of the utility of DNA methylation in COVID-19 disease pathology and serve as a platform to inform future COVID-19 related studies.© 2022. The Author(s).",
+No,20221114,prediction,36309516,The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors.,Nat Commun,"Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples.© 2022. The Author(s).",
+No,20221114,prediction,36281400,5-Hydroxymethylcytosines in circulating cell-free DNA reveal a diagnostic biomarker for glioma.,Heliyon,"Gliomas typically have unfavorable prognosis, due to late detection and interventions. However, effective biomarkers for early glioma diagnosis based on 5-hydroxymethylcytosines (5 hm C) in circulating cell-free DNA (cfDNA) are not currently available. 5 hm C profiles in GSE132118 set were subjected for establishment of diagnostic model using the LASSO (least absolute shrinkage and selection operator) algorithm. The 5 hm C-based models demonstrated great potency in differentiating healthy subjects from gliomas, with area under the curves (AUCs) > 0.91 in the training and validation sets. Moreover, the indicator performed well in combination with clinicopathological characteristics to differentiate glioblastomas (GBMs) from lower grade glioma (LGGs). Enrichment analysis on 5 hm C profiles displayed great correlation with glioma pathophysiology. The 5 hm C-derived biomarker might act as an effective and non-invasive measure in glioma screening.© 2022 The Authors.",
+No,20221114,pwas,36253349,Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke.,Nat Commun,"Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10-4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.© 2022. The Author(s).",
+No,20221114,pwas,36273219,Plasma proteome profiling identifies changes associated to AD but not to FTD.,Acta Neuropathol Commun,"Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process.Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis.Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified.We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.© 2022. The Author(s).",
+No,20221114,reference,36330950,LncBook 2.0: integrating human long non-coding RNAs with multi-omics annotations.,Nucleic Acids Res,"LncBook, a comprehensive resource of human long non-coding RNAs (lncRNAs), has been used in a wide range of lncRNA studies across various biological contexts. Here, we present LncBook 2.0 (https://ngdc.cncb.ac.cn/lncbook), with significant updates and enhancements as follows: (i) incorporation of 119 722 new transcripts, 9632 new genes, and gene structure update of 21 305 lncRNAs; (ii) characterization of conservation features of human lncRNA genes across 40 vertebrates; (iii) integration of lncRNA-encoded small proteins; (iv) enrichment of expression and DNA methylation profiles with more biological contexts and (v) identification of lncRNA-protein interactions and improved prediction of lncRNA-miRNA interactions. Collectively, LncBook 2.0 accommodates a high-quality collection of 95 243 lncRNA genes and 323 950 transcripts and incorporates their abundant annotations at different omics levels, thereby enabling users to decipher functional significance of lncRNAs in different biological contexts.© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.",
+No,20221114,reference,36320053,A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples.,Clin Epigenetics,"Epigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal swabs, and saliva as surrogates. To aid the functional interpretation of EWAS findings in such settings, there is a need to assess the correlation of DNAm variability across tissues in the same individuals. In this study, we performed a correlation analysis between DNAm data of a total of n = 120 matched post-mortem buccal and prefrontal cortex samples. We identified nearly 25,000 (3% of approximately 730,000) cytosine-phosphate-guanine (CpG) sites showing significant (false discovery rate q < 0.05) correlations between buccal and PFC samples. Correlated CpG sites showed a preponderance to being located in promoter regions and showed a significant enrichment of being determined by genetic factors, i.e. methylation quantitative trait loci (mQTL), based on buccal and dorsolateral prefrontal cortex mQTL databases. Our novel buccal-brain DNAm correlation map will provide a valuable resource for future EWAS using buccal samples for studying DNAm effects on phenotypes relating to the brain. All correlation results are made freely available to the public online.© 2022. The Author(s).",
+No,20221114,reference,36270064,"Genome-wide DNA methylation analysis of post-operative delirium with brain, blood, saliva, and buccal samples from neurosurgery patients.",J Psychiatr Res,"No previous study demonstrates the difference in the genome-wide DNA methylation status of post-operative delirium (POD) using human brain tissue obtained from neurosurgery and multiple peripheral tissues such as blood, saliva, and buccal samples from the same individuals. We aimed to identify epigenetic marks of DNA methylation in the brain and peripheral tissues to elucidate the potential pathophysiological mechanism of POD.The four tissue types (brain, blood, saliva, buccal) of DNA samples from up to 40 patients, including 11 POD cases, were analyzed using Illumina EPIC array. DNAm differences between patients with and without POD were examined. We also conducted enrichment analysis based on the top DNAm signals.The most different CpG site between control and POD was found at cg16526133 near the ADAMTS9 gene from the brain tissue(p = 8.66E-08). However, there are no CpG sites to reach the genome-wide significant level. The enrichment analysis based on the 1000 top hit CpG site (p < 0.05) on the four tissues showed several intriguing pathways. In the brain, there are pathways including ""positive regulation of glial cell differentiation"". Blood samples showed also pathways related to immune function. Besides, both saliva and the buccal sample showed pathways related to circadian rhythm, although these findings were not FDR significant.Enrichment analysis found several intriguing pathways related to potential delirium pathophysiology. Present data may further support the role of epigenetics, especially DNA methylation, in the molecular mechanisms of delirium pathogenesis.Copyright © 2022 Elsevier Ltd. All rights reserved.",
+No,20221114,reference,36229504,Assessment of variability in the plasma 7k SomaScan proteomics assay.,Sci Rep,"SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current version, the 7k SomaScan assay v4.1 is capable of measuring 7288 human proteins. In this work, we present an extensive technical assessment of this platform based on a study of 2050 samples across 22 plates. Included in the study design were inter-plate technical duplicates from 102 human subjects, which allowed us to characterize different normalization procedures, evaluate assay variability by multiple analytical approaches, present signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments on this wide range of technical aspects, we aim for this work to serve as a valuable resource for the growing community of SomaScan users.© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
+No,20221114,epigenetics,36163261,Single-cell multi-omics profiling links dynamic DNA methylation to cell fate decisions during mouse early organogenesis,Genome Biol,"Background: Perturbation of DNA methyltransferases (DNMTs) and of the active DNA demethylation pathway via ten-eleven translocation (TET) methylcytosine dioxygenases results in severe developmental defects and embryonic lethality. Dynamic control of DNA methylation is therefore vital for embryogenesis, yet the underlying mechanisms remain poorly understood.
 
 Results: Here we report a single-cell transcriptomic atlas from Dnmt and Tet mutant mouse embryos during early organogenesis. We show that both the maintenance and de novo methyltransferase enzymes are dispensable for the formation of all major cell types at E8.5. However, DNA methyltransferases are required for silencing of prior or alternative cell fates such as pluripotency and extraembryonic programmes. Deletion of all three TET enzymes produces substantial lineage biases, in particular, a failure to generate primitive erythrocytes. Single-cell multi-omics profiling moreover reveals that this is linked to a failure to demethylate distal regulatory elements in Tet triple-knockout embryos.
 
 Conclusions: This study provides a detailed analysis of the effects of perturbing DNA methylation on mouse organogenesis at a whole organism scale and affords new insights into the regulatory mechanisms of cell fate decisions.",
-,No,20221114,dnam age,31554804,Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells,Nat Commun,"Age-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here we present a single cell multi-omics study of mouse muscle stem cells, combining single-cell transcriptome and DNA methylome profiling. Aged cells show a global increase of uncoordinated transcriptional heterogeneity biased towards genes regulating cell-niche interactions. We find context-dependent alterations of DNA methylation in aged stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is associated with the degradation of coherent transcriptional networks during stem cell ageing. Furthermore, our observations also shed light on the mechanisms underlying the DNA methylation clock.",
-,No,20221114,epigenetics,35948369,Single-cell multi-omics of human preimplantation embryos shows susceptibility to glucocorticoids,Genome Res,"The preconceptual, intrauterine, and early life environments can have a profound and long-lasting impact on the developmental trajectories and health outcomes of the offspring. Given the relatively low success rates of assisted reproductive technologies (ART; ?25%), additives and adjuvants, such as glucocorticoids, are used to improve the success rate. Considering the dynamic developmental events that occur during this window, these exposures may alter blastocyst formation at a molecular level, and as such, affect not only the viability of the embryo and the ability of the blastocyst to implant, but also the developmental trajectory of the first three cell lineages, ultimately influencing the physiology of the embryo. In this study, we present a comprehensive single-cell transcriptome, methylome, and small RNA atlas in the day 7 human embryo. We show that, despite no change in morphology and developmental features, preimplantation glucocorticoid exposure reprograms the molecular profile of the TE lineage, and these changes are associated with an altered metabolic and inflammatory response. Our data also suggest that glucocorticoids can precociously mature the TE sublineages, supported by the presence of extravillous trophoblast markers in the polar sublineage and presence of X Chromosome dosage compensation. Further, we have elucidated that epigenetic regulation-DNA methylation and microRNAs (miRNAs)-likely underlies the transcriptional changes observed. This study suggests that exposures to exogenous compounds during preimplantation may unintentionally reprogram the human embryo, possibly leading to suboptimal development and longer-term health outcomes.",
-,No,20230202,asthma,36704932,Global hypomethylation in childhood asthma identified by genome-wide DNA-methylation sequencing preferentially affects enhancer regions.,Allergy,"Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls.Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally-primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level.In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n=267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure.This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.This article is protected by copyright. All rights reserved.",
-,No,20230202,lung cancer,36404465,Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program,Ann Epidemiol,"The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.",
-,No,20230202,dnam age,36671726,Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age.,Biology (Basel),"In this manuscript we studied the relationship between WMH and biological age (B-age) in patients with acute stroke. We included in this study 247 patients with acute stroke recruited at Hospital del Mar having both epigenetic (DNA methylation) and magnetic resonance imaging data. WMH were measured using a semi-automated method. B-age was calculated using two widely used methods: the Hannum and Horvath formulas. We used multiple linear regression models to interrogate the role of B-age on WMH volume after adjusting for chronological age (C-age) and other covariables. Average C-age of the sample was 68.4 (±11.8) and we observed a relatively high median WMH volume (median = 8.8 cm3, Q1-Q3 = 4.05-18.8). After adjusting for potential confounders, we observed a significant effect of B-ageHannumon WMH volume (βHannum= 0.023,p-value = 0.029) independently of C-age, which remained significant (βC-age= 0.021,p-value = 0.036). Finally, we performed a mediation analysis, which allowed us to discover that 42.7% of the effect of C-age on WMH is mediated by B-ageHannum. On the other hand, B-ageHoarvathshowed no significant associations with WMH after being adjusted for C-age. In conclusion, we show for the first time that biological age, measured through DNA methylation, contributes substantially to explain WMH volumetric burden irrespective of chronological age.",
-,No,20230202,dnam age,36711749,Phenome-wide analysis identifies parent-of-origin effects on the human methylome associated with changes in the rate of aging.,bioRxiv,"Variation in the rate at which humans age may be rooted in early life events acting through genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions either enriched for genetically controlled imprinting effects (the typical type of POE) or atypical POE introduced by environmental effects associated with parents. This part of the methylome is heavily influenced by early life events, making it a potential route connecting early environmental exposures, the epigenome and the rate of aging. Here, we aim to test the association of POE-influenced methylation of CpG dinucleotides (POE-CpG sites) with early and later environmental exposures and subsequently with health-related phenotypes and adult aging phenotypes. We do this by performing phenome-wide association analyses of the POE-influenced methylome using a large family-based population cohort (GS:SFHS, Ndiscovery=5,087, Nreplication=4,450). At the single CpG level, 92 associations of POE-CpGs with phenotypic variation were identified and replicated. Most of the associations were contributed by POE-CpGs belonging to the atypical class and the most strongly enriched associations were with aging (DNAmTL acceleration), intelligence and parental (maternal) smoking exposure phenotypes. We further found that a proportion of the atypical-POE-CpGs formed co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased internal module connectivity (strength of methylation correlation across constituent CpGs) with age. Atypical POE-CpGs also displayed high levels of methylation heterogeneity and epigenetic drift (i.e. information loss with age) and a strong correlation with CpGs contained within epigenetic clocks. These results identified associations between the atypical-POE-influenced methylome and aging and provided new evidence for the ""early development of origin"" hypothesis for aging in humans.",
-,No,20230202,methods,36711917,EpiMix: an integrative tool for epigenomic subtyping using DNA methylation.,bioRxiv,"DNA methylation (DNAme) is a major epigenetic factor influencing gene expression with alterations leading to cancer, immunological, and cardiovascular diseases. Recent technological advances enable genome-wide quantification of DNAme in large human cohorts. So far, existing methods have not been evaluated to identify differential DNAme present in large and heterogeneous patient cohorts. We developed an end-to-end analytical framework named ""EpiMix"" for population-level analysis of DNAme and gene expression. Compared to existing methods, EpiMix showed higher sensitivity in detecting abnormal DNAme that was present in only small patient subsets. We extended the model-based analyses of EpiMix to cis-regulatory elements within protein-coding genes, distal enhancers, and genes encoding microRNAs and lncRNAs. Using cell-type specific data from two separate studies, we discovered novel epigenetic mechanisms underlying childhood food allergy and survival-associated, methylation-driven non-coding RNAs in non-small cell lung cancer.",
-,No,20230202,ml,36609221,Machine learning to analyse omic-data for COVID-19 diagnosis and prognosis.,BMC Bioinformatics,"With the global spread of COVID-19, the world has seen many patients, including many severe cases. The rapid development of machine learning (ML) has made significant disease diagnosis and prediction achievements. Current studies have confirmed that omics data at the host level can reflect the development process and prognosis of the disease. Since early diagnosis and effective treatment of severe COVID-19 patients remains challenging, this research aims to use omics data in different ML models for COVID-19 diagnosis and prognosis. We used several ML models on omics data of a large number of individuals to first predict whether patients are COVID-19 positive or negative, followed by the severity of the disease.On the COVID-19 diagnosis task, we got the best AUC of 0.99 with our multilayer perceptron model and the highest F1-score of 0.95 with our logistic regression (LR) model. For the severity prediction task, we achieved the highest accuracy of 0.76 with an LR model. Beyond classification and predictive modeling, our study founds ML models performed better on integrated multi-omics data, rather than single omics. By comparing top features from different omics dataset, we also found the robustness of our model, with a wider range of applicability in diverse dataset related to COVID-19. Additionally, we have found that omics-based models performed better than image or physiological feature-based models, proving the importance of the omics-based dataset for future model development.This study diagnoses COVID-19 positive cases and predicts accurate severity levels. It lowers the dependence on clinical data and professional judgment, by leveraging the utilization of state-of-the-art models. our model showed wider applicability across different omics dataset, which is highly transferable in other respiratory or similar diseases. Hospital and public health care mechanisms can optimize the distribution of medical resources and improve the robustness of the medical system.© 2023. The Author(s).",
-,No,20230202,dnam age,36638792,Loss of epigenetic information as a cause of mammalian aging,Cell,"All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called ""ICE"" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.",
-,No,20230202,drugs,36631803,Drugging the epigenome in the age of precision medicine.,Clin Epigenetics,"Modulating the epigenome has long been considered a potential opportunity for therapeutic intervention in numerous disease areas with several approved therapies marketed, primarily for cancer. Despite the overall promise of early approaches, however, these drugs have been plagued by poor pharmacokinetic and safety/tolerability profiles due in large part to off-target effects and a lack of specificity.Recently, there has been marked progress in the field on a new generation of epigenomic therapies which address these challenges directly by targeting defined loci with highly precise, durable, and tunable approaches. Here, we review the promise and pitfalls of epigenetic drug development to date and provide an outlook on recent advances and their promise for future therapeutic applications.Novel therapeutic modalities leveraging epigenetics and epigenomics with increased precision are well positioned to advance the field and treat patients across disease areas in the coming years.© 2023. The Author(s).",
-,No,20230202,methods,36609459,Who's afraid of the X? Incorporating the X and Y chromosomes into the analysis of DNA methylation array data.,Epigenetics Chromatin,"Many human disease phenotypes manifest differently by sex, making the development of methods for incorporating X and Y-chromosome data into analyses vital. Unfortunately, X and Y chromosome data are frequently excluded from large-scale analyses of the human genome and epigenome due to analytical complexity associated with sex chromosome dosage differences between XX and XY individuals, and the impact of X-chromosome inactivation (XCI) on the epigenome. As such, little attention has been given to considering the methods by which sex chromosome data may be included in analyses of DNA methylation (DNAme) array data.With Illumina Infinium HumanMethylation450 DNAme array data from 634 placental samples, we investigated the effects of probe filtering, normalization, and batch correction on DNAme data from the X and Y chromosomes. Processing steps were evaluated in both mixed-sex and sex-stratified subsets of the analysis cohort to identify whether including both sexes impacted processing results. We found that identification of probes that have a high detection p-value, or that are non-variable, should be performed in sex-stratified data subsets to avoid over- and under-estimation of the quantity of probes eligible for removal, respectively. All normalization techniques investigated returned X and Y DNAme data that were highly correlated with the raw data from the same samples. We found no difference in batch correction results after application to mixed-sex or sex-stratified cohorts. Additionally, we identify two analytical methods suitable for XY chromosome data, the choice between which should be guided by the research question of interest, and we performed a proof-of-concept analysis studying differential DNAme on the X and Y chromosome in the context of placental acute chorioamnionitis. Finally, we provide an annotation of probe types that may be desirable to filter in X and Y chromosome analyses, including probes in repetitive elements, the X-transposed region, and cancer-testis gene promoters.While there may be no single ""best"" approach for analyzing DNAme array data from the X and Y chromosome, analysts must consider key factors during processing and analysis of sex chromosome data to accommodate the underlying biology of these chromosomes, and the technical limitations of DNA methylation arrays.© 2023. The Author(s).",
-,No,20230202,lung cancer,33446580,Biomarkers in lung cancer screening: the importance of study design,Eur Respir J,,
-,No,20230202,lung cancer,33122336,"Validation of Lung EpiCheck, a novel methylation-based blood assay, for the detection of lung cancer in European and Chinese high-risk individuals",Eur Respir J,"Aim: Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples.
+No,20221114,dnam age,31554804,Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells,Nat Commun,"Age-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here we present a single cell multi-omics study of mouse muscle stem cells, combining single-cell transcriptome and DNA methylome profiling. Aged cells show a global increase of uncoordinated transcriptional heterogeneity biased towards genes regulating cell-niche interactions. We find context-dependent alterations of DNA methylation in aged stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is associated with the degradation of coherent transcriptional networks during stem cell ageing. Furthermore, our observations also shed light on the mechanisms underlying the DNA methylation clock.",
+No,20221114,epigenetics,35948369,Single-cell multi-omics of human preimplantation embryos shows susceptibility to glucocorticoids,Genome Res,"The preconceptual, intrauterine, and early life environments can have a profound and long-lasting impact on the developmental trajectories and health outcomes of the offspring. Given the relatively low success rates of assisted reproductive technologies (ART; ?25%), additives and adjuvants, such as glucocorticoids, are used to improve the success rate. Considering the dynamic developmental events that occur during this window, these exposures may alter blastocyst formation at a molecular level, and as such, affect not only the viability of the embryo and the ability of the blastocyst to implant, but also the developmental trajectory of the first three cell lineages, ultimately influencing the physiology of the embryo. In this study, we present a comprehensive single-cell transcriptome, methylome, and small RNA atlas in the day 7 human embryo. We show that, despite no change in morphology and developmental features, preimplantation glucocorticoid exposure reprograms the molecular profile of the TE lineage, and these changes are associated with an altered metabolic and inflammatory response. Our data also suggest that glucocorticoids can precociously mature the TE sublineages, supported by the presence of extravillous trophoblast markers in the polar sublineage and presence of X Chromosome dosage compensation. Further, we have elucidated that epigenetic regulation-DNA methylation and microRNAs (miRNAs)-likely underlies the transcriptional changes observed. This study suggests that exposures to exogenous compounds during preimplantation may unintentionally reprogram the human embryo, possibly leading to suboptimal development and longer-term health outcomes.",
+No,20230202,asthma,36704932,Global hypomethylation in childhood asthma identified by genome-wide DNA-methylation sequencing preferentially affects enhancer regions.,Allergy,"Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls.Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally-primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level.In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n=267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure.This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.This article is protected by copyright. All rights reserved.",
+No,20230202,lung cancer,36404465,Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program,Ann Epidemiol,"The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.",
+No,20230202,dnam age,36671726,Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age.,Biology (Basel),"In this manuscript we studied the relationship between WMH and biological age (B-age) in patients with acute stroke. We included in this study 247 patients with acute stroke recruited at Hospital del Mar having both epigenetic (DNA methylation) and magnetic resonance imaging data. WMH were measured using a semi-automated method. B-age was calculated using two widely used methods: the Hannum and Horvath formulas. We used multiple linear regression models to interrogate the role of B-age on WMH volume after adjusting for chronological age (C-age) and other covariables. Average C-age of the sample was 68.4 (±11.8) and we observed a relatively high median WMH volume (median = 8.8 cm3, Q1-Q3 = 4.05-18.8). After adjusting for potential confounders, we observed a significant effect of B-ageHannumon WMH volume (βHannum= 0.023,p-value = 0.029) independently of C-age, which remained significant (βC-age= 0.021,p-value = 0.036). Finally, we performed a mediation analysis, which allowed us to discover that 42.7% of the effect of C-age on WMH is mediated by B-ageHannum. On the other hand, B-ageHoarvathshowed no significant associations with WMH after being adjusted for C-age. In conclusion, we show for the first time that biological age, measured through DNA methylation, contributes substantially to explain WMH volumetric burden irrespective of chronological age.",
+No,20230202,dnam age,36711749,Phenome-wide analysis identifies parent-of-origin effects on the human methylome associated with changes in the rate of aging.,bioRxiv,"Variation in the rate at which humans age may be rooted in early life events acting through genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions either enriched for genetically controlled imprinting effects (the typical type of POE) or atypical POE introduced by environmental effects associated with parents. This part of the methylome is heavily influenced by early life events, making it a potential route connecting early environmental exposures, the epigenome and the rate of aging. Here, we aim to test the association of POE-influenced methylation of CpG dinucleotides (POE-CpG sites) with early and later environmental exposures and subsequently with health-related phenotypes and adult aging phenotypes. We do this by performing phenome-wide association analyses of the POE-influenced methylome using a large family-based population cohort (GS:SFHS, Ndiscovery=5,087, Nreplication=4,450). At the single CpG level, 92 associations of POE-CpGs with phenotypic variation were identified and replicated. Most of the associations were contributed by POE-CpGs belonging to the atypical class and the most strongly enriched associations were with aging (DNAmTL acceleration), intelligence and parental (maternal) smoking exposure phenotypes. We further found that a proportion of the atypical-POE-CpGs formed co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased internal module connectivity (strength of methylation correlation across constituent CpGs) with age. Atypical POE-CpGs also displayed high levels of methylation heterogeneity and epigenetic drift (i.e. information loss with age) and a strong correlation with CpGs contained within epigenetic clocks. These results identified associations between the atypical-POE-influenced methylome and aging and provided new evidence for the ""early development of origin"" hypothesis for aging in humans.",
+No,20230202,methods,36711917,EpiMix: an integrative tool for epigenomic subtyping using DNA methylation.,bioRxiv,"DNA methylation (DNAme) is a major epigenetic factor influencing gene expression with alterations leading to cancer, immunological, and cardiovascular diseases. Recent technological advances enable genome-wide quantification of DNAme in large human cohorts. So far, existing methods have not been evaluated to identify differential DNAme present in large and heterogeneous patient cohorts. We developed an end-to-end analytical framework named ""EpiMix"" for population-level analysis of DNAme and gene expression. Compared to existing methods, EpiMix showed higher sensitivity in detecting abnormal DNAme that was present in only small patient subsets. We extended the model-based analyses of EpiMix to cis-regulatory elements within protein-coding genes, distal enhancers, and genes encoding microRNAs and lncRNAs. Using cell-type specific data from two separate studies, we discovered novel epigenetic mechanisms underlying childhood food allergy and survival-associated, methylation-driven non-coding RNAs in non-small cell lung cancer.",
+No,20230202,ml,36609221,Machine learning to analyse omic-data for COVID-19 diagnosis and prognosis.,BMC Bioinformatics,"With the global spread of COVID-19, the world has seen many patients, including many severe cases. The rapid development of machine learning (ML) has made significant disease diagnosis and prediction achievements. Current studies have confirmed that omics data at the host level can reflect the development process and prognosis of the disease. Since early diagnosis and effective treatment of severe COVID-19 patients remains challenging, this research aims to use omics data in different ML models for COVID-19 diagnosis and prognosis. We used several ML models on omics data of a large number of individuals to first predict whether patients are COVID-19 positive or negative, followed by the severity of the disease.On the COVID-19 diagnosis task, we got the best AUC of 0.99 with our multilayer perceptron model and the highest F1-score of 0.95 with our logistic regression (LR) model. For the severity prediction task, we achieved the highest accuracy of 0.76 with an LR model. Beyond classification and predictive modeling, our study founds ML models performed better on integrated multi-omics data, rather than single omics. By comparing top features from different omics dataset, we also found the robustness of our model, with a wider range of applicability in diverse dataset related to COVID-19. Additionally, we have found that omics-based models performed better than image or physiological feature-based models, proving the importance of the omics-based dataset for future model development.This study diagnoses COVID-19 positive cases and predicts accurate severity levels. It lowers the dependence on clinical data and professional judgment, by leveraging the utilization of state-of-the-art models. our model showed wider applicability across different omics dataset, which is highly transferable in other respiratory or similar diseases. Hospital and public health care mechanisms can optimize the distribution of medical resources and improve the robustness of the medical system.© 2023. The Author(s).",
+No,20230202,dnam age,36638792,Loss of epigenetic information as a cause of mammalian aging,Cell,"All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called ""ICE"" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.",
+No,20230202,drugs,36631803,Drugging the epigenome in the age of precision medicine.,Clin Epigenetics,"Modulating the epigenome has long been considered a potential opportunity for therapeutic intervention in numerous disease areas with several approved therapies marketed, primarily for cancer. Despite the overall promise of early approaches, however, these drugs have been plagued by poor pharmacokinetic and safety/tolerability profiles due in large part to off-target effects and a lack of specificity.Recently, there has been marked progress in the field on a new generation of epigenomic therapies which address these challenges directly by targeting defined loci with highly precise, durable, and tunable approaches. Here, we review the promise and pitfalls of epigenetic drug development to date and provide an outlook on recent advances and their promise for future therapeutic applications.Novel therapeutic modalities leveraging epigenetics and epigenomics with increased precision are well positioned to advance the field and treat patients across disease areas in the coming years.© 2023. The Author(s).",
+No,20230202,methods,36609459,Who's afraid of the X? Incorporating the X and Y chromosomes into the analysis of DNA methylation array data.,Epigenetics Chromatin,"Many human disease phenotypes manifest differently by sex, making the development of methods for incorporating X and Y-chromosome data into analyses vital. Unfortunately, X and Y chromosome data are frequently excluded from large-scale analyses of the human genome and epigenome due to analytical complexity associated with sex chromosome dosage differences between XX and XY individuals, and the impact of X-chromosome inactivation (XCI) on the epigenome. As such, little attention has been given to considering the methods by which sex chromosome data may be included in analyses of DNA methylation (DNAme) array data.With Illumina Infinium HumanMethylation450 DNAme array data from 634 placental samples, we investigated the effects of probe filtering, normalization, and batch correction on DNAme data from the X and Y chromosomes. Processing steps were evaluated in both mixed-sex and sex-stratified subsets of the analysis cohort to identify whether including both sexes impacted processing results. We found that identification of probes that have a high detection p-value, or that are non-variable, should be performed in sex-stratified data subsets to avoid over- and under-estimation of the quantity of probes eligible for removal, respectively. All normalization techniques investigated returned X and Y DNAme data that were highly correlated with the raw data from the same samples. We found no difference in batch correction results after application to mixed-sex or sex-stratified cohorts. Additionally, we identify two analytical methods suitable for XY chromosome data, the choice between which should be guided by the research question of interest, and we performed a proof-of-concept analysis studying differential DNAme on the X and Y chromosome in the context of placental acute chorioamnionitis. Finally, we provide an annotation of probe types that may be desirable to filter in X and Y chromosome analyses, including probes in repetitive elements, the X-transposed region, and cancer-testis gene promoters.While there may be no single ""best"" approach for analyzing DNAme array data from the X and Y chromosome, analysts must consider key factors during processing and analysis of sex chromosome data to accommodate the underlying biology of these chromosomes, and the technical limitations of DNA methylation arrays.© 2023. The Author(s).",
+No,20230202,lung cancer,33446580,Biomarkers in lung cancer screening: the importance of study design,Eur Respir J,,
+No,20230202,lung cancer,33122336,"Validation of Lung EpiCheck, a novel methylation-based blood assay, for the detection of lung cancer in European and Chinese high-risk individuals",Eur Respir J,"Aim: Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples.
 
 Methods: A case-control European training set (n=102 lung cancer cases, n=265 controls) was used to define the panel and algorithm. Two cut-offs were selected, low cut-off (LCO) for high sensitivity and high cut-off (HCO) for high specificity. The performance was validated in case-control European and Chinese validation sets (cases/controls 179/137 and 30/15, respectively).
 
 Results: The European and Chinese validation sets achieved AUCs of 0.882 and 0.899, respectively. The sensitivities/specificities with LCO were 87.2%/64.2% and 76.7%/93.3%, and with HCO they were 74.3%/90.5% and 56.7%/100.0%, respectively. Stage I nonsmall cell lung cancer (NSCLC) sensitivity in European and Chinese samples with LCO was 78.4% and 70.0% and with HCO was 62.2% and 30.0%, respectively. Small cell lung cancer (SCLC) was represented only in the European set and sensitivities with LCO and HCO were 100.0% and 93.3%, respectively. In multivariable analyses of the European validation set, the assay's ability to predict lung cancer was independent of established risk factors (age, smoking, COPD), and overall AUC was 0.942.
 
 Conclusions: Lung EpiCheck demonstrated strong performance in lung cancer prediction in case-control European and Chinese samples, detecting high proportions of early-stage NSCLC and SCLC and significantly improving predictive accuracy when added to established risk factors. Prospective studies are required to confirm these findings. Utilising such a simple and inexpensive blood test has the potential to improve compliance and broaden access to screening for at-risk populations.",
-,No,20230202,mqtl,36631879,Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong genetic control,Genome Biol,"Background: Genetic variants can modulate phenotypic outcomes via epigenetic intermediates, for example at methylation quantitative trait loci (mQTL). We present the first large-scale assessment of mQTL at human genomic regions selected for interindividual variation in CpG methylation, which we call correlated regions of systemic interindividual variation (CoRSIVs). These can be assayed in blood DNA and do not reflect interindividual variation in cellular composition.
+No,20230202,mqtl,36631879,Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong genetic control,Genome Biol,"Background: Genetic variants can modulate phenotypic outcomes via epigenetic intermediates, for example at methylation quantitative trait loci (mQTL). We present the first large-scale assessment of mQTL at human genomic regions selected for interindividual variation in CpG methylation, which we call correlated regions of systemic interindividual variation (CoRSIVs). These can be assayed in blood DNA and do not reflect interindividual variation in cellular composition.
 
 Results: We use target-capture bisulfite sequencing to assess DNA methylation at 4086 CoRSIVs in multiple tissues from each of 188 donors in the NIH Gene-Tissue Expression (GTEx) program. At CoRSIVs, DNA methylation in peripheral blood correlates with methylation and gene expression in internal organs. We also discover unprecedented mQTL at these regions. Genetic influences on CoRSIV methylation are extremely strong (median R2=0.76), cumulatively comprising over 70-fold more human mQTL than detected in the most powerful previous study. Moreover, mQTL beta coefficients at CoRSIVs are highly skewed (i.e., the major allele predicts higher methylation). Both surprising findings are independently validated in a cohort of 47 non-GTEx individuals. Genomic regions flanking CoRSIVs show long-range enrichments for LINE-1 and LTR transposable elements; the skewed beta coefficients may therefore reflect evolutionary selection of genetic variants that promote their methylation and silencing. Analyses of GWAS summary statistics show that mQTL polymorphisms at CoRSIVs are associated with metabolic and other classes of disease.
 
 Conclusions: A focus on systemic interindividual epigenetic variants, clearly enhanced in mQTL content, should likewise benefit studies attempting to link human epigenetic variation to the risk of disease.",
-,No,20230202,tandem repeats,36577521,Genome-wide evaluation of the effect of short tandem repeat variation on local DNA methylation,Genome Res,"Short tandem repeats (STRs) contribute significantly to genetic diversity in humans, including disease-causing variation. While the effect of STR variation on gene expression has been extensively assessed, their impact on epigenetics has been poorly studied and limited to specific genomic regions. Here, we investigated the hypothesis that some STRs act as independent regulators of local DNA methylation in the human genome, and modify risk of common human traits. To address these questions, we first analyzed two independent datasets comprising PCR-free whole genome sequencing (WGS) and genome-wide DNA methylation levels derived from whole blood samples in 245 (discovery cohort) and 484 individuals (replication cohort). Utilizing genotypes for 131,635 polymorphic STRs derived from WGS using HipSTR, we identified 11,870 STRs that associated with DNA methylation levels (mSTRs) of 11,774 CpGs (Bonferroni p<0.001) in our discovery cohort, with 90% successfully replicating in our second cohort. Subsequently, through fine-mapping using CAVIAR we defined 585 of these mSTRs as the likely causal variants underlying the observed associations (fm-mSTRs), and linked a fraction of these to previously reported genome-wide association study signals, providing insights into the mechanisms underlying complex human traits. Furthermore, by integrating gene expression data, we observed that 12.5% of the tested fm-mSTRs also modulate expression levels of nearby genes, reinforcing their regulatory potential. Overall, our findings expand the catalog of functional sequence variants that affect genome regulation, highlighting the importance of incorporating STRs in future genetic association analysis and epigenetics data for the interpretation of trait-associated variants.",
-,No,20230202,lung cancer,32134462,Assessment of Biomarker Testing for Lung Cancer Screening Eligibility,JAMA Netw Open,This exploratory study analyzes the cost-effectiveness of incorporating biomarkers into eligibility assessment for lung screening.,
-,No,20230202,lung cancer,10.1101/2022.07.31.22277301,The Blood Proteome of Imminent Lung Cancer Diagnosis,medarxiv,"Identification of novel risk biomarkers may enhance early detection of smoking-related lung cancer. We measured 1,162 proteins in blood samples drawn at most three years before diagnosis in 731 smoking-matched case-control sets nested within six prospective cohorts from the US, Europe, Singapore, and Australia.
+No,20230202,tandem repeats,36577521,Genome-wide evaluation of the effect of short tandem repeat variation on local DNA methylation,Genome Res,"Short tandem repeats (STRs) contribute significantly to genetic diversity in humans, including disease-causing variation. While the effect of STR variation on gene expression has been extensively assessed, their impact on epigenetics has been poorly studied and limited to specific genomic regions. Here, we investigated the hypothesis that some STRs act as independent regulators of local DNA methylation in the human genome, and modify risk of common human traits. To address these questions, we first analyzed two independent datasets comprising PCR-free whole genome sequencing (WGS) and genome-wide DNA methylation levels derived from whole blood samples in 245 (discovery cohort) and 484 individuals (replication cohort). Utilizing genotypes for 131,635 polymorphic STRs derived from WGS using HipSTR, we identified 11,870 STRs that associated with DNA methylation levels (mSTRs) of 11,774 CpGs (Bonferroni p<0.001) in our discovery cohort, with 90% successfully replicating in our second cohort. Subsequently, through fine-mapping using CAVIAR we defined 585 of these mSTRs as the likely causal variants underlying the observed associations (fm-mSTRs), and linked a fraction of these to previously reported genome-wide association study signals, providing insights into the mechanisms underlying complex human traits. Furthermore, by integrating gene expression data, we observed that 12.5% of the tested fm-mSTRs also modulate expression levels of nearby genes, reinforcing their regulatory potential. Overall, our findings expand the catalog of functional sequence variants that affect genome regulation, highlighting the importance of incorporating STRs in future genetic association analysis and epigenetics data for the interpretation of trait-associated variants.",
+No,20230202,lung cancer,32134462,Assessment of Biomarker Testing for Lung Cancer Screening Eligibility,JAMA Netw Open,This exploratory study analyzes the cost-effectiveness of incorporating biomarkers into eligibility assessment for lung screening.,
+No,20230202,lung cancer,10.1101/2022.07.31.22277301,The Blood Proteome of Imminent Lung Cancer Diagnosis,medarxiv,"Identification of novel risk biomarkers may enhance early detection of smoking-related lung cancer. We measured 1,162 proteins in blood samples drawn at most three years before diagnosis in 731 smoking-matched case-control sets nested within six prospective cohorts from the US, Europe, Singapore, and Australia.
 
 We identified 36 proteins with replicable associations with risk of imminent lung cancer diagnosis (all p<4×10-5). These included several documented tumor markers (e.g. CA-125/MUC-16 and CEACAM5/CEA) but most had not been previously reported. The 36 proteins included several growth factors (e.g. HGF, IGFBP-1, IGFP-2), tumor necrosis factor-receptors (e.g. TNFRSF6B, TNFRSF13B), and chemokines and cytokines (e.g. CXL17, GDF-15, SCF). The odds ratio per standard deviation ranged from 1.31 for IGFBP-1 (95% CI: 1.17-1.47) to 2.43 for CEACAM5 (95% CI: 2.04-2.89). We mapped the 36 proteins to the hallmarks of cancer and found that proliferative signaling, tumor-promoting inflammation, and activation of invasion and metastasis were most frequently implicated.",
-,No,20230202,methods,36601577,MC profiling: a novel approach to analyze DNA methylation heterogeneity in genome-wide bisulfite sequencing data.,NAR Genom Bioinform,"DNA methylation is an epigenetic mark implicated in crucial biological processes. Most of the knowledge about DNA methylation is based on bulk experiments, in which DNA methylation of genomic regions is reported as average methylation. However, average methylation does not inform on how methylated cytosines are distributed in each single DNA molecule. Here, we propose Methylation Class (MC) profiling as a genome-wide approach to the study of DNA methylation heterogeneity from bulk bisulfite sequencing experiments. The proposed approach is built on the concept of MCs, groups of DNA molecules sharing the same number of methylated cytosines. The relative abundances of MCs from sequencing reads incorporates the information on the average methylation, and directly informs on the methylation level of each molecule. By applying our approach to publicly available bisulfite-sequencing datasets, we individuated cell-to-cell differences as the prevalent contributor to methylation heterogeneity. Moreover, we individuated signatures of loci undergoing imprinting and X-inactivation, and highlighted differences between the two processes. When applying MC profiling to compare different conditions, we identified methylation changes occurring in regions with almost constant average methylation. Altogether, our results indicate that MC profiling can provide useful insights on the epigenetic status and its evolution at multiple genomic regions.© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
-,No,20230202,methods,36601578,Targeted DNA methylation from cell-free DNA using hybridization probe capture.,NAR Genom Bioinform,"Cell-free (cf)DNA signatures are quickly becoming the target of choice for non-invasive screening, diagnosis, treatment and monitoring of human tumors. DNA methylation changes occur early in tumorigenesis and are widespread, making cfDNA methylation an attractive cancer biomarker. Already a proven technology for targeted genome sequencing, hybridization probe capture is emerging as a method for high-throughput targeted methylation profiling suitable to liquid biopsy samples. However, to date there are no reports describing the performance of this approach in terms of reproducibility, scalability, and accuracy. In the current study we performed hybridization probe capture using the myBaits®Custom Methyl-seq kit on 172 plasma samples and standards to evaluate its performance on cfDNA methylation analysis. The myBaits®assay showed high target recovery (>90%), demonstrated excellent reproducibility between captures (R2 = 0.92 on average), and was unaffected by increasing the number of targets in a capture. Finally, myBaits®accurately replicated 'gold standard' beta values from WGBS (averageR2 = 0.79). The results of this study show that custom targeted methylation sequencing with myBaits®offers a cost-effective, reliable platform to profile DNA methylation at a set of discrete custom regions, with potential applicability to liquid biopsies for cancer monitoring.© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
-,No,20230202,reference,36646694,"Comparative analysis of genome-scale, base-resolution DNA methylation profiles across 580 animal species.",Nat Commun,"Methylation of cytosines is a prototypic epigenetic modification of the DNA. It has been implicated in various regulatory mechanisms across the animal kingdom and particularly in vertebrates. We mapped DNA methylation in 580 animal species (535 vertebrates, 45 invertebrates), resulting in 2443 genome-scale DNA methylation profiles of multiple organs. Bioinformatic analysis of this large dataset quantified the association of DNA methylation with the underlying genomic DNA sequence throughout vertebrate evolution. We observed a broadly conserved link with two major transitions-once in the first vertebrates and again with the emergence of reptiles. Cross-species comparisons focusing on individual organs supported a deeply conserved association of DNA methylation with tissue type, and cross-mapping analysis of DNA methylation at gene promoters revealed evolutionary changes for orthologous genes. In summary, this study establishes a large resource of vertebrate and invertebrate DNA methylomes, it showcases the power of reference-free epigenome analysis in species for which no reference genomes are available, and it contributes an epigenetic perspective to the study of vertebrate evolution.© 2023. The Author(s).",
-,No,20230202,cell-free dna,36653380,DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation.,Nat Commun,"Plasma cell-free DNA (cfDNA) are small molecules generated through a non-random fragmentation procedure. Despite commendable translational values in cancer liquid biopsy, however, the biology of cfDNA, especially the principles of cfDNA fragmentation, remains largely elusive. Through orientation-aware analyses of cfDNA fragmentation patterns against the nucleosome structure and integration with multidimensional functional genomics data, here we report a DNA methylation - nuclease preference - cutting end - size distribution axis, demonstrating the role of DNA methylation as a functional molecular regulator of cfDNA fragmentation. Hence, low-level DNA methylation could increase nucleosome accessibility and alter the cutting activities of nucleases during DNA fragmentation, which further leads to variation in cutting sites and size distribution of cfDNA. We further develop a cfDNA ending preference-based metric for cancer diagnosis, whose performance has been validated by multiple pan-cancer datasets. Our work sheds light on the molecular basis of cfDNA fragmentation towards broader applications in cancer liquid biopsy.© 2023. The Author(s).",
-,No,20230202,methods,36624346,SPICEMIX enables integrative single-cell spatial modeling of cell identity.,Nat Genet,"Spatial transcriptomics can reveal spatially resolved gene expression of diverse cells in complex tissues. However, the development of computational methods that can use the unique properties of spatial transcriptome data to unveil cell identities remains a challenge. Here we introduce SPICEMIX, an interpretable method based on probabilistic, latent variable modeling for joint analysis of spatial information and gene expression from spatial transcriptome data. Both simulation and real data evaluations demonstrate that SPICEMIX markedly improves on the inference of cell types and their spatial patterns compared with existing approaches. By applying to spatial transcriptome data of brain regions in human and mouse acquired by seqFISH+, STARmap and Visium, we show that SPICEMIX can enhance the inference of complex cell identities, reveal interpretable spatial metagenes and uncover differentiation trajectories. SPICEMIX is a generalizable analysis framework for spatial transcriptome data to investigate cell-type composition and spatial organization of cells in complex tissues.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20230202,mqtl,36510025,"DNA methylation QTL mapping across diverse human tissues provides molecular
+No,20230202,methods,36601577,MC profiling: a novel approach to analyze DNA methylation heterogeneity in genome-wide bisulfite sequencing data.,NAR Genom Bioinform,"DNA methylation is an epigenetic mark implicated in crucial biological processes. Most of the knowledge about DNA methylation is based on bulk experiments, in which DNA methylation of genomic regions is reported as average methylation. However, average methylation does not inform on how methylated cytosines are distributed in each single DNA molecule. Here, we propose Methylation Class (MC) profiling as a genome-wide approach to the study of DNA methylation heterogeneity from bulk bisulfite sequencing experiments. The proposed approach is built on the concept of MCs, groups of DNA molecules sharing the same number of methylated cytosines. The relative abundances of MCs from sequencing reads incorporates the information on the average methylation, and directly informs on the methylation level of each molecule. By applying our approach to publicly available bisulfite-sequencing datasets, we individuated cell-to-cell differences as the prevalent contributor to methylation heterogeneity. Moreover, we individuated signatures of loci undergoing imprinting and X-inactivation, and highlighted differences between the two processes. When applying MC profiling to compare different conditions, we identified methylation changes occurring in regions with almost constant average methylation. Altogether, our results indicate that MC profiling can provide useful insights on the epigenetic status and its evolution at multiple genomic regions.© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
+No,20230202,methods,36601578,Targeted DNA methylation from cell-free DNA using hybridization probe capture.,NAR Genom Bioinform,"Cell-free (cf)DNA signatures are quickly becoming the target of choice for non-invasive screening, diagnosis, treatment and monitoring of human tumors. DNA methylation changes occur early in tumorigenesis and are widespread, making cfDNA methylation an attractive cancer biomarker. Already a proven technology for targeted genome sequencing, hybridization probe capture is emerging as a method for high-throughput targeted methylation profiling suitable to liquid biopsy samples. However, to date there are no reports describing the performance of this approach in terms of reproducibility, scalability, and accuracy. In the current study we performed hybridization probe capture using the myBaits®Custom Methyl-seq kit on 172 plasma samples and standards to evaluate its performance on cfDNA methylation analysis. The myBaits®assay showed high target recovery (>90%), demonstrated excellent reproducibility between captures (R2 = 0.92 on average), and was unaffected by increasing the number of targets in a capture. Finally, myBaits®accurately replicated 'gold standard' beta values from WGBS (averageR2 = 0.79). The results of this study show that custom targeted methylation sequencing with myBaits®offers a cost-effective, reliable platform to profile DNA methylation at a set of discrete custom regions, with potential applicability to liquid biopsies for cancer monitoring.© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.",
+No,20230202,reference,36646694,"Comparative analysis of genome-scale, base-resolution DNA methylation profiles across 580 animal species.",Nat Commun,"Methylation of cytosines is a prototypic epigenetic modification of the DNA. It has been implicated in various regulatory mechanisms across the animal kingdom and particularly in vertebrates. We mapped DNA methylation in 580 animal species (535 vertebrates, 45 invertebrates), resulting in 2443 genome-scale DNA methylation profiles of multiple organs. Bioinformatic analysis of this large dataset quantified the association of DNA methylation with the underlying genomic DNA sequence throughout vertebrate evolution. We observed a broadly conserved link with two major transitions-once in the first vertebrates and again with the emergence of reptiles. Cross-species comparisons focusing on individual organs supported a deeply conserved association of DNA methylation with tissue type, and cross-mapping analysis of DNA methylation at gene promoters revealed evolutionary changes for orthologous genes. In summary, this study establishes a large resource of vertebrate and invertebrate DNA methylomes, it showcases the power of reference-free epigenome analysis in species for which no reference genomes are available, and it contributes an epigenetic perspective to the study of vertebrate evolution.© 2023. The Author(s).",
+No,20230202,cell-free dna,36653380,DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation.,Nat Commun,"Plasma cell-free DNA (cfDNA) are small molecules generated through a non-random fragmentation procedure. Despite commendable translational values in cancer liquid biopsy, however, the biology of cfDNA, especially the principles of cfDNA fragmentation, remains largely elusive. Through orientation-aware analyses of cfDNA fragmentation patterns against the nucleosome structure and integration with multidimensional functional genomics data, here we report a DNA methylation - nuclease preference - cutting end - size distribution axis, demonstrating the role of DNA methylation as a functional molecular regulator of cfDNA fragmentation. Hence, low-level DNA methylation could increase nucleosome accessibility and alter the cutting activities of nucleases during DNA fragmentation, which further leads to variation in cutting sites and size distribution of cfDNA. We further develop a cfDNA ending preference-based metric for cancer diagnosis, whose performance has been validated by multiple pan-cancer datasets. Our work sheds light on the molecular basis of cfDNA fragmentation towards broader applications in cancer liquid biopsy.© 2023. The Author(s).",
+No,20230202,methods,36624346,SPICEMIX enables integrative single-cell spatial modeling of cell identity.,Nat Genet,"Spatial transcriptomics can reveal spatially resolved gene expression of diverse cells in complex tissues. However, the development of computational methods that can use the unique properties of spatial transcriptome data to unveil cell identities remains a challenge. Here we introduce SPICEMIX, an interpretable method based on probabilistic, latent variable modeling for joint analysis of spatial information and gene expression from spatial transcriptome data. Both simulation and real data evaluations demonstrate that SPICEMIX markedly improves on the inference of cell types and their spatial patterns compared with existing approaches. By applying to spatial transcriptome data of brain regions in human and mouse acquired by seqFISH+, STARmap and Visium, we show that SPICEMIX can enhance the inference of complex cell identities, reveal interpretable spatial metagenes and uncover differentiation trajectories. SPICEMIX is a generalizable analysis framework for spatial transcriptome data to investigate cell-type composition and spatial organization of cells in complex tissues.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20230202,mqtl,36510025,"DNA methylation QTL mapping across diverse human tissues provides molecular
 links between genetic variation and
 complex traits",Nat Genet,"Studies of DNA methylation (DNAm) in solid human tissues are relatively scarce; tissue-specific characterization of DNAm is needed to understand its role in gene regulation and its relevance to complex traits. We generated array-based DNAm profiles for 987 human samples from the Genotype-Tissue Expression (GTEx) project, representing 9 tissue types and 424 subjects. We characterized methylome and transcriptome correlations (eQTMs), genetic regulation in cis (mQTLs and eQTLs) across tissues and e/mQTLs links to complex traits. We identified mQTLs for 286,152 CpG sites, many of which (>5%) show tissue specificity, and mQTL colocalizations with 2,254 distinct GWAS hits across 83 traits. For 91% of these loci, a candidate gene link was identified by integration of functional maps, including eQTMs, and/or eQTL colocalization, but only 33% of loci involved an eQTL and mQTL present in the same tissue type. With this DNAm-focused integrative analysis, we contribute to the understanding of molecular regulatory mechanisms in human tissues and their impact on complex traits.",
-,No,20230202,epigenetics,36471057,Deciphering the mechanical code of the genome and epigenome,Nat Struct Mol Biol,"Diverse DNA-deforming processes are impacted by the local mechanical and structural properties of DNA, which in turn depend on local sequence and epigenetic modifications. Deciphering this mechanical code (that is, this dependence) has been challenging due to the lack of high-throughput experimental methods. Here we present a comprehensive characterization of the mechanical code. Utilizing high-throughput measurements of DNA bendability via loop-seq, we quantitatively established how the occurrence and spatial distribution of dinucleotides, tetranucleotides and methylated CpG impact DNA bendability. We used our measurements to develop a physical model for the sequence and methylation dependence of DNA bendability. We validated the model by performing loop-seq on mouse genomic sequences around transcription start sites and CTCF-binding sites. We applied our model to test the predictions of all-atom molecular dynamics simulations and to demonstrate that sequence and epigenetic modifications can mechanically encode regulatory information in diverse contexts.",
-,No,20230202,reference,36599988,A DNA methylation atlas of normal human cell types,Nature,"DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.",
-,No,20230202,ml,36602952,Ten quick tips for computational analysis of medical images.,PLoS Comput Biol,"Medical imaging is a great asset for modern medicine, since it allows physicians to spatially interrogate a disease site, resulting in precise intervention for diagnosis and treatment, and to observe particular aspect of patients' conditions that otherwise would not be noticeable. Computational analysis of medical images, moreover, can allow the discovery of disease patterns and correlations among cohorts of patients with the same disease, thus suggesting common causes or providing useful information for better therapies and cures. Machine learning and deep learning applied to medical images, in particular, have produced new, unprecedented results that can pave the way to advanced frontiers of medical discoveries. While computational analysis of medical images has become easier, however, the possibility to make mistakes or generate inflated or misleading results has become easier, too, hindering reproducibility and deployment. In this article, we provide ten quick tips to perform computational analysis of medical images avoiding common mistakes and pitfalls that we noticed in multiple studies in the past. We believe our ten guidelines, if taken into practice, can help the computational-medical imaging community to perform better scientific research that eventually can have a positive impact on the lives of patients worldwide.Copyright: © 2023 Chicco, Shiradkar. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
-,No,20230202,epigenetics,36656803,Using epigenomics to understand cellular responses to environmental influences in diseases.,PLoS Genet,"It is a generally accepted model that environmental influences can exert their effects, at least in part, by changing the molecular regulators of transcription that are described as epigenetic. As there is biochemical evidence that some epigenetic regulators of transcription can maintain their states long term and through cell division, an epigenetic model encompasses the idea of maintenance of the effect of an exposure long after it is no longer present. The evidence supporting this model is mostly from the observation of alterations of molecular regulators of transcription following exposures. With the understanding that the interpretation of these associations is more complex than originally recognised, this model may be oversimplistic; therefore, adopting novel perspectives and experimental approaches when examining how environmental exposures are linked to phenotypes may prove worthwhile. In this review, we have chosen to use the example of nonalcoholic fatty liver disease (NAFLD), a common, complex human disease with strong environmental and genetic influences. We describe how epigenomic approaches combined with emerging functional genetic and single-cell genomic techniques are poised to generate new insights into the pathogenesis of environmentally influenced human disease phenotypes exemplified by NAFLD.Copyright: © 2023 Wattacheril et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
-,No,20230202,dnam age,36548410,"Epigenetic clocks, aging, and cancer",Science,"Cancer and aging are accompanied by stereotyped changes to the epigenetic landscape, including progressive loss of DNA methylation over gene-poor genomic regions (1, 2). Global hypomethylation arises in cells that have undergone many divisions, likely owing to imperfect maintenance. Evidence suggests that global hypomethylation represents a “mitotic clock” that counts divisions in somatic cells and functions to restrain aging cells and limit malignant progression. Therapies that modulate the pace of methylation loss or eliminate hypomethylated cells could alleviate agingassociated diseases or cancers.",
-,Yes,20230202,ewas,36649705,Epigenome-wide meta-analysis of BMI in nine cohorts: Examining the utility of epigenetically predicted BMI.,Am J Hum Genet,"This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E-7) and 1,238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European and African descent, as defined by self-reported race/ethnicity. We found that five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log-normalized BMI in the WHI (80% training/20% testing). This model found that 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides and lower HDL cholesterol and LDL cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL cholesterol and lower glucose and triglycerides. This study confirmed 553 and identified 685 CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health, suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.Copyright © 2022 American Society of Human Genetics. All rights reserved.",
-,Yes,20230202,ewas,36609850,Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder.,Autism Res,"Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.© 2023 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.",
-,Yes,20230202,ewas,36617561,Prenatal social support in low-risk pregnancy shapes placental epigenome.,BMC Med,"Poor social support during pregnancy has been linked to inflammation and adverse pregnancy and childhood health outcomes. Placental epigenetic alterations may underlie these links but are still unknown in humans.In a cohort of low-risk pregnant women (n = 301) from diverse ethnic backgrounds, social support was measured using the ENRICHD Social Support Inventory (ESSI) during the first trimester. Placental samples collected at delivery were analyzed for DNA methylation and gene expression using Illumina 450K Beadchip Array and RNA-seq, respectively. We examined association between maternal prenatal social support and DNA methylation in placenta. Associated cytosine-(phosphate)-guanine sites (CpGs) were further assessed for correlation with nearby gene expression in placenta.The mean age (SD) of the women was 27.7 (5.3) years. The median (interquartile range) of ESSI scores was 24 (22-25). Prenatal social support was significantly associated with methylation level at seven CpGs (PFDR < 0.05). The methylation levels at two of the seven CpGs correlated with placental expression of VGF and ILVBL (PFDR < 0.05), genes known to be involved in neurodevelopment and energy metabolism. The genes annotated with the top 100 CpGs were enriched for pathways related to fetal growth, coagulation system, energy metabolism, and neurodevelopment. Sex-stratified analysis identified additional significant associations at nine CpGs in male-bearing pregnancies and 35 CpGs in female-bearing pregnancies.The findings suggest that prenatal social support is linked to placental DNA methylation changes in a low-stress setting, including fetal sex-dependent epigenetic changes. Given the relevance of some of these changes in fetal neurodevelopmental outcomes, the findings signal important methylation targets for future research on molecular mechanisms of effect of the broader social environment on pregnancy and fetal outcomes.NCT00912132 ( ClinicalTrials.gov ).© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
-,Yes,20230202,ewas,36627699,Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth.,BMC Med,"Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming.Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings.Forty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e-05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e-07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e-04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weight growth. Both CpGs (N=3) and DMRs (N=3) were associated with differential expression of transcripts (N=10 and 7, respectively), including long non-coding RNAs. An AURKC DMR was associated with childhood overweight. We observed enrichment of CpGs previously reported associated with birthweight.Our findings provide evidence of the association between cord blood DNA methylation and rapid weight growth and suggest links with prenatal exposures and association with childhood obesity providing opportunities for early prevention.© 2023. The Author(s).",
-,Yes,20230202,ewas,36612042,"A Race-Specific, DNA Methylation Analysis of Aging in Normal Rectum: Implications for the Biology of Aging and Its Relationship to Rectal Cancer.",Cancers (Basel),"Approximately 90% of colorectal cancer (CRC) develop over the age of 50, highlighting the important role of aging in CRC risk. African Americans (AAs) shoulder a greater CRC burden than European Americans (EA) and are more likely to develop CRC at a younger age. The effects of aging in AA and EA normal rectal tissue have yet to be defined. Here, we performed epigenome-wide DNA methylation analysis in the first, large-scale biracial cohort of normal rectum (n= 140 samples). We identified increased epigenetic age acceleration in EA than AA rectum (p= 3.91 Ă— 10-4) using linear regression. We also identified differentially methylated regions (DMRs) associated with chronological aging in AA and EA, separately using DMRcate. Next, a consensus set of regions associated with cancer was identified through DMR analysis of two rectal cancer cohorts. The vast majority of AA DMRs were present in our analysis of aging in rectum of EA subjects, though rates of epigenetic drift were significantly greater in AA (p= 1.94 Ă— 10-45). However, 3.66-fold more DMRs were associated with aging in rectum of EA subjects, many of which were also associated with rectal cancer. Our findings reveal a novel relationship between race, age, DNA methylation and rectal cancer risk that warrants further investigation.",
-,Yes,20230202,ewas,36600305,Methylation in MAD1L1 is associated with the severity of suicide attempt and phenotypes of depression.,Clin Epigenetics,"Depression is a multifactorial disorder representing a significant public health burden. Previous studies have linked multiple single nucleotide polymorphisms with depressive phenotypes and suicidal behavior. MAD1L1 is a mitosis metaphase checkpoint protein that has been linked to depression in GWAS. Using a longitudinal EWAS approach in an adolescent cohort at two time points (n = 216 and n = 154), we identified differentially methylated sites that were associated with depression-related genetic variants in MAD1L1. Three methylation loci (cg02825527, cg18302629, and cg19624444) were consistently hypomethylated in the minor allele carriers, being cross-dependent on several SNPs. We further investigated whether DNA methylation at these CpGs is associated with depressive psychiatric phenotypes in independent cohorts. The first site (cg02825527) was hypomethylated in blood (exp(β) = 84.521, p value ~ 0.003) in participants with severe suicide attempts (n = 88). The same locus showed increased methylation in glial cells (exp(β) = 0.041, p value ~ 0.004) in the validation cohort, involving 29 depressed patients and 29 controls, and showed a trend for association with suicide (n = 40, p value ~ 0.089) and trend for association with depression treatment (n = 377, p value ~ 0.075). The second CpG (cg18302629) was significantly hypomethylated in depressed participants (exp(β) = 56.374, p value ~ 0.023) in glial cells, but did not show associations in the discovery cohorts. The last methylation site (cg19624444) was hypomethylated in the whole blood of severe suicide attempters; however, this association was at the borderline for statistical significance (p value ~ 0.061). This locus, however, showed a strong association with depression treatment in the validation cohort (exp(β) = 2.237, p value ~ 0.003) with 377 participants. The direction of associations between psychiatric phenotypes appeared to be different in the whole blood in comparison with brain samples for cg02825527 and cg19624444. The association analysis between methylation at cg18302629 and cg19624444 and MAD1L1 transcript levels in CD14+cells shows a potential link between methylation at these CpGs and MAD1L1 expression. This study suggests evidence that methylation at MAD1L1 is important for psychiatric health as supported by several independent cohorts.© 2023. The Author(s).",
-,Yes,20230202,ewas,36640455,Effect of HIV infection and antiretroviral therapy initiation on genome-wide DNA methylation patterns.,EBioMedicine,"Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications.184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition.We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio.Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection.NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.Copyright © 2022 Fundacion Investigacion Biomedica del Hospital La Paz. Published by Elsevier B.V. All rights reserved.",
-,Yes,20230202,ewas,36700736,Opioid medication use and blood DNA methylation: epigenome-wide association meta-analysis.,Epigenomics,"Aim:To identify differential methylation related to prescribed opioid use.Methods:This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting.Results:Differential methylation (false discovery rate <0.05) was observed at six CpGs annotated to the following genes:KIAA0226,CPLX2,TDRP,RNF38,TTC23andGPR179. Integrative epigenomic analyses linked implicated loci to regulatory elements in blood and/or brain. Additionally, 74 CpGs were differentially methylated in males or females. Methylation at significant CpGs correlated with gene expression in blood and/or brain.Conclusion:This study identified DNA methylation related to opioid medication use in general populations. The results could inform the development of blood methylation biomarkers of opioid use.",
-,Yes,20230202,ewas,36633903,Reduced methylation corresponds with diabetic nephropathy risk in type 1 diabetes.,J Clin Invest,"Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome wide methylation patterns are poorly defined. While methylation is known to alter gene expression the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n=39) that was subsequently replicated in a larger validation cohort (n=296). Gene body related regions made up >60% of the methylation differences and emphasised the importance of methylation sequencing. We observe differentially methylated genes associated with DN (DDN) in three independent T1D registries originating from Denmark (n=445), Hong Kong (n=107) and Thailand (n=130). Reduced DNA methylation at CTCF and Pol2B sites were tightly connected with DN pathways that include insulin signalling, lipid metabolism and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubules. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding and the activation of insulin signalling phosphoproteins in hyperglycaemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophage and vascular endothelial cells.",
-,Yes,20230202,ewas,36550108,Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease,Nat Commun,"Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes.",
-,Yes,20230202,ewas,36638096,Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.,PLoS Genet,"Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; βz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; β = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.",
-,Yes,20230202,ewas,36708841,Associations of selenium exposure with blood lipids: Exploring mediating DNA methylation sites in general Chinese urban non-smokers.,Sci Total Environ,"Selenium (Se) is widely distributed in the total environment and people are commonly exposed to Se, while the potential effects and mechanisms of Se exposure on blood lipids have not been well established. This study aimed to assess the associations of urinary Se (SeU) with blood lipids and explore the potential mediating DNA methylation sites. We included 2844 non-smoke participants from the second follow-up (2017-2018) of the Wuhan-Zhuhai cohort (WHZH) in this study. SeU and blood lipids [i.e., total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL)] for all participants were determined. The associations of SeU with blood lipids were analyzed by generalized linear models. Then, we conducted the blood lipids related epigenome-wide association studies (EWAS) among 221 never smokers, and the mediation analysis was conducted to explore the potential mediating cytosine-phosphoguanine (CpG) sites in the above associations. In this study, the SeU concentration of the participants in this study was 1.40 (0.94, 2.08) μg/mmol Cr. The SeU was positively associated with TC and LDL, and not associated with TG and HDL. We found 131, 3, and 1 new CpG sites related to TC, HDL, and LDL, respectively. Mediation analyses found that the methylation of cg06964030 (within MIR1306) and cg15824094 (within PLCH2) significantly mediated the positive association between SeU and TC. In conclusion, high levels of Se exposure were associated with increased TC and LDL among non-smokers, and the methylation of MIR1306 and PLCH2 partly mediated Se-associated TC increase. These findings provide new insights into the effects and mechanisms of Se exposure on lipids metabolism and highlight the importance of controlling Se exposure and intake for preventing high blood lipids.Copyright © 2023. Published by Elsevier B.V.",
-,Yes,20230202,ewas,36719767,Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9.,Thyroid,"Thyroid hormones play a key role in differentiation and metabolism, and are known regulators of gene expression through both genomic and epigenetic processes including DNA methylation. The aim of this study was to examine associations between thyroid hormones and DNA methylation.We carried out a fixed-effect meta-analysis of epigenome-wide association study of blood DNA methylation sites from 8 cohorts from the ThyroidOmics Consortium, incorporating up to 7,073 participants of both European and African ancestry, implementing a discovery and replication stage. Statistical analyses were conducted using normalized beta CpG values as dependent and log-transformed thyrotropin (TSH), free thyroxine and free triiodothyronine levels, respectively, as independent variable in a linear model. The replicated findings were correlated with gene expression levels in whole-blood, and tested for causal influence of TSH and free thyroxine by two-sample Mendelian randomization.Epigenome-wide significant associations (p-value < 1.1E-7) of 3 CpGs for free thyroxine, 5 for free triiodothyronine, and 2 for TSH concentrations were discovered and replicated (combined p-values = 1.5E-9 to 4.3E-28). The associations included CpG sites annotated to KLF9 (cg00049440) and DOT1L (cg04173586) that overlap with all three traits, consistent with hypothalamic-pituitary-thyroid axis physiology. Significant associations were also found for CpGs in FKBP5 for free thyroxine, and at CSNK1D/LINCO1970 and LRRC8D for free triiodothyronine. Mendelian randomization analyses supported a causal effect of thyroid status on DNA methylation of KLF9. DNA methylation of cg00049440 in KLF9 was inversely correlated with KLF9 gene expression in blood. The CpG at CSNK1D/LINC01970 overlapped with thyroid hormone receptor alpha binding peaks in liver cells. The total additive heritability of the methylation levels of the six significant CpG sites was between 25% and 57%. Significant methylation QTLs were identified for CpGs at KLF9, FKBP5, LRRC8D and CSNK1D/LINC01970.We report novel associations between TSH, thyroid hormones and blood-based DNA methylation. This study advances our understanding of thyroid hormone action particularly related to KLF9, and serves as a proof-of-concept that integrations of EWAS with other -omics data can provide a valuable tool for unravelling thyroid hormone signaling in humans by complementing and feeding classical in-vitro and animal studies.",
-,No,20230209,dnamage,36516495,DNA methylation GrimAge version 2,Aging (Albany NY),"We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10-167 versus P=2.6x10-144) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10-136), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome. DNAm logCRP is positively correlated with morbidity count (P=1.3x10-54). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10-155). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10-267) and visceral fat (cor=0.41, P=4.7x10-41). Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.",
-,Yes,20230209,ewas,36738748,Epigenetic profile of Japanese supercentenarians: a cross-sectional study.,Lancet Healthy Longev,"Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline.In this cross-sectional study, we enrolled Japanese non-centenarians (eligible participants aged 20-80 years) from the Tohoku Medical Megabank Community-Based Cohort Study and centenarians and supercentenarians (aged 101-115 years) from the Tokyo Centenarian Study and the Japanese Semi-supercentenarian Study. We assessed participants' whole-blood DNA methylation profiles and then developed sex-specific and non-specific first-generation epigenetic clocks by elastic net regression, calculated individuals' epigenetic ages, and assessed their age acceleration. We also screened for age-related CpG sites in non-centenarians by epigenome-wide linear regression analyses and ANOVA. We subsequently investigated which CpG sites in centenarians and supercentenarians had DNA methylation patterns following the age-related findings obtained from non-centenarians and which did not. We further characterised CpG sites with hypermethylation or hypomethylation in the centenarians and supercentenarians using enrichment and protein-protein interaction network analyses.We enrolled 421 non-centenarians (231 [55%] women and 190 [45%] men; age range 20-78 years), recruited between May 20, 2013, and March 31, 2016, and 94 centenarians and supercentenarians (66 women [70%] and 28 [30%] men; age range 101-115 years), recruited between Jan 20, 2001, and April 17, 2018. Non-sex-specific epigenetic clock showed the highest accuracy (r=0·96) based on which centenarians and supercentenarians had negative epigenetic age acceleration. Epigenome-wide association analyses further showed that centenarians and supercentenarians had younger-than-expected epigenetic states (DNA methylation profiles similar to those of non-centenarians) for 557 CpG sites enriched in cancer-related and neuropsychiatric-related genes, whereas these individuals had advanced (or older) epigenetic states for 163 CpG sites represented by genes related to TGF-β signalling, which is involved in anti-inflammatory responses and known to contribute to healthy ageing.These results indicate that exceptionally healthy longevity depends not only on maintaining young epigenetic states but also on advanced states of specific epigenetic regions.The Japan Agency for Medical Research and Development, KDDI Research, and Keio University.For the Japanese translation of the abstract see Supplementary Materials section.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.",
-,Yes,20230209,ewas,36737504,Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence.,Hepatol Int,"Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks.We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value < 0.007. EWAS identified dmCpGs related to three genes (ANK1, MIR10a, PTPRN2) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced (ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p < 2.3 × 10-3).We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.© 2023. The Author(s).",
-,Yes,20230209,ewas,36734879,Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity.,Aging (Albany NY),"Metformin, a commonly prescribed anti-diabetic medication, has repeatedly been shown to hinder aging in pre-clinical models and to be associated with lower mortality for humans. It is, however, not well understood how metformin can potentially prolong lifespan from a biological standpoint. We hypothesized that metformin's potential mechanism of action for longevity is through its epigenetic modifications.To test our hypothesis, we conducted a post-hoc analysis of available genome-wide DNA methylation (DNAm) data obtained from whole blood collected from inpatients with and without a history of metformin use. We assessed the methylation profile of 171 patients (first run) and only among 63 diabetic patients (second run) and compared the DNAm rates between metformin users and nonusers.Enrichment analysis from the Kyoto Encyclopedia of Genes and Genome (KEGG) showed pathways relevant to metformin's mechanism of action, such as longevity, AMPK, and inflammatory pathways. We also identified several pathways related to delirium whose risk factor is aging. Moreover, top hits from the Gene Ontology (GO) included HIF-1α pathways. However, no individual CpG site showed genome-wide statistical significance (p< 5E-08).This study may elucidate metformin's potential role in longevity through epigenetic modifications and other possible mechanisms of action.",
-,No,20230209,mitochondria,36726473,Genome-wide characterization of mitochondrial DNA methylation in human brain.,Front Endocrinol (Lausanne),"There is growing interest in the role of DNA methylation in regulating the transcription of mitochondrial genes, particularly in brain disorders characterized by mitochondrial dysfunction. Here, we present a novel approach to interrogate the mitochondrial DNA methylome at single base resolution using targeted bisulfite sequencing. We applied this method to investigate mitochondrial DNA methylation patterns in post-mortem superior temporal gyrus and cerebellum brain tissue from seven human donors.We show that mitochondrial DNA methylation patterns are relatively low but conserved, with peaks in DNA methylation at several sites, such as within theD-LOOPand the genesMT-ND2,MT-ATP6,MT-ND4,MT-ND5andMT-ND6, predominantly in a non-CpG context. The elevated DNA methylation we observe in theD-LOOPwe validate using pyrosequencing. We identify loci that show differential DNA methylation patterns associated with age, sex and brain region. Finally, we replicate previously reported differentially methylated regions between brain regions from a methylated DNA immunoprecipitation sequencing study.We have annotated patterns of DNA methylation at single base resolution across the mitochondrial genome in human brain samples. Looking to the future this approach could be utilized to investigate the role of mitochondrial epigenetic mechanisms in disorders that display mitochondrial dysfunction.Copyright © 2023 Devall, Soanes, Smith, Dempster, Smith, Burrage, Iatrou, Hannon, Troakes, Moore, O’Neill, Al-Sarraj, Schalkwyk, Mill, Weedon and Lunnon.",
-,No,20230209,methods,36721080,Systematic and benchmarking studies of pipelines for mammal WGBS data in the novel NGS platform.,BMC Bioinformatics,"Whole genome bisulfite sequencing (WGBS), possesses the aptitude to dissect methylation status at the nucleotide-level resolution of 5-methylcytosine (5-mC) on a genome-wide scale. It is a powerful technique for epigenome in various cell types, and tissues. As a recently established next-generation sequencing (NGS) platform, GenoLab M is a promising alternative platform. However, its comprehensive evaluation for WGBS has not been reported. We sequenced two bisulfite-converted mammal DNA in this research using our GenoLab M and NovaSeq 6000, respectively. Then, we systematically compared those data via four widely used WGBS tools (BSMAP, Bismark, BatMeth2, BS-Seeker2) and a new bisulfite-seq tool (BSBolt). We interrogated their computational time, genome depth and coverage, and evaluated their percentage of methylated Cs.Here, benchmarking a combination of pre- and post-processing methods, we found that trimming improved the performance of mapping efficiency in eight datasets. The data from two platforms uncovered ~ 80% of CpG sites genome-wide in the human cell line. Those data sequenced by GenoLab M achieved a far lower proportion of duplicates (~ 5.5%). Among pipelines, BSMAP provided an intriguing representation of 5-mC distribution at CpG sites with 5-mC levels > ~ 78% in datasets from human cell lines, especially in the GenoLab M. BSMAP performed more advantages in running time, uniquely mapped reads percentages, genomic coverage, and quantitative accuracy. Finally, compared with the previous methylation pattern of human cell line and mouse tissue, we confirmed that the data from GenoLab M performed similar consistency and accuracy in methylation levels of CpG sites with that from NovaSeq 6000.Together we confirmed that GenoLab M was a qualified NGS platform for WGBS with high performance. Our results showed that BSMAP was the suitable pipeline that allowed for WGBS studies on the GenoLab M platform.© 2023. The Author(s).",
-,No,20230209,methods,36617464,Comparative epigenome analysis using Infinium DNA methylation BeadChips,Brief Bioinform,"The arrival of the Infinium DNA methylation BeadChips for mice and other nonhuman mammalian species has outpaced the development of the informatics that supports their use for epigenetics study in model organisms. Here, we present informatics infrastructure and methods to allow easy DNA methylation analysis on multiple species, including domesticated animals and inbred laboratory mice (in SeSAMe version 1.16.0+). First, we developed a data-driven analysis pipeline covering species inference, genome-specific data preprocessing and regression modeling. We targeted genomes of 310 species and 37 inbred mouse strains and showed that genome-specific preprocessing prevents artifacts and yields more accurate measurements than generic pipelines. Second, we uncovered the dynamics of the epigenome evolution in different genomic territories and tissue types through comparative analysis. We identified a catalog of inbred mouse strain-specific methylation differences, some of which are linked to the strains' immune, metabolic and neurological phenotypes. By streamlining DNA methylation array analysis for undesigned genomes, our methods extend epigenome research to broad species contexts.",
-,No,20230209,cell type,33588693,Saliva cell type DNA methylation reference panel for epidemiological studies in children,Epigenetics,"Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7-16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 181,577 (22.8%) DNA methylation sites (t-test p < 6.28 × 10-8). Immune cell hypomethylated sites are mapped to genes enriched for immune pathways (p < 3.2 × 10-5). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10-4), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole-saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions. https://github.com/bakulskilab/BeadSorted.Saliva.EPIC",
-,No,20230209,dnamage,36721372,Use of incorrect and correct methods to account for age in studies on epigenetic accelerated aging: implications and recommendations for best practices,Am J Epidemiol,"Motivated by our conduct of a literature review on social exposures and accelerated aging as measured by a growing number of epigenetic ""clocks"" (which estimate age via DNA methylation patterns (DNAm)), we report on three different approaches - 1 incorrect and 2 correct - in the epidemiologic literature on treatment of age in these and other studies using other common exposures (i.e., body mass index and alcohol consumption). Among the 50 empirical articles reviewed, the majority (n = 29; 58%) used the incorrect method of analyzing accelerated aging detrended for age as the outcome and did not control for age as a covariate. By contrast, only 42% used the correct methods, which are either to analyze accelerated aging detrended for age as the outcome and control for age as a covariate (n = 16; 32%), or to analyze raw DNAm age as the outcome and control for age as a covariate (n = 5; 10%). In accord with prior demonstrations of bias introduced by the incorrect approach, we provide simulation analyses and additional empirical analyses to illustrate how the incorrect method can lead to bias to the null, and we discuss implications for extant research and recommendations for best practices.",
-,No,20230209,omics,36717624,Molecular mechanisms of environmental exposures and human disease,Nat Rev Genet,"A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome - the cumulative measure of environmental influences over the lifespan - and its integration into future environmental health research.",
-,No,20230209,ewas,36716967,DNA methylation analysis identifies novel genetic loci associated with circulating fibrinogen levels in blood,J Thromb Haemost,"Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa.
+No,20230202,epigenetics,36471057,Deciphering the mechanical code of the genome and epigenome,Nat Struct Mol Biol,"Diverse DNA-deforming processes are impacted by the local mechanical and structural properties of DNA, which in turn depend on local sequence and epigenetic modifications. Deciphering this mechanical code (that is, this dependence) has been challenging due to the lack of high-throughput experimental methods. Here we present a comprehensive characterization of the mechanical code. Utilizing high-throughput measurements of DNA bendability via loop-seq, we quantitatively established how the occurrence and spatial distribution of dinucleotides, tetranucleotides and methylated CpG impact DNA bendability. We used our measurements to develop a physical model for the sequence and methylation dependence of DNA bendability. We validated the model by performing loop-seq on mouse genomic sequences around transcription start sites and CTCF-binding sites. We applied our model to test the predictions of all-atom molecular dynamics simulations and to demonstrate that sequence and epigenetic modifications can mechanically encode regulatory information in diverse contexts.",
+No,20230202,reference,36599988,A DNA methylation atlas of normal human cell types,Nature,"DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.",
+No,20230202,ml,36602952,Ten quick tips for computational analysis of medical images.,PLoS Comput Biol,"Medical imaging is a great asset for modern medicine, since it allows physicians to spatially interrogate a disease site, resulting in precise intervention for diagnosis and treatment, and to observe particular aspect of patients' conditions that otherwise would not be noticeable. Computational analysis of medical images, moreover, can allow the discovery of disease patterns and correlations among cohorts of patients with the same disease, thus suggesting common causes or providing useful information for better therapies and cures. Machine learning and deep learning applied to medical images, in particular, have produced new, unprecedented results that can pave the way to advanced frontiers of medical discoveries. While computational analysis of medical images has become easier, however, the possibility to make mistakes or generate inflated or misleading results has become easier, too, hindering reproducibility and deployment. In this article, we provide ten quick tips to perform computational analysis of medical images avoiding common mistakes and pitfalls that we noticed in multiple studies in the past. We believe our ten guidelines, if taken into practice, can help the computational-medical imaging community to perform better scientific research that eventually can have a positive impact on the lives of patients worldwide.Copyright: © 2023 Chicco, Shiradkar. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+No,20230202,epigenetics,36656803,Using epigenomics to understand cellular responses to environmental influences in diseases.,PLoS Genet,"It is a generally accepted model that environmental influences can exert their effects, at least in part, by changing the molecular regulators of transcription that are described as epigenetic. As there is biochemical evidence that some epigenetic regulators of transcription can maintain their states long term and through cell division, an epigenetic model encompasses the idea of maintenance of the effect of an exposure long after it is no longer present. The evidence supporting this model is mostly from the observation of alterations of molecular regulators of transcription following exposures. With the understanding that the interpretation of these associations is more complex than originally recognised, this model may be oversimplistic; therefore, adopting novel perspectives and experimental approaches when examining how environmental exposures are linked to phenotypes may prove worthwhile. In this review, we have chosen to use the example of nonalcoholic fatty liver disease (NAFLD), a common, complex human disease with strong environmental and genetic influences. We describe how epigenomic approaches combined with emerging functional genetic and single-cell genomic techniques are poised to generate new insights into the pathogenesis of environmentally influenced human disease phenotypes exemplified by NAFLD.Copyright: © 2023 Wattacheril et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+No,20230202,dnam age,36548410,"Epigenetic clocks, aging, and cancer",Science,"Cancer and aging are accompanied by stereotyped changes to the epigenetic landscape, including progressive loss of DNA methylation over gene-poor genomic regions (1, 2). Global hypomethylation arises in cells that have undergone many divisions, likely owing to imperfect maintenance. Evidence suggests that global hypomethylation represents a “mitotic clock” that counts divisions in somatic cells and functions to restrain aging cells and limit malignant progression. Therapies that modulate the pace of methylation loss or eliminate hypomethylated cells could alleviate agingassociated diseases or cancers.",
+Yes,20230202,ewas,36649705,Epigenome-wide meta-analysis of BMI in nine cohorts: Examining the utility of epigenetically predicted BMI.,Am J Hum Genet,"This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E-7) and 1,238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European and African descent, as defined by self-reported race/ethnicity. We found that five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log-normalized BMI in the WHI (80% training/20% testing). This model found that 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides and lower HDL cholesterol and LDL cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL cholesterol and lower glucose and triglycerides. This study confirmed 553 and identified 685 CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health, suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.Copyright © 2022 American Society of Human Genetics. All rights reserved.",
+Yes,20230202,ewas,36609850,Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder.,Autism Res,"Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.© 2023 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.",
+Yes,20230202,ewas,36617561,Prenatal social support in low-risk pregnancy shapes placental epigenome.,BMC Med,"Poor social support during pregnancy has been linked to inflammation and adverse pregnancy and childhood health outcomes. Placental epigenetic alterations may underlie these links but are still unknown in humans.In a cohort of low-risk pregnant women (n = 301) from diverse ethnic backgrounds, social support was measured using the ENRICHD Social Support Inventory (ESSI) during the first trimester. Placental samples collected at delivery were analyzed for DNA methylation and gene expression using Illumina 450K Beadchip Array and RNA-seq, respectively. We examined association between maternal prenatal social support and DNA methylation in placenta. Associated cytosine-(phosphate)-guanine sites (CpGs) were further assessed for correlation with nearby gene expression in placenta.The mean age (SD) of the women was 27.7 (5.3) years. The median (interquartile range) of ESSI scores was 24 (22-25). Prenatal social support was significantly associated with methylation level at seven CpGs (PFDR < 0.05). The methylation levels at two of the seven CpGs correlated with placental expression of VGF and ILVBL (PFDR < 0.05), genes known to be involved in neurodevelopment and energy metabolism. The genes annotated with the top 100 CpGs were enriched for pathways related to fetal growth, coagulation system, energy metabolism, and neurodevelopment. Sex-stratified analysis identified additional significant associations at nine CpGs in male-bearing pregnancies and 35 CpGs in female-bearing pregnancies.The findings suggest that prenatal social support is linked to placental DNA methylation changes in a low-stress setting, including fetal sex-dependent epigenetic changes. Given the relevance of some of these changes in fetal neurodevelopmental outcomes, the findings signal important methylation targets for future research on molecular mechanisms of effect of the broader social environment on pregnancy and fetal outcomes.NCT00912132 ( ClinicalTrials.gov ).© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
+Yes,20230202,ewas,36627699,Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth.,BMC Med,"Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming.Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings.Forty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e-05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e-07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e-04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weight growth. Both CpGs (N=3) and DMRs (N=3) were associated with differential expression of transcripts (N=10 and 7, respectively), including long non-coding RNAs. An AURKC DMR was associated with childhood overweight. We observed enrichment of CpGs previously reported associated with birthweight.Our findings provide evidence of the association between cord blood DNA methylation and rapid weight growth and suggest links with prenatal exposures and association with childhood obesity providing opportunities for early prevention.© 2023. The Author(s).",
+Yes,20230202,ewas,36612042,"A Race-Specific, DNA Methylation Analysis of Aging in Normal Rectum: Implications for the Biology of Aging and Its Relationship to Rectal Cancer.",Cancers (Basel),"Approximately 90% of colorectal cancer (CRC) develop over the age of 50, highlighting the important role of aging in CRC risk. African Americans (AAs) shoulder a greater CRC burden than European Americans (EA) and are more likely to develop CRC at a younger age. The effects of aging in AA and EA normal rectal tissue have yet to be defined. Here, we performed epigenome-wide DNA methylation analysis in the first, large-scale biracial cohort of normal rectum (n= 140 samples). We identified increased epigenetic age acceleration in EA than AA rectum (p= 3.91 Ă— 10-4) using linear regression. We also identified differentially methylated regions (DMRs) associated with chronological aging in AA and EA, separately using DMRcate. Next, a consensus set of regions associated with cancer was identified through DMR analysis of two rectal cancer cohorts. The vast majority of AA DMRs were present in our analysis of aging in rectum of EA subjects, though rates of epigenetic drift were significantly greater in AA (p= 1.94 Ă— 10-45). However, 3.66-fold more DMRs were associated with aging in rectum of EA subjects, many of which were also associated with rectal cancer. Our findings reveal a novel relationship between race, age, DNA methylation and rectal cancer risk that warrants further investigation.",
+Yes,20230202,ewas,36600305,Methylation in MAD1L1 is associated with the severity of suicide attempt and phenotypes of depression.,Clin Epigenetics,"Depression is a multifactorial disorder representing a significant public health burden. Previous studies have linked multiple single nucleotide polymorphisms with depressive phenotypes and suicidal behavior. MAD1L1 is a mitosis metaphase checkpoint protein that has been linked to depression in GWAS. Using a longitudinal EWAS approach in an adolescent cohort at two time points (n = 216 and n = 154), we identified differentially methylated sites that were associated with depression-related genetic variants in MAD1L1. Three methylation loci (cg02825527, cg18302629, and cg19624444) were consistently hypomethylated in the minor allele carriers, being cross-dependent on several SNPs. We further investigated whether DNA methylation at these CpGs is associated with depressive psychiatric phenotypes in independent cohorts. The first site (cg02825527) was hypomethylated in blood (exp(β) = 84.521, p value ~ 0.003) in participants with severe suicide attempts (n = 88). The same locus showed increased methylation in glial cells (exp(β) = 0.041, p value ~ 0.004) in the validation cohort, involving 29 depressed patients and 29 controls, and showed a trend for association with suicide (n = 40, p value ~ 0.089) and trend for association with depression treatment (n = 377, p value ~ 0.075). The second CpG (cg18302629) was significantly hypomethylated in depressed participants (exp(β) = 56.374, p value ~ 0.023) in glial cells, but did not show associations in the discovery cohorts. The last methylation site (cg19624444) was hypomethylated in the whole blood of severe suicide attempters; however, this association was at the borderline for statistical significance (p value ~ 0.061). This locus, however, showed a strong association with depression treatment in the validation cohort (exp(β) = 2.237, p value ~ 0.003) with 377 participants. The direction of associations between psychiatric phenotypes appeared to be different in the whole blood in comparison with brain samples for cg02825527 and cg19624444. The association analysis between methylation at cg18302629 and cg19624444 and MAD1L1 transcript levels in CD14+cells shows a potential link between methylation at these CpGs and MAD1L1 expression. This study suggests evidence that methylation at MAD1L1 is important for psychiatric health as supported by several independent cohorts.© 2023. The Author(s).",
+Yes,20230202,ewas,36640455,Effect of HIV infection and antiretroviral therapy initiation on genome-wide DNA methylation patterns.,EBioMedicine,"Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications.184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition.We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio.Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection.NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.Copyright © 2022 Fundacion Investigacion Biomedica del Hospital La Paz. Published by Elsevier B.V. All rights reserved.",
+Yes,20230202,ewas,36700736,Opioid medication use and blood DNA methylation: epigenome-wide association meta-analysis.,Epigenomics,"Aim:To identify differential methylation related to prescribed opioid use.Methods:This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting.Results:Differential methylation (false discovery rate <0.05) was observed at six CpGs annotated to the following genes:KIAA0226,CPLX2,TDRP,RNF38,TTC23andGPR179. Integrative epigenomic analyses linked implicated loci to regulatory elements in blood and/or brain. Additionally, 74 CpGs were differentially methylated in males or females. Methylation at significant CpGs correlated with gene expression in blood and/or brain.Conclusion:This study identified DNA methylation related to opioid medication use in general populations. The results could inform the development of blood methylation biomarkers of opioid use.",
+Yes,20230202,ewas,36633903,Reduced methylation corresponds with diabetic nephropathy risk in type 1 diabetes.,J Clin Invest,"Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome wide methylation patterns are poorly defined. While methylation is known to alter gene expression the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n=39) that was subsequently replicated in a larger validation cohort (n=296). Gene body related regions made up >60% of the methylation differences and emphasised the importance of methylation sequencing. We observe differentially methylated genes associated with DN (DDN) in three independent T1D registries originating from Denmark (n=445), Hong Kong (n=107) and Thailand (n=130). Reduced DNA methylation at CTCF and Pol2B sites were tightly connected with DN pathways that include insulin signalling, lipid metabolism and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubules. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding and the activation of insulin signalling phosphoproteins in hyperglycaemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophage and vascular endothelial cells.",
+Yes,20230202,ewas,36550108,Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease,Nat Commun,"Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes.",
+Yes,20230202,ewas,36638096,Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.,PLoS Genet,"Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; βz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; β = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.",
+Yes,20230202,ewas,36708841,Associations of selenium exposure with blood lipids: Exploring mediating DNA methylation sites in general Chinese urban non-smokers.,Sci Total Environ,"Selenium (Se) is widely distributed in the total environment and people are commonly exposed to Se, while the potential effects and mechanisms of Se exposure on blood lipids have not been well established. This study aimed to assess the associations of urinary Se (SeU) with blood lipids and explore the potential mediating DNA methylation sites. We included 2844 non-smoke participants from the second follow-up (2017-2018) of the Wuhan-Zhuhai cohort (WHZH) in this study. SeU and blood lipids [i.e., total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL)] for all participants were determined. The associations of SeU with blood lipids were analyzed by generalized linear models. Then, we conducted the blood lipids related epigenome-wide association studies (EWAS) among 221 never smokers, and the mediation analysis was conducted to explore the potential mediating cytosine-phosphoguanine (CpG) sites in the above associations. In this study, the SeU concentration of the participants in this study was 1.40 (0.94, 2.08) μg/mmol Cr. The SeU was positively associated with TC and LDL, and not associated with TG and HDL. We found 131, 3, and 1 new CpG sites related to TC, HDL, and LDL, respectively. Mediation analyses found that the methylation of cg06964030 (within MIR1306) and cg15824094 (within PLCH2) significantly mediated the positive association between SeU and TC. In conclusion, high levels of Se exposure were associated with increased TC and LDL among non-smokers, and the methylation of MIR1306 and PLCH2 partly mediated Se-associated TC increase. These findings provide new insights into the effects and mechanisms of Se exposure on lipids metabolism and highlight the importance of controlling Se exposure and intake for preventing high blood lipids.Copyright © 2023. Published by Elsevier B.V.",
+Yes,20230202,ewas,36719767,Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9.,Thyroid,"Thyroid hormones play a key role in differentiation and metabolism, and are known regulators of gene expression through both genomic and epigenetic processes including DNA methylation. The aim of this study was to examine associations between thyroid hormones and DNA methylation.We carried out a fixed-effect meta-analysis of epigenome-wide association study of blood DNA methylation sites from 8 cohorts from the ThyroidOmics Consortium, incorporating up to 7,073 participants of both European and African ancestry, implementing a discovery and replication stage. Statistical analyses were conducted using normalized beta CpG values as dependent and log-transformed thyrotropin (TSH), free thyroxine and free triiodothyronine levels, respectively, as independent variable in a linear model. The replicated findings were correlated with gene expression levels in whole-blood, and tested for causal influence of TSH and free thyroxine by two-sample Mendelian randomization.Epigenome-wide significant associations (p-value < 1.1E-7) of 3 CpGs for free thyroxine, 5 for free triiodothyronine, and 2 for TSH concentrations were discovered and replicated (combined p-values = 1.5E-9 to 4.3E-28). The associations included CpG sites annotated to KLF9 (cg00049440) and DOT1L (cg04173586) that overlap with all three traits, consistent with hypothalamic-pituitary-thyroid axis physiology. Significant associations were also found for CpGs in FKBP5 for free thyroxine, and at CSNK1D/LINCO1970 and LRRC8D for free triiodothyronine. Mendelian randomization analyses supported a causal effect of thyroid status on DNA methylation of KLF9. DNA methylation of cg00049440 in KLF9 was inversely correlated with KLF9 gene expression in blood. The CpG at CSNK1D/LINC01970 overlapped with thyroid hormone receptor alpha binding peaks in liver cells. The total additive heritability of the methylation levels of the six significant CpG sites was between 25% and 57%. Significant methylation QTLs were identified for CpGs at KLF9, FKBP5, LRRC8D and CSNK1D/LINC01970.We report novel associations between TSH, thyroid hormones and blood-based DNA methylation. This study advances our understanding of thyroid hormone action particularly related to KLF9, and serves as a proof-of-concept that integrations of EWAS with other -omics data can provide a valuable tool for unravelling thyroid hormone signaling in humans by complementing and feeding classical in-vitro and animal studies.",
+No,20230209,dnamage,36516495,DNA methylation GrimAge version 2,Aging (Albany NY),"We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10-167 versus P=2.6x10-144) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10-136), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome. DNAm logCRP is positively correlated with morbidity count (P=1.3x10-54). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10-155). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10-267) and visceral fat (cor=0.41, P=4.7x10-41). Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.",
+Yes,20230209,ewas,36738748,Epigenetic profile of Japanese supercentenarians: a cross-sectional study.,Lancet Healthy Longev,"Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline.In this cross-sectional study, we enrolled Japanese non-centenarians (eligible participants aged 20-80 years) from the Tohoku Medical Megabank Community-Based Cohort Study and centenarians and supercentenarians (aged 101-115 years) from the Tokyo Centenarian Study and the Japanese Semi-supercentenarian Study. We assessed participants' whole-blood DNA methylation profiles and then developed sex-specific and non-specific first-generation epigenetic clocks by elastic net regression, calculated individuals' epigenetic ages, and assessed their age acceleration. We also screened for age-related CpG sites in non-centenarians by epigenome-wide linear regression analyses and ANOVA. We subsequently investigated which CpG sites in centenarians and supercentenarians had DNA methylation patterns following the age-related findings obtained from non-centenarians and which did not. We further characterised CpG sites with hypermethylation or hypomethylation in the centenarians and supercentenarians using enrichment and protein-protein interaction network analyses.We enrolled 421 non-centenarians (231 [55%] women and 190 [45%] men; age range 20-78 years), recruited between May 20, 2013, and March 31, 2016, and 94 centenarians and supercentenarians (66 women [70%] and 28 [30%] men; age range 101-115 years), recruited between Jan 20, 2001, and April 17, 2018. Non-sex-specific epigenetic clock showed the highest accuracy (r=0·96) based on which centenarians and supercentenarians had negative epigenetic age acceleration. Epigenome-wide association analyses further showed that centenarians and supercentenarians had younger-than-expected epigenetic states (DNA methylation profiles similar to those of non-centenarians) for 557 CpG sites enriched in cancer-related and neuropsychiatric-related genes, whereas these individuals had advanced (or older) epigenetic states for 163 CpG sites represented by genes related to TGF-β signalling, which is involved in anti-inflammatory responses and known to contribute to healthy ageing.These results indicate that exceptionally healthy longevity depends not only on maintaining young epigenetic states but also on advanced states of specific epigenetic regions.The Japan Agency for Medical Research and Development, KDDI Research, and Keio University.For the Japanese translation of the abstract see Supplementary Materials section.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.",
+Yes,20230209,ewas,36737504,Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence.,Hepatol Int,"Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks.We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value < 0.007. EWAS identified dmCpGs related to three genes (ANK1, MIR10a, PTPRN2) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced (ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p < 2.3 × 10-3).We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.© 2023. The Author(s).",
+Yes,20230209,ewas,36734879,Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity.,Aging (Albany NY),"Metformin, a commonly prescribed anti-diabetic medication, has repeatedly been shown to hinder aging in pre-clinical models and to be associated with lower mortality for humans. It is, however, not well understood how metformin can potentially prolong lifespan from a biological standpoint. We hypothesized that metformin's potential mechanism of action for longevity is through its epigenetic modifications.To test our hypothesis, we conducted a post-hoc analysis of available genome-wide DNA methylation (DNAm) data obtained from whole blood collected from inpatients with and without a history of metformin use. We assessed the methylation profile of 171 patients (first run) and only among 63 diabetic patients (second run) and compared the DNAm rates between metformin users and nonusers.Enrichment analysis from the Kyoto Encyclopedia of Genes and Genome (KEGG) showed pathways relevant to metformin's mechanism of action, such as longevity, AMPK, and inflammatory pathways. We also identified several pathways related to delirium whose risk factor is aging. Moreover, top hits from the Gene Ontology (GO) included HIF-1α pathways. However, no individual CpG site showed genome-wide statistical significance (p< 5E-08).This study may elucidate metformin's potential role in longevity through epigenetic modifications and other possible mechanisms of action.",
+No,20230209,mitochondria,36726473,Genome-wide characterization of mitochondrial DNA methylation in human brain.,Front Endocrinol (Lausanne),"There is growing interest in the role of DNA methylation in regulating the transcription of mitochondrial genes, particularly in brain disorders characterized by mitochondrial dysfunction. Here, we present a novel approach to interrogate the mitochondrial DNA methylome at single base resolution using targeted bisulfite sequencing. We applied this method to investigate mitochondrial DNA methylation patterns in post-mortem superior temporal gyrus and cerebellum brain tissue from seven human donors.We show that mitochondrial DNA methylation patterns are relatively low but conserved, with peaks in DNA methylation at several sites, such as within theD-LOOPand the genesMT-ND2,MT-ATP6,MT-ND4,MT-ND5andMT-ND6, predominantly in a non-CpG context. The elevated DNA methylation we observe in theD-LOOPwe validate using pyrosequencing. We identify loci that show differential DNA methylation patterns associated with age, sex and brain region. Finally, we replicate previously reported differentially methylated regions between brain regions from a methylated DNA immunoprecipitation sequencing study.We have annotated patterns of DNA methylation at single base resolution across the mitochondrial genome in human brain samples. Looking to the future this approach could be utilized to investigate the role of mitochondrial epigenetic mechanisms in disorders that display mitochondrial dysfunction.Copyright © 2023 Devall, Soanes, Smith, Dempster, Smith, Burrage, Iatrou, Hannon, Troakes, Moore, O’Neill, Al-Sarraj, Schalkwyk, Mill, Weedon and Lunnon.",
+No,20230209,methods,36721080,Systematic and benchmarking studies of pipelines for mammal WGBS data in the novel NGS platform.,BMC Bioinformatics,"Whole genome bisulfite sequencing (WGBS), possesses the aptitude to dissect methylation status at the nucleotide-level resolution of 5-methylcytosine (5-mC) on a genome-wide scale. It is a powerful technique for epigenome in various cell types, and tissues. As a recently established next-generation sequencing (NGS) platform, GenoLab M is a promising alternative platform. However, its comprehensive evaluation for WGBS has not been reported. We sequenced two bisulfite-converted mammal DNA in this research using our GenoLab M and NovaSeq 6000, respectively. Then, we systematically compared those data via four widely used WGBS tools (BSMAP, Bismark, BatMeth2, BS-Seeker2) and a new bisulfite-seq tool (BSBolt). We interrogated their computational time, genome depth and coverage, and evaluated their percentage of methylated Cs.Here, benchmarking a combination of pre- and post-processing methods, we found that trimming improved the performance of mapping efficiency in eight datasets. The data from two platforms uncovered ~ 80% of CpG sites genome-wide in the human cell line. Those data sequenced by GenoLab M achieved a far lower proportion of duplicates (~ 5.5%). Among pipelines, BSMAP provided an intriguing representation of 5-mC distribution at CpG sites with 5-mC levels > ~ 78% in datasets from human cell lines, especially in the GenoLab M. BSMAP performed more advantages in running time, uniquely mapped reads percentages, genomic coverage, and quantitative accuracy. Finally, compared with the previous methylation pattern of human cell line and mouse tissue, we confirmed that the data from GenoLab M performed similar consistency and accuracy in methylation levels of CpG sites with that from NovaSeq 6000.Together we confirmed that GenoLab M was a qualified NGS platform for WGBS with high performance. Our results showed that BSMAP was the suitable pipeline that allowed for WGBS studies on the GenoLab M platform.© 2023. The Author(s).",
+No,20230209,methods,36617464,Comparative epigenome analysis using Infinium DNA methylation BeadChips,Brief Bioinform,"The arrival of the Infinium DNA methylation BeadChips for mice and other nonhuman mammalian species has outpaced the development of the informatics that supports their use for epigenetics study in model organisms. Here, we present informatics infrastructure and methods to allow easy DNA methylation analysis on multiple species, including domesticated animals and inbred laboratory mice (in SeSAMe version 1.16.0+). First, we developed a data-driven analysis pipeline covering species inference, genome-specific data preprocessing and regression modeling. We targeted genomes of 310 species and 37 inbred mouse strains and showed that genome-specific preprocessing prevents artifacts and yields more accurate measurements than generic pipelines. Second, we uncovered the dynamics of the epigenome evolution in different genomic territories and tissue types through comparative analysis. We identified a catalog of inbred mouse strain-specific methylation differences, some of which are linked to the strains' immune, metabolic and neurological phenotypes. By streamlining DNA methylation array analysis for undesigned genomes, our methods extend epigenome research to broad species contexts.",
+No,20230209,cell type,33588693,Saliva cell type DNA methylation reference panel for epidemiological studies in children,Epigenetics,"Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7-16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 181,577 (22.8%) DNA methylation sites (t-test p < 6.28 × 10-8). Immune cell hypomethylated sites are mapped to genes enriched for immune pathways (p < 3.2 × 10-5). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10-4), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole-saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions. https://github.com/bakulskilab/BeadSorted.Saliva.EPIC",
+No,20230209,dnamage,36721372,Use of incorrect and correct methods to account for age in studies on epigenetic accelerated aging: implications and recommendations for best practices,Am J Epidemiol,"Motivated by our conduct of a literature review on social exposures and accelerated aging as measured by a growing number of epigenetic ""clocks"" (which estimate age via DNA methylation patterns (DNAm)), we report on three different approaches - 1 incorrect and 2 correct - in the epidemiologic literature on treatment of age in these and other studies using other common exposures (i.e., body mass index and alcohol consumption). Among the 50 empirical articles reviewed, the majority (n = 29; 58%) used the incorrect method of analyzing accelerated aging detrended for age as the outcome and did not control for age as a covariate. By contrast, only 42% used the correct methods, which are either to analyze accelerated aging detrended for age as the outcome and control for age as a covariate (n = 16; 32%), or to analyze raw DNAm age as the outcome and control for age as a covariate (n = 5; 10%). In accord with prior demonstrations of bias introduced by the incorrect approach, we provide simulation analyses and additional empirical analyses to illustrate how the incorrect method can lead to bias to the null, and we discuss implications for extant research and recommendations for best practices.",
+No,20230209,omics,36717624,Molecular mechanisms of environmental exposures and human disease,Nat Rev Genet,"A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome - the cumulative measure of environmental influences over the lifespan - and its integration into future environmental health research.",
+No,20230209,ewas,36716967,DNA methylation analysis identifies novel genetic loci associated with circulating fibrinogen levels in blood,J Thromb Haemost,"Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa.
 
 Methods: We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without C-reactive protein (CRP) adjustment to examine the role of inflammation.
 
 Results: We identified 208 and 87 significant CpG sites associated with fibrinogen from the 450K (p-value<1.03×10-7) and EPIC arrays (p-value<5.78×10-8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for the overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. Examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations for all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant.
 
 Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.",
-,No,20230209,review,36694711,DNA methylation signatures as biomarkers of socioeconomic position,Environ Epigenet,"This review article provides a framework for the use of deoxyribonucleic acid (DNA) methylation (DNAm) biomarkers to study the biological embedding of socioeconomic position (SEP) and summarizes the latest developments in the area. It presents the emerging literature showing associations between individual- and neighborhood-level SEP exposures and DNAm across the life course. In contrast to questionnaire-based methods of assessing SEP, we suggest that DNAm biomarkers may offer an accessible metric to study questions about SEP and health outcomes, acting as a personal dosimeter of exposure. However, further work remains in standardizing SEP measures across studies and evaluating consistency across domains, tissue types, and time periods. Meta-analyses of epigenetic associations with SEP are offered as one approach to confirm the replication of DNAm loci across studies. The development of DNAm biomarkers of SEP would provide a method for examining its impact on health outcomes in a more robust way, increasing the rigor of epidemiological studies.",
-,No,20230216,transgenerational epigenetic inheritance,36754048,Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice,Cell,"Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.",
-,Yes,20230216,ewas,36782224,DNA methylation in peripheral blood leukocytes for the association with glucose metabolism and invasive breast cancer.,Clin Epigenetics,"Insulin resistance (IR) is a well-established factor for breast cancer (BC) risk in postmenopausal women, but the interrelated molecular pathways on the methylome are not explicitly described. We conducted a population-level epigenome-wide association (EWA) study for DNA methylation (DNAm) probes that are associated with IR and prospectively correlated with BC development, both overall and in BC subtypes among postmenopausal women.We used data from Women's Health Initiative (WHI) ancillary studies for our EWA analyses and evaluated the associations of site-specific DNAm across the genome with IR phenotypes by multiple regressions adjusting for age and leukocyte heterogeneities. For our analysis of the top 20 IR-CpGs with BC risk, we used the WHI and the Cancer Genomic Atlas (TCGA), using multiple Cox proportional hazards and logit regressions, respectively, accounting for age, diabetes, obesity, leukocyte heterogeneities, and tumor purity (for TCGA). We further conducted a Gene Set Enrichment Analysis.We detected several EWA-CpGs in TXNIP, CPT1A, PHGDH, and ABCG1. In particular, cg19693031 in TXNIP was replicated in all IR phenotypes, measured by fasting levels of glucose, insulin, and homeostatic model assessment-IR. Of those replicated IR-genes, 3 genes (CPT1A, PHGDH, and ABCG1) were further correlated with BC risk; and 1 individual CpG (cg01676795 in POR) was commonly detected across the 2 cohorts.Our study contributes to better understanding of the interconnected molecular pathways on the methylome between IR and BC carcinogenesis and suggests potential use of DNAm markers in the peripheral blood cells as preventive targets to detect an at-risk group for IR and BC in postmenopausal women.© 2023. The Author(s).",
-,Yes,20230216,ewas,36778507,A Higher Dysregulation Burden of Brain DNA Methylation in Female Patients Implicated in the Sex Bias of Schizophrenia.,Res Sq,"Sex differences are pervasive in schizophrenia (SCZ), but the extent and magnitude of DNA methylation (DNAm) changes underlying these differences remain uncharacterized. In this study, sex-stratified differential DNAm analysis was performed in postmortem brain samples from 117 SCZ and 137 controls, partitioned into discovery and replication datasets. Three differentially methylated positions (DMPs) were identified (adj.p < 0.05) in females and 29 DMPs in males without overlap between them. Over 81% of these sex-stratified DMPs were directionally consistent between sexes but with different effect sizes. Down-sampling analysis revealed more DMPs in females than in males when the sample sizes matched. Females had higher DNAm levels in healthy individuals and larger magnitude of DNAm changes in patients than males. Despite similar proportions of female-related DMPs (fDMPs, 8%) being under genetic control compared with males (10%), significant enrichment of DMP-related SNPs in signals of genome-wide association studies was identified only in fDMPs. One DMP in each sex connected the SNPs and gene expression ofCALHM1in females andCCDC149in males. PPI subnetworks revealed that both female- and male-related differential DNAm interacted with synapse-related dysregulation. Immune-related pathways were unique for females and neuron-related pathways were associated with males. This study reveals remarkable quantitative differences in DNAm-related sexual dimorphism in SCZ and that females have a higher dysregulation burden of SCZ-associated DNAm than males.",
-,Yes,20230216,ewas,36765422,Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis.,Clin Epigenetics,"Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS.We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5-44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+and eight in CD8+T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women.Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential 'CNS signature' of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.© 2023. The Author(s).",
-,No,20230216,cell-free dna,36758479,UCseek: ultrasensitive early detection and recurrence monitoring of urothelial carcinoma by shallow-depth genome-wide bisulfite sequencing of urinary sediment DNA.,EBioMedicine,"Current methods for the detection and surveillance of urothelial carcinomas (UCs) are often invasive, costly, and not effective for low-grade, early-stage, and minimal residual disease (MRD) tumors. We aimed to develop and validate a model from urine sediments to predict different grade and stage UCs with low cost and high accuracy.We collected 167 samples, including 90 tumors and 77 individuals without tumors, as a discovery cohort. We assessed copy number variations and methylation values for them and constructed a diagnostic classifier to detect UC, UCseek, by using an individual read-based method and support vector machine. The performance of UCseek was validated in an independent cohort derived from three hospitals (n = 206) and a relapse cohort (n = 42) for monitoring recurrence.We constructed UCseek, which could predict UCs with high sensitivity (92.7%), high specificity (90.7%), and high accuracy (91.7%) in the independent validation set. The accuracy of UCseek in low-grade and early-stage patients reached 91.8% and 94.3%, respectively. Notably, UCseek retained great performance at ultralow sequencing depths (0.3X-0.5X). It also demonstrated a powerful ability to monitor recurrence in a surveillance cohort compared with cystoscopy (90.91% vs. 59.09%).We optimized an improved approach named UCseek for the noninvasive diagnosis and monitoring of UCs in both low- and high-grade tumors and in early- and advanced-stage tumors, even at ultralow sequencing depths, which may reduce the burden of cystoscopy and blind second surgery.A full list of funding bodies that contributed to this study can be found in the Acknowledgments section.Copyright © 2023. Published by Elsevier B.V.",
-,Yes,20230216,omics,36752523,Circulating triglycerides are associated with human adipose tissue DNA methylation of genes linked to metabolic disease.,Hum Mol Genet,"Dysregulation of circulating lipids is a central element for the metabolic syndrome. However, it is not well established whether human subcutaneous adipose tissue is affected by or affect circulating lipids through epigenetic mechanisms. Hence, our aim was to investigate the association between circulating lipids and DNA methylation levels in human adipose tissue.DNA methylation and gene expression were analyzed genome-wide in subcutaneous adipose tissue from two different cohorts, including 85 men and 93 women, respectively. Associations between DNA methylation and circulating levels of triglycerides, LDL, HDL and total cholesterol were analysed. Causal mediation analyses tested if adipose tissue DNA methylation mediates the effects of triglycerides on gene expression or insulin resistance.We found 115 novel associations between triglycerides and adipose tissue DNA methylation, e.g. in the promoter of RFS1, ARID2, and HOXA5 in the male cohort (p ≤ 1.1x10-7), and 63 associations e.g. within the gene body of PTPRN2 and COL6A3 in the female cohort. We further connected these findings to altered mRNA expression levels in adipose tissue (e.g. HOXA5, IL11 and FAM45B). Interestingly, there was no overlap between methylation sites associated with triglycerides in men and the sites found in women, which points towards sex-specific effects of triglycerides on the epigenome. Finally, a causal mediation analysis provided support for adipose tissue DNA methylation as a partial mediating factor between circulating triglycerides and insulin resistance.This study identified novel epigenetic alterations in adipose tissue associated with circulating lipids. Identified epigenetic changes seem to mediate effects of triglycerides on insulin resistance.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
-,Yes,20230223,ewas,36800980,Role of epigenetics in the clinical evolution of COVID-19 disease. Epigenome-wide association study identifies markers of severe outcome.,Eur J Med Res,"COVID-19 has a wide spectrum of clinical manifestations and given its impact on morbidity and mortality, there is an unmet medical need to discover endogenous cellular and molecular biomarkers that predict the expected clinical course of the disease. Recently, epigenetics and especially DNA methylation have been pointed out as a promising tool for outcome prediction in several diseases.Using the Illumina Infinium Methylation EPIC BeadChip850K, we investigated genome-wide differences in DNA methylation in an Italian Cohort of patients with comorbidities and compared severe (n = 64) and mild (123) prognosis. Results showed that the epigenetic signature, already present at the time of Hospital admission, can significantly predict risk of severe outcomes. Further analyses provided evidence of an association between age acceleration and a severe prognosis after COVID-19 infection. The burden of Stochastic Epigenetic Mutation (SEMs) has been significantly increased in patients with poor prognosis. Results have been replicated in silico considering COVID-19 negative subjects and available previously published datasets.Using original methylation data and taking advantage of already published datasets, we confirmed in the blood that epigenetics is actively involved in immune response after COVID-19 infection, allowing the identification of a specific signature able to discriminate the disease evolution. Furthermore, the study showed that epigenetic drift and age acceleration are associated with severe prognosis. All these findings prove that host epigenetics undergoes notable and specific rearrangements to respond to COVID-19 infection which can be used for a personalized, timely, and targeted management of COVID-19 patients during the first stages of hospitalization.© 2023. The Author(s).",
-,No,20230223,methods,36797751,An overview of DNA methylation-derived trait score methods and applications.,Genome Biol,"Microarray technology has been used to measure genome-wide DNA methylation in thousands of individuals. These studies typically test the associations between individual DNA methylation sites (""probes"") and complex traits or diseases. The results can be used to generate methylation profile scores (MPS) to predict outcomes in independent data sets. Although there are many parallels between MPS and polygenic (risk) scores (PGS), there are key differences. Here, we review motivations, methods, and applications of DNA methylation-based trait prediction, with a focus on common diseases. We contrast MPS with PGS, highlighting where assumptions made in genetic modeling may not hold in epigenetic data.© 2023. The Author(s).",
-,Yes,20230223,ewas,36796456,Multi-Omic Approach Associates Blood Methylome with Bronchodilator Drug Response in Pediatric Asthma.,J Allergy Clin Immunol,"Albuterol is the drug most widely used as asthma treatment among African Americans despite having a lower bronchodilator drug response (BDR) than other populations. Although BDR is affected by gene and environmental factors, the influence of DNA methylation (DNAm) is unknown.This study aims to identify epigenetic markers in whole blood associated with BDR, study their functional consequences by multi-omic integration, and assess their clinical applicability in admixed populations with a high asthma burden.We studied 414 children and young adults asthma patients (8-21 years old) in a discovery and replication design. We performed an epigenome-wide association study on 221 African Americans and replicated the results on 193 Latinos. Functional consequences were assessed by integrating epigenomics with genomics, transcriptomics, and environmental exposure data. Furthermore, a machine learning approach was used to develop a panel of epigenetic markers to classify treatment response.We identified five differentially methylated regions and two CpGs genome-wide significantly associated with BDR in African Americans located in FGL2 (cg08241295, p=6.8x10-9) and DNASE2 (cg15341340, p=7.8x10-8), which were regulated by genetic variation and/or associated with gene expression of nearby genes (false discovery rate<0.05). The CpG cg15341340 was replicated in Latinos (p=3.5x10-3). Moreover, a panel of 70 CpGs showed good classification for albuterol responders and nonresponders in African American and Latino children (AUCtraining:0.99, AUCvalidation:0.70-0.71). DNAm model showed similar discrimination as clinical predictors (p>0.05).We report novel associations of epigenetic markers with BDR in pediatric asthma and demonstrate for the first time the applicability of pharmacoepigenetics in precision medicine of respiratory diseases.Copyright © 2023. Published by Elsevier Inc.",
-,Yes,20230223,ewas,36791658,Epigenome-wide association study of plasma lipids in West Africans: the RODAM study.,EBioMedicine,"DNA-methylation has been associated with plasma lipid concentration in populations of diverse ethnic backgrounds, but epigenome-wide association studies (EWAS) in West-Africans are lacking. The aim of this study was to identify DNA-methylation loci associated with plasma lipids in Ghanaians.We conducted an EWAS using Illumina 450k DNA-methylation array profiles of extracted DNA from 663 Ghanaian participants. Differentially methylated positions (DMPs) were examined for association with plasma total cholesterol (TC), LDL-cholesterol, HDL-cholesterol, and triglycerides concentrations using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, and technical covariates. Findings were replicated in independent cohorts of different ethnicities.We identified one significantly associated DMP with triglycerides (cg19693031 annotated to TXNIP, regression coefficient beta -0.26, false discovery rate adjusted p-value 0.001), which replicated in-silico in South African Batswana, African American, and European populations. From the top five DMPs with the lowest nominal p-values, two additional DMPs for triglycerides (CPT1A, ABCG1), two DMPs for LDL-cholesterol (EPSTI1, cg13781819), and one for TC (TXNIP) replicated. With the exception of EPSTI1, these loci are involved in lipid transport/metabolism or are known GWAS-associated loci. The top 5 DMPs per lipid trait explained 9.5% in the variance of TC, 8.3% in LDL-cholesterol, 6.1% in HDL-cholesterol, and 11.0% in triglycerides.The top DMPs identified in this study are in loci that play a role in lipid metabolism across populations, including West-Africans. Future studies including larger sample size, longitudinal study design and translational research is needed to increase our understanding on the epigenetic regulation of lipid metabolism among West-African populations.European Commission under the Framework Programme (grant number: 278901).Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.",
-,Yes,20230223,ewas,36581877,Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders.,BMC Med,"Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programming of embryo and consequently cause the complex phenotype of developmental disorders. To explore the etiology of FASD, we collected unique biological samples of 80 severely alcohol-exposed and 100 control newborns at birth.We performed genome-wide DNA methylation (DNAm) and gene expression analyses of placentas by using microarrays (EPIC, Illumina) and mRNA sequencing, respectively. To test the manifestation of observed PAE-associated DNAm changes in embryonic tissues as well as potential biomarkers for PAE, we examined if the changes can be detected also in white blood cells or buccal epithelial cells of the same newborns by EpiTYPER. To explore the early effects of alcohol on extraembryonic placental tissue, we selected 27 newborns whose mothers had consumed alcohol up to gestational week 7 at maximum to the separate analyses. Furthermore, to explore the effects of early alcohol exposure on embryonic cells, human embryonic stem cells (hESCs) as well as hESCs during differentiation into endodermal, mesodermal, and ectodermal cells were exposed to alcohol in vitro.DPPA4, FOXP2, and TACR3 with significantly decreased DNAm were discovered-particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When hESCs were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNAm similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNAm changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways in the enrichment analysis, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development.Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.© 2022. The Author(s).",
-,Yes,20230223,ewas,36577721,Dissecting the epigenomic differences between smoking and nicotine dependence in a veteran cohort.,Addict Biol,"Smoking is a serious public health issue linked to more than 8 million deaths per year worldwide and may lead to nicotine dependence (ND). Although the epigenomic literature on smoking is well established, studies evaluating the role of epigenetics in ND are limited. In this study, we examined the epigenomic signatures of ND and how these differ from smoking exposure to identify biomarkers specific to ND. We investigated the peripheral epigenetic profile of smoking status (SS) and ND in a US male veteran cohort. DNA from saliva was collected from 1135 European American (EA) male US military veterans. DNAm was assessed using the Illumina Infinium Human MethylationEPIC BeadChip array. SS was evaluated as current smokers (n = 137; 12.1%) and non-current smokers (never and former; n = 998; 87.9%). NDFTNDwas assessed as a continuous variable using the Fagerström Test for ND (FTND; n = 1135; mean = 2.54 ± 2.29). Epigenome-wide association studies (EWAS) and co-methylation analyses were conducted for SS and NDFTND. A total of 450 and 22 genome-wide significant differentially methylated sites (DMS) were associated with SS and NDFTND, respectively (15 overlapped DMS). We identified 97 DMS (43 genes) in SS-EWAS previously reported in the literature, including AHRR and F2RL3 genes (p-value: 1.95 × 10-83to 4.55 × 10-33). NDFTNDnovel DMS mapped to NEUROG1, ANPEP, and SLC29A1. Co-methylation analysis identified 386 modules (11 SS-related and 19 NDFTND-related). SS-related modules showed enrichment for alcoholism, while NDFTND-related modules were enriched for nicotine addiction. This study confirms previous findings associated with SS and identifies novel and-potentially specific-epigenetic biomarkers of ND that may inform prognosis and novel treatment strategies.© 2022 Society for the Study of Addiction.",
-,Yes,20230223,ewas,36571600,"Pooled analysis of epigenome-wide association studies of food consumption in KORA, TwinsUK and LLS.",Eur J Nutr,"Examining epigenetic patterns is a crucial step in identifying molecular changes of disease pathophysiology, with DNA methylation as the most accessible epigenetic measure. Diet is suggested to affect metabolism and health via epigenetic modifications. Thus, our aim was to explore the association between food consumption and DNA methylation.Epigenome-wide association studies were conducted in three cohorts: KORA FF4, TwinsUK, and Leiden Longevity Study, and 37 dietary exposures were evaluated. Food group definition was harmonized across the three cohorts. DNA methylation was measured using Infinium MethylationEPIC BeadChip in KORA and Infinium HumanMethylation450 BeadChip in the Leiden study and the TwinsUK study. Overall, data from 2293 middle-aged men and women were included. A fixed-effects meta-analysis pooled study-specific estimates. The significance threshold was set at 0.05 for false-discovery rate-adjusted p values per food group.We identified significant associations between the methylation level of CpG sites and the consumption of onions and garlic (2), nuts and seeds (18), milk (1), cream (11), plant oils (4), butter (13), and alcoholic beverages (27). The signals targeted genes of metabolic health relevance, for example, GLI1, RPTOR, and DIO1, among others.This EWAS is unique with its focus on food groups that are part of a Western diet. Significant findings were mostly related to food groups with a high-fat content.© 2022. The Author(s).",
-,No,20230223,dnam age,36566336,Social mobility across the lifecourse and DNA methylation age acceleration in adults in the UK.,Sci Rep,"Disadvantaged socio-economic position (SEP) is associated with greater biological age, relative to chronological age, measured by DNA methylation (positive 'age acceleration', AA). Social mobility has been proposed to ameliorate health inequalities. This study aimed to understand the association of social mobility with positive AA. Diagonal reference modelling and ordinary least square regression techniques were applied to explore social mobility and four measures of age acceleration (first-generation: 'Horvath', 'Hannum' and second-generation: 'Phenoage', DunedinPoAm) in n = 3140 participants of the UK Household Longitudinal Study. Disadvantaged SEP in early life is associated with positive AA for three (Hannum, Phenoage and DunedinPoAm) of the four measures examined while the second generation biomarkers are associated with SEP in adulthood (p < 0.01). Social mobility was associated with AA measured with Hannum only such that compared to no mobility, upward mobility was associated with greater age independently of origin and destination SEP. Compared to continuously advantaged groups, downward mobility was associated with positive Phenoage (1.06y [- 0.03, 2.14]) and DunedinPoAm assessed AA (0.96y [0.24, 1.68]). For these two measures, upward mobility was associated with negative AA (Phenoage, - 0.65y [- 1.30, - 0.002]; DunedinPoAm, - 0.96y [- 1.47, - 0.46]) compared to continually disadvantaged groups. While we find some support for three models of lifecourse epidemiology with early life as a sensitive period, SEP across the lifecourse and social mobility for age acceleration measured with DNA methylation, our findings suggest that disadvantaged SEP across the lifecourse is most consistently associated with positive AA.© 2022. The Author(s).",
-,No,20230223,cancer,35609926,Extrachromosomal DNA in Cancer,Annu Rev Genomics Hum Genet,"In cancer, complex genome rearrangements and other structural alterations, including the amplification of oncogenes on circular extrachromosomal DNA (ecDNA) elements, drive the formation and progression of tumors. ecDNA is a particularly challenging structural alteration. By untethering oncogenes from chromosomal constraints, it elevates oncogene copy number, drives intratumoral genetic heterogeneity, promotes rapid tumor evolution, and results in treatment resistance. The profound changes in DNA shape and nuclear architecture generated by ecDNA alter the transcriptional landscape of tumors by catalyzing new types of regulatory interactions that do not occur on chromosomes. The current suite of tools for interrogating cancer genomes is well suited for deciphering sequence but has limited ability to resolve the complex changes in DNA structure and dynamics that ecDNA generates. Here, we review the challenges of resolving ecDNA form and function and discuss the emerging tool kit for deciphering ecDNA architecture and spatial organization, including what has been learned to date about how this dramatic change in shape alters tumor development, progression, and drug resistance.",
-,No,20230223,methods,31911605,Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization,Nat Commun,"Modern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors. Here, we propose a two-sample multivariable MR approach based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.",
-,No,20230223,pwas,36790168,"Proteome-wide antigenic profiling in Ugandan cohorts identifies associations between age, exposure intensity, and responses to repeat-containing antigens in Plasmodium falciparum",Elife,"Protection against Plasmodium falciparum, which is primarily antibody-mediated, requires recurrent exposure to develop. The study of both naturally acquired limited immunity and vaccine induced protection against malaria remains critical for ongoing eradication efforts. Towards this goal, we deployed a customized P. falciparum PhIP-seq T7 phage display library containing 238,068 tiled 62-amino acid peptides, covering all known coding regions, including antigenic variants, to systematically profile antibody targets in 198 Ugandan children and adults from high and moderate transmission settings. Repeat elements - short amino acid sequences repeated within a protein - were significantly enriched in antibody targets. While breadth of responses to repeat-containing peptides was twofold higher in children living in the high versus moderate exposure setting, no such differences were observed for peptides without repeats, suggesting that antibody responses to repeat-containing regions may be more exposure dependent and/or less durable in children than responses to regions without repeats. Additionally, short motifs associated with seroreactivity were extensively shared among hundreds of antigens, potentially representing cross-reactive epitopes. PfEMP1 shared motifs with the greatest number of other antigens, partly driven by the diversity of PfEMP1 sequences. These data suggest that the large number of repeat elements and potential cross-reactive epitopes found within antigenic regions of P. falciparum could contribute to the inefficient nature of malaria immunity.",
-,No,20230223,pqtl,35501419,Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies,Nat Genet,"Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative trait loci. Elastic Net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies to serum urate and gout implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study to investigate the genetic mechanisms of molecular phenotypes and their relationship with complex traits.",
-,Yes,20230302,ewas,36849614,Nucleated red blood cells explain most of the association between DNA methylation and gestational age.,Commun Biol,"Determining if specific cell type(s) are responsible for an association between DNA methylation (DNAm) and a given phenotype is important for understanding the biological mechanisms underlying the association. Our EWAS of gestational age (GA) in 953 newborns from the Norwegian MoBa study identified 13,660 CpGs significantly associated with GA (pBonferroni<0.05) after adjustment for cell type composition. When the CellDMC algorithm was applied to explore cell-type specific effects, 2,330 CpGs were significantly associated with GA, mostly in nucleated red blood cells [nRBCs; n = 2,030 (87%)]. Similar patterns were found in another dataset based on a different array and when applying an alternative algorithm to CellDMC called Tensor Composition Analysis (TCA). Our findings point to nRBCs as the main cell type driving the DNAm-GA association, implicating an epigenetic signature of erythropoiesis as a likely mechanism. They also explain the poor correlation observed between epigenetic age clocks for newborns and those for adults.© 2023. The Author(s).",
-,Yes,20230302,ewas,36849136,Age-related methylation changes in the human sperm epigenome.,Aging (Albany NY),"Advanced paternal age is associated with increased risks for reproductive and offspring medical problems. Accumulating evidence suggests age-related changes in the sperm epigenome as one underlying mechanism. Using reduced representation bisulfite sequencing on 73 sperm samples of males attending a fertility center, we identified 1,162 (74%) regions which were significantly (FDR-adjusted) hypomethylated and 403 regions (26%) being hypermethylated with age. There were no significant correlations with paternal BMI, semen quality, or ART outcome. The majority (1,152 of 1,565; 74%) of age-related differentially methylated regions (ageDMRs) were located within genic regions, including 1,002 genes with symbols. Hypomethylated ageDMRs were closer to transcription start sites than hypermethylated DMRs, half of which reside in gene-distal regions. In this and conceptually related genome-wide studies, so far 2,355 genes have been reported with significant sperm ageDMRs, however most (90%) of them in only one study. The 241 genes which have been replicated at least once showed significant functional enrichments in 41 biological processes associated with development and the nervous system and in 10 cellular components associated with synapses and neurons. This supports the hypothesis that paternal age effects on the sperm methylome affect offspring behaviour and neurodevelopment. It is interesting to note that sperm ageDMRs were not randomly distributed throughout the human genome; chromosome 19 showed a highly significant twofold enrichment with sperm ageDMRs. Although the high gene density and CpG content have been conserved, the orthologous marmoset chromosome 22 did not appear to exhibit an increased regulatory potential by age-related DNA methylation changes.",
-,No,20230302,cross-tissue,36843037,"Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and blood, saliva, and buccal epithelial tissues.",Transl Psychiatry,"Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13-73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva-brain correlation (r = 0.90) was higher than that for blood-brain (r = 0.87) and buccal-brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, cross-database correlations of the correlation coefficients revealed a relatively low (brain vs. blood: r = 0.27, saliva: r = 0.18, and buccal: r = 0.24). To the best of our knowledge, this is the fifth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.© 2023. The Author(s).",
-,Yes,20230302,ewas,36842935,Maternal and Paternal Dietary Quality and Dietary Inflammation Associations with Offspring DNA Methylation and Epigenetic Biomarkers of Aging in the Lifeways Cross-Generation Study.,J Nutr,"Early-life nutritional exposures may contribute to offspring epigenetic modifications. However, few studies have evaluated parental dietary quality effects on offspring DNA methylation (DNAm).We aim to fill this gap by elucidating the influence of maternal and paternal whole-diet quality and inflammatory potential on offspring DNAm in the Lifeways Cross-generation cohort.Families (n = 1124) were recruited around 16 weeks of gestation in the Republic of Ireland between 2001 and 2003. Maternal dietary intake during the first trimester and paternal diet during the 12 previous months were assessed with an FFQ. Parental dietary inflammatory potential and quality were determined using the energy-adjusted Dietary Inflammatory Index (E-DII), the Healthy Eating Index-2015 (HEI-2015), and the maternal DASH score. DNAm in the saliva of 246 children at age nine was measured using the Illumina Infinium HumanMethylationEPIC array. DNAm-derived biomarkers of aging, the Pediatric-Buccal-Epigenetic clock and DNAm estimator of telomere length, were calculated. Parental diet associations with the DNAm concentrations of 850K Cytosine-phosphate-guanine sites (CpG sites) and with DNAm-derived biomarkers of aging were examined using an epigenome-wide association study and linear regressions, respectively.Maternal HEI-2015 scores were inversely associated with DNAm at CpG site (cg21840035) located near the PLEKHM1 gene, whose functions involve regulation of bone development (β = -0.0036, per 1 point increase in the score; P = 5.6 × 10-8). Higher paternal HEI-2015 score was related to lower methylation at CpG site (cg22431767), located near cell signaling gene LUZP1 (β = -0.0022, per 1 point increase in the score, P = 4.1 × 10-8). There were no associations with parental E-DII and DASH scores, and no evidence of major effects on biomarkers of aging.Parental dietary quality in the prenatal period, evaluated by the HEI-2015, may influence offspring DNAm during childhood. Further research to improve our understanding of parental nutritional programming is warranted. J Nutr 2023;xx:xx-xx.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.",
-,Yes,20230302,ewas,36834337,DNA-Methylation Signatures of Tobacco Smoking in a High Cardiovascular Risk Population: Modulation by the Mediterranean Diet.,Int J Environ Res Public Health,"Biomarkers based on DNA methylation are relevant in the field of environmental health for precision health. Although tobacco smoking is one of the factors with a strong and consistent impact on DNA methylation, there are very few studies analyzing its methylation signature in southern European populations and none examining its modulation by the Mediterranean diet at the epigenome-wide level. We examined blood methylation smoking signatures on the EPIC 850 K array in this population (n = 414 high cardiovascular risk subjects). Epigenome-wide methylation studies (EWASs) were performed analyzing differential methylation CpG sites by smoking status (never, former, and current smokers) and the modulation by adherence to a Mediterranean diet score was explored. Gene-set enrichment analysis was performed for biological and functional interpretation. The predictive value of the top differentially methylated CpGs was analyzed using receiver operative curves. We characterized the DNA methylation signature of smoking in this Mediterranean population by identifying 46 differentially methylated CpGs at the EWAS level in the whole population. The strongest association was observed at the cg21566642 (p= 2.2 Ă— 10-32) in the 2q37.1 region. We also detected other CpGs that have been consistently reported in prior research and discovered some novel differentially methylated CpG sites in subgroup analyses. In addition, we found distinct methylation profiles based on the adherence to the Mediterranean diet. Particularly, we obtained a significant interaction between smoking and diet modulating the cg5575921 methylation in the AHRR gene. In conclusion, we have characterized biomarkers of the methylation signature of tobacco smoking in this population, and suggest that the Mediterranean diet can increase methylation of certain hypomethylated sites.",
-,Yes,20230302,ewas,36815102,Longitudinal Epigenome-Wide Analysis of Kidney Transplant Recipients Pretransplant and Posttransplant.,Kidney Int Rep,"Kidney transplantation remains the gold standard of treatment for end-stage renal disease (ESRD), with improved patient outcomes compared with dialysis. Epigenome-Wide Association Analysis (EWAS) of DNA methylation may identify markers that contribute to an individual's risk of adverse transplant outcomes, yet only a limited number of EWAS have been conducted in kidney transplant recipients. This EWAS aimed to interrogate the methylation profile of a kidney transplant recipient cohort with minimal posttransplant complications, exploring differences in samples pretransplant and posttransplant.We compared differentially methylated cytosine-phosphate-guanine sites (dmCpGs) in samples derived from peripheral blood mononuclear cells of the same kidney transplant recipients, collected both pretransplant and posttransplant (N = 154), using the Infinium MethylationEPIC microarray (Illumina, San Diego, CA). Recipients received kidneys from deceased donors and had a mean of 17 years of follow-up.Five top-ranked dmCpGs were significantly different at false discovery rate (FDR) adjustedP ≤ 9 × 10-8; cg23597162 withinJAZF1, cg25187293 withinBTNL8, cg17944885, located betweenZNF788PandZNF625-ZNF20,cg14655917 located betweenASB4andPDK4and cg09839120 located betweenGIMAP6andEIF2AP3.Five dmCpGs were identified at the generally accepted EWAS critical significance level of FDR adjustedP(PFDRadj) ≤ 9 × 10-8, including cg23597162 (withinJAZF1) and cg17944885, which have prior associations with chronic kidney disease (CKD). Comparing individuals with no evidence of posttransplant complications (N = 105) demonstrated that 693,555 CpGs (89.57%) did not display any significant difference in methylation (PFDRadj ≥ 0.05), thereby this study establishes an important reference for future epigenetic studies that seek to identify markers of posttransplant complications.© 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology.",
-,Yes,20230302,ewas,36811307,Genome-wide methylomic regulation of multiscale gene networks in Alzheimer's disease.,Alzheimers Dement,"Recent studies revealed the association of abnormal methylomic changes with Alzheimer's disease (AD) but there is a lack of systematic study of the impact of methylomic alterations over the molecular networks underlying AD.We profiled genome-wide methylomic variations in the parahippocampal gyrus from 201 post mortem control, mild cognitive impaired, and AD brains.We identified 270 distinct differentially methylated regions (DMRs) associated with AD. We quantified the impact of these DMRs on each gene and each protein as well as gene and protein co-expression networks. DNA methylation had a profound impact on both AD-associated gene/protein modules and their key regulators. We further integrated the matched multi-omics data to show the impact of DNA methylation on chromatin accessibility, which further modulates gene and protein expression.The quantified impact of DNA methylation on gene and protein networks underlying AD identified potential upstream epigenetic regulators of AD.A cohort of DNA methylation data in the parahippocampal gyrus was developed from 201 post mortem control, mild cognitive impaired, and Alzheimer's disease (AD) brains. Two hundred seventy distinct differentially methylated regions (DMRs) were found to be associated with AD compared to normal control. A metric was developed to quantify methylation impact on each gene and each protein. DNA methylation was found to have a profound impact on not only the AD-associated gene modules but also key regulators of the gene and protein networks. Key findings were validated in an independent multi-omics cohort in AD. The impact of DNA methylation on chromatin accessibility was also investigated by integrating the matched methylomic, epigenomic, transcriptomic, and proteomic data.© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
-,Yes,20230309,ewas,36869404,Epigenome-wide association study in Chinese monozygotic twins identifies DNA methylation loci associated with blood pressure.,Clin Epigenetics,"Hypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively.Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data.The median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10-4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10-4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms.We detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.© 2023. The Author(s).",
-,Yes,20230309,ewas,36855205,Distinct DNA methylation signatures associated with blood lipids as exposures or outcomes among survivors of childhood cancer: a report from the St. Jude lifetime cohort.,Clin Epigenetics,"DNA methylation (DNAm) plays an important role in lipid metabolism, however, no epigenome-wide association study (EWAS) of lipid levels has been conducted among childhood cancer survivors. Here, we performed EWAS analysis with longitudinally collected blood lipid data from survivors in the St. Jude lifetime cohort study.Among 2052 childhood cancer survivors of European ancestry (EA) and 370 survivors of African ancestry (AA), four types of blood lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), were measured during follow-up beyond 5-years from childhood cancer diagnosis. For the exposure EWAS (i.e., lipids measured before blood draw for DNAm), the DNAm level was an outcome variable and each of the blood lipid level was an exposure variable; vice versa for the outcome EWAS (i.e., lipids measured after blood draw for DNAm).Among EA survivors, we identified 43 lipid-associated CpGs in the HDL (n = 7), TC (n = 3), and TG (n = 33) exposure EWAS, and 106 lipid-associated CpGs in the HDL (n = 5), LDL (n = 3), TC (n = 4), and TG (n = 94) outcome EWAS. Among AA survivors, we identified 15 lipid-associated CpGs in TG exposure (n = 6), HDL (n = 1), LDL (n = 1), TG (n = 5) and TC (n = 2) outcome EWAS with epigenome-wide significance (P < 9 × 10-8). There were no overlapping lipids-associated CpGs between exposure and outcome EWAS among EA and AA survivors, suggesting that the DNAm changes of different CpGs could be the cause or consequence of blood lipid levels. In the meta-EWAS, 12 additional CpGs reached epigenome-wide significance. Notably, 32 out of 74 lipid-associated CpGs showed substantial heterogeneity (Phet < 0.1 or I2 > 70%) between EA and AA survivors, highlighting differences in DNAm markers of blood lipids between populations with diverse genetic ancestry. Ten lipid-associated CpGs were cis-expression quantitative trait methylation with their DNAm levels associated with the expression of corresponding genes, out of which seven were negatively associated.We identified distinct signatures of DNAm for blood lipids as exposures or outcomes and between EA and AA survivors, revealing additional genes involved in lipid metabolism and potential novel targets for controlling blood lipids in childhood cancer survivors.© 2023. The Author(s).",
-,Yes,20230309,dnamage,36855161,Refining epigenetic prediction of chronological and biological age.,Genome Med,"Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to develop accurate epigenetic predictors of cAge and bAge, whilst improving our understanding of their epigenomic architecture.First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to create a cAge predictor, we use methylation data from 24,674 participants from the Generation Scotland study, the Lothian Birth Cohorts (LBC) of 1921 and 1936, and 8 other cohorts with publicly available data. In addition, we train a predictor of time to all-cause mortality as a proxy for bAge using the Generation Scotland cohort (1214 observed deaths). For this purpose, we use epigenetic surrogates (EpiScores) for 109 plasma proteins and the 8 component parts of GrimAge, one of the current best epigenetic predictors of survival. We test this bAge predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Women's Health Initiative study).Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross-validation framework, we obtain cAge prediction with a median absolute error equal to 2.3 years. Our bAge predictor was found to slightly outperform GrimAge in terms of the strength of its association to survival (HRGrimAge = 1.47 [1.40, 1.54] with p = 1.08 × 10-52, and HRbAge = 1.52 [1.44, 1.59] with p = 2.20 × 10-60). Finally, we introduce MethylBrowsR, an online tool to visualise epigenome-wide CpG-age associations.The integration of multiple large datasets, EpiScores, non-linear DNAm effects, and new approaches to feature selection has facilitated improvements to the blood-based epigenetic prediction of biological and chronological age.© 2023. The Author(s).",
-,No,20230309,methods,36855165,CeDAR: incorporating cell type hierarchy improves cell type-specific differential analyses in bulk omics data.,Genome Biol,"Bulk high-throughput omics data contain signals from a mixture of cell types. Recent developments of deconvolution methods facilitate cell type-specific inferences from bulk data. Our real data exploration suggests that differential expression or methylation status is often correlated among cell types. Based on this observation, we develop a novel statistical method named CeDAR to incorporate the cell type hierarchy in cell type-specific differential analyses of bulk data. Extensive simulation and real data analyses demonstrate that this approach significantly improves the accuracy and power in detecting cell type-specific differential signals compared with existing methods, especially in low-abundance cell types.© 2023. The Author(s).",
-,Yes,20230309,ewas,36855151,DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort.,Clin Epigenetics,"Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 μm or less (PM10) was measured inside participants' homes during the second trimester of pregnancy.A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM10and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582.Our findings suggest that DNAm may mediate the association between prenatal PM10exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations.© 2023. The Author(s).",
-,No,20230309,proxy,36712110,Measuring the long arm of childhood in real-time: Epigenetic predictors of BMI and social determinants of health across childhood and adolescence.,bioRxiv,"Children who are socioeconomically disadvantaged are at increased risk for high body mass index (BMI) and multiple diseases in adulthood. The developmental origins of health and disease hypothesis proposes that early life conditions affect later-life health in a manner that is only partially modifiable by later-life experiences. Epigenetic mechanisms may regulate the influence of early life conditions on later life health. Recent epigenetic studies of adult blood samples have identified DNA-methylation sites associated with higher BMI and worse health (epigenetic-BMI). Here, we used longitudinal and twin study designs to examine whether epigenetic predictors of BMI developed in adults are valid biomarkers of child BMI and are sensitive to early life social determinants of health. Salivary epigenetic-BMI was calculated from two samples: (1) N=1,183 8-to-19-year-olds (609 female,meanage=13.4) from the Texas Twin Project (TTP), and (2) N=2,020 children (1,011 female) measured at 9 and 15 years from the Future of Families and Child Well-Being Study (FFCWS). We found that salivary epigenetic-BMI is robustly associated with children’s BMI (r=0.36 tor=0.50). Longitudinal analysis suggested that epigenetic-BMI is highly stable across adolescence, but remains both a leading and lagging indicator of BMI change. Twin analyses showed that epigenetic-BMI captures differences in BMI between monozygotic twins. Moreover, children from more disadvantaged socioeconomic status (SES) and marginalized race/ethnic groups had higher epigenetic-BMI, even when controlling for concurrent BMI, pubertal development, and tobacco exposure. SES at birth relative to concurrent SES best predicted epigenetic-BMI in childhood and adolescence. We show for the first time that epigenetic predictors of BMI calculated from pediatric saliva samples are valid biomarkers of childhood BMI that are sensitive to social inequalities. Our findings are in line with the hypothesis that early life conditions are especially important factors in epigenetic regulation of later life health. Research showing that health later in life is linked to early life conditions have important implications for the development of early-life interventions that could significantly extend healthy life span.",
-,No,20230309,prediction,36852276,Association between biological aging and lung cancer risk: Cohort study and Mendelian randomization analysis.,iScience,"Chronological age only represents the passage of time, whereas biological age reflects the physiology states and the susceptibility to morbidity and mortality. The association between biological age and lung cancer risk remains controversial. Hence, we conducted a prospective analysis in the UK Biobank study and two-sample Mendelian randomization analysis to investigate this association. Biological aging was evaluated by PhenoAgeAccel, derived from routine clinical biomarkers. Independent of chronological age, PhenoAgeAccel was positively associated with the risk of overall and histological subtypes of lung cancer. There was a joint effect of PhenoAgeAccel and genetics in lung cancer incidence. In Mendelian randomization analysis, the genetically predicted PhenoAgeAccel was associated with the increased risk of overall lung cancer, small cell, and squamous cell carcinoma. Our findings suggest PhenoAgeAccel is an independent risk factor for lung cancer, which could be incorporated with polygenic risk score to identify high-risk individuals for lung cancer.© 2023 The Authors.",
-,No,20230309,dnamage,36759656,A new blood based epigenetic age predictor for adolescents and young adults.,Sci Rep,"Children have special rights for protection compared to adults in our society. However, more than 1/4 of children globally have no documentation of their date of birth. Hence, there is a pressing need to develop biological methods for chronological age prediction, robust to differences in genetics, psychosocial events and physical living conditions. At present, DNA methylation is the most promising biological biomarker applied for age assessment. The human genome contains around 28 million DNA methylation sites, many of which change with age. Several epigenetic clocks accurately predict chronological age using methylation levels at age associated GpG-sites. However, variation in DNA methylation increases with age, and there is no epigenetic clock specifically designed for adolescents and young adults. Here we present a novel age Predictor for Adolescents and Young Adults (PAYA), using 267 CpG methylation sites to assess the chronological age of adolescents and young adults. We compared different preprocessing approaches and investigated the effect on prediction performance of the epigenetic clock. We evaluated performance using an independent validation data set consisting of 18-year-old individuals, where we obtained a median absolute deviation of just below 0.7 years. This tool may be helpful in age assessment of adolescents and young adults. However, there is a need to investigate the robustness of the age predictor across geographical and disease populations as well as environmental effects.© 2023. The Author(s).",
-,No,20230309,gwas,36755099,"Polygenic architecture of rare coding variation across 394,783 exomes.",Nature,"Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes1-3. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear4. Here we quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes5. Rare coding variants (allele frequency < 1 × 10-3) explain 1.3% (s.e. = 0.03%) of phenotypic variance on average-much less than common variants-and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency < 1 × 10-5). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in significant genes, while common-variant heritability is more polygenic, and burden heritability is also more strongly concentrated in constrained genes. Finally, we find that burden heritability for schizophrenia and bipolar disorder6,7is approximately 2%. Our results indicate that rare coding variants will implicate a tractable number of large-effect genes, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20230309,pqtl,36797296,Genome-wide genotype-serum proteome mapping provides insights into the cross-ancestry differences in cardiometabolic disease susceptibility.,Nat Commun,"Identification of protein quantitative trait loci (pQTL) helps understand the underlying mechanisms of diseases and discover promising targets for pharmacological intervention. For most important class of drug targets, genetic evidence needs to be generalizable to diverse populations. Given that the majority of the previous studies were conducted in European ancestry populations, little is known about the protein-associated genetic variants in East Asians. Based on data-independent acquisition mass spectrometry technique, we conduct genome-wide association analyses for 304 unique proteins in 2,958 Han Chinese participants. We identify 195 genetic variant-protein associations. Colocalization and Mendelian randomization analyses highlight 60 gene-protein-phenotype associations, 45 of which (75%) have not been prioritized in Europeans previously. Further cross-ancestry analyses uncover key proteins that contributed to the differences in the obesity-induced diabetes and coronary artery disease susceptibility. These findings provide novel druggable proteins as well as a unique resource for the trans-ancestry evaluation of protein-targeted drug discovery.© 2023. The Author(s).",
-,No,20230309,methods,36711575,Phenotypic subtyping via contrastive learning.,bioRxiv,"Defining and accounting for subphenotypic structure has the potential to increase statistical power and provide a deeper understanding of the heterogeneity in the molecular basis of complex disease. Existing phenotype subtyping methods primarily rely on clinically observed heterogeneity or metadata clustering. However, they generally tend to capture the dominant sources of variation in the data, which often originate from variation that is not descriptive of the mechanistic heterogeneity of the phenotype of interest; in fact, such dominant sources of variation, such as population structure or technical variation, are, in general, expected to be independent of subphenotypic structure. We instead aim to find a subspace with signal that is unique to a group of samples for which we believe that subphenotypic variation exists (e.g., cases of a disease). To that end, we introduce Phenotype Aware Components Analysis (PACA), a contrastive learning approach leveraging canonical correlation analysis to robustly capture weak sources of subphenotypic variation. In the context of disease, PACA learns a gradient of variation unique to cases in a given dataset, while leveraging control samples for accounting for variation and imbalances of biological and technical confounders between cases and controls. We evaluated PACA using an extensive simulation study, as well as on various subtyping tasks using genotypes, transcriptomics, and DNA methylation data. Our results provide multiple strong evidence that PACA allows us to robustly capture weak unknown variation of interest while being calibrated and well-powered, far superseding the performance of alternative methods. This renders PACA as a state-of-the-art tool for definingde novosubtypes that are more likely to reflect molecular heterogeneity, especially in challenging cases where the phenotypic heterogeneity may be masked by a myriad of strong unrelated effects in the data.PACA is available as an open source R package on GitHub: https://github.com/Adigorla/PACA.",
-,No,20230309,circadian rhythm,36745672,Day-night and seasonal variation of human gene expression across tissues.,PLoS Biol,"Circadian and circannual cycles trigger physiological changes whose reflection on human transcriptomes remains largely uncharted. We used the time and season of death of 932 individuals from GTEx to jointly investigate transcriptomic changes associated with those cycles across multiple tissues. Overall, most variation across tissues during day-night and among seasons was unique to each cycle. Although all tissues remodeled their transcriptomes, brain and gonadal tissues exhibited the highest seasonality, whereas those in the thoracic cavity showed stronger day-night regulation. Core clock genes displayed marked day-night differences across multiple tissues, which were largely conserved in baboon and mouse, but adapted to their nocturnal or diurnal habits. Seasonal variation of expression affected multiple pathways, and it was enriched among genes associated with the immune response, consistent with the seasonality of viral infections. Furthermore, they unveiled cytoarchitectural changes in brain regions. Altogether, our results provide the first combined atlas of how transcriptomes from human tissues adapt to major cycling environmental conditions. This atlas may have multiple applications; for example, drug targets with day-night or seasonal variation in gene expression may benefit from temporally adjusted doses.Copyright: © 2023 Wucher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
-,No,20230309,circadian rhythm,36791105,The circadian demethylation of a unique intronic deoxymethylCpG-rich island boosts the transcription of its cognate circadian clock output gene.,Proc Natl Acad Sci U S A,"We demonstrate that there is a tight functional relationship between two highly evolutionary conserved cell processes, i.e., the circadian clock (CC) and the circadian DNA demethylation-methylation of cognate deoxyCpG-rich islands. We have discovered that every circadian clock-controlled output gene (CCG), but not the core clock nor its immediate-output genes, contains a single cognate intronic deoxyCpG-rich island, the demethylation-methylation of which is controlled by the CC. During the transcriptional activation period, these intronic islands are demethylated and, upon dimerization of two YY1 protein binding sites located upstream to the transcriptional enhancer and downstream from the deoxyCpG-rich island, store activating components initially assembled on a cognate active enhancer (a RORE, a D-box or an E-box), in keeping with the generation of a transcriptionally active condensate that boosts the initiation of transcription of their cognate pre-mRNAs. We report how these single intronic deoxyCpG-rich islands are instrumental in such a circadian activation/repression transcriptional process.",
-,Yes,20230309,ewas,36840948,Sex-based differences in placental DNA methylation profiles related to gestational age: an NIH ECHO meta-analysis.,Epigenetics,"The placenta undergoes many changes throughout gestation to support the evolving needs of the foetus. There is also a growing appreciation that male and female foetuses develop differentlyin utero, with unique epigenetic changes in placental tissue. Here, we report meta-analysed sex-specific associations between gestational age and placental DNA methylation from four cohorts in the National Institutes of Health (NIH) Environmental influences on Child Health Outcomes (ECHO) Programme (355 females/419 males, gestational ages 23-42 weeks). We identified 407 cytosine-guanine dinucleotides (CpGs) in females and 794 in males where placental methylation levels were associated with gestational age. After cell-type adjustment, 55 CpGs in females and 826 in males were significant. These were enriched for biological processes critical to the immune system in females and transmembrane transport in males. Our findings are distinct between the sexes: in females, associations with gestational age are largely explained by differences in placental cellular composition, whereas in males, gestational age is directly associated with numerous alterations in methylation levels.",
-,No,20230309,epigenetics,36802379,Escape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable.,PLoS Genet,"X-chromosome inactivation (XCI) silences one X in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. To characterize incidence and variability of escape across individuals and tissues, we conducted a transcriptomic study of escape in adipose, skin, lymphoblastoid cell lines and immune cells in 248 healthy individuals exhibiting skewed XCI. We quantify XCI escape from a linear model of genes' allelic fold-change and XIST-based degree of XCI skewing. We identify 62 genes, including 19 lncRNAs, with previously unknown patterns of escape. We find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 23% demonstrating tissue-restricted escape, including cell type-specific escape across immune cells of the same individual. We also detect substantial inter-individual variability in escape. Monozygotic twins share more similar escape than dizygotic twins, indicating that genetic factors may underlie inter-individual differences in escape. However, discordant escape also occurs within monozygotic co-twins, suggesting environmental factors also influence escape. Altogether, these data indicate that XCI escape is an under-appreciated source of transcriptional differences, and an intricate phenotype impacting variable trait expressivity in females.Copyright: © 2023 Zito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
-,No,20230309,gwas,36798175,Identification and analysis of individuals who deviate from their genetically-predicted phenotype.,bioRxiv,"Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol. We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL cholesterol and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions.Human genetics is becoming increasingly useful to help predict human traits across a population owing to findings from large-scale genetic association studies and advances in the power of genetic predictors. This provides an opportunity to potentially identify individuals that deviate from genetic predictions for a common phenotype under investigation. For example, an individual may be genetically predicted to be tall, but be shorter than expected. It is potentially important to identify individuals who deviate from genetic predictions as this can facilitate further follow-up to assess likely causes. Using 158,951 unrelated individuals from the UK Biobank, with height and LDL cholesterol, as exemplar traits, we demonstrate that approximately 0.15% & 0.12% of individuals deviate from their genetically predicted phenotypes respectively. We observed these individuals to be enriched for a range of rare clinical diagnoses, as well as rare genetic factors that may be causal. Our analyses also demonstrate several methods for detecting individuals who deviate from genetic predictions that can be applied to a range of continuous human phenotypes.",
-,Yes,20230309,ewas,36694712,"Duration of exposure to epidural anesthesia at delivery, DNA methylation in umbilical cord blood and their association with offspring asthma in Non-Hispanic Black women.",Environ Epigenet,"Epidural anesthesia is an effective pain relief modality, widely used for labor analgesia. Childhood asthma is one of the commonest chronic medical illnesses in the USA which places a significant burden on the health-care system. We recently demonstrated a negative association between the duration of epidural anesthesia and the development of childhood asthma; however, the underlying molecular mechanisms still remain unclear. In this study of 127 mother-child pairs comprised of 75 Non-Hispanic Black (NHB) and 52 Non-Hispanic White (NHW) from the Newborn Epigenetic Study, we tested the hypothesis that umbilical cord blood DNA methylation mediates the association between the duration of exposure to epidural anesthesia at delivery and the development of childhood asthma and whether this differed by race/ethnicity. In the mother-child pairs of NHB ancestry, the duration of exposure to epidural anesthesia was associated with a marginally lower risk of asthma (odds ratio = 0.88, 95% confidence interval = 0.76-1.01) for each 1-h increase in exposure to epidural anesthesia. Of the 20 CpGs in the NHB population showing the strongest mediation effect, 50% demonstrated an average mediation proportion of 52%, with directional consistency of direct and indirect effects. These top 20 CpGs mapped to 21 genes enriched for pathways engaged in antigen processing, antigen presentation, protein ubiquitination and regulatory networks related to the Major Histocompatibility Complex (MHC) class I complex and Nuclear Factor Kappa-B (NFkB) complex. Our findings suggest that DNA methylation in immune-related pathways contributes to the effects of the duration of exposure to epidural anesthesia on childhood asthma risk in NHB offspring.© The Author(s) 2023. Published by Oxford University Press.",
-,No,20230309,gwas,36755145,How rare mutations contribute to complex traits.,Nature,NA,
-,No,20230309,dnamage,36824863,Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.,bioRxiv,"DNA hydroxymethylation (5hmC) is the most abundant oxidative derivative of DNA methylation (5mC) and is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in many age-related diseases, the functional role of the modification in aging remains largely unknown. Here, we report that 5hmC is stably enriched in multiple aged organs. Using the liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and thereby restricts the magnitude of gene expression changes during aging. Mechanistically, we found that 5hmC decreases binding affinity of splicing factors compared to unmodified cytosine and 5mC, and is correlated with age-related alternative splicing events, suggesting RNA splicing as a potential mediator of 5hmC’s transcriptionally restrictive function. Furthermore, we show that various age-related contexts, such as prolonged quiescence and senescence, are partially responsible for driving the accumulation of 5hmC with age. We provide evidence that this age-related function is conserved in mouse and human tissues, and further show that the modification is altered by regimens known to modulate lifespan. Our findings reveal that 5hmC is a regulator of tissue-specific function and may play a role in regulating longevity.",
-,No,20230309,dataset,36711769,"curatedPCaData: Integration of clinical, genomic, and signature features in a curated and harmonized prostate cancer data resource.",bioRxiv,"Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets. The full potential of such data is yet to be realized as independent datasets exist in different repositories, have been processed using different pipelines, and derived and clinical features are often not provided or unstandardized. Here, we present thecuratedPCaDataR package, a harmonized data resource representing >2900 primary tumor, >200 normal tissue, and >500 metastatic PCa samples across 19 datasets processed using standardized pipelines with updated gene annotations. We show that meta-analysis across harmonized studies has great potential for robust and clinically meaningful insights.curatedPCaDatais an open and accessible community resource with code made available for reproducibility.",
-,No,20230309,methods,36699372,reComBat: batch-effect removal in large-scale multi-source gene-expression data integration.,Bioinform Adv,"With the steadily increasing abundance of omics data produced all over the world under vastly different experimental conditions residing in public databases, a crucial step in many data-driven bioinformatics applications is that of data integration. The challenge of batch-effect removal for entire databases lies in the large number of batches and biological variation, which can result in design matrix singularity. This problem can currently not be solved satisfactorily by any common batch-correction algorithm.We presentreComBat, a regularized version of the empirical Bayes method to overcome this limitation and benchmark it against popular approaches for the harmonization of public gene-expression data (both microarray and bulkRNAsq) of the human opportunistic pathogenPseudomonas aeruginosa. Batch-effects are successfully mitigated while biologically meaningful gene-expression variation is retained.reComBatfills the gap in batch-correction approaches applicable to large-scale, public omics databases and opens up new avenues for data-driven analysis of complex biological processes beyond the scope of a single study.The code is available at https://github.com/BorgwardtLab/reComBat, all data and evaluation code can be found at https://github.com/BorgwardtLab/batchCorrectionPublicData.Supplementary data are available atBioinformatics Advancesonline.© The Author(s) 2022. Published by Oxford University Press.",
-,No,20230309,review,36658435,The Singapore National Precision Medicine Strategy.,Nat Genet,"Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic-phenotypic databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world's population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption.© 2023. Springer Nature America, Inc.",
-,No,20230309,pqtl,36823471,Proteogenomic links to human metabolic diseases,Nat Metab,"Studying the plasma proteome as the intermediate layer between the genome and the phenome has the potential to identify new disease processes. Here, we conducted a cis-focused proteogenomic analysis of 2,923 plasma proteins measured in 1,180 individuals using antibody-based assays. We (1) identify 256 unreported protein quantitative trait loci (pQTL); (2) demonstrate shared genetic regulation of 224 cis-pQTLs with 575 specific health outcomes, revealing examples for notable metabolic diseases (such as gastrin-releasing peptide as a potential therapeutic target for type 2 diabetes); (3) improve causal gene assignment at 40% (n = 192) of overlapping risk loci; and (4) observe convergence of phenotypic consequences of cis-pQTLs and rare loss-of-function gene burden for 12 proteins, such as TIMD4 for lipoprotein metabolism. Our findings demonstrate the value of integrating complementary proteomic technologies with genomics even at moderate scale to identify new mediators of metabolic diseases with the potential for therapeutic interventions.",
-,No,20230309,cohort,36745618,"Cohort profile: The Clinical and Multi-omic (CAMO) cohort, part of the Norwegian Women and Cancer (NOWAC) study.",PLoS One,"Breast cancer is the most common cancer worldwide and the leading cause of cancer related deaths among women. The high incidence and mortality of breast cancer calls for improved prevention, diagnostics, and treatment, including identification of new prognostic and predictive biomarkers for use in precision medicine.With the aim of compiling a cohort amenable to integrative study designs, we collected detailed epidemiological and clinical data, blood samples, and tumor tissue from a subset of participants from the prospective, population-based Norwegian Women and Cancer (NOWAC) study. These study participants were diagnosed with invasive breast cancer in North Norway before 2013 according to the Cancer Registry of Norway and constitute the Clinical and Multi-omic (CAMO) cohort. Prospectively collected questionnaire data on lifestyle and reproductive factors and blood samples were extracted from the NOWAC study, clinical and histopathological data were manually curated from medical records, and archived tumor tissue collected.The lifestyle and reproductive characteristics of the study participants in the CAMO cohort (n = 388) were largely similar to those of the breast cancer patients in NOWAC (n = 10 356). The majority of the cancers in the CAMO cohort were tumor grade 2 and of the luminal A subtype. Approx. 80% were estrogen receptor positive, 13% were HER2 positive, and 12% were triple negative breast cancers. Lymph node metastases were present in 31% at diagnosis. The epidemiological dataset in the CAMO cohort is complemented by mRNA, miRNA, and metabolomics analyses in plasma, as well as miRNA profiling in tumor tissue. Additionally, histological analyses at the level of proteins and miRNAs in tumor tissue are currently ongoing.The CAMO cohort provides data suitable for epidemiological, clinical, molecular, and multi-omics investigations, thereby enabling a systems epidemiology approach to translational breast cancer research.Copyright: © 2023 Delgado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
-,No,20230309,aging,36658433,Genome-wide RNA polymerase stalling shapes the transcriptome during aging.,Nat Genet,"Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.© 2023. The Author(s).",
-,No,20230309,transgenerational epigenetic inheritance,36854803,Engineering transgenerational epigenetic inheritance in mammals.,Nat Rev Genet,NA,
-,No,20230323,dnamage,36865294,Higher testosterone and testosterone/estradiol ratio in men are associated with better epigenetic estimators of mortality risk.,medRxiv,"Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations.We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort (FHS), the Baltimore Longitudinal Study of Aging (BLSA), and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex hormone concentrations were standardized with mean 0 and standard deviation of 1, for each study and sex separately. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sensitivity analysis was performed excluding the previously used training-set for the development of Pheno and Grim age.Sex Hormone Binding Globulin (SHBG) is associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, 1 SD increase in total testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11).SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1.",
-,Yes,20230323,ewas,36937723,"Longitudinal multi-omics alterations response to 8-week risperidone monotherapy: Evidence linking cortical thickness, transcriptomics and epigenetics.",Front Psychiatry,"Antipsychotic treatment-related alterations of cortical thickness (CT) and clinical symptoms have been previously corroborated, but less is known about whether the changes are driven by gene expression and epigenetic modifications.Utilizing a prospective design, we recruited 42 treatment-naive first-episode schizophrenia patients (FESP) and 38 healthy controls. Patients were scanned by TI weighted imaging before and after 8-week risperidone monotherapy. CT estimation was automatically performed with the FreeSurfer software package. Participants' peripheral blood genomic DNA methylation (DNAm) status, quantified by using Infinium®Human Methylation 450K BeadChip, was examined in parallel with T1 scanning. In total, CT measures from 118 subjects and genomic DNAm status from 114 subjects were finally collected. Partial least squares (PLS) regression was used to detect the spatial associations between longitudinal CT variations after treatment and cortical transcriptomic data acquired from the Allen Human Brain Atlas. Canonical correlation analysis (CCA) was then performed to identify multivariate associations between DNAm of PLS1 genes and patients' clinical improvement.We detected the significant PLS1 component (2,098 genes) related to longitudinal alterations of CT, and the PLS1 genes were significantly enriched in neurobiological processes, and dopaminergic- and cancer-related pathways. Combining Laplacian score and CCA analysis, we further linked DNAm of 33 representative genes from the 2,098 PLS1 genes with patients' reduction rate of clinical symptoms.This study firstly revealed that changes of CT and clinical behaviors after treatment may be transcriptionally and epigenetically underlied. We define a ""three-step"" roadmap which represents a vital step toward the exploration of treatment- and treatment response-related biomarkers on the basis of multiple omics rather than a single omics type as a strategy for advancing precise care.Copyright © 2023 Zong, Wang, Nie, Ma, Kang, Zhang, Weng, Tan, Zheng and Hu.",
-,No,20230323,short tandem repeats,36940239,Native functions of short tandem repeats.,Elife,"Over a third of the human genome is comprised of repetitive sequences, including more than a million short tandem repeats (STRs). While studies of the pathologic consequences of repeat expansions that cause syndromic human diseases are extensive, the potential native functions of STRs are often ignored. Here, we summarize a growing body of research into the normal biological functions for repetitive elements across the genome, with a particular focus on the roles of STRs in regulating gene expression. We propose reconceptualizing the pathogenic consequences of repeat expansions as aberrancies in normal gene regulation. From this altered viewpoint, we predict that future work will reveal broader roles for STRs in neuronal function and as risk alleles for more common human neurological diseases.",
-,No,20230323,methods,36909524,Pretraining strategies for effective promoter-driven gene expression prediction.,bioRxiv,"Advances in gene delivery technologies are enabling rapid progress in molecular medicine, but require precise expression of genetic cargo in desired cell types, which is predominantly achieved via a regulatory DNA sequence called a promoter; however, only a handful of cell type-specific promoters are known. Efficiently designing compact promoter sequences with a high density of regulatory information by leveraging machine learning models would therefore be broadly impactful for fundamental research and direct therapeutic applications. However, models of expression from such compact promoter sequences are lacking, despite the recent success of deep learning in modelling expression from endogenous regulatory sequences. Despite the lack of large datasets measuring promoter-driven expression in many cell types, data from a few well-studied cell types or from endogenous gene expression may provide relevant information for transfer learning, which has not yet been explored in this setting. Here, we evaluate a variety of pretraining tasks and transfer strategies for modelling cell type-specific expression from compact promoters and demonstrate the effectiveness of pretraining on existing promoter-driven expression datasets from other cell types. Our approach is broadly applicable for modelling promoter-driven expression in any data-limited cell type of interest, and will enable the use of model-based optimization techniques for promoter design for gene delivery applications. Our code and data are available at https://github.com/anikethjr/promoter_models .",
-,No,20230323,epigenetics,36762477,DNA methylation entropy is associated with DNA sequence features and developmental epigenetic divergence.,Nucleic Acids Res,"Epigenetic information defines tissue identity and is largely inherited in development through DNA methylation. While studied mostly for mean differences, methylation also encodes stochastic change, defined as entropy in information theory. Analyzing allele-specific methylation in 49 human tissue sample datasets, we find that methylation entropy is associated with specific DNA binding motifs, regulatory DNA, and CpG density. Then applying information theory to 42 mouse embryo methylation datasets, we find that the contribution of methylation entropy to time- and tissue-specific patterns of development is comparable to the contribution of methylation mean, and methylation entropy is associated with sequence and chromatin features conserved with human. Moreover, methylation entropy is directly related to gene expression variability in development, suggesting a role for epigenetic entropy in developmental plasticity.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.",
-,No,20230323,kidney,36932062,Kidney fibrosis: from mechanisms to therapeutic medicines.,Signal Transduct Target Ther,"Chronic kidney disease (CKD) is estimated to affect 10-14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading to scarring, is a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. Kidney fibrosis is identified by tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, and vascular rarefaction. Fibrotic niche, where organ fibrosis initiates, is a complex interplay between injured parenchyma (like tubular cells) and multiple non-parenchymal cell lineages (immune and mesenchymal cells) located spatially within scarring areas. Although the mechanisms of kidney fibrosis are complicated due to the kinds of cells involved, with the help of single-cell technology, many key questions have been explored, such as what kind of renal tubules are profibrotic, where myofibroblasts originate, which immune cells are involved, and how cells communicate with each other. In addition, genetics and epigenetics are deeper mechanisms that regulate kidney fibrosis. And the reversible nature of epigenetic changes including DNA methylation, RNA interference, and chromatin remodeling, gives an opportunity to stop or reverse kidney fibrosis by therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) have been developed to delay CKD progression in recent years. Furthermore, a better understanding of renal fibrosis is also favored to discover biomarkers of fibrotic injury. In the review, we update recent advances in the mechanism of renal fibrosis and summarize novel biomarkers and antifibrotic treatment for CKD.© 2023. The Author(s).",
-,Yes,20230323,ewas,36929108,"Gestational weight gain in pregnant women with obesity is associated with cord blood DNA methylation, which partially mediates offspring anthropometrics.",Clin Transl Med,NA,
-,No,20230323,multiomics,36941332,Multiomic signatures of body mass index identify heterogeneous health phenotypes and responses to a lifestyle intervention.,Nat Med,"Multiomic profiling can reveal population heterogeneity for both health and disease states. Obesity drives a myriad of metabolic perturbations and is a risk factor for multiple chronic diseases. Here we report an atlas of cross-sectional and longitudinal changes in 1,111 blood analytes associated with variation in body mass index (BMI), as well as multiomic associations with host polygenic risk scores and gut microbiome composition, from a cohort of 1,277 individuals enrolled in a wellness program (Arivale). Machine learning model predictions of BMI from blood multiomics captured heterogeneous phenotypic states of host metabolism and gut microbiome composition better than BMI, which was also validated in an external cohort (TwinsUK). Moreover, longitudinal analyses identified variable BMI trajectories for different omics measures in response to a healthy lifestyle intervention; metabolomics-inferred BMI decreased to a greater extent than actual BMI, whereas proteomics-inferred BMI exhibited greater resistance to change. Our analyses further identified blood analyte-analyte associations that were modified by metabolomics-inferred BMI and partially reversed in individuals with metabolic obesity during the intervention. Taken together, our findings provide a blood atlas of the molecular perturbations associated with changes in obesity status, serving as a resource to quantify metabolic health for predictive and preventive medicine.© 2023. The Author(s).",
-,No,20230323,epigenetics,36922587,Spatial epigenome-transcriptome co-profiling of mammalian tissues.,Nature,"Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context1-5. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research.© 2023. The Author(s).",
-,No,20230323,methods,36908043,Pruning and thresholding approach for methylation risk scores in multi-ancestry populations.,Epigenetics,"Recent efforts have focused on developing methylation risk scores (MRS), a weighted sum of the individual's DNA methylation (DNAm) values of pre-selected CpG sites. Most of the current MRS approaches that utilize Epigenome-wide association studies (EWAS) summary statistics only include genome-wide significant CpG sites and do not consider co-methylation. New methods that relax the p-value threshold to include more CpG sites and account for the inter-correlation of DNAm might improve the predictive performance of MRS. We paired informed co-methylation pruning with P-value thresholding to generate pruning and thresholding (P+T) MRS and evaluated its performance among multi-ancestry populations. Through simulation studies and real data analyses, we demonstrated that pruning provides an improvement over simple thresholding methods for prediction of phenotypes. We demonstrated that European-derived summary statistics can be used to develop P+T MRS among other populations such as African populations. However, the prediction accuracy of P+T MRS may differ across multi-ancestry population due to environmental/cultural/social differences.",
-,No,20230323,sinets,36907174,Chromosome 18 loss of heterozygosity in small intestinal neuroendocrine tumours: Multi-omic and tumour composition analyses.,Neuroendocrinology,"Small intestinal neuroendocrine tumours (siNETs) are rare neoplasms which present with low mutational burden and can be subtyped based on copy number variation (CNV). Currently, siNETs can be molecularly classified as having chromosome 18 loss of heterozygosity (18LOH), multiple CNVs (MultiCNV), or no CNVs. 18LOH tumours have better progression free survival when compared to MultiCNV and NoCNV tumours, however the mechanism underlying this is unknown, and clinical practice does not currently consider CNV status.Here, we use genome-wide tumour DNA methylation (n=54) and gene expression (n=20 matched to DNA methylation) to better understand how gene regulation varies by 18LOH status. We then use multiple cell deconvolution methods to analyse how cell composition varies between 18LOH status, and determine potential associations with progression free survival.We identified 27,464 differentially methylated CpG sites and 12 differentially expressed genes between 18LOH and non-18LOH (MultiCNV + NoCNV) siNETs. Although few differentially expressed genes were identified, these genes were highly enriched with the differentially methylated CpG sites compared to the rest of the genome. We identified differences in tumour micro-environment between 18LOH and non-18LOH tumours, including CD14+ infiltration in a subset of non-18LOH tumours which had the poorest clinical outcomes.We identify a small number of genes which appear to be linked to the 18LOH status of siNETs, and find evidence of potential epigenetic dysregulation of these genes. We also find a potential prognostic marker for worse progression free outcomes in the form of higher CD14 infiltration in non-18LOH siNETs.S. Karger AG, Basel.",
-,Yes,20230323,ewas,36899042,Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.,Mol Psychiatry,"Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20230323,multiomics,36891970,Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations.,Elife,"Despite the success of genome-wide association studies (GWASs) in identifying genetic variants associated with complex traits, understanding the mechanisms behind these statistical associations remains challenging. Several methods that integrate methylation, gene expression, and protein quantitative trait loci (QTLs) with GWAS data to determine their causal role in the path from genotype to phenotype have been proposed. Here, we developed and applied a multi-omics Mendelian randomization (MR) framework to study how metabolites mediate the effect of gene expression on complex traits. We identified 216 transcript-metabolite-trait causal triplets involving 26 medically relevant phenotypes. Among these associations, 58% were missed by classical transcriptome-wide MR, which only uses gene expression and GWAS data. This allowed the identification of biologically relevant pathways, such as betweenANKHand calcium levels mediated by citrate levels andSLC6A12and serum creatinine through modulation of the levels of the renal osmolyte betaine. We show that the signals missed by transcriptome-wide MR are found, thanks to the increase in power conferred by integrating multiple omics layer. Simulation analyses show that with larger molecular QTL studies and in case of mediated effects, our multi-omics MR framework outperforms classical MR approaches designed to detect causal relationships between single molecular traits and complex phenotypes.© 2023, Auwerx et al.",
-,No,20230323,aging,36911092,Characteristics of circulating small noncoding RNAs in plasma and serum during human aging.,Aging Med (Milton),"Aging is a complicated process that triggers age-related disease susceptibility through intercellular communication in the microenvironment. While the classic secretome of senescence-associated secretory phenotype (SASP) including soluble factors, growth factors, and extracellular matrix remodeling enzymes are known to impact tissue homeostasis during the aging process, the effects of novel SASP components, extracellular small noncoding RNAs (sncRNAs), on human aging are not well established.Here, by utilizing 446 small RNA-seq samples from plasma and serum of healthy donors found in the Extracellular RNA (exRNA) Atlas data repository, we correlated linear and nonlinear features between circulating sncRNAs expression and age by the maximal information coefficient (MIC) relationship determination. Age predictors were generated by ensemble machine learning methods (Adaptive Boosting, Gradient Boosting, and Random Forest) and core age-related sncRNAs were determined through weighted coefficients in machine learning models. Functional investigation was performed via target prediction of age-related miRNAs.We observed the number of highly expressed transfer RNAs (tRNAs) and microRNAs (miRNAs) showed positive and negative associations with age respectively. Two-variable (sncRNA expression and individual age) relationships were detected by MIC and sncRNAs-based age predictors were established, resulting in a forecast performance where allR2values were greater than 0.96 and root-mean-square errors (RMSE) were less than 3.7 years in three ensemble machine learning methods. Furthermore, important age-related sncRNAs were identified based on modeling and the biological pathways of age-related miRNAs were characterized by their predicted targets, including multiple pathways in intercellular communication, cancer and immune regulation.In summary, this study provides valuable insights into circulating sncRNAs expression dynamics during human aging and may lead to advanced understanding of age-related sncRNAs functions with further elucidation.© 2023 The Authors. Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.",
-,No,20230323,dnamage,36802439,Epigenetic-based age acceleration in a representative sample of older Americans: Associations with aging-related morbidity and mortality.,Proc Natl Acad Sci U S A,"Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from a representative, panel study of US older adults to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality. We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, SES, and health behaviors. In our sample, age acceleration calculated using ""second and third generation clocks,"" PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 y after DNAm measurement, and 4-y mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.",
-,No,20230323,pqtls,36824751,Genetic mechanisms of 184 neuro-related proteins in human plasma.,medRxiv,"Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.",
-,No,20230323,mitochondria,36778249,Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate in aging fibroblasts.,bioRxiv,"The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in some non-human species. We investigated their association with human aging in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples. Human brains exhibited a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to the cerebellum, suggesting that they arose spontaneously during development or with aging. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts in a repeated-measures WGS study in a human fibroblast model that recapitulates several molecular features of human aging. These longitudinal experiments revealed a gradual accumulation of one Numt every ~9 days, independent of large-scale genomic instability. Targeted genetic and pharmacological perturbations of mitochondrial oxidative phosphorylation did not affect numtogenesis, whereas chronic glucocorticoid stress increased the Numts transfer rate by 39.8%. Combined, our data document spontaneous numtogenesis in aging human cells and demonstrate an association between brain cortical somatic Numts and human lifespan.",
-,No,20230323,methods,36906598,A systematic evaluation of normalization methods and probe replicability using infinium EPIC methylation data.,Clin Epigenetics,"The Infinium EPIC array measures the methylation status of > 850,000 CpG sites. The EPIC BeadChip uses a two-array design: Infinium Type I and Type II probes. These probe types exhibit different technical characteristics which may confound analyses. Numerous normalization and pre-processing methods have been developed to reduce probe type bias as well as other issues such as background and dye bias.This study evaluates the performance of various normalization methods using 16 replicated samples and three metrics: absolute beta-value difference, overlap of non-replicated CpGs between replicate pairs, and effect on beta-value distributions. Additionally, we carried out Pearson's correlation and intraclass correlation coefficient (ICC) analyses using both raw and SeSAMe 2 normalized data.The method we define as SeSAMe 2, which consists of the application of the regular SeSAMe pipeline with an additional round of QC, pOOBAH masking, was found to be the best performing normalization method, while quantile-based methods were found to be the worst performing methods. Whole-array Pearson's correlations were found to be high. However, in agreement with previous studies, a substantial proportion of the probes on the EPIC array showed poor reproducibility (ICC < 0.50). The majority of poor performing probes have beta values close to either 0 or 1, and relatively low standard deviations. These results suggest that probe reliability is largely the result of limited biological variation rather than technical measurement variation. Importantly, normalizing the data with SeSAMe 2 dramatically improved ICC estimates, with the proportion of probes with ICC values > 0.50 increasing from 45.18% (raw data) to 61.35% (SeSAMe 2).© 2023. The Author(s).",
-,No,20230323,circadian rhythm,36791098,The HP1α protein is mandatory to repress the circadian clock and its output genes during the 12 h period of transcriptional repression.,Proc Natl Acad Sci U S A,"The transcriptional repressions driven by the circadian core clock repressors RevErbα, E4BP4, and CRY1/PER1 involve feedback loops which are mandatory for generating the circadian rhythms. These repressors are known to bind to cognate DNA binding sites, but how their circadian bindings trigger the cascade of events leading to these repressions remain to be elucidated. Through molecular and genetic analyses, we now demonstrate that the chromatin protein HP1α plays a key role in these transcriptional repressions of both the circadian clock (CC) genes and their cognate output genes (CCGs). We show that these CC repressors recruit the HP1α protein downstream from a repressive cascade, and that this recruitment is mandatory for the maintenance of both the CC integrity and the expression of the circadian genes. We further show that the presence of HP1α is critical for both the repressor-induced chromatin compaction and the generation of ""transcriptionally repressed biomolecular hydrophobic condensates"" and demonstrates that HP1α is mandatory within the CC output genes for both the recruitment of DNA methylating enzymes on the intronic deoxyCpG islands and their subsequent methylation.",
-,Yes,20230330,ewas,36974632,Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes.,Epigenomics,"Aim:To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood.Methods:Cross-ancestry (Europeans = 302, South Asians = 161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from the MoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood.Results & conclusion:cg19888088 (cross-ancestry) inEBF3, cg01952260 (Europeans) and cg07077240 (South Asians) inHERC3were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants inCASC15. The findings were not replicated and were not significant in cord blood.",
-,Yes,20230330,ewas,36966332,Sex differences in the intergenerational link between maternal and neonatal whole blood DNA methylation: a genome-wide analysis in 2 birth cohorts.,Clin Epigenetics,"The mother-child inheritance of DNA methylation (DNAm) variations could contribute to the inheritance of disease susceptibility across generations. However, no study has investigated patterns of mother-child associations in DNAm at the genome-wide scale. It remains unknown whether there are sex differences in mother-child DNAm associations.Using genome-wide DNAm profiling data (721,331 DNAm sites, including 704,552 on autosomes and 16,779 on the X chromosome) of 396 mother-newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother-newborn correlations in genome-wide DNAm patterns (Spearman's rho = 0.91-0.98; p = 4.0 × 10-8), with female newborns having stronger correlations. Sex differences in correlations were attenuated but remained significant after excluding X-chromosomal DNAm sites (Spearman's rho = 0.91-0.98; p = 0.035). Moreover, 89,267 DNAm sites (12.4% of all analyzed, including 88,051 [12.5% of analyzed] autosomal and 1,216 [7.2% of analyzed] X-chromosomal sites) showed significant mother-newborn associations in methylation levels, and the top autosomal DNAm sites had high heritability than the genome-wide background (e.g., the top 100 autosomal DNAm sites had a medium h2of 0.92). Additionally, significant interactions between newborn sex and methylation levels were observed for 11 X-chromosomal and 4 autosomal DNAm sites that were mapped to genes that have been associated with sex-specific disease/traits or early development (e.g., EFHC2, NXY, ADCYAP1R1, and BMP4). Finally, 18,769 DNAm sites (14,482 [77.2%] on the X chromosome) showed mother-newborn differences in methylation levels that were significantly associated with newborn sex, and the top autosomal DNAm sites had relatively small heritability (e.g., the top 100 autosomal DNAm sites had a medium h2of 0.23). These DNAm sites were mapped to 2,532 autosomal genes and 978 X-chromosomal genes with significant enrichment in pathways involved in neurodegenerative and psychological diseases, development, neurophysiological process, immune response, and sex-specific cancers. Replication analysis in the Isle of Wight birth cohort yielded consistent results.In two independent birth cohorts, we demonstrated strong mother-newborn correlations in whole blood DNAm on both autosomes and ChrX, and such correlations vary substantially by sex. Future studies are needed to examine to what extent our findings contribute to developmental origins of pediatric and adult diseases with well-observed sex differences.© 2023. The Author(s).",
-,Yes,20230330,ewas,36964596,"Longitudinal DNA methylation profiling of the rectal mucosa identifies cell-specific signatures of disease status, severity and clinical outcomes in ulcerative colitis cell-specific DNA methylation signatures of UC.",Clin Epigenetics,"In peripheral blood, DNA methylation (DNAm) patterns in inflammatory bowel disease patients reflect inflammatory status rather than disease status. Here, we examined DNAm in diseased rectal mucosa from ulcerative colitis (UC) patients, focusing on constituent cell types with the goal of identifying therapeutic targets for UC other than the immune system. We profiled DNAm of rectal mucosal biopsies of pediatric UC at diagnosis (n = 211) and non-IBD control (n = 85) patients and performed epigenome-wide association studies (EWAS) of specific cell types to understand DNAm changes in epithelial, immune and fibroblast cells across disease states, course, and clinical outcomes. We also examined longitudinal analysis on follow-up samples (n = 73), and comparisons were made among patients with clinical outcomes including those undergoing colectomy versus those who did not. Additionally, we included RNA-seq from the same subjects to assess the impact of CpG sites on the transcription of nearby genes during the disease course.At diagnosis, UC rectal mucosa exhibited a lower proportion of epithelial cells and fibroblasts, and higher proportion of immune cells, in conjunction with variation in the DNAm pattern. While treatment had significant effects on the methylation signature of immune cells, its effects on fibroblasts and epithelial cells were attenuated. Individuals who required colectomy exhibited cell composition and DNAm patterns at follow-up more similar to disease onset than patients who did not require colectomy. Combining these results with gene expression profiles, we identify CpG sites whose methylation patterns are most consistent with a contribution to poor disease outcomes and could thus be potential therapeutic targets.Cell-specific epigenetic changes in the rectal mucosa in UC are associated with disease severity and outcome. Current therapeutics may more effectively target the immune than the epithelial and fibroblast compartments.© 2023. Crown.",
-,Yes,20230330,ewas,36964402,Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity.,Geroscience,"Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated (r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.© 2023. The Author(s).",
-,Yes,20230330,ewas,36959629,DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight.,Clin Epigenetics,"Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented.Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E-11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults.These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.© 2023. The Author(s).",
-,No,20230330,placenta,36945560,Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders.,medRxiv,"Increasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placentalcis-mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type- and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placentalcis-mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type- imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.",
-,No,20230330,dnam age,36973715,Ageing as a software design flaw.,Genome Biol,"Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that ageing is caused by the accumulation of one or more forms of molecular damage. Here, I propose that we age not because of inevitable damage to the hardware but rather because of intrinsic design flaws in the software, defined as the DNA code that orchestrates how a single cell develops into an adult organism. As the developmental software runs, its sequence of events is reflected in shifting cellular epigenetic states. Overall, I suggest that to understand ageing we need to decode our software and the flow of epigenetic information throughout the life course.© 2023. The Author(s).",
-,No,20230330,mediation,36824903,Methods for Mediation Analysis with High-Dimensional DNA Methylation Data: Possible Choices and Comparison.,medRxiv,"Epigenetic researchers often evaluate DNA methylation as a mediator between social/environmental exposures and disease, but modern statistical methods for jointly evaluating many mediators have not been widely adopted. We compare seven methods for high-dimensional mediation analysis with continuous outcomes through both diverse simulations and analysis of DNAm data from a large national cohort in the United States, while providing an R package for their implementation. Among the considered choices, the best-performing methods for detecting active mediators in simulations are the Bayesian sparse linear mixed model by Song et al. (2020) and high-dimensional mediation analysis by Gao et al. (2019); while the superior methods for estimating the global mediation effect are high-dimensional linear mediation analysis by Zhou et al. (2021) and principal component mediation analysis by Huang and Pan (2016). We provide guidelines for epigenetic researchers on choosing the best method in practice and offer suggestions for future methodological development.",
-,Yes,20230330,ewas,36964604,Mediation effects of DNA methylation and hydroxymethylation on birth outcomes after prenatal per- and polyfluoroalkyl substances (PFAS) exposure in the Michigan mother-infant Pairs cohort.,Clin Epigenetics,"Per- and polyfluoroalkyl substances (PFAS) are chemicals that are resistant to degradation and ubiquitous in our environments. PFAS may impact the developing epigenome, but current human evidence is limited to assessments of total DNA methylation. We assessed associations between first trimester PFAS exposures with newborn DNA methylation, including 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC). DNA methylation mediation of associations between PFAS and birth outcomes were explored in the Michigan Mother Infant Pairs cohort. Nine PFAS were measured in maternal first trimester blood. Seven were highly detected and included for analysis: PFHxS, PFOA, PFOS, PFNA, PFDA, PFUnDA, and MeFOSAA. Bisulfite-converted cord blood DNA (n = 141) and oxidative-bisulfite-converted cord blood (n = 70) were assayed on Illumina MethylationEPIC BeadChips to measure total DNA methylation (5-mC + 5-hmC) and 5-mC/5-hmC. Correcting for multiple comparisons, beta regressions were used to assess associations between levels of PFAS and total methylation, 5-mC, or 5-hmC. Nonlinear mediation analyses were used to assess the epigenetic meditation effect between PFAS and birth outcomes.PFAS was significantly associated with total methylation (q < 0.05: PFHxS-12 sites; PFOS-19 sites; PFOA-2 sites; PFNA-3 sites; PFDA-4 sites). In 72 female infants and 69 male infants, there were sex-specific associations between five PFAS and DNA methylation. 5-mC and 5-hmC were each significantly associated with thousands of sites for PFHxS, PFOS, PFNA, PFDA, PFUnDA, and MeFOSAA (q < 0.05). Clusters of 5-mC and 5-hmC sites were significant mediators between PFNA and PFUnDA and decreased gestational age (q < 0.05).This study demonstrates the mediation role of specific types of DNA methylation on the relationship between PFAS exposure and birth outcomes. These results suggest that 5-mC and 5-hmC may be more sensitive to the developmental impacts of PFAS than total DNA methylation.© 2023. The Author(s).",
-,No,20230330,splicing,36949544,Evidence for the role of transcription factors in the co-transcriptional regulation of intron retention.,Genome Biol,"Alternative splicing is a widespread regulatory phenomenon that enables a single gene to produce multiple transcripts. Among the different types of alternative splicing, intron retention is one of the least explored despite its high prevalence in both plants and animals. The recent discovery that the majority of splicing is co-transcriptional has led to the finding that chromatin state affects alternative splicing. Therefore, it is plausible that transcription factors can regulate splicing outcomes.We provide evidence for the hypothesis that transcription factors are involved in the regulation of intron retention by studying regions of open chromatin in retained and excised introns. Using deep learning models designed to distinguish between regions of open chromatin in retained introns and non-retained introns, we identified motifs enriched in IR events with significant hits to known human transcription factors. Our model predicts that the majority of transcription factors that affect intron retention come from the zinc finger family. We demonstrate the validity of these predictions using ChIP-seq data for multiple zinc finger transcription factors and find strong over-representation for their peaks in intron retention events.This work opens up opportunities for further studies that elucidate the mechanisms by which transcription factors affect intron retention and other forms of splicing.Source code available at https://github.com/fahadahaf/chromir.© 2023. The Author(s).",
-,No,20230330,epigenetics,36978128,X chromosome dosage and the genetic impact across human tissues.,Genome Med,"Sex chromosome aneuploidies (SCAs) give rise to a broad range of phenotypic traits and diseases. Previous studies based on peripheral blood samples have suggested the presence of ripple effects, caused by altered X chromosome number, affecting the methylome and transcriptome. Whether these alterations can be connected to disease-specific tissues, and thereby having clinical implication for the phenotype, remains to be elucidated.We performed a comprehensive analysis of X chromosome number on the transcriptome and methylome in blood, fat, and muscle tissue from individuals with 45,X, 46,XX, 46,XY, and 47,XXY.X chromosome number affected the transcriptome and methylome globally across all chromosomes in a tissue-specific manner. Furthermore, 45,X and 47,XXY demonstrated a divergent pattern of gene expression and methylation, with overall gene downregulation and hypomethylation in 45,X and gene upregulation and hypermethylation in 47,XXY. In fat and muscle, a pronounced effect of sex was observed. We identified X chromosomal genes with an expression pattern different from what would be expected based on the number of X and Y chromosomes. Our data also indicate a regulatory function of Y chromosomal genes on X chromosomal genes. Fourteen X chromosomal genes were downregulated in 45,X and upregulated in 47,XXY, respectively, in all three tissues (AKAP17A, CD99, DHRSX, EIF2S3, GTPBP6, JPX, KDM6A, PP2R3B, PUDP, SLC25A6, TSIX, XIST, ZBED1, ZFX). These genes may be central in the epigenetic and genomic regulation of sex chromosome aneuploidies.We highlight a tissue-specific and complex effect of X chromosome number on the transcriptome and methylome, elucidating both shared and non-shared gene-regulatory mechanism between SCAs.© 2023. The Author(s).",
-,No,20230330,intergenerational,36320451,Regular smoking of male ancestors in adolescence and fat mass in young adult grandchildren and great-grandchildren.,Wellcome Open Res,"Background: Previous studies using the Avon Longitudinal Study of Parents and Children (ALSPAC) have shown that if men commenced smoking prior to the onset of puberty their sons, their granddaughters and great-granddaughters were more likely to have excess fat (but not lean) mass during childhood, adolescence and early adulthood. In this study we assess associations between ancestral smoking during adolescence (ages 11-16 years) with fat and lean mass of subsequent generations at two ages.Methods:We analysed data on exposures of grandparents and great-grandparents collected by ALSPAC. The outcomes were the fat masses of their grandchildren and great-grandchildren measured at ages 17 and 24. Measures of lean mass were used as controls. Adjustment was made for 8-10 demographic factors using multiple regression.Results:We found associations between adolescent smoking of thepaternalgrandfathers and the adjusted fat mass of their grandchildren, but no associations with the grandchildren's lean mass. Grandchildren at age 17 had an average excess fat mass of +1.65 [95% CI +0.04, +3.26] Kg, and at age 24 an average excess of +1.55 [95% CI -0.27, +3.38] Kg. Adolescent smoking by thematernalgrandfather showed similar, but weaker, associations: at 17 an average excess fat mass of +1.02 Kg [95% CI -0.20, +2.25] Kg, and at 24 an average excess of +1.28 [95% CI -0.11, +2.66] Kg. There were no pronounced differences between the sexes of the children. For the great-grandparents there were few convincing results, although numbers were small.Conclusions:We have shown associations between grandfathers' smoking in adolescence and increased fat (but not lean) mass in their children. Confirmation of these associations is required, either in a further data set or by demonstrating the presence of supportive biomarkers.Copyright: © 2023 Gregory S et al.",
-,No,20230420,methods,"10.1038/s43588-023-00429-y
+No,20230209,review,36694711,DNA methylation signatures as biomarkers of socioeconomic position,Environ Epigenet,"This review article provides a framework for the use of deoxyribonucleic acid (DNA) methylation (DNAm) biomarkers to study the biological embedding of socioeconomic position (SEP) and summarizes the latest developments in the area. It presents the emerging literature showing associations between individual- and neighborhood-level SEP exposures and DNAm across the life course. In contrast to questionnaire-based methods of assessing SEP, we suggest that DNAm biomarkers may offer an accessible metric to study questions about SEP and health outcomes, acting as a personal dosimeter of exposure. However, further work remains in standardizing SEP measures across studies and evaluating consistency across domains, tissue types, and time periods. Meta-analyses of epigenetic associations with SEP are offered as one approach to confirm the replication of DNAm loci across studies. The development of DNAm biomarkers of SEP would provide a method for examining its impact on health outcomes in a more robust way, increasing the rigor of epidemiological studies.",
+No,20230216,transgenerational epigenetic inheritance,36754048,Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice,Cell,"Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.",
+Yes,20230216,ewas,36782224,DNA methylation in peripheral blood leukocytes for the association with glucose metabolism and invasive breast cancer.,Clin Epigenetics,"Insulin resistance (IR) is a well-established factor for breast cancer (BC) risk in postmenopausal women, but the interrelated molecular pathways on the methylome are not explicitly described. We conducted a population-level epigenome-wide association (EWA) study for DNA methylation (DNAm) probes that are associated with IR and prospectively correlated with BC development, both overall and in BC subtypes among postmenopausal women.We used data from Women's Health Initiative (WHI) ancillary studies for our EWA analyses and evaluated the associations of site-specific DNAm across the genome with IR phenotypes by multiple regressions adjusting for age and leukocyte heterogeneities. For our analysis of the top 20 IR-CpGs with BC risk, we used the WHI and the Cancer Genomic Atlas (TCGA), using multiple Cox proportional hazards and logit regressions, respectively, accounting for age, diabetes, obesity, leukocyte heterogeneities, and tumor purity (for TCGA). We further conducted a Gene Set Enrichment Analysis.We detected several EWA-CpGs in TXNIP, CPT1A, PHGDH, and ABCG1. In particular, cg19693031 in TXNIP was replicated in all IR phenotypes, measured by fasting levels of glucose, insulin, and homeostatic model assessment-IR. Of those replicated IR-genes, 3 genes (CPT1A, PHGDH, and ABCG1) were further correlated with BC risk; and 1 individual CpG (cg01676795 in POR) was commonly detected across the 2 cohorts.Our study contributes to better understanding of the interconnected molecular pathways on the methylome between IR and BC carcinogenesis and suggests potential use of DNAm markers in the peripheral blood cells as preventive targets to detect an at-risk group for IR and BC in postmenopausal women.© 2023. The Author(s).",
+Yes,20230216,ewas,36778507,A Higher Dysregulation Burden of Brain DNA Methylation in Female Patients Implicated in the Sex Bias of Schizophrenia.,Res Sq,"Sex differences are pervasive in schizophrenia (SCZ), but the extent and magnitude of DNA methylation (DNAm) changes underlying these differences remain uncharacterized. In this study, sex-stratified differential DNAm analysis was performed in postmortem brain samples from 117 SCZ and 137 controls, partitioned into discovery and replication datasets. Three differentially methylated positions (DMPs) were identified (adj.p < 0.05) in females and 29 DMPs in males without overlap between them. Over 81% of these sex-stratified DMPs were directionally consistent between sexes but with different effect sizes. Down-sampling analysis revealed more DMPs in females than in males when the sample sizes matched. Females had higher DNAm levels in healthy individuals and larger magnitude of DNAm changes in patients than males. Despite similar proportions of female-related DMPs (fDMPs, 8%) being under genetic control compared with males (10%), significant enrichment of DMP-related SNPs in signals of genome-wide association studies was identified only in fDMPs. One DMP in each sex connected the SNPs and gene expression ofCALHM1in females andCCDC149in males. PPI subnetworks revealed that both female- and male-related differential DNAm interacted with synapse-related dysregulation. Immune-related pathways were unique for females and neuron-related pathways were associated with males. This study reveals remarkable quantitative differences in DNAm-related sexual dimorphism in SCZ and that females have a higher dysregulation burden of SCZ-associated DNAm than males.",
+Yes,20230216,ewas,36765422,Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis.,Clin Epigenetics,"Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS.We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5-44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+and eight in CD8+T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women.Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential 'CNS signature' of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.© 2023. The Author(s).",
+No,20230216,cell-free dna,36758479,UCseek: ultrasensitive early detection and recurrence monitoring of urothelial carcinoma by shallow-depth genome-wide bisulfite sequencing of urinary sediment DNA.,EBioMedicine,"Current methods for the detection and surveillance of urothelial carcinomas (UCs) are often invasive, costly, and not effective for low-grade, early-stage, and minimal residual disease (MRD) tumors. We aimed to develop and validate a model from urine sediments to predict different grade and stage UCs with low cost and high accuracy.We collected 167 samples, including 90 tumors and 77 individuals without tumors, as a discovery cohort. We assessed copy number variations and methylation values for them and constructed a diagnostic classifier to detect UC, UCseek, by using an individual read-based method and support vector machine. The performance of UCseek was validated in an independent cohort derived from three hospitals (n = 206) and a relapse cohort (n = 42) for monitoring recurrence.We constructed UCseek, which could predict UCs with high sensitivity (92.7%), high specificity (90.7%), and high accuracy (91.7%) in the independent validation set. The accuracy of UCseek in low-grade and early-stage patients reached 91.8% and 94.3%, respectively. Notably, UCseek retained great performance at ultralow sequencing depths (0.3X-0.5X). It also demonstrated a powerful ability to monitor recurrence in a surveillance cohort compared with cystoscopy (90.91% vs. 59.09%).We optimized an improved approach named UCseek for the noninvasive diagnosis and monitoring of UCs in both low- and high-grade tumors and in early- and advanced-stage tumors, even at ultralow sequencing depths, which may reduce the burden of cystoscopy and blind second surgery.A full list of funding bodies that contributed to this study can be found in the Acknowledgments section.Copyright © 2023. Published by Elsevier B.V.",
+Yes,20230216,omics,36752523,Circulating triglycerides are associated with human adipose tissue DNA methylation of genes linked to metabolic disease.,Hum Mol Genet,"Dysregulation of circulating lipids is a central element for the metabolic syndrome. However, it is not well established whether human subcutaneous adipose tissue is affected by or affect circulating lipids through epigenetic mechanisms. Hence, our aim was to investigate the association between circulating lipids and DNA methylation levels in human adipose tissue.DNA methylation and gene expression were analyzed genome-wide in subcutaneous adipose tissue from two different cohorts, including 85 men and 93 women, respectively. Associations between DNA methylation and circulating levels of triglycerides, LDL, HDL and total cholesterol were analysed. Causal mediation analyses tested if adipose tissue DNA methylation mediates the effects of triglycerides on gene expression or insulin resistance.We found 115 novel associations between triglycerides and adipose tissue DNA methylation, e.g. in the promoter of RFS1, ARID2, and HOXA5 in the male cohort (p ≤ 1.1x10-7), and 63 associations e.g. within the gene body of PTPRN2 and COL6A3 in the female cohort. We further connected these findings to altered mRNA expression levels in adipose tissue (e.g. HOXA5, IL11 and FAM45B). Interestingly, there was no overlap between methylation sites associated with triglycerides in men and the sites found in women, which points towards sex-specific effects of triglycerides on the epigenome. Finally, a causal mediation analysis provided support for adipose tissue DNA methylation as a partial mediating factor between circulating triglycerides and insulin resistance.This study identified novel epigenetic alterations in adipose tissue associated with circulating lipids. Identified epigenetic changes seem to mediate effects of triglycerides on insulin resistance.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
+Yes,20230223,ewas,36800980,Role of epigenetics in the clinical evolution of COVID-19 disease. Epigenome-wide association study identifies markers of severe outcome.,Eur J Med Res,"COVID-19 has a wide spectrum of clinical manifestations and given its impact on morbidity and mortality, there is an unmet medical need to discover endogenous cellular and molecular biomarkers that predict the expected clinical course of the disease. Recently, epigenetics and especially DNA methylation have been pointed out as a promising tool for outcome prediction in several diseases.Using the Illumina Infinium Methylation EPIC BeadChip850K, we investigated genome-wide differences in DNA methylation in an Italian Cohort of patients with comorbidities and compared severe (n = 64) and mild (123) prognosis. Results showed that the epigenetic signature, already present at the time of Hospital admission, can significantly predict risk of severe outcomes. Further analyses provided evidence of an association between age acceleration and a severe prognosis after COVID-19 infection. The burden of Stochastic Epigenetic Mutation (SEMs) has been significantly increased in patients with poor prognosis. Results have been replicated in silico considering COVID-19 negative subjects and available previously published datasets.Using original methylation data and taking advantage of already published datasets, we confirmed in the blood that epigenetics is actively involved in immune response after COVID-19 infection, allowing the identification of a specific signature able to discriminate the disease evolution. Furthermore, the study showed that epigenetic drift and age acceleration are associated with severe prognosis. All these findings prove that host epigenetics undergoes notable and specific rearrangements to respond to COVID-19 infection which can be used for a personalized, timely, and targeted management of COVID-19 patients during the first stages of hospitalization.© 2023. The Author(s).",
+No,20230223,methods,36797751,An overview of DNA methylation-derived trait score methods and applications.,Genome Biol,"Microarray technology has been used to measure genome-wide DNA methylation in thousands of individuals. These studies typically test the associations between individual DNA methylation sites (""probes"") and complex traits or diseases. The results can be used to generate methylation profile scores (MPS) to predict outcomes in independent data sets. Although there are many parallels between MPS and polygenic (risk) scores (PGS), there are key differences. Here, we review motivations, methods, and applications of DNA methylation-based trait prediction, with a focus on common diseases. We contrast MPS with PGS, highlighting where assumptions made in genetic modeling may not hold in epigenetic data.© 2023. The Author(s).",
+Yes,20230223,ewas,36796456,Multi-Omic Approach Associates Blood Methylome with Bronchodilator Drug Response in Pediatric Asthma.,J Allergy Clin Immunol,"Albuterol is the drug most widely used as asthma treatment among African Americans despite having a lower bronchodilator drug response (BDR) than other populations. Although BDR is affected by gene and environmental factors, the influence of DNA methylation (DNAm) is unknown.This study aims to identify epigenetic markers in whole blood associated with BDR, study their functional consequences by multi-omic integration, and assess their clinical applicability in admixed populations with a high asthma burden.We studied 414 children and young adults asthma patients (8-21 years old) in a discovery and replication design. We performed an epigenome-wide association study on 221 African Americans and replicated the results on 193 Latinos. Functional consequences were assessed by integrating epigenomics with genomics, transcriptomics, and environmental exposure data. Furthermore, a machine learning approach was used to develop a panel of epigenetic markers to classify treatment response.We identified five differentially methylated regions and two CpGs genome-wide significantly associated with BDR in African Americans located in FGL2 (cg08241295, p=6.8x10-9) and DNASE2 (cg15341340, p=7.8x10-8), which were regulated by genetic variation and/or associated with gene expression of nearby genes (false discovery rate<0.05). The CpG cg15341340 was replicated in Latinos (p=3.5x10-3). Moreover, a panel of 70 CpGs showed good classification for albuterol responders and nonresponders in African American and Latino children (AUCtraining:0.99, AUCvalidation:0.70-0.71). DNAm model showed similar discrimination as clinical predictors (p>0.05).We report novel associations of epigenetic markers with BDR in pediatric asthma and demonstrate for the first time the applicability of pharmacoepigenetics in precision medicine of respiratory diseases.Copyright © 2023. Published by Elsevier Inc.",
+Yes,20230223,ewas,36791658,Epigenome-wide association study of plasma lipids in West Africans: the RODAM study.,EBioMedicine,"DNA-methylation has been associated with plasma lipid concentration in populations of diverse ethnic backgrounds, but epigenome-wide association studies (EWAS) in West-Africans are lacking. The aim of this study was to identify DNA-methylation loci associated with plasma lipids in Ghanaians.We conducted an EWAS using Illumina 450k DNA-methylation array profiles of extracted DNA from 663 Ghanaian participants. Differentially methylated positions (DMPs) were examined for association with plasma total cholesterol (TC), LDL-cholesterol, HDL-cholesterol, and triglycerides concentrations using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, and technical covariates. Findings were replicated in independent cohorts of different ethnicities.We identified one significantly associated DMP with triglycerides (cg19693031 annotated to TXNIP, regression coefficient beta -0.26, false discovery rate adjusted p-value 0.001), which replicated in-silico in South African Batswana, African American, and European populations. From the top five DMPs with the lowest nominal p-values, two additional DMPs for triglycerides (CPT1A, ABCG1), two DMPs for LDL-cholesterol (EPSTI1, cg13781819), and one for TC (TXNIP) replicated. With the exception of EPSTI1, these loci are involved in lipid transport/metabolism or are known GWAS-associated loci. The top 5 DMPs per lipid trait explained 9.5% in the variance of TC, 8.3% in LDL-cholesterol, 6.1% in HDL-cholesterol, and 11.0% in triglycerides.The top DMPs identified in this study are in loci that play a role in lipid metabolism across populations, including West-Africans. Future studies including larger sample size, longitudinal study design and translational research is needed to increase our understanding on the epigenetic regulation of lipid metabolism among West-African populations.European Commission under the Framework Programme (grant number: 278901).Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.",
+Yes,20230223,ewas,36581877,Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders.,BMC Med,"Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programming of embryo and consequently cause the complex phenotype of developmental disorders. To explore the etiology of FASD, we collected unique biological samples of 80 severely alcohol-exposed and 100 control newborns at birth.We performed genome-wide DNA methylation (DNAm) and gene expression analyses of placentas by using microarrays (EPIC, Illumina) and mRNA sequencing, respectively. To test the manifestation of observed PAE-associated DNAm changes in embryonic tissues as well as potential biomarkers for PAE, we examined if the changes can be detected also in white blood cells or buccal epithelial cells of the same newborns by EpiTYPER. To explore the early effects of alcohol on extraembryonic placental tissue, we selected 27 newborns whose mothers had consumed alcohol up to gestational week 7 at maximum to the separate analyses. Furthermore, to explore the effects of early alcohol exposure on embryonic cells, human embryonic stem cells (hESCs) as well as hESCs during differentiation into endodermal, mesodermal, and ectodermal cells were exposed to alcohol in vitro.DPPA4, FOXP2, and TACR3 with significantly decreased DNAm were discovered-particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When hESCs were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNAm similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNAm changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways in the enrichment analysis, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development.Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.© 2022. The Author(s).",
+Yes,20230223,ewas,36577721,Dissecting the epigenomic differences between smoking and nicotine dependence in a veteran cohort.,Addict Biol,"Smoking is a serious public health issue linked to more than 8 million deaths per year worldwide and may lead to nicotine dependence (ND). Although the epigenomic literature on smoking is well established, studies evaluating the role of epigenetics in ND are limited. In this study, we examined the epigenomic signatures of ND and how these differ from smoking exposure to identify biomarkers specific to ND. We investigated the peripheral epigenetic profile of smoking status (SS) and ND in a US male veteran cohort. DNA from saliva was collected from 1135 European American (EA) male US military veterans. DNAm was assessed using the Illumina Infinium Human MethylationEPIC BeadChip array. SS was evaluated as current smokers (n = 137; 12.1%) and non-current smokers (never and former; n = 998; 87.9%). NDFTNDwas assessed as a continuous variable using the Fagerström Test for ND (FTND; n = 1135; mean = 2.54 ± 2.29). Epigenome-wide association studies (EWAS) and co-methylation analyses were conducted for SS and NDFTND. A total of 450 and 22 genome-wide significant differentially methylated sites (DMS) were associated with SS and NDFTND, respectively (15 overlapped DMS). We identified 97 DMS (43 genes) in SS-EWAS previously reported in the literature, including AHRR and F2RL3 genes (p-value: 1.95 × 10-83to 4.55 × 10-33). NDFTNDnovel DMS mapped to NEUROG1, ANPEP, and SLC29A1. Co-methylation analysis identified 386 modules (11 SS-related and 19 NDFTND-related). SS-related modules showed enrichment for alcoholism, while NDFTND-related modules were enriched for nicotine addiction. This study confirms previous findings associated with SS and identifies novel and-potentially specific-epigenetic biomarkers of ND that may inform prognosis and novel treatment strategies.© 2022 Society for the Study of Addiction.",
+Yes,20230223,ewas,36571600,"Pooled analysis of epigenome-wide association studies of food consumption in KORA, TwinsUK and LLS.",Eur J Nutr,"Examining epigenetic patterns is a crucial step in identifying molecular changes of disease pathophysiology, with DNA methylation as the most accessible epigenetic measure. Diet is suggested to affect metabolism and health via epigenetic modifications. Thus, our aim was to explore the association between food consumption and DNA methylation.Epigenome-wide association studies were conducted in three cohorts: KORA FF4, TwinsUK, and Leiden Longevity Study, and 37 dietary exposures were evaluated. Food group definition was harmonized across the three cohorts. DNA methylation was measured using Infinium MethylationEPIC BeadChip in KORA and Infinium HumanMethylation450 BeadChip in the Leiden study and the TwinsUK study. Overall, data from 2293 middle-aged men and women were included. A fixed-effects meta-analysis pooled study-specific estimates. The significance threshold was set at 0.05 for false-discovery rate-adjusted p values per food group.We identified significant associations between the methylation level of CpG sites and the consumption of onions and garlic (2), nuts and seeds (18), milk (1), cream (11), plant oils (4), butter (13), and alcoholic beverages (27). The signals targeted genes of metabolic health relevance, for example, GLI1, RPTOR, and DIO1, among others.This EWAS is unique with its focus on food groups that are part of a Western diet. Significant findings were mostly related to food groups with a high-fat content.© 2022. The Author(s).",
+No,20230223,dnam age,36566336,Social mobility across the lifecourse and DNA methylation age acceleration in adults in the UK.,Sci Rep,"Disadvantaged socio-economic position (SEP) is associated with greater biological age, relative to chronological age, measured by DNA methylation (positive 'age acceleration', AA). Social mobility has been proposed to ameliorate health inequalities. This study aimed to understand the association of social mobility with positive AA. Diagonal reference modelling and ordinary least square regression techniques were applied to explore social mobility and four measures of age acceleration (first-generation: 'Horvath', 'Hannum' and second-generation: 'Phenoage', DunedinPoAm) in n = 3140 participants of the UK Household Longitudinal Study. Disadvantaged SEP in early life is associated with positive AA for three (Hannum, Phenoage and DunedinPoAm) of the four measures examined while the second generation biomarkers are associated with SEP in adulthood (p < 0.01). Social mobility was associated with AA measured with Hannum only such that compared to no mobility, upward mobility was associated with greater age independently of origin and destination SEP. Compared to continuously advantaged groups, downward mobility was associated with positive Phenoage (1.06y [- 0.03, 2.14]) and DunedinPoAm assessed AA (0.96y [0.24, 1.68]). For these two measures, upward mobility was associated with negative AA (Phenoage, - 0.65y [- 1.30, - 0.002]; DunedinPoAm, - 0.96y [- 1.47, - 0.46]) compared to continually disadvantaged groups. While we find some support for three models of lifecourse epidemiology with early life as a sensitive period, SEP across the lifecourse and social mobility for age acceleration measured with DNA methylation, our findings suggest that disadvantaged SEP across the lifecourse is most consistently associated with positive AA.© 2022. The Author(s).",
+No,20230223,cancer,35609926,Extrachromosomal DNA in Cancer,Annu Rev Genomics Hum Genet,"In cancer, complex genome rearrangements and other structural alterations, including the amplification of oncogenes on circular extrachromosomal DNA (ecDNA) elements, drive the formation and progression of tumors. ecDNA is a particularly challenging structural alteration. By untethering oncogenes from chromosomal constraints, it elevates oncogene copy number, drives intratumoral genetic heterogeneity, promotes rapid tumor evolution, and results in treatment resistance. The profound changes in DNA shape and nuclear architecture generated by ecDNA alter the transcriptional landscape of tumors by catalyzing new types of regulatory interactions that do not occur on chromosomes. The current suite of tools for interrogating cancer genomes is well suited for deciphering sequence but has limited ability to resolve the complex changes in DNA structure and dynamics that ecDNA generates. Here, we review the challenges of resolving ecDNA form and function and discuss the emerging tool kit for deciphering ecDNA architecture and spatial organization, including what has been learned to date about how this dramatic change in shape alters tumor development, progression, and drug resistance.",
+No,20230223,methods,31911605,Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization,Nat Commun,"Modern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors. Here, we propose a two-sample multivariable MR approach based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.",
+No,20230223,pwas,36790168,"Proteome-wide antigenic profiling in Ugandan cohorts identifies associations between age, exposure intensity, and responses to repeat-containing antigens in Plasmodium falciparum",Elife,"Protection against Plasmodium falciparum, which is primarily antibody-mediated, requires recurrent exposure to develop. The study of both naturally acquired limited immunity and vaccine induced protection against malaria remains critical for ongoing eradication efforts. Towards this goal, we deployed a customized P. falciparum PhIP-seq T7 phage display library containing 238,068 tiled 62-amino acid peptides, covering all known coding regions, including antigenic variants, to systematically profile antibody targets in 198 Ugandan children and adults from high and moderate transmission settings. Repeat elements - short amino acid sequences repeated within a protein - were significantly enriched in antibody targets. While breadth of responses to repeat-containing peptides was twofold higher in children living in the high versus moderate exposure setting, no such differences were observed for peptides without repeats, suggesting that antibody responses to repeat-containing regions may be more exposure dependent and/or less durable in children than responses to regions without repeats. Additionally, short motifs associated with seroreactivity were extensively shared among hundreds of antigens, potentially representing cross-reactive epitopes. PfEMP1 shared motifs with the greatest number of other antigens, partly driven by the diversity of PfEMP1 sequences. These data suggest that the large number of repeat elements and potential cross-reactive epitopes found within antigenic regions of P. falciparum could contribute to the inefficient nature of malaria immunity.",
+No,20230223,pqtl,35501419,Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies,Nat Genet,"Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative trait loci. Elastic Net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies to serum urate and gout implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study to investigate the genetic mechanisms of molecular phenotypes and their relationship with complex traits.",
+Yes,20230302,ewas,36849614,Nucleated red blood cells explain most of the association between DNA methylation and gestational age.,Commun Biol,"Determining if specific cell type(s) are responsible for an association between DNA methylation (DNAm) and a given phenotype is important for understanding the biological mechanisms underlying the association. Our EWAS of gestational age (GA) in 953 newborns from the Norwegian MoBa study identified 13,660 CpGs significantly associated with GA (pBonferroni<0.05) after adjustment for cell type composition. When the CellDMC algorithm was applied to explore cell-type specific effects, 2,330 CpGs were significantly associated with GA, mostly in nucleated red blood cells [nRBCs; n = 2,030 (87%)]. Similar patterns were found in another dataset based on a different array and when applying an alternative algorithm to CellDMC called Tensor Composition Analysis (TCA). Our findings point to nRBCs as the main cell type driving the DNAm-GA association, implicating an epigenetic signature of erythropoiesis as a likely mechanism. They also explain the poor correlation observed between epigenetic age clocks for newborns and those for adults.© 2023. The Author(s).",
+Yes,20230302,ewas,36849136,Age-related methylation changes in the human sperm epigenome.,Aging (Albany NY),"Advanced paternal age is associated with increased risks for reproductive and offspring medical problems. Accumulating evidence suggests age-related changes in the sperm epigenome as one underlying mechanism. Using reduced representation bisulfite sequencing on 73 sperm samples of males attending a fertility center, we identified 1,162 (74%) regions which were significantly (FDR-adjusted) hypomethylated and 403 regions (26%) being hypermethylated with age. There were no significant correlations with paternal BMI, semen quality, or ART outcome. The majority (1,152 of 1,565; 74%) of age-related differentially methylated regions (ageDMRs) were located within genic regions, including 1,002 genes with symbols. Hypomethylated ageDMRs were closer to transcription start sites than hypermethylated DMRs, half of which reside in gene-distal regions. In this and conceptually related genome-wide studies, so far 2,355 genes have been reported with significant sperm ageDMRs, however most (90%) of them in only one study. The 241 genes which have been replicated at least once showed significant functional enrichments in 41 biological processes associated with development and the nervous system and in 10 cellular components associated with synapses and neurons. This supports the hypothesis that paternal age effects on the sperm methylome affect offspring behaviour and neurodevelopment. It is interesting to note that sperm ageDMRs were not randomly distributed throughout the human genome; chromosome 19 showed a highly significant twofold enrichment with sperm ageDMRs. Although the high gene density and CpG content have been conserved, the orthologous marmoset chromosome 22 did not appear to exhibit an increased regulatory potential by age-related DNA methylation changes.",
+No,20230302,cross-tissue,36843037,"Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and blood, saliva, and buccal epithelial tissues.",Transl Psychiatry,"Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13-73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva-brain correlation (r = 0.90) was higher than that for blood-brain (r = 0.87) and buccal-brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, cross-database correlations of the correlation coefficients revealed a relatively low (brain vs. blood: r = 0.27, saliva: r = 0.18, and buccal: r = 0.24). To the best of our knowledge, this is the fifth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.© 2023. The Author(s).",
+Yes,20230302,ewas,36842935,Maternal and Paternal Dietary Quality and Dietary Inflammation Associations with Offspring DNA Methylation and Epigenetic Biomarkers of Aging in the Lifeways Cross-Generation Study.,J Nutr,"Early-life nutritional exposures may contribute to offspring epigenetic modifications. However, few studies have evaluated parental dietary quality effects on offspring DNA methylation (DNAm).We aim to fill this gap by elucidating the influence of maternal and paternal whole-diet quality and inflammatory potential on offspring DNAm in the Lifeways Cross-generation cohort.Families (n = 1124) were recruited around 16 weeks of gestation in the Republic of Ireland between 2001 and 2003. Maternal dietary intake during the first trimester and paternal diet during the 12 previous months were assessed with an FFQ. Parental dietary inflammatory potential and quality were determined using the energy-adjusted Dietary Inflammatory Index (E-DII), the Healthy Eating Index-2015 (HEI-2015), and the maternal DASH score. DNAm in the saliva of 246 children at age nine was measured using the Illumina Infinium HumanMethylationEPIC array. DNAm-derived biomarkers of aging, the Pediatric-Buccal-Epigenetic clock and DNAm estimator of telomere length, were calculated. Parental diet associations with the DNAm concentrations of 850K Cytosine-phosphate-guanine sites (CpG sites) and with DNAm-derived biomarkers of aging were examined using an epigenome-wide association study and linear regressions, respectively.Maternal HEI-2015 scores were inversely associated with DNAm at CpG site (cg21840035) located near the PLEKHM1 gene, whose functions involve regulation of bone development (β = -0.0036, per 1 point increase in the score; P = 5.6 × 10-8). Higher paternal HEI-2015 score was related to lower methylation at CpG site (cg22431767), located near cell signaling gene LUZP1 (β = -0.0022, per 1 point increase in the score, P = 4.1 × 10-8). There were no associations with parental E-DII and DASH scores, and no evidence of major effects on biomarkers of aging.Parental dietary quality in the prenatal period, evaluated by the HEI-2015, may influence offspring DNAm during childhood. Further research to improve our understanding of parental nutritional programming is warranted. J Nutr 2023;xx:xx-xx.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.",
+Yes,20230302,ewas,36834337,DNA-Methylation Signatures of Tobacco Smoking in a High Cardiovascular Risk Population: Modulation by the Mediterranean Diet.,Int J Environ Res Public Health,"Biomarkers based on DNA methylation are relevant in the field of environmental health for precision health. Although tobacco smoking is one of the factors with a strong and consistent impact on DNA methylation, there are very few studies analyzing its methylation signature in southern European populations and none examining its modulation by the Mediterranean diet at the epigenome-wide level. We examined blood methylation smoking signatures on the EPIC 850 K array in this population (n = 414 high cardiovascular risk subjects). Epigenome-wide methylation studies (EWASs) were performed analyzing differential methylation CpG sites by smoking status (never, former, and current smokers) and the modulation by adherence to a Mediterranean diet score was explored. Gene-set enrichment analysis was performed for biological and functional interpretation. The predictive value of the top differentially methylated CpGs was analyzed using receiver operative curves. We characterized the DNA methylation signature of smoking in this Mediterranean population by identifying 46 differentially methylated CpGs at the EWAS level in the whole population. The strongest association was observed at the cg21566642 (p= 2.2 Ă— 10-32) in the 2q37.1 region. We also detected other CpGs that have been consistently reported in prior research and discovered some novel differentially methylated CpG sites in subgroup analyses. In addition, we found distinct methylation profiles based on the adherence to the Mediterranean diet. Particularly, we obtained a significant interaction between smoking and diet modulating the cg5575921 methylation in the AHRR gene. In conclusion, we have characterized biomarkers of the methylation signature of tobacco smoking in this population, and suggest that the Mediterranean diet can increase methylation of certain hypomethylated sites.",
+Yes,20230302,ewas,36815102,Longitudinal Epigenome-Wide Analysis of Kidney Transplant Recipients Pretransplant and Posttransplant.,Kidney Int Rep,"Kidney transplantation remains the gold standard of treatment for end-stage renal disease (ESRD), with improved patient outcomes compared with dialysis. Epigenome-Wide Association Analysis (EWAS) of DNA methylation may identify markers that contribute to an individual's risk of adverse transplant outcomes, yet only a limited number of EWAS have been conducted in kidney transplant recipients. This EWAS aimed to interrogate the methylation profile of a kidney transplant recipient cohort with minimal posttransplant complications, exploring differences in samples pretransplant and posttransplant.We compared differentially methylated cytosine-phosphate-guanine sites (dmCpGs) in samples derived from peripheral blood mononuclear cells of the same kidney transplant recipients, collected both pretransplant and posttransplant (N = 154), using the Infinium MethylationEPIC microarray (Illumina, San Diego, CA). Recipients received kidneys from deceased donors and had a mean of 17 years of follow-up.Five top-ranked dmCpGs were significantly different at false discovery rate (FDR) adjustedP ≤ 9 × 10-8; cg23597162 withinJAZF1, cg25187293 withinBTNL8, cg17944885, located betweenZNF788PandZNF625-ZNF20,cg14655917 located betweenASB4andPDK4and cg09839120 located betweenGIMAP6andEIF2AP3.Five dmCpGs were identified at the generally accepted EWAS critical significance level of FDR adjustedP(PFDRadj) ≤ 9 × 10-8, including cg23597162 (withinJAZF1) and cg17944885, which have prior associations with chronic kidney disease (CKD). Comparing individuals with no evidence of posttransplant complications (N = 105) demonstrated that 693,555 CpGs (89.57%) did not display any significant difference in methylation (PFDRadj ≥ 0.05), thereby this study establishes an important reference for future epigenetic studies that seek to identify markers of posttransplant complications.© 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology.",
+Yes,20230302,ewas,36811307,Genome-wide methylomic regulation of multiscale gene networks in Alzheimer's disease.,Alzheimers Dement,"Recent studies revealed the association of abnormal methylomic changes with Alzheimer's disease (AD) but there is a lack of systematic study of the impact of methylomic alterations over the molecular networks underlying AD.We profiled genome-wide methylomic variations in the parahippocampal gyrus from 201 post mortem control, mild cognitive impaired, and AD brains.We identified 270 distinct differentially methylated regions (DMRs) associated with AD. We quantified the impact of these DMRs on each gene and each protein as well as gene and protein co-expression networks. DNA methylation had a profound impact on both AD-associated gene/protein modules and their key regulators. We further integrated the matched multi-omics data to show the impact of DNA methylation on chromatin accessibility, which further modulates gene and protein expression.The quantified impact of DNA methylation on gene and protein networks underlying AD identified potential upstream epigenetic regulators of AD.A cohort of DNA methylation data in the parahippocampal gyrus was developed from 201 post mortem control, mild cognitive impaired, and Alzheimer's disease (AD) brains. Two hundred seventy distinct differentially methylated regions (DMRs) were found to be associated with AD compared to normal control. A metric was developed to quantify methylation impact on each gene and each protein. DNA methylation was found to have a profound impact on not only the AD-associated gene modules but also key regulators of the gene and protein networks. Key findings were validated in an independent multi-omics cohort in AD. The impact of DNA methylation on chromatin accessibility was also investigated by integrating the matched methylomic, epigenomic, transcriptomic, and proteomic data.© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
+Yes,20230309,ewas,36869404,Epigenome-wide association study in Chinese monozygotic twins identifies DNA methylation loci associated with blood pressure.,Clin Epigenetics,"Hypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively.Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data.The median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10-4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10-4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms.We detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.© 2023. The Author(s).",
+Yes,20230309,ewas,36855205,Distinct DNA methylation signatures associated with blood lipids as exposures or outcomes among survivors of childhood cancer: a report from the St. Jude lifetime cohort.,Clin Epigenetics,"DNA methylation (DNAm) plays an important role in lipid metabolism, however, no epigenome-wide association study (EWAS) of lipid levels has been conducted among childhood cancer survivors. Here, we performed EWAS analysis with longitudinally collected blood lipid data from survivors in the St. Jude lifetime cohort study.Among 2052 childhood cancer survivors of European ancestry (EA) and 370 survivors of African ancestry (AA), four types of blood lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), were measured during follow-up beyond 5-years from childhood cancer diagnosis. For the exposure EWAS (i.e., lipids measured before blood draw for DNAm), the DNAm level was an outcome variable and each of the blood lipid level was an exposure variable; vice versa for the outcome EWAS (i.e., lipids measured after blood draw for DNAm).Among EA survivors, we identified 43 lipid-associated CpGs in the HDL (n = 7), TC (n = 3), and TG (n = 33) exposure EWAS, and 106 lipid-associated CpGs in the HDL (n = 5), LDL (n = 3), TC (n = 4), and TG (n = 94) outcome EWAS. Among AA survivors, we identified 15 lipid-associated CpGs in TG exposure (n = 6), HDL (n = 1), LDL (n = 1), TG (n = 5) and TC (n = 2) outcome EWAS with epigenome-wide significance (P < 9 × 10-8). There were no overlapping lipids-associated CpGs between exposure and outcome EWAS among EA and AA survivors, suggesting that the DNAm changes of different CpGs could be the cause or consequence of blood lipid levels. In the meta-EWAS, 12 additional CpGs reached epigenome-wide significance. Notably, 32 out of 74 lipid-associated CpGs showed substantial heterogeneity (Phet < 0.1 or I2 > 70%) between EA and AA survivors, highlighting differences in DNAm markers of blood lipids between populations with diverse genetic ancestry. Ten lipid-associated CpGs were cis-expression quantitative trait methylation with their DNAm levels associated with the expression of corresponding genes, out of which seven were negatively associated.We identified distinct signatures of DNAm for blood lipids as exposures or outcomes and between EA and AA survivors, revealing additional genes involved in lipid metabolism and potential novel targets for controlling blood lipids in childhood cancer survivors.© 2023. The Author(s).",
+Yes,20230309,dnamage,36855161,Refining epigenetic prediction of chronological and biological age.,Genome Med,"Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to develop accurate epigenetic predictors of cAge and bAge, whilst improving our understanding of their epigenomic architecture.First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to create a cAge predictor, we use methylation data from 24,674 participants from the Generation Scotland study, the Lothian Birth Cohorts (LBC) of 1921 and 1936, and 8 other cohorts with publicly available data. In addition, we train a predictor of time to all-cause mortality as a proxy for bAge using the Generation Scotland cohort (1214 observed deaths). For this purpose, we use epigenetic surrogates (EpiScores) for 109 plasma proteins and the 8 component parts of GrimAge, one of the current best epigenetic predictors of survival. We test this bAge predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Women's Health Initiative study).Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross-validation framework, we obtain cAge prediction with a median absolute error equal to 2.3 years. Our bAge predictor was found to slightly outperform GrimAge in terms of the strength of its association to survival (HRGrimAge = 1.47 [1.40, 1.54] with p = 1.08 × 10-52, and HRbAge = 1.52 [1.44, 1.59] with p = 2.20 × 10-60). Finally, we introduce MethylBrowsR, an online tool to visualise epigenome-wide CpG-age associations.The integration of multiple large datasets, EpiScores, non-linear DNAm effects, and new approaches to feature selection has facilitated improvements to the blood-based epigenetic prediction of biological and chronological age.© 2023. The Author(s).",
+No,20230309,methods,36855165,CeDAR: incorporating cell type hierarchy improves cell type-specific differential analyses in bulk omics data.,Genome Biol,"Bulk high-throughput omics data contain signals from a mixture of cell types. Recent developments of deconvolution methods facilitate cell type-specific inferences from bulk data. Our real data exploration suggests that differential expression or methylation status is often correlated among cell types. Based on this observation, we develop a novel statistical method named CeDAR to incorporate the cell type hierarchy in cell type-specific differential analyses of bulk data. Extensive simulation and real data analyses demonstrate that this approach significantly improves the accuracy and power in detecting cell type-specific differential signals compared with existing methods, especially in low-abundance cell types.© 2023. The Author(s).",
+Yes,20230309,ewas,36855151,DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort.,Clin Epigenetics,"Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 μm or less (PM10) was measured inside participants' homes during the second trimester of pregnancy.A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM10and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582.Our findings suggest that DNAm may mediate the association between prenatal PM10exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations.© 2023. The Author(s).",
+No,20230309,proxy,36712110,Measuring the long arm of childhood in real-time: Epigenetic predictors of BMI and social determinants of health across childhood and adolescence.,bioRxiv,"Children who are socioeconomically disadvantaged are at increased risk for high body mass index (BMI) and multiple diseases in adulthood. The developmental origins of health and disease hypothesis proposes that early life conditions affect later-life health in a manner that is only partially modifiable by later-life experiences. Epigenetic mechanisms may regulate the influence of early life conditions on later life health. Recent epigenetic studies of adult blood samples have identified DNA-methylation sites associated with higher BMI and worse health (epigenetic-BMI). Here, we used longitudinal and twin study designs to examine whether epigenetic predictors of BMI developed in adults are valid biomarkers of child BMI and are sensitive to early life social determinants of health. Salivary epigenetic-BMI was calculated from two samples: (1) N=1,183 8-to-19-year-olds (609 female,meanage=13.4) from the Texas Twin Project (TTP), and (2) N=2,020 children (1,011 female) measured at 9 and 15 years from the Future of Families and Child Well-Being Study (FFCWS). We found that salivary epigenetic-BMI is robustly associated with children’s BMI (r=0.36 tor=0.50). Longitudinal analysis suggested that epigenetic-BMI is highly stable across adolescence, but remains both a leading and lagging indicator of BMI change. Twin analyses showed that epigenetic-BMI captures differences in BMI between monozygotic twins. Moreover, children from more disadvantaged socioeconomic status (SES) and marginalized race/ethnic groups had higher epigenetic-BMI, even when controlling for concurrent BMI, pubertal development, and tobacco exposure. SES at birth relative to concurrent SES best predicted epigenetic-BMI in childhood and adolescence. We show for the first time that epigenetic predictors of BMI calculated from pediatric saliva samples are valid biomarkers of childhood BMI that are sensitive to social inequalities. Our findings are in line with the hypothesis that early life conditions are especially important factors in epigenetic regulation of later life health. Research showing that health later in life is linked to early life conditions have important implications for the development of early-life interventions that could significantly extend healthy life span.",
+No,20230309,prediction,36852276,Association between biological aging and lung cancer risk: Cohort study and Mendelian randomization analysis.,iScience,"Chronological age only represents the passage of time, whereas biological age reflects the physiology states and the susceptibility to morbidity and mortality. The association between biological age and lung cancer risk remains controversial. Hence, we conducted a prospective analysis in the UK Biobank study and two-sample Mendelian randomization analysis to investigate this association. Biological aging was evaluated by PhenoAgeAccel, derived from routine clinical biomarkers. Independent of chronological age, PhenoAgeAccel was positively associated with the risk of overall and histological subtypes of lung cancer. There was a joint effect of PhenoAgeAccel and genetics in lung cancer incidence. In Mendelian randomization analysis, the genetically predicted PhenoAgeAccel was associated with the increased risk of overall lung cancer, small cell, and squamous cell carcinoma. Our findings suggest PhenoAgeAccel is an independent risk factor for lung cancer, which could be incorporated with polygenic risk score to identify high-risk individuals for lung cancer.© 2023 The Authors.",
+No,20230309,dnamage,36759656,A new blood based epigenetic age predictor for adolescents and young adults.,Sci Rep,"Children have special rights for protection compared to adults in our society. However, more than 1/4 of children globally have no documentation of their date of birth. Hence, there is a pressing need to develop biological methods for chronological age prediction, robust to differences in genetics, psychosocial events and physical living conditions. At present, DNA methylation is the most promising biological biomarker applied for age assessment. The human genome contains around 28 million DNA methylation sites, many of which change with age. Several epigenetic clocks accurately predict chronological age using methylation levels at age associated GpG-sites. However, variation in DNA methylation increases with age, and there is no epigenetic clock specifically designed for adolescents and young adults. Here we present a novel age Predictor for Adolescents and Young Adults (PAYA), using 267 CpG methylation sites to assess the chronological age of adolescents and young adults. We compared different preprocessing approaches and investigated the effect on prediction performance of the epigenetic clock. We evaluated performance using an independent validation data set consisting of 18-year-old individuals, where we obtained a median absolute deviation of just below 0.7 years. This tool may be helpful in age assessment of adolescents and young adults. However, there is a need to investigate the robustness of the age predictor across geographical and disease populations as well as environmental effects.© 2023. The Author(s).",
+No,20230309,gwas,36755099,"Polygenic architecture of rare coding variation across 394,783 exomes.",Nature,"Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes1-3. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear4. Here we quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes5. Rare coding variants (allele frequency < 1 × 10-3) explain 1.3% (s.e. = 0.03%) of phenotypic variance on average-much less than common variants-and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency < 1 × 10-5). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in significant genes, while common-variant heritability is more polygenic, and burden heritability is also more strongly concentrated in constrained genes. Finally, we find that burden heritability for schizophrenia and bipolar disorder6,7is approximately 2%. Our results indicate that rare coding variants will implicate a tractable number of large-effect genes, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20230309,pqtl,36797296,Genome-wide genotype-serum proteome mapping provides insights into the cross-ancestry differences in cardiometabolic disease susceptibility.,Nat Commun,"Identification of protein quantitative trait loci (pQTL) helps understand the underlying mechanisms of diseases and discover promising targets for pharmacological intervention. For most important class of drug targets, genetic evidence needs to be generalizable to diverse populations. Given that the majority of the previous studies were conducted in European ancestry populations, little is known about the protein-associated genetic variants in East Asians. Based on data-independent acquisition mass spectrometry technique, we conduct genome-wide association analyses for 304 unique proteins in 2,958 Han Chinese participants. We identify 195 genetic variant-protein associations. Colocalization and Mendelian randomization analyses highlight 60 gene-protein-phenotype associations, 45 of which (75%) have not been prioritized in Europeans previously. Further cross-ancestry analyses uncover key proteins that contributed to the differences in the obesity-induced diabetes and coronary artery disease susceptibility. These findings provide novel druggable proteins as well as a unique resource for the trans-ancestry evaluation of protein-targeted drug discovery.© 2023. The Author(s).",
+No,20230309,methods,36711575,Phenotypic subtyping via contrastive learning.,bioRxiv,"Defining and accounting for subphenotypic structure has the potential to increase statistical power and provide a deeper understanding of the heterogeneity in the molecular basis of complex disease. Existing phenotype subtyping methods primarily rely on clinically observed heterogeneity or metadata clustering. However, they generally tend to capture the dominant sources of variation in the data, which often originate from variation that is not descriptive of the mechanistic heterogeneity of the phenotype of interest; in fact, such dominant sources of variation, such as population structure or technical variation, are, in general, expected to be independent of subphenotypic structure. We instead aim to find a subspace with signal that is unique to a group of samples for which we believe that subphenotypic variation exists (e.g., cases of a disease). To that end, we introduce Phenotype Aware Components Analysis (PACA), a contrastive learning approach leveraging canonical correlation analysis to robustly capture weak sources of subphenotypic variation. In the context of disease, PACA learns a gradient of variation unique to cases in a given dataset, while leveraging control samples for accounting for variation and imbalances of biological and technical confounders between cases and controls. We evaluated PACA using an extensive simulation study, as well as on various subtyping tasks using genotypes, transcriptomics, and DNA methylation data. Our results provide multiple strong evidence that PACA allows us to robustly capture weak unknown variation of interest while being calibrated and well-powered, far superseding the performance of alternative methods. This renders PACA as a state-of-the-art tool for definingde novosubtypes that are more likely to reflect molecular heterogeneity, especially in challenging cases where the phenotypic heterogeneity may be masked by a myriad of strong unrelated effects in the data.PACA is available as an open source R package on GitHub: https://github.com/Adigorla/PACA.",
+No,20230309,circadian rhythm,36745672,Day-night and seasonal variation of human gene expression across tissues.,PLoS Biol,"Circadian and circannual cycles trigger physiological changes whose reflection on human transcriptomes remains largely uncharted. We used the time and season of death of 932 individuals from GTEx to jointly investigate transcriptomic changes associated with those cycles across multiple tissues. Overall, most variation across tissues during day-night and among seasons was unique to each cycle. Although all tissues remodeled their transcriptomes, brain and gonadal tissues exhibited the highest seasonality, whereas those in the thoracic cavity showed stronger day-night regulation. Core clock genes displayed marked day-night differences across multiple tissues, which were largely conserved in baboon and mouse, but adapted to their nocturnal or diurnal habits. Seasonal variation of expression affected multiple pathways, and it was enriched among genes associated with the immune response, consistent with the seasonality of viral infections. Furthermore, they unveiled cytoarchitectural changes in brain regions. Altogether, our results provide the first combined atlas of how transcriptomes from human tissues adapt to major cycling environmental conditions. This atlas may have multiple applications; for example, drug targets with day-night or seasonal variation in gene expression may benefit from temporally adjusted doses.Copyright: © 2023 Wucher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+No,20230309,circadian rhythm,36791105,The circadian demethylation of a unique intronic deoxymethylCpG-rich island boosts the transcription of its cognate circadian clock output gene.,Proc Natl Acad Sci U S A,"We demonstrate that there is a tight functional relationship between two highly evolutionary conserved cell processes, i.e., the circadian clock (CC) and the circadian DNA demethylation-methylation of cognate deoxyCpG-rich islands. We have discovered that every circadian clock-controlled output gene (CCG), but not the core clock nor its immediate-output genes, contains a single cognate intronic deoxyCpG-rich island, the demethylation-methylation of which is controlled by the CC. During the transcriptional activation period, these intronic islands are demethylated and, upon dimerization of two YY1 protein binding sites located upstream to the transcriptional enhancer and downstream from the deoxyCpG-rich island, store activating components initially assembled on a cognate active enhancer (a RORE, a D-box or an E-box), in keeping with the generation of a transcriptionally active condensate that boosts the initiation of transcription of their cognate pre-mRNAs. We report how these single intronic deoxyCpG-rich islands are instrumental in such a circadian activation/repression transcriptional process.",
+Yes,20230309,ewas,36840948,Sex-based differences in placental DNA methylation profiles related to gestational age: an NIH ECHO meta-analysis.,Epigenetics,"The placenta undergoes many changes throughout gestation to support the evolving needs of the foetus. There is also a growing appreciation that male and female foetuses develop differentlyin utero, with unique epigenetic changes in placental tissue. Here, we report meta-analysed sex-specific associations between gestational age and placental DNA methylation from four cohorts in the National Institutes of Health (NIH) Environmental influences on Child Health Outcomes (ECHO) Programme (355 females/419 males, gestational ages 23-42 weeks). We identified 407 cytosine-guanine dinucleotides (CpGs) in females and 794 in males where placental methylation levels were associated with gestational age. After cell-type adjustment, 55 CpGs in females and 826 in males were significant. These were enriched for biological processes critical to the immune system in females and transmembrane transport in males. Our findings are distinct between the sexes: in females, associations with gestational age are largely explained by differences in placental cellular composition, whereas in males, gestational age is directly associated with numerous alterations in methylation levels.",
+No,20230309,epigenetics,36802379,Escape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable.,PLoS Genet,"X-chromosome inactivation (XCI) silences one X in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. To characterize incidence and variability of escape across individuals and tissues, we conducted a transcriptomic study of escape in adipose, skin, lymphoblastoid cell lines and immune cells in 248 healthy individuals exhibiting skewed XCI. We quantify XCI escape from a linear model of genes' allelic fold-change and XIST-based degree of XCI skewing. We identify 62 genes, including 19 lncRNAs, with previously unknown patterns of escape. We find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 23% demonstrating tissue-restricted escape, including cell type-specific escape across immune cells of the same individual. We also detect substantial inter-individual variability in escape. Monozygotic twins share more similar escape than dizygotic twins, indicating that genetic factors may underlie inter-individual differences in escape. However, discordant escape also occurs within monozygotic co-twins, suggesting environmental factors also influence escape. Altogether, these data indicate that XCI escape is an under-appreciated source of transcriptional differences, and an intricate phenotype impacting variable trait expressivity in females.Copyright: © 2023 Zito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+No,20230309,gwas,36798175,Identification and analysis of individuals who deviate from their genetically-predicted phenotype.,bioRxiv,"Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol. We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL cholesterol and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions.Human genetics is becoming increasingly useful to help predict human traits across a population owing to findings from large-scale genetic association studies and advances in the power of genetic predictors. This provides an opportunity to potentially identify individuals that deviate from genetic predictions for a common phenotype under investigation. For example, an individual may be genetically predicted to be tall, but be shorter than expected. It is potentially important to identify individuals who deviate from genetic predictions as this can facilitate further follow-up to assess likely causes. Using 158,951 unrelated individuals from the UK Biobank, with height and LDL cholesterol, as exemplar traits, we demonstrate that approximately 0.15% & 0.12% of individuals deviate from their genetically predicted phenotypes respectively. We observed these individuals to be enriched for a range of rare clinical diagnoses, as well as rare genetic factors that may be causal. Our analyses also demonstrate several methods for detecting individuals who deviate from genetic predictions that can be applied to a range of continuous human phenotypes.",
+Yes,20230309,ewas,36694712,"Duration of exposure to epidural anesthesia at delivery, DNA methylation in umbilical cord blood and their association with offspring asthma in Non-Hispanic Black women.",Environ Epigenet,"Epidural anesthesia is an effective pain relief modality, widely used for labor analgesia. Childhood asthma is one of the commonest chronic medical illnesses in the USA which places a significant burden on the health-care system. We recently demonstrated a negative association between the duration of epidural anesthesia and the development of childhood asthma; however, the underlying molecular mechanisms still remain unclear. In this study of 127 mother-child pairs comprised of 75 Non-Hispanic Black (NHB) and 52 Non-Hispanic White (NHW) from the Newborn Epigenetic Study, we tested the hypothesis that umbilical cord blood DNA methylation mediates the association between the duration of exposure to epidural anesthesia at delivery and the development of childhood asthma and whether this differed by race/ethnicity. In the mother-child pairs of NHB ancestry, the duration of exposure to epidural anesthesia was associated with a marginally lower risk of asthma (odds ratio = 0.88, 95% confidence interval = 0.76-1.01) for each 1-h increase in exposure to epidural anesthesia. Of the 20 CpGs in the NHB population showing the strongest mediation effect, 50% demonstrated an average mediation proportion of 52%, with directional consistency of direct and indirect effects. These top 20 CpGs mapped to 21 genes enriched for pathways engaged in antigen processing, antigen presentation, protein ubiquitination and regulatory networks related to the Major Histocompatibility Complex (MHC) class I complex and Nuclear Factor Kappa-B (NFkB) complex. Our findings suggest that DNA methylation in immune-related pathways contributes to the effects of the duration of exposure to epidural anesthesia on childhood asthma risk in NHB offspring.© The Author(s) 2023. Published by Oxford University Press.",
+No,20230309,gwas,36755145,How rare mutations contribute to complex traits.,Nature,NA,
+No,20230309,dnamage,36824863,Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.,bioRxiv,"DNA hydroxymethylation (5hmC) is the most abundant oxidative derivative of DNA methylation (5mC) and is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in many age-related diseases, the functional role of the modification in aging remains largely unknown. Here, we report that 5hmC is stably enriched in multiple aged organs. Using the liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and thereby restricts the magnitude of gene expression changes during aging. Mechanistically, we found that 5hmC decreases binding affinity of splicing factors compared to unmodified cytosine and 5mC, and is correlated with age-related alternative splicing events, suggesting RNA splicing as a potential mediator of 5hmC’s transcriptionally restrictive function. Furthermore, we show that various age-related contexts, such as prolonged quiescence and senescence, are partially responsible for driving the accumulation of 5hmC with age. We provide evidence that this age-related function is conserved in mouse and human tissues, and further show that the modification is altered by regimens known to modulate lifespan. Our findings reveal that 5hmC is a regulator of tissue-specific function and may play a role in regulating longevity.",
+No,20230309,dataset,36711769,"curatedPCaData: Integration of clinical, genomic, and signature features in a curated and harmonized prostate cancer data resource.",bioRxiv,"Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets. The full potential of such data is yet to be realized as independent datasets exist in different repositories, have been processed using different pipelines, and derived and clinical features are often not provided or unstandardized. Here, we present thecuratedPCaDataR package, a harmonized data resource representing >2900 primary tumor, >200 normal tissue, and >500 metastatic PCa samples across 19 datasets processed using standardized pipelines with updated gene annotations. We show that meta-analysis across harmonized studies has great potential for robust and clinically meaningful insights.curatedPCaDatais an open and accessible community resource with code made available for reproducibility.",
+No,20230309,methods,36699372,reComBat: batch-effect removal in large-scale multi-source gene-expression data integration.,Bioinform Adv,"With the steadily increasing abundance of omics data produced all over the world under vastly different experimental conditions residing in public databases, a crucial step in many data-driven bioinformatics applications is that of data integration. The challenge of batch-effect removal for entire databases lies in the large number of batches and biological variation, which can result in design matrix singularity. This problem can currently not be solved satisfactorily by any common batch-correction algorithm.We presentreComBat, a regularized version of the empirical Bayes method to overcome this limitation and benchmark it against popular approaches for the harmonization of public gene-expression data (both microarray and bulkRNAsq) of the human opportunistic pathogenPseudomonas aeruginosa. Batch-effects are successfully mitigated while biologically meaningful gene-expression variation is retained.reComBatfills the gap in batch-correction approaches applicable to large-scale, public omics databases and opens up new avenues for data-driven analysis of complex biological processes beyond the scope of a single study.The code is available at https://github.com/BorgwardtLab/reComBat, all data and evaluation code can be found at https://github.com/BorgwardtLab/batchCorrectionPublicData.Supplementary data are available atBioinformatics Advancesonline.© The Author(s) 2022. Published by Oxford University Press.",
+No,20230309,review,36658435,The Singapore National Precision Medicine Strategy.,Nat Genet,"Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic-phenotypic databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world's population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption.© 2023. Springer Nature America, Inc.",
+No,20230309,pqtl,36823471,Proteogenomic links to human metabolic diseases,Nat Metab,"Studying the plasma proteome as the intermediate layer between the genome and the phenome has the potential to identify new disease processes. Here, we conducted a cis-focused proteogenomic analysis of 2,923 plasma proteins measured in 1,180 individuals using antibody-based assays. We (1) identify 256 unreported protein quantitative trait loci (pQTL); (2) demonstrate shared genetic regulation of 224 cis-pQTLs with 575 specific health outcomes, revealing examples for notable metabolic diseases (such as gastrin-releasing peptide as a potential therapeutic target for type 2 diabetes); (3) improve causal gene assignment at 40% (n = 192) of overlapping risk loci; and (4) observe convergence of phenotypic consequences of cis-pQTLs and rare loss-of-function gene burden for 12 proteins, such as TIMD4 for lipoprotein metabolism. Our findings demonstrate the value of integrating complementary proteomic technologies with genomics even at moderate scale to identify new mediators of metabolic diseases with the potential for therapeutic interventions.",
+No,20230309,cohort,36745618,"Cohort profile: The Clinical and Multi-omic (CAMO) cohort, part of the Norwegian Women and Cancer (NOWAC) study.",PLoS One,"Breast cancer is the most common cancer worldwide and the leading cause of cancer related deaths among women. The high incidence and mortality of breast cancer calls for improved prevention, diagnostics, and treatment, including identification of new prognostic and predictive biomarkers for use in precision medicine.With the aim of compiling a cohort amenable to integrative study designs, we collected detailed epidemiological and clinical data, blood samples, and tumor tissue from a subset of participants from the prospective, population-based Norwegian Women and Cancer (NOWAC) study. These study participants were diagnosed with invasive breast cancer in North Norway before 2013 according to the Cancer Registry of Norway and constitute the Clinical and Multi-omic (CAMO) cohort. Prospectively collected questionnaire data on lifestyle and reproductive factors and blood samples were extracted from the NOWAC study, clinical and histopathological data were manually curated from medical records, and archived tumor tissue collected.The lifestyle and reproductive characteristics of the study participants in the CAMO cohort (n = 388) were largely similar to those of the breast cancer patients in NOWAC (n = 10 356). The majority of the cancers in the CAMO cohort were tumor grade 2 and of the luminal A subtype. Approx. 80% were estrogen receptor positive, 13% were HER2 positive, and 12% were triple negative breast cancers. Lymph node metastases were present in 31% at diagnosis. The epidemiological dataset in the CAMO cohort is complemented by mRNA, miRNA, and metabolomics analyses in plasma, as well as miRNA profiling in tumor tissue. Additionally, histological analyses at the level of proteins and miRNAs in tumor tissue are currently ongoing.The CAMO cohort provides data suitable for epidemiological, clinical, molecular, and multi-omics investigations, thereby enabling a systems epidemiology approach to translational breast cancer research.Copyright: © 2023 Delgado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+No,20230309,aging,36658433,Genome-wide RNA polymerase stalling shapes the transcriptome during aging.,Nat Genet,"Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.© 2023. The Author(s).",
+No,20230309,transgenerational epigenetic inheritance,36854803,Engineering transgenerational epigenetic inheritance in mammals.,Nat Rev Genet,NA,
+No,20230323,dnamage,36865294,Higher testosterone and testosterone/estradiol ratio in men are associated with better epigenetic estimators of mortality risk.,medRxiv,"Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations.We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort (FHS), the Baltimore Longitudinal Study of Aging (BLSA), and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex hormone concentrations were standardized with mean 0 and standard deviation of 1, for each study and sex separately. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sensitivity analysis was performed excluding the previously used training-set for the development of Pheno and Grim age.Sex Hormone Binding Globulin (SHBG) is associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, 1 SD increase in total testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11).SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1.",
+Yes,20230323,ewas,36937723,"Longitudinal multi-omics alterations response to 8-week risperidone monotherapy: Evidence linking cortical thickness, transcriptomics and epigenetics.",Front Psychiatry,"Antipsychotic treatment-related alterations of cortical thickness (CT) and clinical symptoms have been previously corroborated, but less is known about whether the changes are driven by gene expression and epigenetic modifications.Utilizing a prospective design, we recruited 42 treatment-naive first-episode schizophrenia patients (FESP) and 38 healthy controls. Patients were scanned by TI weighted imaging before and after 8-week risperidone monotherapy. CT estimation was automatically performed with the FreeSurfer software package. Participants' peripheral blood genomic DNA methylation (DNAm) status, quantified by using Infinium®Human Methylation 450K BeadChip, was examined in parallel with T1 scanning. In total, CT measures from 118 subjects and genomic DNAm status from 114 subjects were finally collected. Partial least squares (PLS) regression was used to detect the spatial associations between longitudinal CT variations after treatment and cortical transcriptomic data acquired from the Allen Human Brain Atlas. Canonical correlation analysis (CCA) was then performed to identify multivariate associations between DNAm of PLS1 genes and patients' clinical improvement.We detected the significant PLS1 component (2,098 genes) related to longitudinal alterations of CT, and the PLS1 genes were significantly enriched in neurobiological processes, and dopaminergic- and cancer-related pathways. Combining Laplacian score and CCA analysis, we further linked DNAm of 33 representative genes from the 2,098 PLS1 genes with patients' reduction rate of clinical symptoms.This study firstly revealed that changes of CT and clinical behaviors after treatment may be transcriptionally and epigenetically underlied. We define a ""three-step"" roadmap which represents a vital step toward the exploration of treatment- and treatment response-related biomarkers on the basis of multiple omics rather than a single omics type as a strategy for advancing precise care.Copyright © 2023 Zong, Wang, Nie, Ma, Kang, Zhang, Weng, Tan, Zheng and Hu.",
+No,20230323,short tandem repeats,36940239,Native functions of short tandem repeats.,Elife,"Over a third of the human genome is comprised of repetitive sequences, including more than a million short tandem repeats (STRs). While studies of the pathologic consequences of repeat expansions that cause syndromic human diseases are extensive, the potential native functions of STRs are often ignored. Here, we summarize a growing body of research into the normal biological functions for repetitive elements across the genome, with a particular focus on the roles of STRs in regulating gene expression. We propose reconceptualizing the pathogenic consequences of repeat expansions as aberrancies in normal gene regulation. From this altered viewpoint, we predict that future work will reveal broader roles for STRs in neuronal function and as risk alleles for more common human neurological diseases.",
+No,20230323,methods,36909524,Pretraining strategies for effective promoter-driven gene expression prediction.,bioRxiv,"Advances in gene delivery technologies are enabling rapid progress in molecular medicine, but require precise expression of genetic cargo in desired cell types, which is predominantly achieved via a regulatory DNA sequence called a promoter; however, only a handful of cell type-specific promoters are known. Efficiently designing compact promoter sequences with a high density of regulatory information by leveraging machine learning models would therefore be broadly impactful for fundamental research and direct therapeutic applications. However, models of expression from such compact promoter sequences are lacking, despite the recent success of deep learning in modelling expression from endogenous regulatory sequences. Despite the lack of large datasets measuring promoter-driven expression in many cell types, data from a few well-studied cell types or from endogenous gene expression may provide relevant information for transfer learning, which has not yet been explored in this setting. Here, we evaluate a variety of pretraining tasks and transfer strategies for modelling cell type-specific expression from compact promoters and demonstrate the effectiveness of pretraining on existing promoter-driven expression datasets from other cell types. Our approach is broadly applicable for modelling promoter-driven expression in any data-limited cell type of interest, and will enable the use of model-based optimization techniques for promoter design for gene delivery applications. Our code and data are available at https://github.com/anikethjr/promoter_models .",
+No,20230323,epigenetics,36762477,DNA methylation entropy is associated with DNA sequence features and developmental epigenetic divergence.,Nucleic Acids Res,"Epigenetic information defines tissue identity and is largely inherited in development through DNA methylation. While studied mostly for mean differences, methylation also encodes stochastic change, defined as entropy in information theory. Analyzing allele-specific methylation in 49 human tissue sample datasets, we find that methylation entropy is associated with specific DNA binding motifs, regulatory DNA, and CpG density. Then applying information theory to 42 mouse embryo methylation datasets, we find that the contribution of methylation entropy to time- and tissue-specific patterns of development is comparable to the contribution of methylation mean, and methylation entropy is associated with sequence and chromatin features conserved with human. Moreover, methylation entropy is directly related to gene expression variability in development, suggesting a role for epigenetic entropy in developmental plasticity.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.",
+No,20230323,kidney,36932062,Kidney fibrosis: from mechanisms to therapeutic medicines.,Signal Transduct Target Ther,"Chronic kidney disease (CKD) is estimated to affect 10-14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading to scarring, is a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. Kidney fibrosis is identified by tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, and vascular rarefaction. Fibrotic niche, where organ fibrosis initiates, is a complex interplay between injured parenchyma (like tubular cells) and multiple non-parenchymal cell lineages (immune and mesenchymal cells) located spatially within scarring areas. Although the mechanisms of kidney fibrosis are complicated due to the kinds of cells involved, with the help of single-cell technology, many key questions have been explored, such as what kind of renal tubules are profibrotic, where myofibroblasts originate, which immune cells are involved, and how cells communicate with each other. In addition, genetics and epigenetics are deeper mechanisms that regulate kidney fibrosis. And the reversible nature of epigenetic changes including DNA methylation, RNA interference, and chromatin remodeling, gives an opportunity to stop or reverse kidney fibrosis by therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) have been developed to delay CKD progression in recent years. Furthermore, a better understanding of renal fibrosis is also favored to discover biomarkers of fibrotic injury. In the review, we update recent advances in the mechanism of renal fibrosis and summarize novel biomarkers and antifibrotic treatment for CKD.© 2023. The Author(s).",
+Yes,20230323,ewas,36929108,"Gestational weight gain in pregnant women with obesity is associated with cord blood DNA methylation, which partially mediates offspring anthropometrics.",Clin Transl Med,NA,
+No,20230323,multiomics,36941332,Multiomic signatures of body mass index identify heterogeneous health phenotypes and responses to a lifestyle intervention.,Nat Med,"Multiomic profiling can reveal population heterogeneity for both health and disease states. Obesity drives a myriad of metabolic perturbations and is a risk factor for multiple chronic diseases. Here we report an atlas of cross-sectional and longitudinal changes in 1,111 blood analytes associated with variation in body mass index (BMI), as well as multiomic associations with host polygenic risk scores and gut microbiome composition, from a cohort of 1,277 individuals enrolled in a wellness program (Arivale). Machine learning model predictions of BMI from blood multiomics captured heterogeneous phenotypic states of host metabolism and gut microbiome composition better than BMI, which was also validated in an external cohort (TwinsUK). Moreover, longitudinal analyses identified variable BMI trajectories for different omics measures in response to a healthy lifestyle intervention; metabolomics-inferred BMI decreased to a greater extent than actual BMI, whereas proteomics-inferred BMI exhibited greater resistance to change. Our analyses further identified blood analyte-analyte associations that were modified by metabolomics-inferred BMI and partially reversed in individuals with metabolic obesity during the intervention. Taken together, our findings provide a blood atlas of the molecular perturbations associated with changes in obesity status, serving as a resource to quantify metabolic health for predictive and preventive medicine.© 2023. The Author(s).",
+No,20230323,epigenetics,36922587,Spatial epigenome-transcriptome co-profiling of mammalian tissues.,Nature,"Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context1-5. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research.© 2023. The Author(s).",
+No,20230323,methods,36908043,Pruning and thresholding approach for methylation risk scores in multi-ancestry populations.,Epigenetics,"Recent efforts have focused on developing methylation risk scores (MRS), a weighted sum of the individual's DNA methylation (DNAm) values of pre-selected CpG sites. Most of the current MRS approaches that utilize Epigenome-wide association studies (EWAS) summary statistics only include genome-wide significant CpG sites and do not consider co-methylation. New methods that relax the p-value threshold to include more CpG sites and account for the inter-correlation of DNAm might improve the predictive performance of MRS. We paired informed co-methylation pruning with P-value thresholding to generate pruning and thresholding (P+T) MRS and evaluated its performance among multi-ancestry populations. Through simulation studies and real data analyses, we demonstrated that pruning provides an improvement over simple thresholding methods for prediction of phenotypes. We demonstrated that European-derived summary statistics can be used to develop P+T MRS among other populations such as African populations. However, the prediction accuracy of P+T MRS may differ across multi-ancestry population due to environmental/cultural/social differences.",
+No,20230323,sinets,36907174,Chromosome 18 loss of heterozygosity in small intestinal neuroendocrine tumours: Multi-omic and tumour composition analyses.,Neuroendocrinology,"Small intestinal neuroendocrine tumours (siNETs) are rare neoplasms which present with low mutational burden and can be subtyped based on copy number variation (CNV). Currently, siNETs can be molecularly classified as having chromosome 18 loss of heterozygosity (18LOH), multiple CNVs (MultiCNV), or no CNVs. 18LOH tumours have better progression free survival when compared to MultiCNV and NoCNV tumours, however the mechanism underlying this is unknown, and clinical practice does not currently consider CNV status.Here, we use genome-wide tumour DNA methylation (n=54) and gene expression (n=20 matched to DNA methylation) to better understand how gene regulation varies by 18LOH status. We then use multiple cell deconvolution methods to analyse how cell composition varies between 18LOH status, and determine potential associations with progression free survival.We identified 27,464 differentially methylated CpG sites and 12 differentially expressed genes between 18LOH and non-18LOH (MultiCNV + NoCNV) siNETs. Although few differentially expressed genes were identified, these genes were highly enriched with the differentially methylated CpG sites compared to the rest of the genome. We identified differences in tumour micro-environment between 18LOH and non-18LOH tumours, including CD14+ infiltration in a subset of non-18LOH tumours which had the poorest clinical outcomes.We identify a small number of genes which appear to be linked to the 18LOH status of siNETs, and find evidence of potential epigenetic dysregulation of these genes. We also find a potential prognostic marker for worse progression free outcomes in the form of higher CD14 infiltration in non-18LOH siNETs.S. Karger AG, Basel.",
+Yes,20230323,ewas,36899042,Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.,Mol Psychiatry,"Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20230323,multiomics,36891970,Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations.,Elife,"Despite the success of genome-wide association studies (GWASs) in identifying genetic variants associated with complex traits, understanding the mechanisms behind these statistical associations remains challenging. Several methods that integrate methylation, gene expression, and protein quantitative trait loci (QTLs) with GWAS data to determine their causal role in the path from genotype to phenotype have been proposed. Here, we developed and applied a multi-omics Mendelian randomization (MR) framework to study how metabolites mediate the effect of gene expression on complex traits. We identified 216 transcript-metabolite-trait causal triplets involving 26 medically relevant phenotypes. Among these associations, 58% were missed by classical transcriptome-wide MR, which only uses gene expression and GWAS data. This allowed the identification of biologically relevant pathways, such as betweenANKHand calcium levels mediated by citrate levels andSLC6A12and serum creatinine through modulation of the levels of the renal osmolyte betaine. We show that the signals missed by transcriptome-wide MR are found, thanks to the increase in power conferred by integrating multiple omics layer. Simulation analyses show that with larger molecular QTL studies and in case of mediated effects, our multi-omics MR framework outperforms classical MR approaches designed to detect causal relationships between single molecular traits and complex phenotypes.© 2023, Auwerx et al.",
+No,20230323,aging,36911092,Characteristics of circulating small noncoding RNAs in plasma and serum during human aging.,Aging Med (Milton),"Aging is a complicated process that triggers age-related disease susceptibility through intercellular communication in the microenvironment. While the classic secretome of senescence-associated secretory phenotype (SASP) including soluble factors, growth factors, and extracellular matrix remodeling enzymes are known to impact tissue homeostasis during the aging process, the effects of novel SASP components, extracellular small noncoding RNAs (sncRNAs), on human aging are not well established.Here, by utilizing 446 small RNA-seq samples from plasma and serum of healthy donors found in the Extracellular RNA (exRNA) Atlas data repository, we correlated linear and nonlinear features between circulating sncRNAs expression and age by the maximal information coefficient (MIC) relationship determination. Age predictors were generated by ensemble machine learning methods (Adaptive Boosting, Gradient Boosting, and Random Forest) and core age-related sncRNAs were determined through weighted coefficients in machine learning models. Functional investigation was performed via target prediction of age-related miRNAs.We observed the number of highly expressed transfer RNAs (tRNAs) and microRNAs (miRNAs) showed positive and negative associations with age respectively. Two-variable (sncRNA expression and individual age) relationships were detected by MIC and sncRNAs-based age predictors were established, resulting in a forecast performance where allR2values were greater than 0.96 and root-mean-square errors (RMSE) were less than 3.7 years in three ensemble machine learning methods. Furthermore, important age-related sncRNAs were identified based on modeling and the biological pathways of age-related miRNAs were characterized by their predicted targets, including multiple pathways in intercellular communication, cancer and immune regulation.In summary, this study provides valuable insights into circulating sncRNAs expression dynamics during human aging and may lead to advanced understanding of age-related sncRNAs functions with further elucidation.© 2023 The Authors. Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.",
+No,20230323,dnamage,36802439,Epigenetic-based age acceleration in a representative sample of older Americans: Associations with aging-related morbidity and mortality.,Proc Natl Acad Sci U S A,"Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from a representative, panel study of US older adults to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality. We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, SES, and health behaviors. In our sample, age acceleration calculated using ""second and third generation clocks,"" PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 y after DNAm measurement, and 4-y mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.",
+No,20230323,pqtls,36824751,Genetic mechanisms of 184 neuro-related proteins in human plasma.,medRxiv,"Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.",
+No,20230323,mitochondria,36778249,Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate in aging fibroblasts.,bioRxiv,"The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in some non-human species. We investigated their association with human aging in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples. Human brains exhibited a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to the cerebellum, suggesting that they arose spontaneously during development or with aging. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts in a repeated-measures WGS study in a human fibroblast model that recapitulates several molecular features of human aging. These longitudinal experiments revealed a gradual accumulation of one Numt every ~9 days, independent of large-scale genomic instability. Targeted genetic and pharmacological perturbations of mitochondrial oxidative phosphorylation did not affect numtogenesis, whereas chronic glucocorticoid stress increased the Numts transfer rate by 39.8%. Combined, our data document spontaneous numtogenesis in aging human cells and demonstrate an association between brain cortical somatic Numts and human lifespan.",
+No,20230323,methods,36906598,A systematic evaluation of normalization methods and probe replicability using infinium EPIC methylation data.,Clin Epigenetics,"The Infinium EPIC array measures the methylation status of > 850,000 CpG sites. The EPIC BeadChip uses a two-array design: Infinium Type I and Type II probes. These probe types exhibit different technical characteristics which may confound analyses. Numerous normalization and pre-processing methods have been developed to reduce probe type bias as well as other issues such as background and dye bias.This study evaluates the performance of various normalization methods using 16 replicated samples and three metrics: absolute beta-value difference, overlap of non-replicated CpGs between replicate pairs, and effect on beta-value distributions. Additionally, we carried out Pearson's correlation and intraclass correlation coefficient (ICC) analyses using both raw and SeSAMe 2 normalized data.The method we define as SeSAMe 2, which consists of the application of the regular SeSAMe pipeline with an additional round of QC, pOOBAH masking, was found to be the best performing normalization method, while quantile-based methods were found to be the worst performing methods. Whole-array Pearson's correlations were found to be high. However, in agreement with previous studies, a substantial proportion of the probes on the EPIC array showed poor reproducibility (ICC < 0.50). The majority of poor performing probes have beta values close to either 0 or 1, and relatively low standard deviations. These results suggest that probe reliability is largely the result of limited biological variation rather than technical measurement variation. Importantly, normalizing the data with SeSAMe 2 dramatically improved ICC estimates, with the proportion of probes with ICC values > 0.50 increasing from 45.18% (raw data) to 61.35% (SeSAMe 2).© 2023. The Author(s).",
+No,20230323,circadian rhythm,36791098,The HP1α protein is mandatory to repress the circadian clock and its output genes during the 12 h period of transcriptional repression.,Proc Natl Acad Sci U S A,"The transcriptional repressions driven by the circadian core clock repressors RevErbα, E4BP4, and CRY1/PER1 involve feedback loops which are mandatory for generating the circadian rhythms. These repressors are known to bind to cognate DNA binding sites, but how their circadian bindings trigger the cascade of events leading to these repressions remain to be elucidated. Through molecular and genetic analyses, we now demonstrate that the chromatin protein HP1α plays a key role in these transcriptional repressions of both the circadian clock (CC) genes and their cognate output genes (CCGs). We show that these CC repressors recruit the HP1α protein downstream from a repressive cascade, and that this recruitment is mandatory for the maintenance of both the CC integrity and the expression of the circadian genes. We further show that the presence of HP1α is critical for both the repressor-induced chromatin compaction and the generation of ""transcriptionally repressed biomolecular hydrophobic condensates"" and demonstrates that HP1α is mandatory within the CC output genes for both the recruitment of DNA methylating enzymes on the intronic deoxyCpG islands and their subsequent methylation.",
+Yes,20230330,ewas,36974632,Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes.,Epigenomics,"Aim:To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood.Methods:Cross-ancestry (Europeans = 302, South Asians = 161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from the MoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood.Results & conclusion:cg19888088 (cross-ancestry) inEBF3, cg01952260 (Europeans) and cg07077240 (South Asians) inHERC3were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants inCASC15. The findings were not replicated and were not significant in cord blood.",
+Yes,20230330,ewas,36966332,Sex differences in the intergenerational link between maternal and neonatal whole blood DNA methylation: a genome-wide analysis in 2 birth cohorts.,Clin Epigenetics,"The mother-child inheritance of DNA methylation (DNAm) variations could contribute to the inheritance of disease susceptibility across generations. However, no study has investigated patterns of mother-child associations in DNAm at the genome-wide scale. It remains unknown whether there are sex differences in mother-child DNAm associations.Using genome-wide DNAm profiling data (721,331 DNAm sites, including 704,552 on autosomes and 16,779 on the X chromosome) of 396 mother-newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother-newborn correlations in genome-wide DNAm patterns (Spearman's rho = 0.91-0.98; p = 4.0 × 10-8), with female newborns having stronger correlations. Sex differences in correlations were attenuated but remained significant after excluding X-chromosomal DNAm sites (Spearman's rho = 0.91-0.98; p = 0.035). Moreover, 89,267 DNAm sites (12.4% of all analyzed, including 88,051 [12.5% of analyzed] autosomal and 1,216 [7.2% of analyzed] X-chromosomal sites) showed significant mother-newborn associations in methylation levels, and the top autosomal DNAm sites had high heritability than the genome-wide background (e.g., the top 100 autosomal DNAm sites had a medium h2of 0.92). Additionally, significant interactions between newborn sex and methylation levels were observed for 11 X-chromosomal and 4 autosomal DNAm sites that were mapped to genes that have been associated with sex-specific disease/traits or early development (e.g., EFHC2, NXY, ADCYAP1R1, and BMP4). Finally, 18,769 DNAm sites (14,482 [77.2%] on the X chromosome) showed mother-newborn differences in methylation levels that were significantly associated with newborn sex, and the top autosomal DNAm sites had relatively small heritability (e.g., the top 100 autosomal DNAm sites had a medium h2of 0.23). These DNAm sites were mapped to 2,532 autosomal genes and 978 X-chromosomal genes with significant enrichment in pathways involved in neurodegenerative and psychological diseases, development, neurophysiological process, immune response, and sex-specific cancers. Replication analysis in the Isle of Wight birth cohort yielded consistent results.In two independent birth cohorts, we demonstrated strong mother-newborn correlations in whole blood DNAm on both autosomes and ChrX, and such correlations vary substantially by sex. Future studies are needed to examine to what extent our findings contribute to developmental origins of pediatric and adult diseases with well-observed sex differences.© 2023. The Author(s).",
+Yes,20230330,ewas,36964596,"Longitudinal DNA methylation profiling of the rectal mucosa identifies cell-specific signatures of disease status, severity and clinical outcomes in ulcerative colitis cell-specific DNA methylation signatures of UC.",Clin Epigenetics,"In peripheral blood, DNA methylation (DNAm) patterns in inflammatory bowel disease patients reflect inflammatory status rather than disease status. Here, we examined DNAm in diseased rectal mucosa from ulcerative colitis (UC) patients, focusing on constituent cell types with the goal of identifying therapeutic targets for UC other than the immune system. We profiled DNAm of rectal mucosal biopsies of pediatric UC at diagnosis (n = 211) and non-IBD control (n = 85) patients and performed epigenome-wide association studies (EWAS) of specific cell types to understand DNAm changes in epithelial, immune and fibroblast cells across disease states, course, and clinical outcomes. We also examined longitudinal analysis on follow-up samples (n = 73), and comparisons were made among patients with clinical outcomes including those undergoing colectomy versus those who did not. Additionally, we included RNA-seq from the same subjects to assess the impact of CpG sites on the transcription of nearby genes during the disease course.At diagnosis, UC rectal mucosa exhibited a lower proportion of epithelial cells and fibroblasts, and higher proportion of immune cells, in conjunction with variation in the DNAm pattern. While treatment had significant effects on the methylation signature of immune cells, its effects on fibroblasts and epithelial cells were attenuated. Individuals who required colectomy exhibited cell composition and DNAm patterns at follow-up more similar to disease onset than patients who did not require colectomy. Combining these results with gene expression profiles, we identify CpG sites whose methylation patterns are most consistent with a contribution to poor disease outcomes and could thus be potential therapeutic targets.Cell-specific epigenetic changes in the rectal mucosa in UC are associated with disease severity and outcome. Current therapeutics may more effectively target the immune than the epithelial and fibroblast compartments.© 2023. Crown.",
+Yes,20230330,ewas,36964402,Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity.,Geroscience,"Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated (r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.© 2023. The Author(s).",
+Yes,20230330,ewas,36959629,DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight.,Clin Epigenetics,"Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented.Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E-11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults.These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.© 2023. The Author(s).",
+No,20230330,placenta,36945560,Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders.,medRxiv,"Increasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placentalcis-mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type- and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placentalcis-mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type- imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.",
+No,20230330,dnam age,36973715,Ageing as a software design flaw.,Genome Biol,"Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that ageing is caused by the accumulation of one or more forms of molecular damage. Here, I propose that we age not because of inevitable damage to the hardware but rather because of intrinsic design flaws in the software, defined as the DNA code that orchestrates how a single cell develops into an adult organism. As the developmental software runs, its sequence of events is reflected in shifting cellular epigenetic states. Overall, I suggest that to understand ageing we need to decode our software and the flow of epigenetic information throughout the life course.© 2023. The Author(s).",
+No,20230330,mediation,36824903,Methods for Mediation Analysis with High-Dimensional DNA Methylation Data: Possible Choices and Comparison.,medRxiv,"Epigenetic researchers often evaluate DNA methylation as a mediator between social/environmental exposures and disease, but modern statistical methods for jointly evaluating many mediators have not been widely adopted. We compare seven methods for high-dimensional mediation analysis with continuous outcomes through both diverse simulations and analysis of DNAm data from a large national cohort in the United States, while providing an R package for their implementation. Among the considered choices, the best-performing methods for detecting active mediators in simulations are the Bayesian sparse linear mixed model by Song et al. (2020) and high-dimensional mediation analysis by Gao et al. (2019); while the superior methods for estimating the global mediation effect are high-dimensional linear mediation analysis by Zhou et al. (2021) and principal component mediation analysis by Huang and Pan (2016). We provide guidelines for epigenetic researchers on choosing the best method in practice and offer suggestions for future methodological development.",
+Yes,20230330,ewas,36964604,Mediation effects of DNA methylation and hydroxymethylation on birth outcomes after prenatal per- and polyfluoroalkyl substances (PFAS) exposure in the Michigan mother-infant Pairs cohort.,Clin Epigenetics,"Per- and polyfluoroalkyl substances (PFAS) are chemicals that are resistant to degradation and ubiquitous in our environments. PFAS may impact the developing epigenome, but current human evidence is limited to assessments of total DNA methylation. We assessed associations between first trimester PFAS exposures with newborn DNA methylation, including 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC). DNA methylation mediation of associations between PFAS and birth outcomes were explored in the Michigan Mother Infant Pairs cohort. Nine PFAS were measured in maternal first trimester blood. Seven were highly detected and included for analysis: PFHxS, PFOA, PFOS, PFNA, PFDA, PFUnDA, and MeFOSAA. Bisulfite-converted cord blood DNA (n = 141) and oxidative-bisulfite-converted cord blood (n = 70) were assayed on Illumina MethylationEPIC BeadChips to measure total DNA methylation (5-mC + 5-hmC) and 5-mC/5-hmC. Correcting for multiple comparisons, beta regressions were used to assess associations between levels of PFAS and total methylation, 5-mC, or 5-hmC. Nonlinear mediation analyses were used to assess the epigenetic meditation effect between PFAS and birth outcomes.PFAS was significantly associated with total methylation (q < 0.05: PFHxS-12 sites; PFOS-19 sites; PFOA-2 sites; PFNA-3 sites; PFDA-4 sites). In 72 female infants and 69 male infants, there were sex-specific associations between five PFAS and DNA methylation. 5-mC and 5-hmC were each significantly associated with thousands of sites for PFHxS, PFOS, PFNA, PFDA, PFUnDA, and MeFOSAA (q < 0.05). Clusters of 5-mC and 5-hmC sites were significant mediators between PFNA and PFUnDA and decreased gestational age (q < 0.05).This study demonstrates the mediation role of specific types of DNA methylation on the relationship between PFAS exposure and birth outcomes. These results suggest that 5-mC and 5-hmC may be more sensitive to the developmental impacts of PFAS than total DNA methylation.© 2023. The Author(s).",
+No,20230330,splicing,36949544,Evidence for the role of transcription factors in the co-transcriptional regulation of intron retention.,Genome Biol,"Alternative splicing is a widespread regulatory phenomenon that enables a single gene to produce multiple transcripts. Among the different types of alternative splicing, intron retention is one of the least explored despite its high prevalence in both plants and animals. The recent discovery that the majority of splicing is co-transcriptional has led to the finding that chromatin state affects alternative splicing. Therefore, it is plausible that transcription factors can regulate splicing outcomes.We provide evidence for the hypothesis that transcription factors are involved in the regulation of intron retention by studying regions of open chromatin in retained and excised introns. Using deep learning models designed to distinguish between regions of open chromatin in retained introns and non-retained introns, we identified motifs enriched in IR events with significant hits to known human transcription factors. Our model predicts that the majority of transcription factors that affect intron retention come from the zinc finger family. We demonstrate the validity of these predictions using ChIP-seq data for multiple zinc finger transcription factors and find strong over-representation for their peaks in intron retention events.This work opens up opportunities for further studies that elucidate the mechanisms by which transcription factors affect intron retention and other forms of splicing.Source code available at https://github.com/fahadahaf/chromir.© 2023. The Author(s).",
+No,20230330,epigenetics,36978128,X chromosome dosage and the genetic impact across human tissues.,Genome Med,"Sex chromosome aneuploidies (SCAs) give rise to a broad range of phenotypic traits and diseases. Previous studies based on peripheral blood samples have suggested the presence of ripple effects, caused by altered X chromosome number, affecting the methylome and transcriptome. Whether these alterations can be connected to disease-specific tissues, and thereby having clinical implication for the phenotype, remains to be elucidated.We performed a comprehensive analysis of X chromosome number on the transcriptome and methylome in blood, fat, and muscle tissue from individuals with 45,X, 46,XX, 46,XY, and 47,XXY.X chromosome number affected the transcriptome and methylome globally across all chromosomes in a tissue-specific manner. Furthermore, 45,X and 47,XXY demonstrated a divergent pattern of gene expression and methylation, with overall gene downregulation and hypomethylation in 45,X and gene upregulation and hypermethylation in 47,XXY. In fat and muscle, a pronounced effect of sex was observed. We identified X chromosomal genes with an expression pattern different from what would be expected based on the number of X and Y chromosomes. Our data also indicate a regulatory function of Y chromosomal genes on X chromosomal genes. Fourteen X chromosomal genes were downregulated in 45,X and upregulated in 47,XXY, respectively, in all three tissues (AKAP17A, CD99, DHRSX, EIF2S3, GTPBP6, JPX, KDM6A, PP2R3B, PUDP, SLC25A6, TSIX, XIST, ZBED1, ZFX). These genes may be central in the epigenetic and genomic regulation of sex chromosome aneuploidies.We highlight a tissue-specific and complex effect of X chromosome number on the transcriptome and methylome, elucidating both shared and non-shared gene-regulatory mechanism between SCAs.© 2023. The Author(s).",
+No,20230330,intergenerational,36320451,Regular smoking of male ancestors in adolescence and fat mass in young adult grandchildren and great-grandchildren.,Wellcome Open Res,"Background: Previous studies using the Avon Longitudinal Study of Parents and Children (ALSPAC) have shown that if men commenced smoking prior to the onset of puberty their sons, their granddaughters and great-granddaughters were more likely to have excess fat (but not lean) mass during childhood, adolescence and early adulthood. In this study we assess associations between ancestral smoking during adolescence (ages 11-16 years) with fat and lean mass of subsequent generations at two ages.Methods:We analysed data on exposures of grandparents and great-grandparents collected by ALSPAC. The outcomes were the fat masses of their grandchildren and great-grandchildren measured at ages 17 and 24. Measures of lean mass were used as controls. Adjustment was made for 8-10 demographic factors using multiple regression.Results:We found associations between adolescent smoking of thepaternalgrandfathers and the adjusted fat mass of their grandchildren, but no associations with the grandchildren's lean mass. Grandchildren at age 17 had an average excess fat mass of +1.65 [95% CI +0.04, +3.26] Kg, and at age 24 an average excess of +1.55 [95% CI -0.27, +3.38] Kg. Adolescent smoking by thematernalgrandfather showed similar, but weaker, associations: at 17 an average excess fat mass of +1.02 Kg [95% CI -0.20, +2.25] Kg, and at 24 an average excess of +1.28 [95% CI -0.11, +2.66] Kg. There were no pronounced differences between the sexes of the children. For the great-grandparents there were few convincing results, although numbers were small.Conclusions:We have shown associations between grandfathers' smoking in adolescence and increased fat (but not lean) mass in their children. Confirmation of these associations is required, either in a further data set or by demonstrating the presence of supportive biomarkers.Copyright: © 2023 Gregory S et al.",
+No,20230420,methods,"10.1038/s43588-023-00429-y
 ",Large-scale correlation network construction for unraveling the coordination of complex biological systems.,Nat Comput Sci,"Advanced measurement and data storage technologies have enabled high-dimensional profiling of complex biological systems. For this, modern multiomics studies regularly produce datasets with hundreds of thousands of measurements per sample, enabling a new era of precision medicine. Correlation analysis is an important first step to gain deeper insights into the coordination and underlying processes of such complex systems. However, the construction of large correlation networks in modern high-dimensional datasets remains a major computational challenge owing to rapidly growing runtime and memory requirements. Here we address this challenge by introducing CorALS (Correlation Analysis of Large-scale (biological) Systems), an open-source framework for the construction and analysis of large-scale parametric as well as non-parametric correlation networks for high-dimensional biological data. It features off-the-shelf algorithms suitable for both personal and high-performance computers, enabling workflows and downstream analysis approaches. We illustrate the broad scope and potential of CorALS by exploring perspectives on complex biological processes in large-scale multiomics and single-cell studies.",
-,No,20230427,dnamage,37069357,Transdiagnostic evaluation of epigenetic age acceleration and burden of psychiatric disorders.,Neuropsychopharmacology,"Different psychiatric disorders as well as exposure to adverse life events have individually been associated with multiple age-related diseases and mortality. Age acceleration in different epigenetic clocks can serve as biomarker for such risk and could help to disentangle the interplay of psychiatric comorbidity and early adversity on age-related diseases and mortality. We evaluated five epigenetic clocks (Horvath, Hannum, PhenoAge, GrimAge and DunedinPoAm) in a transdiagnostic psychiatric sample using epigenome-wide DNA methylation data from peripheral blood of 429 subjects from two studies at the Max Planck Institute of Psychiatry. Burden of psychiatric disease, represented by a weighted score, was significantly associated with biological age acceleration as measured by GrimAge and DunedinPoAm (R2-adj. 0.22 and 0.33 for GrimAge and DunedinPoAm, respectively), but not the other investigated clocks. The relation of burden of psychiatric disease appeared independent of differences in socioeconomic status and medication. Our findings indicate that increased burden of psychiatric disease may associate with accelerated biological aging. This highlights the importance of medical management of patients with multiple psychiatric comorbidities and the potential usefulness of specific epigenetic clocks for early detection of risk and targeted intervention to reduce mortality in psychiatric patients.© 2023. The Author(s).",
-,Yes,20230427,ewas,37062770,Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis-findings from the EU-GEI study.,Mol Psychiatry,"Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = <0.001; abuse: OR = 2.16; p < 0.001; neglect: OR = 2.27; p = <0.001). None of the CpG sites significantly mediated the adversity-psychosis association after Bonferroni correction (p < 8.1 × 10-8). However, 28, 34 and 29 differentially methylated probes associated with 21, 27, 20 genes passed a less stringent discovery threshold (p < 5 × 10-5) for composite, abuse and neglect respectively, with a lack of overlap between abuse and neglect. These included genes previously associated to psychosis in EWAS studies, such as PANK1, SPEG TBKBP1, TSNARE1 or H2R. Downstream gene ontology analyses did not reveal any biological pathways that survived false discovery rate correction. Although at a non-significant level, DNAm changes in genes previously associated with schizophrenia in EWAS studies may mediate the CA-psychosis association. These results and associated involved processes such as mitochondrial or histaminergic disfunction, immunity or neural signalling requires replication in well powered samples. The lack of overlap between mediating genes associated with abuse and neglect suggests differential biological trajectories linking CA subtypes and psychosis.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20230427,dnamage,37058531,Cross-national and cross-generational evidence that educational attainment may slow the pace of aging in European-descent individuals.,J Gerontol B Psychol Sci Soc Sci,"Individuals with more education are at lower risk of developing multiple, different age-related diseases than their less educated peers. A reason for this might be that individuals with more education age slower. There are two complications in testing this hypothesis. First, there exists no definitive measure of biological aging. Second, shared genetic factors contribute towards both lower educational attainment and the development of age-related diseases. Here, we tested whether the protective effect of educational attainment was associated with the pace of aging after accounting for genetic factors.We examined data from five studies together totaling almost 17,000 individuals with European ancestry born in different countries during different historical periods, ranging in age from 16 to 98 years old. To assess the pace of aging, we used DunedinPACE, a DNA methylation algorithm that reflects an individual's rate of aging and predicts age-related decline and Alzheimer's Disease and Related Disorders (ADRD). To assess genetic factors related to education we created a polygenic score (PGS) based on results of a genome-wide association study (GWAS) of educational attainment.Across the five studies, and across the lifespan, higher educational attainment was associated with a slower pace of aging even after accounting for genetic factors (meta-analysis effect size=-0.20, 95%CI[-0.30- -0.10]; p-value = 0.006). Further, this effect persisted after taking into account tobacco smoking (meta-analysis effect size=-0.13, 95%CI[-0.21- -0.05]; p-value = 0.01).These results indicate that higher levels of education have positive effects on the pace of aging, and that the benefits can be realized irrespective of individuals' genetics.© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
-,No,20230427,dnamage,37031184,Effects of epigenetic age acceleration on kidney function: a Mendelian randomization study.,Clin Epigenetics,"Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function.Using summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with - 0.01 and - 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR.This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.© 2023. The Author(s).",
-,Yes,20230427,ewas,37029435,Impact of intrauterine exposure to maternal diabetes on preterm birth: fetal DNA methylation alteration is an important mediator.,Clin Epigenetics,"In utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population.This study included 954 mother-newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package.126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%.In this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth.© 2023. The Author(s).",
-,No,20230427,dnamage,37027157,Association of Race and Poverty Status With DNA Methylation-Based Age.,JAMA Netw Open,"The Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE) measure is a newly constructed DNA methylation (DNAm) biomarker associated with morbidity, mortality, and adverse childhood experiences in several cohorts with European ancestry. However, there are few studies of the DunedinPACE measure among socioeconomically and racially diverse cohorts with longitudinal assessments.To investigate the association of race and poverty status with DunedinPACE scores in a socioeconomically diverse middle-aged cohort of African American and White participants.This longitudinal cohort study used data from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study. HANDLS is a population-based study of socioeconomically diverse African American and White adults aged 30 to 64 years at baseline in Baltimore, Maryland, with follow-up approximately every 5 years. The current study was restricted to 470 participants with blood samples at 2 time points: August 14, 2004, to June 22, 2009 (visit 1), and June 23, 2009, to September 12, 2017 (visit 2). Genome-wide DNAm was assessed at visit 1 (chronological age, 30-64 years) and visit 2. Data were analyzed from March 18, 2022, to February 9, 2023.DunedinPACE scores were estimated for each participant at 2 visits. DunedinPACE scores are values scaled to a mean of 1, interpretable with reference to a rate of 1 year of biological aging per 1 year of chronological aging. Linear mixed-model regression analysis was used to examine the trajectories of DunedinPACE scores by chronological age, race, sex, and poverty status.Among 470 participants, the mean (SD) chronological age at visit 1 was 48.7 (8.7) years. Participants were balanced by sex (238 [50.6%] were men and 232 [49.4%] were women), race (237 [50.4%] African American and 233 [49.6%] White), and poverty status (236 [50.2%] living below poverty level and 234 [49.8%] living above poverty level). The mean (SD) time between visits was 5.1 (1.5) years. Overall, the mean (SD) DunedinPACE score was 1.07 (0.14), representing a 7% faster pace of biological aging than chronological aging. Linear mixed-effects regression analysis revealed an association between the 2-way interaction between race and poverty status (White race and household income below poverty level: β = 0.0665; 95% CI, 0.0298-0.1031; P < .001) and significantly higher DunedinPACE scores and an association between quadratic age (age squared: β = -0.0113; 95% CI, -0.0212 to -0.0013; P = .03) and significantly higher DunedinPACE scores.In this cohort study, household income below poverty level and African American race were associated with higher DunedinPACE scores. These findings suggest that the DunedinPACE biomarker varies with race and poverty status as adverse social determinants of health. Consequently, measures of accelerated aging should be based on representative samples.",
-,No,20230427,dnamage,37046280,DNA methylation age at birth and childhood: performance of epigenetic clocks and characteristics associated with epigenetic age acceleration in the Project Viva cohort.,Clin Epigenetics,"Epigenetic age acceleration (EAA) and epigenetic gestational age acceleration (EGAA) are biomarkers of physiological development and may be affected by the perinatal environment. The aim of this study was to evaluate performance of epigenetic clocks and to identify biological and sociodemographic correlates of EGAA and EAA at birth and in childhood. In the Project Viva pre-birth cohort, DNA methylation was measured in nucleated cells in cord blood (leukocytes and nucleated red blood cells, N = 485) and leukocytes in early (N = 120, median age = 3.2 years) and mid-childhood (N = 460, median age = 7.7 years). We calculated epigenetic gestational age (EGA; Bohlin and Knight clocks) and epigenetic age (EA; Horvath and skin & blood clocks), and respective measures of EGAA and EAA. We evaluated the performance of clocks relative to chronological age using correlations and median absolute error. We tested for associations of maternal-child characteristics with EGAA and EAA using mutually adjusted linear models controlling for estimated cell type proportions. We also tested associations of Horvath EA at birth with childhood EAA.Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGA r = 0.82, p < 0.001). Horvath and skin & blood EA were weakly correlated with gestational age, but moderately correlated with chronological age in childhood (r = 0.45-0.65). Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males. When comparing self-reported Asian, Black, Hispanic, and more than one race or other racial/ethnic groups to White, we identified significant differences in EGAA and EAA at birth and in mid-childhood, but associations varied across clocks. Horvath EA at birth was positively associated with childhood Horvath and skin & blood EAA.Maternal smoking during pregnancy and child sex were associated with EGAA and EAA at multiple timepoints. Further research may provide insight into the relationship between perinatal factors, pediatric epigenetic aging, and health and development across the lifespan.© 2023. The Author(s).",
-,Yes,20230427,ewas,37038196,Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects.,Alzheimers Res Ther,"Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis.We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181(pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset.We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau181in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker.Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.© 2023. The Author(s).",
-,No,20230427,sperm,37059740,Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development.,Nat Commun,"Although more studies are demonstrating that a father's environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought that sperm exclusively contributed its genome to the egg. More recently, association studies have shown that various environmental exposures including poor diet, toxicants, and stress, perturbed epigenetic marks in sperm at important reproductive and developmental loci that were associated with offspring phenotypes. The molecular and cellular routes that underlie how epigenetic marks are transmitted at fertilization, to resist epigenetic reprogramming in the embryo, and drive phenotypic changes are only now beginning to be unraveled. Here, we provide an overview of the state of the field of intergenerational paternal epigenetic inheritance in mammals and present new insights into the relationship between embryo development and the three pillars of epigenetic inheritance: chromatin, DNA methylation, and non-coding RNAs. We evaluate compelling evidence of sperm-mediated transmission and retention of paternal epigenetic marks in the embryo. Using landmark examples, we discuss how sperm-inherited regions may escape reprogramming to impact development via mechanisms that implicate transcription factors, chromatin organization, and transposable elements. Finally, we link paternally transmitted epigenetic marks to functional changes in the pre- and post-implantation embryo. Understanding how sperm-inherited epigenetic factors influence embryo development will permit a greater understanding related to the developmental origins of health and disease.© 2023. The Author(s).",
-,No,20230427,methods,37072822,The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles.,Genome Biol,"A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analyzing 23 methods from the ENCODE Imputation Challenge. We find that imputation evaluations are challenging and confounded by distributional shifts from differences in data collection and processing over time, the amount of available data, and redundancy among performance measures. Our analyses suggest simple steps for overcoming these issues and promising directions for more robust research.© 2023. The Author(s).",
-,No,20230427,dnamage,36811674,DNA methylation-based age estimation for adults and minors: considering sex-specific differences and non-linear correlations.,Int J Legal Med,"DNA methylation patterns change during human lifetime; thus, they can be used to estimate an individual's age. It is known, however, that correlation between DNA methylation and aging might not be linear and that the sex might influence the methylation status. In this study, we conducted a comparative evaluation of linear and several non-linear regressions, as well as sex-specific versus unisex models. Buccal swab samples from 230 donors aged 1 to 88 years were analyzed using a minisequencing multiplex array. Samples were divided into a training set (n = 161) and a validation set (n = 69). The training set was used for a sequential replacement regression and a simultaneous 10-fold cross-validation. The resulting model was improved by including a cut-off of 20 years, dividing the younger individuals with non-linear from the older individuals with linear dependence between age and methylation status. Sex-specific models were developed and improved prediction accuracy in females but not in males, which might be explained by a small sample set. We finally established a non-linear, unisex model combining the markers EDARADD, KLF14, ELOVL2, FHL2, C1orf132, and TRIM59. While age- and sex-adjustments did not generally improve the performance of our model, we discuss how other models and large cohorts might benefit from such adjustments. Our model showed a cross-validated MAD and RMSE of 4.680 and 6.436 years in the training set and of 4.695 and 6.602 years in the validation set, respectively. We briefly explain how to apply the model for age prediction.© 2023. The Author(s).",
-,No,20230427,dnamage,36917095,Socioeconomic inequalities in the Pace of Aging,Aging (Albany NY),,
-,No,20230427,dnamage,34951641,Associations Between Life-Course Socioeconomic Conditions and the Pace of Aging,J Gerontol A Biol Sci Med Sci,"Background: Socioeconomic disadvantage is a well-established predictor of morbidity and mortality, and is thought to accelerate the aging process. This study examined associations between life-course socioeconomic conditions and the Pace of Aging, a longitudinal measure of age-related physiological decline.
+No,20230427,dnamage,37069357,Transdiagnostic evaluation of epigenetic age acceleration and burden of psychiatric disorders.,Neuropsychopharmacology,"Different psychiatric disorders as well as exposure to adverse life events have individually been associated with multiple age-related diseases and mortality. Age acceleration in different epigenetic clocks can serve as biomarker for such risk and could help to disentangle the interplay of psychiatric comorbidity and early adversity on age-related diseases and mortality. We evaluated five epigenetic clocks (Horvath, Hannum, PhenoAge, GrimAge and DunedinPoAm) in a transdiagnostic psychiatric sample using epigenome-wide DNA methylation data from peripheral blood of 429 subjects from two studies at the Max Planck Institute of Psychiatry. Burden of psychiatric disease, represented by a weighted score, was significantly associated with biological age acceleration as measured by GrimAge and DunedinPoAm (R2-adj. 0.22 and 0.33 for GrimAge and DunedinPoAm, respectively), but not the other investigated clocks. The relation of burden of psychiatric disease appeared independent of differences in socioeconomic status and medication. Our findings indicate that increased burden of psychiatric disease may associate with accelerated biological aging. This highlights the importance of medical management of patients with multiple psychiatric comorbidities and the potential usefulness of specific epigenetic clocks for early detection of risk and targeted intervention to reduce mortality in psychiatric patients.© 2023. The Author(s).",
+Yes,20230427,ewas,37062770,Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis-findings from the EU-GEI study.,Mol Psychiatry,"Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = <0.001; abuse: OR = 2.16; p < 0.001; neglect: OR = 2.27; p = <0.001). None of the CpG sites significantly mediated the adversity-psychosis association after Bonferroni correction (p < 8.1 × 10-8). However, 28, 34 and 29 differentially methylated probes associated with 21, 27, 20 genes passed a less stringent discovery threshold (p < 5 × 10-5) for composite, abuse and neglect respectively, with a lack of overlap between abuse and neglect. These included genes previously associated to psychosis in EWAS studies, such as PANK1, SPEG TBKBP1, TSNARE1 or H2R. Downstream gene ontology analyses did not reveal any biological pathways that survived false discovery rate correction. Although at a non-significant level, DNAm changes in genes previously associated with schizophrenia in EWAS studies may mediate the CA-psychosis association. These results and associated involved processes such as mitochondrial or histaminergic disfunction, immunity or neural signalling requires replication in well powered samples. The lack of overlap between mediating genes associated with abuse and neglect suggests differential biological trajectories linking CA subtypes and psychosis.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20230427,dnamage,37058531,Cross-national and cross-generational evidence that educational attainment may slow the pace of aging in European-descent individuals.,J Gerontol B Psychol Sci Soc Sci,"Individuals with more education are at lower risk of developing multiple, different age-related diseases than their less educated peers. A reason for this might be that individuals with more education age slower. There are two complications in testing this hypothesis. First, there exists no definitive measure of biological aging. Second, shared genetic factors contribute towards both lower educational attainment and the development of age-related diseases. Here, we tested whether the protective effect of educational attainment was associated with the pace of aging after accounting for genetic factors.We examined data from five studies together totaling almost 17,000 individuals with European ancestry born in different countries during different historical periods, ranging in age from 16 to 98 years old. To assess the pace of aging, we used DunedinPACE, a DNA methylation algorithm that reflects an individual's rate of aging and predicts age-related decline and Alzheimer's Disease and Related Disorders (ADRD). To assess genetic factors related to education we created a polygenic score (PGS) based on results of a genome-wide association study (GWAS) of educational attainment.Across the five studies, and across the lifespan, higher educational attainment was associated with a slower pace of aging even after accounting for genetic factors (meta-analysis effect size=-0.20, 95%CI[-0.30- -0.10]; p-value = 0.006). Further, this effect persisted after taking into account tobacco smoking (meta-analysis effect size=-0.13, 95%CI[-0.21- -0.05]; p-value = 0.01).These results indicate that higher levels of education have positive effects on the pace of aging, and that the benefits can be realized irrespective of individuals' genetics.© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
+No,20230427,dnamage,37031184,Effects of epigenetic age acceleration on kidney function: a Mendelian randomization study.,Clin Epigenetics,"Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function.Using summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with - 0.01 and - 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR.This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.© 2023. The Author(s).",
+Yes,20230427,ewas,37029435,Impact of intrauterine exposure to maternal diabetes on preterm birth: fetal DNA methylation alteration is an important mediator.,Clin Epigenetics,"In utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population.This study included 954 mother-newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package.126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%.In this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth.© 2023. The Author(s).",
+No,20230427,dnamage,37027157,Association of Race and Poverty Status With DNA Methylation-Based Age.,JAMA Netw Open,"The Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE) measure is a newly constructed DNA methylation (DNAm) biomarker associated with morbidity, mortality, and adverse childhood experiences in several cohorts with European ancestry. However, there are few studies of the DunedinPACE measure among socioeconomically and racially diverse cohorts with longitudinal assessments.To investigate the association of race and poverty status with DunedinPACE scores in a socioeconomically diverse middle-aged cohort of African American and White participants.This longitudinal cohort study used data from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study. HANDLS is a population-based study of socioeconomically diverse African American and White adults aged 30 to 64 years at baseline in Baltimore, Maryland, with follow-up approximately every 5 years. The current study was restricted to 470 participants with blood samples at 2 time points: August 14, 2004, to June 22, 2009 (visit 1), and June 23, 2009, to September 12, 2017 (visit 2). Genome-wide DNAm was assessed at visit 1 (chronological age, 30-64 years) and visit 2. Data were analyzed from March 18, 2022, to February 9, 2023.DunedinPACE scores were estimated for each participant at 2 visits. DunedinPACE scores are values scaled to a mean of 1, interpretable with reference to a rate of 1 year of biological aging per 1 year of chronological aging. Linear mixed-model regression analysis was used to examine the trajectories of DunedinPACE scores by chronological age, race, sex, and poverty status.Among 470 participants, the mean (SD) chronological age at visit 1 was 48.7 (8.7) years. Participants were balanced by sex (238 [50.6%] were men and 232 [49.4%] were women), race (237 [50.4%] African American and 233 [49.6%] White), and poverty status (236 [50.2%] living below poverty level and 234 [49.8%] living above poverty level). The mean (SD) time between visits was 5.1 (1.5) years. Overall, the mean (SD) DunedinPACE score was 1.07 (0.14), representing a 7% faster pace of biological aging than chronological aging. Linear mixed-effects regression analysis revealed an association between the 2-way interaction between race and poverty status (White race and household income below poverty level: β = 0.0665; 95% CI, 0.0298-0.1031; P < .001) and significantly higher DunedinPACE scores and an association between quadratic age (age squared: β = -0.0113; 95% CI, -0.0212 to -0.0013; P = .03) and significantly higher DunedinPACE scores.In this cohort study, household income below poverty level and African American race were associated with higher DunedinPACE scores. These findings suggest that the DunedinPACE biomarker varies with race and poverty status as adverse social determinants of health. Consequently, measures of accelerated aging should be based on representative samples.",
+No,20230427,dnamage,37046280,DNA methylation age at birth and childhood: performance of epigenetic clocks and characteristics associated with epigenetic age acceleration in the Project Viva cohort.,Clin Epigenetics,"Epigenetic age acceleration (EAA) and epigenetic gestational age acceleration (EGAA) are biomarkers of physiological development and may be affected by the perinatal environment. The aim of this study was to evaluate performance of epigenetic clocks and to identify biological and sociodemographic correlates of EGAA and EAA at birth and in childhood. In the Project Viva pre-birth cohort, DNA methylation was measured in nucleated cells in cord blood (leukocytes and nucleated red blood cells, N = 485) and leukocytes in early (N = 120, median age = 3.2 years) and mid-childhood (N = 460, median age = 7.7 years). We calculated epigenetic gestational age (EGA; Bohlin and Knight clocks) and epigenetic age (EA; Horvath and skin & blood clocks), and respective measures of EGAA and EAA. We evaluated the performance of clocks relative to chronological age using correlations and median absolute error. We tested for associations of maternal-child characteristics with EGAA and EAA using mutually adjusted linear models controlling for estimated cell type proportions. We also tested associations of Horvath EA at birth with childhood EAA.Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGA r = 0.82, p < 0.001). Horvath and skin & blood EA were weakly correlated with gestational age, but moderately correlated with chronological age in childhood (r = 0.45-0.65). Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males. When comparing self-reported Asian, Black, Hispanic, and more than one race or other racial/ethnic groups to White, we identified significant differences in EGAA and EAA at birth and in mid-childhood, but associations varied across clocks. Horvath EA at birth was positively associated with childhood Horvath and skin & blood EAA.Maternal smoking during pregnancy and child sex were associated with EGAA and EAA at multiple timepoints. Further research may provide insight into the relationship between perinatal factors, pediatric epigenetic aging, and health and development across the lifespan.© 2023. The Author(s).",
+Yes,20230427,ewas,37038196,Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects.,Alzheimers Res Ther,"Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis.We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181(pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset.We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau181in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker.Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.© 2023. The Author(s).",
+No,20230427,sperm,37059740,Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development.,Nat Commun,"Although more studies are demonstrating that a father's environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought that sperm exclusively contributed its genome to the egg. More recently, association studies have shown that various environmental exposures including poor diet, toxicants, and stress, perturbed epigenetic marks in sperm at important reproductive and developmental loci that were associated with offspring phenotypes. The molecular and cellular routes that underlie how epigenetic marks are transmitted at fertilization, to resist epigenetic reprogramming in the embryo, and drive phenotypic changes are only now beginning to be unraveled. Here, we provide an overview of the state of the field of intergenerational paternal epigenetic inheritance in mammals and present new insights into the relationship between embryo development and the three pillars of epigenetic inheritance: chromatin, DNA methylation, and non-coding RNAs. We evaluate compelling evidence of sperm-mediated transmission and retention of paternal epigenetic marks in the embryo. Using landmark examples, we discuss how sperm-inherited regions may escape reprogramming to impact development via mechanisms that implicate transcription factors, chromatin organization, and transposable elements. Finally, we link paternally transmitted epigenetic marks to functional changes in the pre- and post-implantation embryo. Understanding how sperm-inherited epigenetic factors influence embryo development will permit a greater understanding related to the developmental origins of health and disease.© 2023. The Author(s).",
+No,20230427,methods,37072822,The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles.,Genome Biol,"A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analyzing 23 methods from the ENCODE Imputation Challenge. We find that imputation evaluations are challenging and confounded by distributional shifts from differences in data collection and processing over time, the amount of available data, and redundancy among performance measures. Our analyses suggest simple steps for overcoming these issues and promising directions for more robust research.© 2023. The Author(s).",
+No,20230427,dnamage,36811674,DNA methylation-based age estimation for adults and minors: considering sex-specific differences and non-linear correlations.,Int J Legal Med,"DNA methylation patterns change during human lifetime; thus, they can be used to estimate an individual's age. It is known, however, that correlation between DNA methylation and aging might not be linear and that the sex might influence the methylation status. In this study, we conducted a comparative evaluation of linear and several non-linear regressions, as well as sex-specific versus unisex models. Buccal swab samples from 230 donors aged 1 to 88 years were analyzed using a minisequencing multiplex array. Samples were divided into a training set (n = 161) and a validation set (n = 69). The training set was used for a sequential replacement regression and a simultaneous 10-fold cross-validation. The resulting model was improved by including a cut-off of 20 years, dividing the younger individuals with non-linear from the older individuals with linear dependence between age and methylation status. Sex-specific models were developed and improved prediction accuracy in females but not in males, which might be explained by a small sample set. We finally established a non-linear, unisex model combining the markers EDARADD, KLF14, ELOVL2, FHL2, C1orf132, and TRIM59. While age- and sex-adjustments did not generally improve the performance of our model, we discuss how other models and large cohorts might benefit from such adjustments. Our model showed a cross-validated MAD and RMSE of 4.680 and 6.436 years in the training set and of 4.695 and 6.602 years in the validation set, respectively. We briefly explain how to apply the model for age prediction.© 2023. The Author(s).",
+No,20230427,dnamage,36917095,Socioeconomic inequalities in the Pace of Aging,Aging (Albany NY),,
+No,20230427,dnamage,34951641,Associations Between Life-Course Socioeconomic Conditions and the Pace of Aging,J Gerontol A Biol Sci Med Sci,"Background: Socioeconomic disadvantage is a well-established predictor of morbidity and mortality, and is thought to accelerate the aging process. This study examined associations between life-course socioeconomic conditions and the Pace of Aging, a longitudinal measure of age-related physiological decline.
 
 Methods: Data were drawn from a Swiss population-based cohort of individuals originally recruited between 2003 and 2006, and followed up for 11 years (2 834 women, 2 475 men aged 35-75 years [mean 52]). Pace of Aging was measured using 3 repeated assessments of 12 biomarkers reflecting multiple body systems. Analysis tested associations of socioeconomic conditions with physiological status at baseline and with the Pace of Aging.
 
 Results: Participants with more life-course socioeconomic disadvantage were physiologically older at baseline and experienced faster Pace of Aging. Effect sizes (?) for associations of childhood socioeconomic disadvantage with baseline physiological status ranged from 0.1 to 0.2; for adulthood socioeconomic disadvantage, effect sizes ranged from 0.2 to 0.3. Effect sizes were smaller for associations with the Pace of Aging (<0.05 for childhood disadvantage, 0.05-0.1 for adulthood disadvantage). Those who experienced disadvantaged socioeconomic conditions from childhood to adulthood aged 10% faster over the 11 years of follow-up as compared with those who experienced consistently advantaged socioeconomic conditions. Covariate adjustment for health behaviors attenuated associations, but most remained statistically significant.
 
 Conclusions: Socioeconomic inequalities contribute to a faster Pace of Aging, partly through differences in health behaviors. Intervention to slow aging in at-risk individuals is needed by midlife, before etiology of aging-related diseases become established.",
-,No,20230427,ctdna,37055640,Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.,Nature,"Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.© 2023. The Author(s).",
-,No,20230427,aging,37046086,Ageing-associated changes in transcriptional elongation influence longevity,Nature,"Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.",
-,No,20230427,methods,36747096,Simultaneous sequencing of genetic and epigenetic bases in DNA,Nat Biotechnol,"DNA comprises molecular information stored in genetic and epigenetic bases, both of which are vital to our understanding of biology. Most DNA sequencing approaches address either genetics or epigenetics and thus capture incomplete information. Methods widely used to detect epigenetic DNA bases fail to capture common C-to-T mutations or distinguish 5-methylcytosine from 5-hydroxymethylcytosine. We present a single base-resolution sequencing methodology that sequences complete genetics and the two most common cytosine modifications in a single workflow. DNA is copied and bases are enzymatically converted. Coupled decoding of bases across the original and copy strand provides a phased digital readout. Methods are demonstrated on human genomic DNA and cell-free DNA from a blood sample of a patient with cancer. The approach is accurate, requires low DNA input and has a simple workflow and analysis pipeline. Simultaneous, phased reading of genetic and epigenetic bases provides a more complete picture of the information stored in genomes and has applications throughout biomedicine.",
-,Yes,20230525,ewas,37216580,"Impact of tobacco, alcohol, and marijuana on genome-wide DNA methylation and its relationship with hypertension.",Epigenetics,"Tobacco, alcohol, and marijuana consumption is an important public health problem because of their high use worldwide and their association with the risk of mortality and many health conditions, such as hypertension, which is the commonest risk factor for death throughout the world. A likely pathway of action of substance consumption leading to persistent hypertension is DNA methylation. Here, we evaluated the effects of tobacco, alcohol, and marijuana on DNA methylation in the same cohort (N = 3,424). Three epigenome-wide association studies (EWAS) were assessed in whole blood using the InfiniumHumanMethylationEPIC BeadChip. We also evaluated the mediation of the top CpG sites in the association between substance consumption and hypertension. Our analyses showed 2,569 CpG sites differentially methylated by alcohol drinking and 528 by tobacco smoking. We did not find significant associations with marijuana consumption after correcting for multiple comparisons. We found 61 genes overlapping between alcohol and tobacco that were enriched in biological processes involved in the nervous and cardiovascular systems. In the mediation analysis, we found 66 CpG sites that significantly mediated the effect of alcohol consumption on hypertension. The top alcohol-related CpG site (cg06690548, P-value = 5.9·10-83) mapped to SLC7A11 strongly mediated 70.5% of the effect of alcohol consumption on hypertension (P-value = 0.006). Our findings suggest that DNA methylation should be considered for new targets in hypertension prevention and management, particularly concerning alcohol consumption. Our data also encourage further research into the use of methylation in blood to study the neurological and cardiovascular effects of substance consumption.",
-,Yes,20230525,ewas,37212434,Epigenetic Association Analyses and Risk Prediction of RLS.,Mov Disord,"As opposed to other neurobehavioral disorders, epigenetic analyses and biomarkers are largely missing in the case of idiopathic restless legs syndrome (RLS).Our aims were to develop a biomarker for RLS based on DNA methylation in blood and to examine DNA methylation in brain tissues for dissecting RLS pathophysiology.Methylation of blood DNA from three independent cohorts (n = 2283) and post-mortem brain DNA from two cohorts (n = 61) was assessed by Infinium EPIC 850 K BeadChip. Epigenome-wide association study (EWAS) results of individual cohorts were combined by random-effect meta-analysis. A three-stage selection procedure (discovery, n = 884; testing, n = 520; validation, n = 879) established an epigenetic risk score including 30 CpG sites. Epigenetic age was assessed by Horvath's multi-tissue clock and Shireby's cortical clock.EWAS meta-analysis revealed 149 CpG sites linked to 136 genes (P < 0.05 after Bonferroni correction) in blood and 23 CpG linked to 18 genes in brain (false discovery rate [FDR] < 5%). Gene-set analyses of blood EWAS results suggested enrichments in brain tissue types and in subunits of the kainate-selective glutamate receptor complex. Individual candidate genes of the brain EWAS could be assigned to neurodevelopmental or metabolic traits. The blood epigenetic risk score achieved an area under the curve (AUC) of 0.70 (0.67-0.73) in the validation set, comparable to analogous scores in other neurobehavioral disorders. A significant difference in biological age in blood or brain of RLS patients was not detectable.DNA methylation supports the notion of altered neurodevelopment in RLS. Epigenetic risk scores are reliably associated with RLS but require even higher accuracy to be useful as biomarkers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",
-,Yes,20230525,ewas,37210443,Epigenome-wide association study of diabetic chronic kidney disease progression in the Korean population: the KNOW-CKD study.,Sci Rep,"Since the etiology of diabetic chronic kidney disease (CKD) is multifactorial, studies on DNA methylation for kidney function deterioration have rarely been performed despite the need for an epigenetic approach. Therefore, this study aimed to identify epigenetic markers associated with CKD progression based on the decline in the estimated glomerular filtration rate in diabetic CKD in Korea. An epigenome-wide association study was performed using whole blood samples from 180 CKD recruited from the KNOW-CKD cohort. Pyrosequencing was also performed on 133 CKD participants as an external replication analysis. Functional analyses, including the analysis of disease-gene networks, reactome pathways, and protein-protein interaction networks, were conducted to identify the biological mechanisms of CpG sites. A phenome-wide association study was performed to determine the associations between CpG sites and other phenotypes. Two epigenetic markers, cg10297223 on AGTR1 and cg02990553 on KRT28 indicated a potential association with diabetic CKD progression. Based on the functional analyses, other phenotypes (blood pressure and cardiac arrhythmia for AGTR1) and biological pathways (keratinization and cornified envelope for KRT28) related to CKD were also identified. This study suggests a potential association between the cg10297223 and cg02990553 and the progression of diabetic CKD in Koreans. Nevertheless, further validation is needed through additional studies.© 2023. The Author(s).",
-,No,20230525,epigenetics,37205524,Combinatorial quantification of 5mC and 5hmC at individual CpG dyads and the transcriptome in single cells reveals modulators of DNA methylation maintenance fidelity.,bioRxiv,"Transmission of 5-methylcytosine (5mC) from one cell generation to the next plays a key role in regulating cellular identity in mammalian development and diseases. While recent work has shown that the activity of DNMT1, the protein responsible for the stable inheritance of 5mC from mother to daughter cells, is imprecise; it remains unclear how the fidelity of DNMT1 is tuned in different genomic and cell state contexts. Here we describe Dyad-seq, a method that combines enzymatic detection of modified cytosines with nucleobase conversion techniques to quantify the genome-wide methylation status of cytosines at the resolution of individual CpG dinucleotides. We find that the fidelity of DNMT1-mediated maintenance methylation is directly related to the local density of DNA methylation, and for genomic regions that are lowly methylated, histone modifications can dramatically alter the maintenance methylation activity. Further, to gain deeper insights into the methylation and demethylation turnover dynamics, we extended Dyad-seq to quantify all combinations of 5mC and 5-hydroxymethylcytosine (5hmC) at individual CpG dyads to show that TET proteins preferentially hydroxymethylate only one of the two 5mC sites in a symmetrically methylated CpG dyad rather than sequentially convert both 5mC to 5hmC. To understand how cell state transitions impact DNMT1-mediated maintenance methylation, we scaled the method down and combined it with the measurement of mRNA to simultaneously quantify genome-wide methylation levels, maintenance methylation fidelity and the transcriptome from the same cell (scDyad&T-seq). Applying scDyad&T-seq to mouse embryonic stem cells transitioning from serum to 2i conditions, we observe dramatic and heterogenous demethylation and the emergence of transcriptionally distinct subpopulations that are closely linked to the cell-to-cell variability in loss of DNMT1-mediated maintenance methylation activity, with regions of the genome that escape 5mC reprogramming retaining high levels of maintenance methylation fidelity. Overall, our results demonstrate that while distinct cell states can substantially impact the genome-wide activity of the DNA methylation maintenance machinery, locally there exists an intrinsic relationship between DNA methylation density, histone modifications and DNMT1-mediated maintenance methylation fidelity that is independent of cell state.",
-,Yes,20230525,ewas,37204309,Environment- and epigenome-wide association study of obesity in 'Children of 1997' birth cohort.,Elife,"Increasing childhood obesity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of obesity at the onset and end of puberty in Hong Kong, the most economically developed major Chinese city.We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of obesity to systematically assess associations with body mass index (BMI) and waist-hip ratio (WHR) in Hong Kong's population-representative 'Children of 1997' birth cohort. Univariable linear regression was used to select exposures related to obesity at ~11.5 years (BMI and obesity riskn≤ 7119, WHRn= 5691) and ~17.6 years (n= 3618) at Bonferroni-corrected significance, and multivariable regression to adjust for potential confounders followed by replicated multivariable regression (n= 308) and CpG by CpG analysis (n= 286) at ~23 years. Findings were compared with evidence from published randomized controlled trials (RCTs) and Mendelian randomization (MR) studies.At ~11.5 and~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as 7 and 12 associated with WHR, respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with obesity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, and binge eating are consistent with available evidence from RCTs or MR studies. We found 17 CpGs related to BMI and 17 to WHR.These novel insights into potentially modifiable factors associated with obesity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings.This study including the follow-up survey and epigenetics testing was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction of the samples used for epigenetic testing was supported by CFS-HKU1.© 2023, Zhao, Fan et al.",
-,No,20230525,MR,37202507,Investigating causality in the association between DNA methylation and type 2 diabetes using bidirectional two-sample Mendelian randomisation.,Diabetologia,"Several studies have identified associations between type 2 diabetes and DNA methylation (DNAm). However, the causal role of these associations remains unclear. This study aimed to provide evidence for a causal relationship between DNAm and type 2 diabetes.We used bidirectional two-sample Mendelian randomisation (2SMR) to evaluate causality at 58 CpG sites previously detected in a meta-analysis of epigenome-wide association studies (meta-EWAS) of prevalent type 2 diabetes in European populations. We retrieved genetic proxies for type 2 diabetes and DNAm from the largest genome-wide association study (GWAS) available. We also used data from the Avon Longitudinal Study of Parents and Children (ALSPAC, UK) when associations of interest were not available in the larger datasets. We identified 62 independent SNPs as proxies for type 2 diabetes, and 39 methylation quantitative trait loci as proxies for 30 of the 58 type 2 diabetes-related CpGs. We applied the Bonferroni correction for multiple testing and inferred causality based on p<0.001 for the type 2 diabetes to DNAm direction and p<0.002 for the opposing DNAm to type 2 diabetes direction in the 2SMR analysis.We found strong evidence of a causal effect of DNAm at cg25536676 (DHCR24) on type 2 diabetes. An increase in transformed residuals of DNAm at this site was associated with a 43% (OR 1.43, 95% CI 1.15, 1.78, p=0.001) higher risk of type 2 diabetes. We inferred a likely causal direction for the remaining CpG sites assessed. In silico analyses showed that the CpGs analysed were enriched for expression quantitative trait methylation sites (eQTMs) and for specific traits, dependent on the direction of causality predicted by the 2SMR analysis.We identified one CpG mapping to a gene related to the metabolism of lipids (DHCR24) as a novel causal biomarker for risk of type 2 diabetes. CpGs within the same gene region have previously been associated with type 2 diabetes-related traits in observational studies (BMI, waist circumference, HDL-cholesterol, insulin) and in Mendelian randomisation analyses (LDL-cholesterol). Thus, we hypothesise that our candidate CpG in DHCR24 may be a causal mediator of the association between known modifiable risk factors and type 2 diabetes. Formal causal mediation analysis should be implemented to further validate this assumption.© 2023. The Author(s).",
-,No,20230525,methods,37196182,A novel principal component based method for identifying differentially methylated regions in Illumina Infinium MethylationEPIC BeadChip data.,Epigenetics,"Differentially methylated regions (DMRs) are genomic regions with methylation patterns across multiple CpG sites that are associated with a phenotype. In this study, we proposed a Principal Component (PC) based DMR analysis method for use with data generated using the Illumina Infinium MethylationEPIC BeadChip (EPIC) array. We obtained methylation residuals by regressing the M-values of CpGs within a region on covariates, extracted PCs of the residuals, and then combined association information across PCs to obtain regional significance. Simulation-based genome-wide false positive (GFP) rates and true positive rates were estimated under a variety of conditions before determining the final version of our method, which we have named DMRPC. Then, DMRPCand another DMR method, coMethDMR, were used to perform epigenome-wide analyses of several phenotypes known to have multiple associated methylation loci (age, sex, and smoking) in a discovery and a replication cohort. Among regions that were analysed by both methods, DMRPCidentified 50% more genome-wide significant age-associated DMRs than coMethDMR. The replication rate for the loci that were identified by only DMRPCwas higher than the rate for those that were identified by only coMethDMR (90% for DMRPC vs. 76% for coMethDMR). Furthermore, DMRPCidentified replicable associations in regions of moderate between-CpG correlation which are typically not analysed by coMethDMR. For the analyses of sex and smoking, the advantage of DMRPCwas less clear. In conclusion, DMRPCis a new powerful DMR discovery tool that retains power in genomic regions with moderate correlation across CpGs.",
-,No,20230525,imprinting,37189164,Phenome-wide analyses identify an association between the parent-of-origin effects dependent methylome and the rate of aging in humans.,Genome Biol,"The variation in the rate at which humans age may be rooted in early events acting through the genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions enriched for genetically controlled imprinting effects (the typical type of POE) and regions influenced by environmental effects associated with parents (the atypical POE). This part of the methylome is heavily influenced by early events, making it a potential route connecting early exposures, the epigenome, and aging. We aim to test the association of POE-CpGs with early and later exposures and subsequently with health-related phenotypes and adult aging.We perform a phenome-wide association analysis for the POE-influenced methylome using GS:SFHS (Ndiscovery = 5087, Nreplication = 4450). We identify and replicate 92 POE-CpG-phenotype associations. Most of the associations are contributed by the POE-CpGs belonging to the atypical class where the most strongly enriched associations are with aging (DNAmTL acceleration), intelligence, and parental (maternal) smoking exposure phenotypes. A proportion of the atypical POE-CpGs form co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased within-module methylation connectivity with age. The atypical POE-CpGs also display high levels of methylation heterogeneity, fast information loss with age, and a strong correlation with CpGs contained within epigenetic clocks.These results identify the association between the atypical POE-influenced methylome and aging and provide new evidence for the ""early development of origin"" hypothesis for aging in humans.© 2023. The Author(s).",
-,Yes,20230525,ewas,37188674,Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.,Nat Commun,"DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.© 2023. The Author(s).",
-,Yes,20230525,ewas,37188670,DNA methylation markers for kidney function and progression of diabetic kidney disease.,Nat Commun,"Epigenetic markers are potential biomarkers for diabetes and related complications. Using a prospective cohort from the Hong Kong Diabetes Register, we perform two independent epigenome-wide association studies to identify methylation markers associated with baseline estimated glomerular filtration rate (eGFR) and subsequent decline in kidney function (eGFR slope), respectively, in 1,271 type 2 diabetes subjects. Here we show 40 (30 previously unidentified) and eight (all previously unidentified) CpG sites individually reach epigenome-wide significance for baseline eGFR and eGFR slope, respectively. We also develop a multisite analysis method, which selects 64 and 37 CpG sites for baseline eGFR and eGFR slope, respectively. These models are validated in an independent cohort of Native Americans with type 2 diabetes. Our identified CpG sites are near genes enriched for functional roles in kidney diseases, and some show association with renal damage. This study highlights the potential of methylation markers in risk stratification of kidney disease among type 2 diabetes individuals.© 2023. The Author(s).",
-,Yes,20230525,ewas,37184252,Epigenome-wide methylation study identified 2 novel CpGs associated with T2DM risk and a network of co-methylated CpGs capable of patient's classifications.,Hum Mol Genet,"Prevention of Type 2 diabetes mellitus (T2DM) pandemic needs markers that can precisely predict the disease risk in an individual. Alterations in DNA methylations due to exposure towards environmental risk factors are widely sought markers for T2DM risk prediction. To identify such individual DNA methylation signatures and their effect on disease risk, we performed an epigenome-wide association study (EWAS) in 844 Indian individuals of Indo-European origin. We identified and validated methylation alterations at 2 novel CpG sites in MIR1287 (cg01178710), and EDN2-SCMH1 (cg04673737) genes associated with T2DM risk at the epigenome-wide-significance-level (p < 1.2x10-7). Further, we also replicated the association of 2 known CpG sites in TXNIP, and CPT1A in the Indian population. With 535 EWAS significant CpGs (p < 1.2x10-7) identified in the discovery phase samples, we created a co-methylation network using weighted correlation network analysis and identified 4 modules among the CpGs. We observed that methylation of one of the module associates with T2DM risk factors (e.g. BMI, insulin, C-peptide) and can be used as markers to segregate T2DM patients with good glycemic control (e.g. low HbA1c) and dyslipidemia (low HDL and high TG) from the other patients. Additionally, an intronic SNP (rs6503650) in the JUP gene, a member of the same module, associated with methylation at all the 14 hub CpG sites of that module as methQTL. Our network-assisted epigenome-wide association study is the first to systematically explore DNA methylation variations conferring risks to T2DM in Indians and use the identified risk CpG sites for patient segregation with different clinical outcomes. These findings can be useful for better stratification of patients to improve the clinical management and treatment effects.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,Yes,20230525,ewas,37180517,Epigenome-Wide Meta-Analysis Reveals Differential DNA Methylation Associated With Estimated Glomerular Filtration Rate Among African American Men With HIV.,Kidney Int Rep,"People with HIV (PWH) of African ancestry have faster decline of kidney function and faster progression to end-stage renal disease than PWH of European ancestry. DNA methylation have been associated with kidney function in the general population, however, their relationships are unclear for PWH of African ancestry.We performed epigenome-wide association studies (EWAS) of estimated glomerular filtration rate (eGFR) among PWH of African ancestry in 2 subsets of the Veterans Aging Cohort Study cohort (N = 885), followed by a meta-analysis to combine the results. Replication was conducted among independent African American samples without HIV.DNA methylation sites cg17944885 near Zinc Finger Family Member 788 (ZNF788) and Zinc Finger Protein 20 (ZNF20), and cg06930757 inSHANK1were significantly associated with eGFR among PWH of African ancestry (false discovery rate < 0.05). DNA methylation site cg17944885 was also associated with eGFR among different populations including African Americans without HIV.Our study attempted to address an important gap in the literature and to understand the role of DNA methylation in renal diseases in PWH of African ancestry. Replication of cg17944885 among different populations suggests there may be a common pathway for renal diseases progression among PWH and people without HIV, and across different ancestral groups. Our results suggest that genesZNF788/ZNF20andSHANK1could be involved in a pathway linking DNA methylation to renal diseases among PWH and are worth further investigation.",
-,Yes,20230525,mqtl,37169753,meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans.,Nat Commun,"Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fill this critical knowledge gap by performing a large-scale cis-meQTL mapping study in 961 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We identify a total of 4,565,687 cis-acting meQTLs in 320,965 meCpGs. We find that 45% of meCpGs harbor multiple independent meQTLs, suggesting potential polygenic genetic architecture underlying methylation variation. A large percentage of the cis-meQTLs also colocalize with cis-expression QTLs (eQTLs) in the same population. Importantly, the identified cis-meQTLs explain a substantial proportion (median = 24.6%) of methylation variation. In addition, the cis-meQTL associated CpG sites mediate a substantial proportion (median = 24.9%) of SNP effects underlying gene expression. Overall, our results represent an important step toward revealing the co-regulation of methylation and gene expression, facilitating the functional interpretation of epigenetic and gene regulation underlying common diseases in African Americans.© 2023. The Author(s).",
-,Yes,20230525,ewas,37145884,Gene Set Based Integrated Methylome and Transcriptome Analysis Reveals Potential Molecular Mechanisms Linking Cigarette Smoking and Related Diseases.,OMICS,"Advanced integrative analysis of DNA methylation and transcriptomics data may provide deeper insights into smoke-induced epigenetic alterations, their effects on gene expression and related biological processes, linking cigarette smoking and related diseases. We hypothesize that accumulation of DNA methylation changes in CpG sites across genomic locations of different genes might have biological significance. We tested the hypothesis by performing gene set based integrative analysis of blood DNA methylation and transcriptomics data to identify potential transcriptomic consequences of smoking via changes in DNA methylation in the Young Finns Study (YFS) participants (n = 1114, aged 34-49 years, women: 54%, men: 46%). First, we performed epigenome-wide association study (EWAS) of smoking. We then defined sets of genes based on DNA methylation status within their genomic regions, for example, sets of genes containing hyper- or hypomethylated CpG sites in their body or promoter regions. Gene set analysis was performed using transcriptomics data from the same participants. Two sets of genes, one containing 49 genes with hypomethylated CpG sites in their body region and the other containing 33 genes with hypomethylated CpG sites in their promoter region, were differentially expressed among the smokers. Genes in the two gene sets are involved in bone formation, metal ion transport, cell death, peptidyl-serine phosphorylation, and cerebral cortex development process, revealing epigenetic-transcriptomic pathways to smoking-related diseases such as osteoporosis, atherosclerosis, and cognitive impairment. These findings contribute to a deeper understanding of the pathophysiology of smoking-related diseases and may provide potential therapeutic targets.",
-,Yes,20230525,ewas,37139702,DNA methylation at birth and fine motor ability in childhood: an epigenome-wide association study with replication.,Epigenetics,"Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.",
-,No,20230525,dnamage,37163025,Decoding the role of transcriptomic clocks in the human prefrontal cortex.,medRxiv,"Aging is a complex process with interindividual variability, which can be measured by aging biological clocks. Aging clocks are machine-learning algorithms guided by biological information and associated with mortality risk and a wide range of health outcomes. One of these aging clocks are transcriptomic clocks, which uses gene expression data to predict biological age; however, their functional role is unknown. Here, we profiled two transcriptomic clocks (RNAAgeCalc and knowledge-based deep neural network clock) in a large dataset of human postmortem prefrontal cortex (PFC) samples. We identified that deep-learning transcriptomic clock outperforms RNAAgeCalc to predict transcriptomic age in the human PFC. We identified associations of transcriptomic clocks with psychiatric-related traits. Further, we applied system biology algorithms to identify common gene networks among both clocks and performed pathways enrichment analyses to assess its functionality and prioritize genes involved in the aging processes. Identified gene networks showed enrichment for diseases of signal transduction by growth factor receptors and second messenger pathways. We also observed enrichment of genome-wide signals of mental and physical health outcomes and identified genes previously associated with human brain aging. Our findings suggest a link between transcriptomic aging and health disorders, including psychiatric traits. Further, it reveals functional genes within the human PFC that may play an important role in aging and health risk.",
-,No,20230525,dnamage,36812475,DNAmFitAge: biological age indicator incorporating physical fitness,Aging (Albany NY),"Physical fitness is a well-known correlate of health and the aging process and DNA methylation (DNAm) data can capture aging via epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance fitness in their construction. We develop blood-based DNAm biomarkers for fitness parameters gait speed (walking speed), maximum handgrip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max) which have modest correlation with fitness parameters in five large-scale validation datasets (average r between 0.16-0.48). We then use these DNAm fitness parameter biomarkers with DNAmGrimAge, a DNAm mortality risk estimate, to construct DNAmFitAge, a new biological age indicator that incorporates physical fitness. DNAmFitAge is associated with low-intermediate physical activity levels across validation datasets (p = 6.4E-13), and younger/fitter DNAmFitAge corresponds to stronger DNAm fitness parameters in both males and females. DNAmFitAge is lower (p = 0.046) and DNAmVO2max is higher (p = 0.023) in male body builders compared to controls. Physically fit people have a younger DNAmFitAge and experience better age-related outcomes: lower mortality risk (p = 7.2E-51), coronary heart disease risk (p = 2.6E-8), and increased disease-free status (p = 1.1E-7). These new DNAm biomarkers provide researchers a new method to incorporate physical fitness into epigenetic clocks.",
-,No,20230525,dnamage,37209203,DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation.,Geroscience,"DNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm)-based biomarkers that reflect the individual aging process. Here, we examine the relationship between physical fitness and DNAm-based biomarkers in adults aged 33-88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO2max (� = 0.2, p = 6.4E - 4, r = 0.19, p = 1.2E - 3), Jumpmax (p = 0.11, p = 5.5E - 2, r = 0.13, p = 2.8E - 2), Gripmax (� = 0.17, p = 3.5E - 3, r = 0.16, p = 5.6E - 3), and HDL levels (� = 0.18, p = 1.95E - 3, r = 0.19, p = 1.1E - 3) are associated with better verbal short-term memory. In addition, verbal short-term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration (�: - 0.18, p = 0.0017). DNAmFitAge can distinguish high-fitness individuals from low/medium-fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high-fit males and females (1.5 and 2.0 years younger, respectively). Our research shows that regular physical exercise contributes to observable physiological and methylation differences which are beneficial to the aging process. DNAmFitAge has now emerged as a new biological marker of quality of life.© 2023. The Author(s).",
-,No,20230525,pqtl,37148340,Identifying novel genes for amyotrophic lateral sclerosis by integrating human brain proteomes with genome-wide association data.,J Neurol,"Genome-Wide Association Studies (GWAS) have identified numerous risk genes for Amyotrophic Lateral Sclerosis (ALS); however, the mechanisms by which these loci confer ALS risk are uncertain. This study aims to identify novel causal proteins in the brains of patients with ALS using an integrative analytical pipeline.Using the datasets of Protein Quantitative Trait Loci (pQTL) (NpQTL1 = 376, NpQTL2 = 152), expression QTL (eQTL) (N = 452), and the largest ALS GWAS (NALS=27,205, NControls = 110,881), we performed a systematic analytical pipeline including Proteome-Wide Association Study (PWAS), Mendelian Randomization (MR), Bayesian colocalization, and Transcriptome-Wide Association Study (TWAS) to identify novel causal proteins for ALS in the brain.Using PWAS, we found that the altered protein abundance of 12 genes in the brain was associated with ALS. Three genes (SCFD1, SARM1 and CAMLG) were identified as lead causal genes for ALS with solid evidence (False discovery rate < 0.05, in MR analysis; PPH4 > 80% for Bayesian colocalization). Specifically, an increased abundance of SCFD1 and CAMLG led to an increased risk of ALS, whereas a higher abundance of SARM1 led to a decreased risk of developing ALS. TWAS showed that SCFD1 and CAMLG were related to ALS at the transcriptional level.SCFD1, CAMLG, and SARM1 exhibited robust associations and causality with ALS. The study findings provide novel clues for identifying potential therapeutic targets in ALS. Further studies are required to explore the mechanisms underlying the identified genes.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.",
-,No,20230525,single-cell,37161089,Interpreting non-coding disease-associated human variants using single-cell epigenomics.,Nat Rev Genet,"Genome-wide association studies (GWAS) have linked hundreds of thousands of sequence variants in the human genome to common traits and diseases. However, translating this knowledge into a mechanistic understanding of disease-relevant biology remains challenging, largely because such variants are predominantly in non-protein-coding sequences that still lack functional annotation at cell-type resolution. Recent advances in single-cell epigenomics assays have enabled the generation of cell type-, subtype- and state-resolved maps of the epigenome in heterogeneous human tissues. These maps have facilitated cell type-specific annotation of candidate cis-regulatory elements and their gene targets in the human genome, enhancing our ability to interpret the genetic basis of common traits and diseases.© 2023. Springer Nature Limited.",
-,No,20230525,cfdna,37075072,Fragmentation landscape of cell-free DNA revealed by deconvolutional analysis of end motifs.,Proc Natl Acad Sci U S A,"Cell-free DNA (cfDNA) fragmentation is nonrandom, at least partially mediated by various DNA nucleases, forming characteristic cfDNA end motifs. However, there is a paucity of tools for deciphering the relative contributions of cfDNA cleavage patterns related to underlying fragmentation factors. In this study, through non-negative matrix factorization algorithm, we used 256 5' 4-mer end motifs to identify distinct types of cfDNA cleavage patterns, referred to as ""founder"" end-motif profiles (F-profiles). F-profiles were associated with different DNA nucleases based on whether such patterns were disrupted in nuclease-knockout mouse models. Contributions of individual F-profiles in a cfDNA sample could be determined by deconvolutional analysis. We analyzed 93 murine cfDNA samples of different nuclease-deficient mice and identified six types of F-profiles. F-profiles I, II, and III were linked to deoxyribonuclease 1 like 3 (DNASE1L3), deoxyribonuclease 1 (DNASE1), and DNA fragmentation factor subunit beta (DFFB), respectively. We revealed that 42.9% of plasma cfDNA molecules were attributed to DNASE1L3-mediated fragmentation, whereas 43.4% of urinary cfDNA molecules involved DNASE1-mediated fragmentation. We further demonstrated that the relative contributions of F-profiles were useful to inform pathological states, such as autoimmune disorders and cancer. Among the six F-profiles, the use of F-profile I could inform the human patients with systemic lupus erythematosus. F-profile VI could be used to detect individuals with hepatocellular carcinoma, with an area under the receiver operating characteristic curve of 0.97. F-profile VI was more prominent in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. We proposed that this profile might be related to oxidative stress.",
-,No,20230525,prediction,37127594,Early antidepressant treatment response prediction in major depression using clinical and TPH2 DNA methylation features based on machine learning approaches.,BMC Psychiatry,"To identify DNA methylation and clinical features, and to construct machine learning classifiers to assign the patients with major depressive disorder (MDD) into responders and non-responders after a 2-week treatment into responders and non-responders.Han Chinese patients (291 in total) with MDD comprised the study population. Datasets contained demographic information, environment stress factors, and the methylation levels of 38 methylated sites of tryptophan hydroxylase 2 (TPH2) genes in peripheral blood samples. Recursive Feature Elimination (RFE) was employed to select features. Five classification algorithms (logistic regression, classification and regression trees, support vector machine, logitboost and random forests) were used to establish the models. Performance metrics (AUC, F-Measure, G-Mean, accuracy, sensitivity, specificity, positive predictive value and negative predictive value) were computed with 5-fold-cross-validation. Variable importance was evaluated by random forest algorithm.RF with RFE outperformed the other models in our samples based on the demographic information and clinical features (AUC = 61.2%, 95%CI: 60.1-62.4%) / TPH2 CpGs features (AUC = 66.6%, 95%CI: 65.4-67.8%) / both clinical and TPH2 CpGs features (AUC = 72.9%, 95%CI: 71.8-74.0%).The effects of TPH2 on the early-stage antidepressant response were explored by machine learning algorithms. On the basis of the baseline depression severity and TPH2 CpG sites, machine learning approaches can enhance our ability to predict the early-stage antidepressant response. Some potentially important predictors (e.g., TPH2-10-60 (rs2129575), TPH2-2-163 (rs11178998), age of first onset, age) in early-stage treatment response could be utilized in future fundamental research, drug development and clinical practice.© 2023. The Author(s).",
-,No,20230525,transgenerational,37170330,Loss of CpG island immunity to DNA methylation induced by mutation.,Epigenetics Chromatin,"The inheritance of acquired traits in mammals is a highly controversial topic in biology. Recently, Takahashi et al. (Cell 186:715-731, 2023) have reported that insertion of CpG-free DNA into a CpG island (CGI) can induce DNA methylation of the CGI and that this aberrant methylation pattern can be transmitted across generations, even after removal of the foreign DNA. These results were interpreted as evidence for transgenerational inheritance of acquired DNA methylation patterns. Here, we discuss several interpretational issues raised by this study and consider alternative explanations.© 2023. The Author(s).",
-,No,20230525,methods,37161088,Beyond assembly: the increasing flexibility of single-molecule sequencing technology.,Nat Rev Genet,"The maturation of high-throughput short-read sequencing technology over the past two decades has shaped the way genomes are studied. Recently, single-molecule, long-read sequencing has emerged as an essential tool in deciphering genome structure and function, including filling gaps in the human reference genome, measuring the epigenome and characterizing splicing variants in the transcriptome. With recent technological developments, these single-molecule technologies have moved beyond genome assembly and are being used in a variety of ways, including to selectively sequence specific loci with long reads, measure chromatin state and protein-DNA binding in order to investigate the dynamics of gene regulation, and rapidly determine copy number variation. These increasingly flexible uses of single-molecule technologies highlight a young and fast-moving part of the field that is leading to a more accessible era of nucleic acid sequencing.© 2023. Springer Nature Limited.",
-,No,20230525,pangenome,37165242,A draft human pangenome reference.,Nature,"Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.© 2023. The Author(s).",
-,No,20230525,pangenome,37165241,Recombination between heterologous human acrocentric chromosomes.,Nature,"The short arms of the human acrocentric chromosomes 13, 14, 15, 21 and 22 (SAACs) share large homologous regions, including ribosomal DNA repeats and extended segmental duplications1,2. Although the resolution of these regions in the first complete assembly of a human genome-the Telomere-to-Telomere Consortium's CHM13 assembly (T2T-CHM13)-provided a model of their homology3, it remained unclear whether these patterns were ancestral or maintained by ongoing recombination exchange. Here we show that acrocentric chromosomes contain pseudo-homologous regions (PHRs) indicative of recombination between non-homologous sequences. Utilizing an all-to-all comparison of the human pangenome from the Human Pangenome Reference Consortium4(HPRC), we find that contigs from all of the SAACs form a community. A variation graph5constructed from centromere-spanning acrocentric contigs indicates the presence of regions in which most contigs appear nearly identical between heterologous acrocentric chromosomes in T2T-CHM13. Except on chromosome 15, we observe faster decay of linkage disequilibrium in the pseudo-homologous regions than in the corresponding short and long arms, indicating higher rates of recombination6,7. The pseudo-homologous regions include sequences that have previously been shown to lie at the breakpoint of Robertsonian translocations8, and their arrangement is compatible with crossover in inverted duplications on chromosomes 13, 14 and 21. The ubiquity of signals of recombination between heterologous acrocentric chromosomes seen in the HPRC draft pangenome suggests that these shared sequences form the basis for recurrent Robertsonian translocations, providing sequence and population-based confirmation of hypotheses first developed from cytogenetic studies 50 years ago9.© 2023. The Author(s).",
-,No,20230525,genetics,37165237,Increased mutation and gene conversion within human segmental duplications.,Nature,"Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data1,2. Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions3,4. We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have 'relocated' on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences5,6.© 2023. The Author(s).",
-,No,20230525,nanopore,37217507,Linear time complexity de novo long read genome assembly with GoldRush.,Nat Commun,"Current state-of-the-art de novo long read genome assemblers follow the Overlap-Layout-Consensus paradigm. While read-to-read overlap - its most costly step - was improved in modern long read genome assemblers, these tools still often require excessive RAM when assembling a typical human dataset. Our work departs from this paradigm, foregoing all-vs-all sequence alignments in favor of a dynamic data structure implemented in GoldRush, a de novo long read genome assembly algorithm with linear time complexity. We tested GoldRush on Oxford Nanopore Technologies long sequencing read datasets with different base error profiles sourced from three human cell lines, rice, and tomato. Here, we show that GoldRush achieves assembly scaffold NGA50 lengths of 18.3-22.2, 0.3 and 2.6 Mbp, for the genomes of human, rice, and tomato, respectively, and assembles each genome within a day, using at most 54.5 GB of random-access memory, demonstrating the scalability of our genome assembly paradigm and its implementation.© 2023. The Author(s).",
-,No,20230525,methods,37149669,Generalising uncertainty improves accuracy and safety of deep learning analytics applied to oncology.,Sci Rep,"Uncertainty estimation is crucial for understanding the reliability of deep learning (DL) predictions, and critical for deploying DL in the clinic. Differences between training and production datasets can lead to incorrect predictions with underestimated uncertainty. To investigate this pitfall, we benchmarked one pointwise and three approximate Bayesian DL models for predicting cancer of unknown primary, using three RNA-seq datasets with 10,968 samples across 57 cancer types. Our results highlight that simple and scalable Bayesian DL significantly improves the generalisation of uncertainty estimation. Moreover, we designed a prototypical metric-the area between development and production curve (ADP), which evaluates the accuracy loss when deploying models from development to production. Using ADP, we demonstrate that Bayesian DL improves accuracy under data distributional shifts when utilising 'uncertainty thresholding'. In summary, Bayesian DL is a promising approach for generalising uncertainty, improving performance, transparency, and safety of DL models for deployment in the real world.© 2023. The Author(s).",
-,No,20230525,cfdna,37138315,Single-molecule methylation profiles of cell-free DNA in cancer with nanopore sequencing.,Genome Med,"Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to 200 million reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.© 2023. The Author(s).",
-,No,20230504,methods,37081487,pycoMeth: a toolbox for differential methylation testing from Nanopore methylation calls,Genome Biol,"We present pycoMeth, a toolbox to store, manage and analyze DNA methylation calls from long-read sequencing data obtained using the Oxford Nanopore Technologies sequencing platform. Building on a novel, rapid-access, read-level and reference-anchored methylation storage format MetH5, we propose efficient algorithms for haplotype aware, multi-sample consensus segmentation and differential methylation testing. We show that MetH5 is more efficient than existing solutions for storing Oxford Nanopore Technologies methylation calls, and carry out benchmarking for pycoMeth segmentation and differential methylation testing, demonstrating increased performance and sensitivity compared to existing solutions designed for short-read methylation data.",
-,No,20230504,methods,37072822,The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles,Genome Biol,"A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analyzing 23 methods from the ENCODE Imputation Challenge. We find that imputation evaluations are challenging and confounded by distributional shifts from differences in data collection and processing over time, the amount of available data, and redundancy among performance measures. Our analyses suggest simple steps for overcoming these issues and promising directions for more robust research.",
-,No,20230504,single-cell,37131654,Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain.,bioRxiv,"Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brain's 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq1) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH2) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq3dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brain's cellular-spatial and regulatory genome diversity.",
-,Yes,20230504,ewas,37106120,Genes implicated by a methylome-wide schizophrenia study in neonatal blood show differential expression in adult brain samples.,Mol Psychiatry,"Schizophrenia is a disabling disorder involving genetic predisposition in combination with environmental influences that likely act via dynamic alterations of the epigenome and the transcriptome but its detailed pathophysiology is largely unknown. We performed cell-type specific methylome-wide association study of neonatal blood (N = 333) from individuals who later in life developed schizophrenia and controls. Suggestively significant associations (P < 1.0 × 10-6) were detected in all cell-types and in whole blood with methylome-wide significant associations in monocytes (P = 2.85 × 10-9-4.87 × 10-9), natural killer cells (P = 1.72 × 10-9-7.82 × 10-9) and B cells (P = 3.8 × 10-9). Validation of methylation findings in post-mortem brains (N = 596) from independent schizophrenia cases and controls showed significant enrichment of transcriptional differences (enrichment ratio = 1.98-3.23, P = 2.3 × 10-3-1.0 × 10-5), with specific highly significant differential expression for, for example, BDNF (t = -6.11, P = 1.90 × 10-9). In addition, expression difference in brain significantly predicted schizophrenia (multiple correlation = 0.15-0.22, P = 3.6 × 10-4-4.5 × 10-8). In summary, using a unique design combining pre-disease onset (neonatal) blood methylomic data and post-disease onset (post-mortem) brain transcriptional data, we have identified genes of likely functional relevance that are associated with schizophrenia susceptibility, rather than confounding disease associated artifacts. The identified loci may be of clinical value as a methylation-based biomarker for early detection of increased schizophrenia susceptibility.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20230504,ewas,37101222,An epigenome-wide analysis of socioeconomic position and tumor DNA methylation in breast cancer patients.,Clin Epigenetics,"Disadvantaged socioeconomic position (SEP), including lower educational attainment and household income, may influence cancer risk and outcomes. We hypothesized that DNA methylation could function as an intermediary epigenetic mechanism that internalizes and reflects the biological impact of SEP.Based on tumor DNA methylation data from the Illumina 450 K array from 694 breast cancer patients in the Women's Circle of Health Study, we conducted an epigenome-wide analysis in relation to educational attainment and household income. Functional impact of the identified CpG sites was explored in silico using data from publicly available databases.We identified 25 CpG sites associated with household income at an array-wide significance level, but none with educational attainment. Two of the top CpG sites, cg00452016 and cg01667837, were in promoter regions of NNT and GPR37, respectively, with multiple epigenetic regulatory features identified in each region. NNT is involved in β-adrenergic stress signaling and inflammatory responses, whereas GPR37 is involved in neurological and immune responses. For both loci, gene expression was inversely correlated to the levels of DNA methylation. The associations were consistent between Black and White women and did not differ by tumor estrogen receptor (ER) status.In a large breast cancer patient population, we discovered evidence of the significant biological impact of household income on the tumor DNA methylome, including genes in the β-adrenergic stress and immune response pathways. Our findings support biological effects of socioeconomic status on tumor tissues, which might be relevant to cancer development and progression.© 2023. The Author(s).",
-,Yes,20230504,ewas,37093107,A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation.,Epigenetics,"Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery RateP-value <0.05). Persistent associations with DNA methylation in the peripheral blood of up to 482 children aged 4-10 y were observed for 40.7% of CpGs associated with maternal vitamin B12 and 57.1% of CpGs associated with newborn vitamin B12. Of the CpGs identified in the maternal meta-analyses, 4.6% were associated with either birth weight or gestational age in a previous work. For the newborn meta-analysis, this was the case for 14.3% of the identified CpGs. Also, of the CpGs identified in the newborn meta-analysis, 14.3% and 28.6%, respectively, were associated with childhood cognitive skills and nonverbal IQ. Of the 109 CpGs associated with maternal vitamin B12, 18.3% were associated with nearby gene expression. In this study, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood (PFDR<0.05). Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies.",
-,Yes,20230504,ewas,37088033,Umbilical cord DNA methylation is associated with body mass index trajectories from birth to adolescence.,EBioMedicine,"DNA methylation (DNAm) in cord blood has been associated with various prenatal factors and birth outcomes. This study sought to fill an important knowledge gap: the link of cord DNAm with child postnatal growth trajectories from birth to age 18 years (y).Using data from a US predominantly urban, low-income, multi-ethnic birth cohort (N = 831), we first applied non-parametric methods to identify body-mass-index percentile (BMIPCT) trajectories from birth to age 18 y (the outcome); then, conducted epigenome-wide association study (EWAS) of the outcome, interrogating over 700,000 CpG sites profiled by the Illumina Infinium MethylationEPIC BeadChip. Multivariate linear regression models and likelihood ratio tests (LRT) were applied to examine the DNAm-outcome association in the overall sample and sex strata.We identified four distinct patterns of BMIPCT trajectories: normal weight (NW), Early overweight or obesity (OWO), Late OWO, and normal to very late OWO. DNAm at CpG18582997 annotated to TPGS1, CpG15241084 of TLR7, and cg24350936 of RAB31 were associated with BMIPCT at birth-to-3 y, 10 y, and 14 y, respectively (LRT FDR < 0.05 for all).In this prospective birth cohort study, we identified 4 distinct and robust patterns of growth trajectories from birth to 18 y, which were associated with variations in cord blood DNAm at genes implicated in inflammation induction pathways. These findings, if further replicated, raise the possibility that these DNAm markers along with early assessment of BMIPCT trajectories may help identify young children at high-risk for obesity later in life.Detailed in the Acknowledgements section.Copyright © 2023. Published by Elsevier B.V.",
-,No,20230504,ewas,37085889,The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?,Hum Genomics,"Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian 'Clinical review of the Health of adults conceived following Assisted Reproductive Technologies' (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies ('XWASs' hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset.In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort.Genes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.© 2023. The Author(s).",
-,No,20230504,mr,37085538,Role of DNA methylation in the relationship between glioma risk factors and glioma incidence: a two-step Mendelian randomization study.,Sci Rep,"Genetic evidence suggests glioma risk is altered by leukocyte telomere length, allergic disease (asthma, hay fever or eczema), alcohol consumption, childhood obesity, low-density lipoprotein cholesterol (LDLc) and triglyceride levels. DNA methylation (DNAm) variation influences many of these glioma-related traits and is an established feature of glioma. Yet the causal relationship between DNAm variation with both glioma incidence and glioma risk factors is unknown. We applied a two-step Mendelian randomization (MR) approach and several sensitivity analyses (including colocalization and Steiger filtering) to assess the association of DNAm with glioma risk factors and glioma incidence. We used data from a recently published catalogue of germline genetic variants robustly associated with DNAm variation in blood (32,851 participants) and data from a genome-wide association study of glioma risk (12,488 cases and 18,169 controls, sub-divided into 6191 glioblastoma cases and 6305 non-glioblastoma cases). MR evidence indicated that DNAm at 3 CpG sites (cg01561092, cg05926943, cg01584448) in one genomic region (HEATR3) had a putative association with glioma and glioblastoma risk (False discovery rate [FDR] < 0.05). Steiger filtering provided evidence against reverse causation. Colocalization presented evidence against genetic confounding and suggested that differential DNAm at the 3 CpG sites and glioma were driven by the same genetic variant. MR provided little evidence to suggest that DNAm acts as a mediator on the causal pathway between risk factors previously examined and glioma onset. To our knowledge, this is the first study to use MR to appraise the causal link of DNAm with glioma risk factors and glioma onset. Subsequent analyses are required to improve the robustness of our results and rule out horizontal pleiotropy.© 2023. The Author(s).",
-,No,20230504,methods,37074140,Effects of Repeated Freeze and Thaw Cycles on the Genome-Wide DNA Methylation Profile of Isolated Genomic DNA.,Biopreserv Biobank,"The characterization of DNA methylation patterns to identify epigenetic markers for complex human diseases is an important and rapidly evolving part in biomedical research. DNA samples collected and stored in clinical biobanks over the past years are an important source for future epigenetic studies. Isolated gDNA is considered stable when stored at low temperatures for several years. However, the effect of multiple use and the associated repeated thawing of long-term stored DNA samples on DNA methylation patterns has not yet been investigated. In this study, we examined the influence of up to 10 freeze and thaw cycles on global DNA methylation by comparing genome-wide methylation profiles. DNA samples from 19 healthy volunteers were either frozen at -80°C or subjected to up to 10 freeze and thaw cycles. Genome-wide DNA methylation was analyzed after 0, 1, 3, 5, or 10 thaw cycles using the Illumina Infinium MethylationEPIC BeadChip. Evaluation of the global DNA methylation profile by beta-value density plots and multidimensional scaling plots revealed an expected clear participant-dependent variability, but a very low variability depending on the freeze and thaw cycles. In accordance, no significant difference in any of the methylated cytosine/guanine sites studied could be detected in the performed statistical analyses. Our results suggest that long-term frozen DNA samples are still suitable for epigenetic studies after multiple thaw cycles.",
-,No,20230504,dnamage,37118759,Associations of socioeconomic disparities with buccal DNA-methylation measures of biological aging.,Clin Epigenetics,"Individuals who are socioeconomically disadvantaged are at increased risk for aging-related diseases and perform less well on tests of cognitive function. The weathering hypothesis proposes that these disparities in physical and cognitive health arise from an acceleration of biological processes of aging. Theories of how life adversity is biologically embedded identify epigenetic alterations, including DNA methylation (DNAm), as a mechanistic interface between the environment and health. Consistent with the weathering hypothesis and theories of biological embedding, recently developed DNAm algorithms have revealed profiles reflective of more advanced aging and lower cognitive function among socioeconomically-at-risk groups. These DNAm algorithms were developed using blood-DNA, but social and behavioral science research commonly collect saliva or cheek-swab DNA. This discrepancy is a potential barrier to research to elucidate mechanisms through which socioeconomic disadvantage affects aging and cognition. We therefore tested if social gradients observed in blood DNAm measures could be reproduced using buccal-cell DNA obtained from cheek swabs.We analyzed three DNAm measures of biological aging and one DNAm measure of cognitive performance, all of which showed socioeconomic gradients in previous studies: the PhenoAge and GrimAge DNAm clocks, DunedinPACE, and Epigenetic-g. We first computed blood-buccal cross-tissue correlations in n = 21 adults (GEO111165). Cross-tissue correlations were low-to-moderate (r = .25 to r = .48). We next conducted analyses of socioeconomic gradients using buccal DNAm data from SOEP-G (n = 1128, 57% female; age mean = 42 yrs, SD = 21.56, range 0-72). Associations of socioeconomic status with DNAm measures of aging were in the expected direction, but were smaller as compared to reports from blood DNAm datasets (r = - .08 to r = - .13).Our findings are consistent with the hypothesis that socioeconomic disadvantage is associated with DNAm indicators of worse physical health. However, relatively low cross-tissue correlations and attenuated effect sizes for socioeconomic gradients in buccal DNAm compared with reports from analysis of blood DNAm suggest that in order to take full advantage of buccal DNA samples, DNAm algorithms customized to buccal DNAm are needed.© 2023. The Author(s).",
-,No,20230504,dnamage,37118425,Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.,Nat Aging,"The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref.10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.© 2023. The Author(s).",
-,No,20230504,dnamage,37107599,"Changes in Loneliness, BDNF, and Biological Aging Predict Trajectories in a Blood-Based Epigenetic Measure of Cortical Aging: A Study of Older Black Americans.",Genes (Basel),"A recent epigenetic measure of aging has developed based on human cortex tissue. This cortical clock (CC) dramatically outperformed extant blood-based epigenetic clocks in predicting brain age and neurological degeneration. Unfortunately, measures that require brain tissue are of limited utility to investigators striving to identify everyday risk factors for dementia. The present study investigated the utility of using the CpG sites included in the CC to formulate a peripheral blood-based cortical measure of brain age (CC-Bd). To establish the utility of CC-Bd, we used growth curves with individually varying time points and longitudinal data from a sample of 694 aging African Americans. We examined whether three risk factors that have been linked to cognitive decline-loneliness, depression, and BDNFm-predicted CC-Bd after controlling for several factors, including three new-generation epigenetic clocks. Our findings showed that two clocks-DunedinPACE and PoAm-predicted CC-BD, but that increases in loneliness and BDNFm continued to be robust predictors of accelerated CC-Bd even after taking these effects into account. This suggests that CC-Bd is assessing something more than the pan-tissue epigenetic clocks but that, at least in part, brain health is also associated with the general aging of the organism.",
-,No,20230504,prediction,37127563,A comparison of feature selection methodologies and learning algorithms in the development of a DNA methylation-based telomere length estimator.,BMC Bioinformatics,"The field of epigenomics holds great promise in understanding and treating disease with advances in machine learning (ML) and artificial intelligence being vitally important in this pursuit. Increasingly, research now utilises DNA methylation measures at cytosine-guanine dinucleotides (CpG) to detect disease and estimate biological traits such as aging. Given the challenge of high dimensionality of DNA methylation data, feature-selection techniques are commonly employed to reduce dimensionality and identify the most important subset of features. In this study, our aim was to test and compare a range of feature-selection methods and ML algorithms in the development of a novel DNA methylation-based telomere length (TL) estimator. We utilised both nested cross-validation and two independent test sets for the comparisons.We found that principal component analysis in advance of elastic net regression led to the overall best performing estimator when evaluated using a nested cross-validation analysis and two independent test cohorts. This approach achieved a correlation between estimated and actual TL of 0.295 (83.4% CI [0.201, 0.384]) on the EXTEND test data set. Contrastingly, the baseline model of elastic net regression with no prior feature reduction stage performed less well in general-suggesting a prior feature-selection stage may have important utility. A previously developed TL estimator, DNAmTL, achieved a correlation of 0.216 (83.4% CI [0.118, 0.310]) on the EXTEND data. Additionally, we observed that different DNA methylation-based TL estimators, which have few common CpGs, are associated with many of the same biological entities.The variance in performance across tested approaches shows that estimators are sensitive to data set heterogeneity and the development of an optimal DNA methylation-based estimator should benefit from the robust methodological approach used in this study. Moreover, our methodology which utilises a range of feature-selection approaches and ML algorithms could be applied to other biological markers and disease phenotypes, to examine their relationship with DNA methylation and predictive value.© 2023. The Author(s).",
-,Yes,20230504,ewas,37120575,Prenatal phthalate exposure and cord blood DNA methylation.,Sci Rep,"Exposure to phthalates has been shown to impede the human endocrine system, resulting in deleterious effects on pregnant women and their children. Phthalates modify DNA methylation patterns in infant cord blood. We examined the association between prenatal phthalate exposure and DNA methylation patterns in cord blood in a Korean birth cohort. Phthalate levels were measured in 274 maternal urine samples obtained during late pregnancy and 102 neonatal urine samples obtained at birth, and DNA methylation levels were measured in cord blood samples. For each infant in the cohort, associations between CpG methylation and both maternal and neonate phthalate levels were analyzed using linear mixed models. The results were combined with those from a meta-analysis of the levels of phthalates in maternal and neonatal urine samples, which were also analyzed for MEOHP, MEHHP, MnBP, and DEHP. This meta-analysis revealed significant associations between the methylation levels of CpG sites near the CHN2 and CUL3 genes, which were also associated with MEOHP and MnBP in neonatal urine. When the data were stratified by the sex of the infant, MnBP concentration was found to be associated with one CpG site near the OR2A2 and MEGF11 genes in female infants. In contrast, the concentrations of the three maternal phthalates showed no significant association with CpG site methylation. Furthermore, the data identified distinct differentially methylated regions in maternal and neonatal urine samples following exposure to phthalates. The CpGs with methylation levels that were positively associated with phthalate levels (particularly MEOHP and MnBP) were found to be enriched genes and related pathways. These results indicate that prenatal phthalate exposure is significantly associated with DNA methylation at multiple CpG sites. These alterations in DNA methylation may serve as biomarkers of maternal exposure to phthalates in infants and are potential candidates for investigating the mechanisms by which phthalates impact maternal and neonatal health.© 2023. The Author(s).",
-,No,20230504,dnamage,37076473,Multi-omic underpinnings of epigenetic aging and human longevity.,Nat Commun,"Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
-,No,20230504,single-cell,37085594,Single-cell genomics meets human genetics.,Nat Rev Genet,"Single-cell genomic technologies are revealing the cellular composition, identities and states in tissues at unprecedented resolution. They have now scaled to the point that it is possible to query samples at the population level, across thousands of individuals. Combining single-cell information with genotype data at this scale provides opportunities to link genetic variation to the cellular processes underpinning key aspects of human biology and disease. This strategy has potential implications for disease diagnosis, risk prediction and development of therapeutic solutions. But, effectively integrating large-scale single-cell genomic data, genetic variation and additional phenotypic data will require advances in data generation and analysis methods. As single-cell genetics begins to emerge as a field in its own right, we review its current state and the challenges and opportunities ahead.© 2023. Springer Nature Limited.",
-,No,20230504,prediction,37117793,Development and validation of DNA methylation scores in two European cohorts augment 10-year risk prediction of type 2 diabetes.,Nat Aging,"Type 2 diabetes mellitus (T2D) presents a major health and economic burden that could be alleviated with improved early prediction and intervention. While standard risk factors have shown good predictive performance, we show that the use of blood-based DNA methylation information leads to a significant improvement in the prediction of 10-year T2D incidence risk. Previous studies have been largely constrained by linear assumptions, the use of cytosine-guanine pairs one-at-a-time and binary outcomes. We present a flexible approach (via an R package, MethylPipeR) based on a range of linear and tree-ensemble models that incorporate time-to-event data for prediction. Using the Generation Scotland cohort (training set ncases = 374, ncontrols = 9,461; test set ncases = 252, ncontrols = 4,526) our best-performing model (area under the receiver operating characteristic curve (AUC) = 0.872, area under the precision-recall curve (PRAUC) = 0.302) showed notable improvement in 10-year onset prediction beyond standard risk factors (AUC = 0.839, precision-recall AUC = 0.227). Replication was observed in the German-based KORA study (n = 1,451, ncases = 142, P = 1.6 × 10-5).© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,No,20230504,single-cell,37034737,A single-nucleus transcriptome-wide association study implicates novel genes in depression pathogenesis.,medRxiv,"Depression is a common psychiatric illness and global public health problem. However, our limited understanding of the biological basis of depression has hindered the development of novel treatments and interventions.To identify new candidate genes for therapeutic development, we examined single-nucleus RNA sequencing (snucRNAseq) data from the dorsolateral prefrontal cortex (N=424) in relation to ante-mortem depressive symptoms. To complement these direct analyses, we also used genome- wide association study (GWAS) results for depression (N=500,199) along with genetic tools for inferring the expression of 22,159 genes in 7 cell types and 55 cell subtypes to perform transcriptome-wide association studies (TWAS) of depression followed by Mendelian randomization (MR).Our single-nucleus TWAS analysis identified 71 causal genes in depression that have a role in specific neocortical cell subtypes; 59 of 71 genes were novel compared to previous studies. Depression TWAS genes showed a cell type specific pattern, with the greatest enrichment being in both excitatory and inhibitory neurons as well as astrocytes. Gene expression in different neuron subtypes have different directions of effect on depression risk. Compared to lower genetically correlated traits (e.g. body mass index) with depression, higher correlated traits (e.g., neuroticism) have more common TWAS genes with depression. In parallel, we performed differential gene expression analysis in relation to depression in 55 cortical cell subtypes, and we found that genes such asANKRD36,MADD,TAOK3,SCAIandCHUKare associated with depression in specific cell subtypes.These two sets of analyses illustrate the utility of large snucRNAseq data to uncover both genes whose expression is altered in specific cell subtypes in the context of depression and to enhance the interpretation of well-powered GWAS so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.",
-,No,20230504,eqtl,37076491,Mapping genomic regulation of kidney disease and traits through high-resolution and interpretable eQTLs.,Nat Commun,"Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). Efforts to maximize their accuracy are ongoing. Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5371 GLOM and 9787 TUBE genes with at least one variant significantly associated with expression (eGene) by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an ""integrative prior"" for Bayesian statistical fine-mapping. The use of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of variants in credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS of two kidney traits, (3) an increased number of variants colocalized with the GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants. A subset of variants and genes were validated experimentally in vitro and using a Drosophila nephrocyte model. More broadly, this study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses.© 2023. The Author(s).",
-,No,20230504,gwas,37120605,Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.,Nat Commun,"Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.© 2023. The Author(s).",
-,No,20230504,omics,37117186,A precision environmental health approach to prevention of human disease.,Nat Commun,"Human health is determined by the interaction of our environment with the genome, epigenome, and microbiome, which shape the transcriptomic, proteomic, and metabolomic landscape of cells and tissues. Precision environmental health is an emerging field leveraging environmental and system-level ('omic) data to understand underlying environmental causes of disease, identify biomarkers of exposure and response, and develop new prevention and intervention strategies. In this article we provide real-life illustrations of the utility of precision environmental health approaches, identify current challenges in the field, and outline new opportunities to promote health through a precision environmental health framework.© 2023. The Author(s).",
-,No,20230504,omics,37082508,Multi-omic integration via similarity network fusion to detect molecular subtypes of ageing.,Brain Commun,"Molecular subtyping of brain tissue provides insights into the heterogeneity of common neurodegenerative conditions, such as Alzheimer's disease. However, existing subtyping studies have mostly focused on single data modalities and only those individuals with severe cognitive impairment. To address these gaps, we applied similarity network fusion, a method capable of integrating multiple high-dimensional multi-omic data modalities simultaneously, to an elderly sample spanning the full spectrum of cognitive ageing trajectories. We analyzed human frontal cortex brain samples characterized by five omic modalities: bulk RNA sequencing (18 629 genes), DNA methylation (53 932 CpG sites), histone acetylation (26 384 peaks), proteomics (7737 proteins) and metabolomics (654 metabolites). Similarity network fusion followed by spectral clustering was used for subtype detection, and subtype numbers were determined by Eigen-gap and rotation cost statistics. Normalized mutual information determined the relative contribution of each modality to the fused network. Subtypes were characterized by associations with 13 age-related neuropathologies and cognitive decline. Fusion of all five data modalities (n= 111) yielded two subtypes (nS1= 53,nS2= 58), which were nominally associated with diffuse amyloid plaques; however, this effect was not significant after correction for multiple testing. Histone acetylation (normalized mutual information = 0.38), DNA methylation (normalized mutual information = 0.18) and RNA abundance (normalized mutual information = 0.15) contributed most strongly to this network. Secondary analysis integrating only these three modalities in a larger subsample (n= 513) indicated support for both three- and five-subtype solutions, which had significant overlap, but showed varying degrees of internal stability and external validity. One subtype showed marked cognitive decline, which remained significant even after correcting for tests across both three- and five-subtype solutions (pBonf= 5.9 × 10-3). Comparison to single-modality subtypes demonstrated that the three-modal subtypes were able to uniquely capture cognitive variability. Comprehensive sensitivity analyses explored influences of sample size and cluster number parameters. We identified highly integrative molecular subtypes of ageing derived from multiple high dimensional, multi-omic data modalities simultaneously. Fusing RNA abundance, DNA methylation, and histone acetylation measures generated subtypes that were associated with cognitive decline. This work highlights the potential value and challenges of multi-omic integration in unsupervised subtyping of post-mortem brain.© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.",
-,No,20230504,methods,37066421,The ENCODE Uniform Analysis Pipelines.,bioRxiv,"The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of theHomo sapiensandMus musculusgenomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and availableviathe ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL; https://openwdl.org/ ) is publicly available in GitHub, with images available on Dockerhub ( https://hub.docker.com ), enabling access to a diverse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environmentsviaCromwell. Access to the pipelines and dataviathe cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses.Database URL:https://www.encodeproject.org/.",
-,No,20230504,pqtl,37085628,Proteome-wide Mendelian randomization reveals the causal effects of immune-related plasma proteins on psychiatric disorders.,Hum Genet,"Immune dysregulation has been consistently reported in psychiatric disorders, however, the causes and mechanisms underlying immune dysregulation in psychiatric disorders remain largely unclear. Here we conduct a Mendelian randomization study by integrating plasma proteome and GWASs of schizophrenia, bipolar disorder and depression. The primate-specific immune-related protein BTN3A3 showed the most significant associations with all three psychiatric disorders. In addition, other immune-related proteins, including AIF1, FOXO3, IRF3, CFHR4, IGLON5, FKBP2, and PI3, also showed significant associations with psychiatric disorders. Our study showed that a proportion of psychiatric risk variants may contribute to disease risk by regulating immune-related plasma proteins, providing direct evidence that connect the genetic risk of psychiatric disorders to immune system.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",
-,No,20230629,methods,37369639,E-value: a superior alternative to P-value and its adjustments in DNA methylation studies.,Brief Bioinform,"DNA methylation plays a crucial role in transcriptional regulation. Reduced representation bisulfite sequencing (RRBS) is a technique of increasing use for analyzing genome-wide methylation profiles. Many computational tools such as Metilene, MethylKit, BiSeq and DMRfinder have been developed to use RRBS data for the detection of the differentially methylated regions (DMRs) potentially involved in epigenetic regulations of gene expression. For DMR detection tools, as for countless other medical applications, P-values and their adjustments are among the most standard reporting statistics used to assess the statistical significance of biological findings. However, P-values are coming under increasing criticism relating to their questionable accuracy and relatively high levels of false positive or negative indications. Here, we propose a method to calculate E-values, as likelihood ratios falling into the null hypothesis over the entire parameter space, for DMR detection in RRBS data. We also provide the R package 'metevalue' as a user-friendly interface to implement E-value calculations into various DMR detection tools. To evaluate the performance of E-values, we generated various RRBS benchmarking datasets using our simulator 'RRBSsim' with eight samples in each experimental group. Our comprehensive benchmarking analyses showed that using E-values not only significantly improved accuracy, area under ROC curve and power, over that of P-values or adjusted P-values, but also reduced false discovery rates and type I errors. In applications using real RRBS data of CRL rats and a clinical trial on low-salt diet, the use of E-values detected biologically more relevant DMRs and also improved the negative association between DNA methylation and gene expression.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
-,No,20230629,transgenerational,37365578,Associations between DNA methylation and gene regulation depend on chromatin accessibility during transgenerational plasticity.,BMC Biol,"Epigenetic processes are proposed to be a mechanism regulating gene expression during phenotypic plasticity. However, environmentally induced changes in DNA methylation exhibit little-to-no association with differential gene expression in metazoans at a transcriptome-wide level. It remains unexplored whether associations between environmentally induced differential methylation and expression are contingent upon other epigenomic processes such as chromatin accessibility. We quantified methylation and gene expression in larvae of the purple sea urchin Strongylocentrotus purpuratus exposed to different ecologically relevant conditions during gametogenesis (maternal conditioning) and modeled changes in gene expression and splicing resulting from maternal conditioning as functions of differential methylation, incorporating covariates for genomic features and chromatin accessibility. We detected significant interactions between differential methylation, chromatin accessibility, and genic feature type associated with differential expression and splicing.Differential gene body methylation had significantly stronger effects on expression among genes with poorly accessible transcriptional start sites while baseline transcript abundance influenced the direction of this effect. Transcriptional responses to maternal conditioning were 4-13 × more likely when accounting for interactions between methylation and chromatin accessibility, demonstrating that the relationship between differential methylation and gene regulation is partially explained by chromatin state.DNA methylation likely possesses multiple associations with gene regulation during transgenerational plasticity in S. purpuratus and potentially other metazoans, but its effects are dependent on chromatin accessibility and underlying genic features.© 2023. The Author(s).",
-,Yes,20230629,ewas,37341931,NSAIDs use history: impact on the genome-wide DNA methylation profile and possible mechanisms of action.,Clin Exp Med,"NSAIDs inhibit cyclooxygenase, but their role in aging and other diseases is not well understood. Our group previously showed the potential benefit of NSAIDs in decreasing the risk of delirium and mortality. Concurrently, epigenetics signals have also been associated with delirium. Therefore, we sought to find differentially methylated genes and biological pathways related to exposure with NSAIDs by comparing the genome-wide DNA methylation profiles of patients with and without a history of NSAIDs use.Whole blood samples were collected from 171 patients at the University of Iowa Hospital and Clinics from November 2017 to March 2020. History of NSAIDs use was assessed through a word-search function in the subjects' electronic medical records. DNA was extracted from the blood samples, processed with bisulfite conversion, and analyzed using Illumina's EPIC array. The analysis of top differentially methylated CpG sites and subsequent enrichment analysis were conducted using an established pipeline using R statistical software.Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) showed several biological pathways relevant to NSAIDs' function. The identified GO terms included ""arachidonic acid metabolic process,"" while KEGG results included ""linoleic acid metabolism,"" ""cellular senescence,"" and ""circadian rhythm."" Nonetheless, none of the top GO and KEGG pathways and the top differentially methylated CpG sites reached statistical significance.Our results suggest a potential role of epigenetics in the mechanisms of the action of NSAIDs. However, the results should be viewed with caution as exploratory and hypothesis-generating given the lack of statistically significant findings.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.",
-,No,20230629,methods,37337720,Calculating detection limits and uncertainty of reference-based deconvolution of whole-blood DNA methylation data.,Epigenomics,"DNA methylation (DNAm)-based cell mixture deconvolution (CMD) has become a quintessential part of epigenome-wide association studies where DNAm is profiled in heterogeneous tissue types. Despite being introduced over a decade ago, detection limits, which represent the smallest fraction of a cell type in a mixed biospecimen that can be reliably detected, have yet to be determined in the context of DNAm-based CMD. Moreover, there has been little attention given to approaches for quantifying the uncertainty associated with DNAm-based CMD. Here, analytical frameworks for determining both cell-specific limits of detection and quantification of uncertainty associated with DNAm-based CMD are described. This work may contribute to improved rigor, reproducibility and replicability of epigenome-wide association studies involving CMD.",
-,Yes,20230629,ewas,37330044,Epigenetic Intergenerational Transmission: Mothers' Adverse Childhood Experiences and DNA Methylation.,J Am Acad Child Adolesc Psychiatry,"Individual differences in risk for mental disorders over the lifespan are shaped by forces acting before the individual is born-in utero, but likely even earlier, during the mother's own childhood. The environmental epigenetics hypothesis proposes that sustained effects of environmental conditions on gene expression are mediated by epigenetic mechanisms. Recent human studies have shown that adversities in childhood are correlated with DNA methylation (DNAm) in adulthood. In the current study, we tested the following pre-registered hypotheses: Mothers' adverse childhood experiences (ACEs) are correlated with DNAm in peripheral blood during pregnancy (hypothesis 1) and in cord blood samples from newborn infants (hypothesis 2), and women's depression and anxiety symptoms during pregnancy mediate the association between mothers' ACE exposure and prenatal/neonatal DNA methylation (hypothesis 3).Data were from the Avon Longitudinal Study of Parents and Children Accessible Resource for Integrated Epigenomic Studies substudy. Women provided retrospective self-reports during pregnancy of ACE exposure. We conducted an epigenome-wide association study testing whether mothers' ACE exposure, cumulative score (0-10), was associated with DNAm in maternal antenatal blood and infant cord blood in more than 450,000 CpG (point on DNA sequence where Cytosine and Guanine base pairs are linked by a phosphate, where methylation usually occurs) sites on the Illumina 450K BeadChip. Analyses for cord blood were separated by infant sex, a pre-registered analysis.Hypothesis 1: In 896 mother-infant pairs with available methylation and ACE exposure data, there were no significant associations between mothers' ACE score and DNAm from antenatal peripheral blood, after controlling for covariates. Hypothesis 2: In infant cord blood, there were 5 CpG sites significantly differentially methylated in relation to mothers' ACEs (false discovery rate [FDR] < .05), but only in male offspring. Effect sizes were medium, with partial eta squared values ranging from 0.060 to 0.078. CpG sites were in genes related to mitochondrial function and neuronal development in the cerebellum. Hypothesis 3: There was no mediation by maternal anxiety/depression symptoms found between mothers' ACEs score and DNAm in the significant CpG sites in male cord blood. Mediation was not tested in antenatal peripheral blood, because no direct association between mothers' ACE score and antenatal peripheral blood was found.Our results show that mothers' ACE exposure is associated with DNAm in male offspring, supporting the notion that DNAm could be a marker of intergenerational biological embedding of mothers' childhood adversity.Epigenetic Intergenerational Transmission: Mothers' Adverse Childhood Experiences and DNA Methylation; https://doi.org/10.1016/j.jaac.2020.03.008.Copyright © 2023. Published by Elsevier Inc.",
-,Yes,20230629,ewas,37327798,Association between the timing of childhood adversity and epigenetic patterns across childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort.,Lancet Child Adolesc Health,"Childhood adversity is a potent determinant of health across development and is associated with altered DNA methylation signatures, which might be more common in children exposed during sensitive periods in development. However, it remains unclear whether adversity has persistent epigenetic associations across childhood and adolescence. We aimed to examine the relationship between time-varying adversity (defined through sensitive period, accumulation of risk, and recency life course hypotheses) and genome-wide DNA methylation, measured three times from birth to adolescence, using data from a prospective, longitudinal cohort study.We first investigated the relationship between the timing of exposure to childhood adversity between birth and 11 years and blood DNA methylation at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study. Our analytic sample included ALSPAC participants with DNA methylation data and complete childhood adversity data between birth and 11 years. We analysed seven types of adversity (caregiver physical or emotional abuse, sexual or physical abuse [by anyone], maternal psychopathology, one-adult households, family instability, financial hardship, and neighbourhood disadvantage) reported by mothers five to eight times between birth and 11 years. We used the structured life course modelling approach (SLCMA) to identify time-varying associations between childhood adversity and adolescent DNA methylation. Top loci were identified using an R2threshold of 0·035 (ie, ≥3·5% of DNA methylation variance explained by adversity). We attempted to replicate these associations using data from the Raine Study and Future of Families and Child Wellbeing Study (FFCWS). We also assessed the persistence of adversity-DNA methylation associations we previously identified from age 7 blood DNA methylation into adolescence and the influence of adversity on DNA methylation trajectories from ages 0-15 years.Of 13 988 children in the ALSPAC cohort, 609-665 children (311-337 [50-51%] boys and 298-332 [49-50%] girls) had complete data available for at least one of the seven childhood adversities and DNA methylation at 15 years. Exposure to adversity was associated with differences in DNA methylation at 15 years for 41 loci (R2≥0·035). Sensitive periods were the most often selected life course hypothesis by the SLCMA. 20 (49%) of 41 loci were associated with adversities occurring between age 3 and 5 years. Exposure to one-adult households was associated with differences in DNA methylation at 20 [49%] of 41 loci, exposure to financial hardship was associated with changes at nine (22%) loci, and physical or sexual abuse was associated with changes at four (10%) loci. We replicated the direction of associations for 18 (90%) of 20 loci associated with exposure to one-adult household using adolescent blood DNA methylation from the Raine Study and 18 (64%) of 28 loci using saliva DNA methylation from the FFCWS. The directions of effects for 11 one-adult household loci were replicated in both cohorts. Differences in DNA methylation at 15 years were not present at 7 years and differences identified at 7 years were no longer apparent by 15 years. We also identified six distinct DNA methylation trajectories from these patterns of stability and persistence.These findings highlight the time-varying effect of childhood adversity on DNA methylation profiles across development, which might link exposure to adversity to potential adverse health outcomes in children and adolescents. If replicated, these epigenetic signatures could ultimately serve as biological indicators or early warning signs of initiated disease processes, helping identify people at greater risk for the adverse health consequences of childhood adversity.Canadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.Copyright © 2023 Elsevier Ltd. All rights reserved.",
-,No,20230629,dnamage,37306997,Association of Adverse Childhood Experiences With Accelerated Epigenetic Aging in Midlife.,JAMA Netw Open,"Adverse childhood experiences (ACEs) are associated with the risk of poorer health, and identifying molecular mechanisms may lay the foundation for health promotion in people with ACEs.To investigate the associations of ACEs with changes in epigenetic age acceleration (EAA), a biomarker associated with various health outcomes in middle-aged adults, in a population with balanced race and sex demographics.Data for this cohort study were from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants in CARDIA underwent 8 follow-up exams from baseline (year 0 [Y0]; 1985-1986) to Y30 (2015-2016), and participant blood DNA methylation information was obtained at Y15 (2000-2001) and Y20 (2005-2006). Individuals from Y15 and Y20 with available DNA methylation data and complete variables for ACEs and covariates were included. Data were analyzed from September 2021 to August 2022.Participant ACEs (general negligence, emotional negligence, physical violence, physical negligence, household substance abuse, verbal and emotional abuse, and household dysfunction) were obtained at Y15.The primary outcome consisted of results from 5 DNA methylation-based EAA measurements known to be associated with biological aging and long-term health: intrinsic EAA (IEAA), extrinsic EAA (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), measured at Y15 and Y20. Linear regression and generalized estimating equations were used to assess associations of the burden of ACEs (≥4 vs <4 ACEs) with EAA adjusting for demographics, health-related behaviors, and early life and adult socioeconomic status.A total of 895 participants for Y15 (mean [SD] age, 40.4 [3.5] years; 450 males [50.3%] and 445 females [49.7%]; 319 Black [35.6%] and 576 White [64.4%]) and 867 participants for Y20 (mean [SD] age, 45.4 [3.5] years; 432 males [49.8%] and 435 females [50.2%]; 306 Black [35.3%] and 561 White [64.7%]) were included after excluding participants with missing data. There were 185 participants with (20.7%) vs 710 participants without (79.3%) 4 or more ACEs at Y15 and 179 participants with (20.6%) vs 688 participants without (79.4%) 4 or more ACEs at Y20. Having 4 or more ACEs was positively associated with EAA in years at Y15 (EEAA: β = 0.60 years; 95% CI, 0.18-1.02 years; PhenoAA: β = 0.62 years; 95% CI = 0.13-1.11 years; GrimAA: β = 0.71 years; 95% CI, 0.42-1.00 years; DunedinPACE: β = 0.01; 95% CI, 0.01-0.02) and Y20 (IEAA: β = 0.41 years; 95% CI, 0.05-0.77 years; EEAA: β = 1.05 years; 95% CI, 0.66-1.44 years; PhenoAA: β = 0.57 years; 95% CI, 0.08-1.05 years; GrimAA: β = 0.57 years; 95% CI, 0.28-0.87 years; DunedinPACE: β = 0.01; 95% CI, 0.01-0.02) after adjusting for demographics, health-related behaviors, and socioeconomic status.In this cohort study, ACEs were associated with EAA among middle-aged adults after controlling for demographics, behavior, and socioeconomic status. These findings of the associations between early life experience and the biological aging process in midlife may contribute to health promotion in a life course perspective.",
-,Yes,20230629,EWAS,37300821,Prenatal maternal stress is associated with site-specific and age acceleration changes in maternal and newborn DNA methylation.,Epigenetics,"Prenatal maternal stress has a negative impact on child health but the mechanisms through which maternal stress affects child health are unclear. Epigenetic variation, such as DNA methylation, is a likely mechanistic candidate as DNA methylation is sensitive to environmental insults and can regulate long-term changes in gene expression. We recruited 155 mother-newborn dyads in the Democratic Republic of Congo to investigate the effects of maternal stress on DNA methylation in mothers and newborns. We used four measures of maternal stress to capture a range of stressful experiences: general trauma, sexual trauma, war trauma, and chronic stress. We identified differentially methylated positions (DMPs) associated with general trauma, sexual trauma, and war trauma in both mothers and newborns. No DMPs were associated with chronic stress. Sexual trauma was positively associated with epigenetic age acceleration across several epigenetic clocks in mothers. General trauma and war trauma were positively associated with newborn epigenetic age acceleration using the extrinsic epigenetic age clock. We tested the top DMPs for enrichment of DNase I hypersensitive sites (DHS) and found no enrichment in mothers. In newborns, top DMPs associated with war trauma were enriched for DHS in embryonic and foetal cell types. Finally, one of the top DMPs associated with war trauma in newborns also predicted birthweight, completing the cycle from maternal stress to DNA methylation to newborn health outcome. Our results indicate that maternal stress is associated with site-specific changes in DNAm and epigenetic age acceleration in both mothers and newborns.",
-,No,20230629,omics,37326626,Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation.,Elife,"Obesity is a major risk factor for cardiovascular disease, stroke, and type 2 diabetes (T2D). Excessive accumulation of fat in the abdomen further increases T2D risk. Abdominal obesity is measured by calculating the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI), a trait with a significant genetic inheritance. Genetic loci associated with WHRadjBMI identified in genome-wide association studies are predicted to act through adipose tissues, but many of the exact molecular mechanisms underlying fat distribution and its consequences for T2D risk are poorly understood. Further, mechanisms that uncouple the genetic inheritance of abdominal obesity from T2D risk have not yet been described. Here we utilize multi-omic data to predict mechanisms of action at loci associated with discordant effects on abdominal obesity and T2D risk. We find six genetic signals in five loci associated with protection from T2D but also with increased abdominal obesity. We predict the tissues of action at these discordant loci and the likely effector Genes (eGenes) at three discordant loci, from which we predict significant involvement of adipose biology. We then evaluate the relationship between adipose gene expression of eGenes with adipogenesis, obesity, and diabetic physiological phenotypes. By integrating these analyses with prior literature, we propose models that resolve the discordant associations at two of the five loci. While experimental validation is required to validate predictions, these hypotheses provide potential mechanisms underlying T2D risk stratification within abdominal obesity.© 2023, Aberra et al.",
-,No,20230629,omics,37365616,Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage.,Genome Biol,"The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage.Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are supported as putatively causal. We then prioritize 153 of these genomic regions using additional colocalization analyses. Our genome-wide findings are supported by existing knowledge (animal models for MANBA, DACH1, SH3YL1, INHBB), exceed the underlying GWAS signals (28 region-trait combinations without significant GWAS hit), identify independent gene/protein-trait associations within the same genomic region (INHBC, SPRYD4), nominate tissues underlying the associations (tubule expression of NRBP1), and distinguish markers of kidney filtration from those with a role in creatinine and cystatin C metabolism. Furthermore, we follow up on members of the TGF-beta superfamily of proteins and find a prognostic value of INHBC for kidney disease progression even after adjustment for measured glomerular filtration rate (GFR).In summary, this study combines multimodal, genome-wide association studies to generate a catalog of putatively causal target genes and proteins relevant to kidney function and damage which can guide follow-up studies in physiology, basic science, and clinical medicine.© 2023. The Author(s).",
-,No,20230629,cancer,37344596,Y chromosome loss in cancer drives growth by evasion of adaptive immunity.,Nature,"Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers1-6, but its clinical and biological significance is unknown. Here, using genomic and transcriptomic studies, we report that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells as well as those with targeted deletion of Y chromosome by CRISPR-Cas9. Y-positive (Y+) and Y-negative (Y-) tumours grew similarly in vitro, whereas Y-tumours were more aggressive than Y+tumours in immune-competent hosts in a T cell-dependent manner. High-dimensional flow cytometric analyses demonstrated that Y-tumours promote striking dysfunction or exhaustion of CD8+T cells in the tumour microenvironment. These findings were validated using single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Of note, compared with Y+tumours, Y-tumours exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. This work provides insights into the basic biology of LOY mutation and potential biomarkers for improving cancer immunotherapy.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
-,No,20230629,ctdna,37330511,Early detection and stratification of lung cancer aided by a cost-effective assay targeting circulating tumor DNA (ctDNA) methylation.,Respir Res,"Detection of lung cancer at earlier stage can greatly improve patient survival. We aim to develop, validate, and implement a cost-effective ctDNA-methylation-based plasma test to aid lung cancer early detection.Case-control studies were designed to select the most relevant markers to lung cancer. Patients with lung cancer or benign lung disease and healthy individuals were recruited from different clinical centers. A multi-locus qPCR assay, LunaCAM, was developed for lung cancer alertness by ctDNA methylation. Two LunaCAM models were built for screening (-S) or diagnostic aid (-D) to favor sensitivity or specificity, respectively. The performance of the models was validated for different intended uses in clinics.Profiling DNA methylation on 429 plasma samples including 209 lung cancer, 123 benign diseases and 97 healthy participants identified the top markers that detected lung cancer from benign diseases and healthy with an AUC of 0.85 and 0.95, respectively. The most effective methylation markers were verified individually in 40 tissues and 169 plasma samples to develop LunaCAM assay. Two models corresponding to different intended uses were trained with 513 plasma samples, and validated with an independent collection of 172 plasma samples. In validation, LunaCAM-S model achieved an AUC of 0.90 (95% CI: 0.88-0.94) between lung cancer and healthy individuals, whereas LunaCAM-D model stratified lung cancer from benign pulmonary diseases with an AUC of 0.81 (95% CI: 0.78-0.86). When implemented sequentially in the validation set, LunaCAM-S enables to identify 58 patients of lung cancer (90.6% sensitivity), followed by LunaCAM-D to remove 20 patients with no evidence of cancer (83.3% specificity). LunaCAM-D significantly outperformed the blood test of carcinoembryonic antigen (CEA), and the combined model can further improve the predictive power for lung cancer to an overall AUC of 0.86.We developed two different models by ctDNA methylation assay to sensitively detect early-stage lung cancer or specifically classify lung benign diseases. Implemented at different clinical settings, LunaCAM models has a potential to provide a facile and inexpensive avenue for early screening and diagnostic aids for lung cancer.© 2023. The Author(s).",
-,No,20230629,tandem repeats,37307504,Genome-wide identification of tandem repeats associated with splicing variation across 49 tissues in humans.,Genome Res,"Tandem repeats (TRs) are one of the largest sources of polymorphism, and their length is associated with gene regulation. Although previous studies reported several tandem repeats regulating gene splicing incis(spl-TRs), no large-scale study has been conducted. In this study, we established a genome-wide catalog of 9537 spl-TRs with a total of 58,290 significant TR-splicing associations across 49 tissues (false discovery rate 5%) by using Genotype-Tissue expression (GTex) Project data. Regression models explaining splicing variation by using spl-TRs and other flanking variants suggest that at least some of the spl-TRs directly modulate splicing. In our catalog, two spl-TRs are known loci for repeat expansion diseases, spinocerebellar ataxia 6 (SCA6) and 12 (SCA12). Splicing alterations by these spl-TRs were compatible with those observed in SCA6 and SCA12. Thus, our comprehensive spl-TR catalog may help elucidate the pathomechanism of genetic diseases.© 2023 Hamanaka et al.; Published by Cold Spring Harbor Laboratory Press.",
-,No,20230629,circadian rhythm,37262074,The circadian clock is disrupted in pancreatic cancer.,PLoS Genet,"Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.Copyright: © 2023 Schwartz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
-,Yes,20230706,ewas,37405801,No association between war-related trauma or PTSD symptom severity and epigenome-wide DNA methylation in Burundian refugees.,Eur J Psychotraumatol,"Background:War-related trauma is associated with varying posttraumatic stress disorder (PTSD) prevalence rates in refugees. In PTSD development, differential DNA methylation (DNAm) levels associated with trauma exposure might be involved in risk versus resilience processes. Studies investigating DNAm profiles related to trauma exposure and PTSD among refugees remain sparse.Objective:The present epigenome-wide association study investigated associations between war-related trauma, PTSD, and altered DNAm patterns in Burundian refugee families with 110 children and their 207 female and male caregivers.Method:War-related trauma load and PTSD symptom severity were assessed in structured clinical interviews with standardised instruments. Epigenome-wide DNAm levels were quantified from buccal epithelia using the Illumina EPIC beadchip.Results:Controlling for biological confounders, no significant epigenome-wide DNAm alterations associated with trauma exposure or PTSD were identified in children or caregivers (FDRs > .05). Co-methylated positions derived as modules from weighted gene correlation network analyses were not significantly associated with either war-related trauma experience in children or caregivers or with PTSD.Conclusions:These results do not provide evidence for altered DNAm patterns associated with exposure to war-related trauma or PTSD.",
-,Yes,20230706,ewas,37398583,Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans.,Front Psychiatry,"The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown.To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans.Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDRq-value <0.05), including cg13301722 on chromosome 7, which lies between the genesSLC4A2andCDK5; cg04724646 inPDE3A; and cg04999352 inRARRES3.cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans.Taken together, the present findings suggest thatSLC4A2,CDK5,PDE3A, andRARRES3may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples.Copyright © 2023 Kimbrel, Garrett, Evans, Mellows, Dennis, Hair, Hauser, the VA Mid-Atlantic MIRECC Workgroup, Ashley-Koch and Beckham.",
-,Yes,20230706,ewas,37394087,Epigenome-wide association study identifies Vogt-Koyanagi-Harada disease-associated DNA methylation loci in Chinese.,Exp Eye Res,"DNA methylation is one of the important epigenetic mechanisms for modulating gene expression. By performing a genome-wide methylation association analysis of whole peripheral blood from 60 Vogt-Koyanagi-Harada disease (VKH) patients and 60 healthy controls, we depicted the global DNA methylation status of VKH disease. Further pyrosequencing validation in 160 patients and 159 controls identified 3 aberrant CpG sites in HLA gene regions including cg04026937 and cg18052547 (located in HLA-DRB1 region), and cg13778567 (HLA-DQA1). We also identified 9 aberrant CpG sites in non-HLA gene regions including cg13979407, cg21075643, cg24290586, cg10135747 and cg22707857 (BTNL2), cg22155039 (NOTCH4), cg02605387 (TNXB), cg06255004 (AGPAT2) and cg18855195 (RIBC2). Increased mRNA levels of BTNL2, NOTCH4 and TNXB were identified in VKH patients when compared with healthy controls, consistent with the hypomethylated CpG status in these gene regions. Moreover, seven aberrantly methylated CpG sites may serve as a diagnostic marker for VKH disease (AUC = 84.95%, 95%CI: 79.49%-90.41%).Copyright © 2023 Elsevier Ltd. All rights reserved.",
-,Yes,20230706,ewas,37393498,Sixteen-Year Longitudinal Evaluation of Blood-Based DNA Methylation Biomarkers for Early Prediction of Alzheimer's Disease.,J Alzheimers Dis,"DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer's disease (AD) prediction.Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers.EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10-16 years), and post-AD-onset time-points.EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (ps: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOEɛ4-carriership (OR = 1.38 per 1 SD DNAm score increase versus OR = 13.58 for ɛ4-allele carriage; AUCs = 77.2% versus 87.0%). Literature review showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.",
-,Yes,20230706,ewas,37393279,DNA methylation is differentially associated with glycemic outcomes by different types of weight-loss interventions: an epigenome-wide association study.,Clin Epigenetics,"Alterations in DNA methylation (DNAm) have been reported to be a mechanism by which bariatric surgeries resulted in considerable metabolic improvements. Previous studies have mostly focused on change in DNAm following weight-loss interventions, yet whether DNAm prior to intervention can explain the variability in glycemic outcomes has not been investigated. Here, we aim to examine whether baseline DNAm is differentially associated with glycemic outcomes induced by different types of weight-loss interventions.Participants were 75 adults with severe obesity who underwent non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) or Roux-en-Y gastric bypass (RYGB) (n = 25 each). Changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) were measured at 1-year after intervention. DNAm was quantified by Illumina 450 K arrays in baseline peripheral blood DNA. Epigenome-wide association studies were performed to identify CpG probes that modify the effects of different weight-loss interventions on glycemic outcomes, i.e., changes in FPG and HbA1c, by including an interaction term between types of intervention and DNAm. Models were adjusted for weight loss and baseline clinical factors.Baseline DNAm levels at 3216 and 117 CpGs were differentially associated with changes in FPG and HbA1c, respectively, when comparing RYGB versus IMI. Of these, 79 CpGs were significant for both FPG and HbA1c. The identified genes are enriched in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation. Additionally, DNAm at 6 CpGs was differentially associated with changes in HbA1c when comparing RYGB versus BAND.Baseline DNAm is differentially associated with glycemic outcomes in response to different types of weight-loss interventions, independent of weight loss and other clinical factors. Such findings provided initial evidence that baseline DNAm levels may serve as potential biomarkers predictive of differential glycemic outcomes in response to different types of weight-loss interventions.© 2023. The Author(s).",
-,Yes,20230706,ewas,37356726,DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes.,Diabetes Res Clin Pract,"Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newly-diagnosed individuals with type 2 diabetes.We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for � 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin's effects on HbA1c.Metformin-associated alterations in DNA methylation partially mediates metformin's antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes.Copyright © 2023. Published by Elsevier B.V.",
-,No,20230706,dnamage,37386259,"The meaning of adaptation in aging: insights from cellular senescence, epigenetic clocks and stem cell alterations.",Nat Aging,"With recent rapid progress in research on aging, there is increasing evidence that many features commonly considered to be mechanisms or drivers of aging in fact represent adaptations. Here, we examine several such features, including cellular senescence, epigenetic aging and stem cell alterations. We draw a distinction between the causes and consequences of aging and define short-term consequences as 'responses' and long-term ones as 'adaptations'. We also discuss 'damaging adaptations', which despite having beneficial effects in the short term, lead to exacerbation of the initial insult and acceleration of aging. Features commonly recognized as 'basic mechanisms of the aging process' are critically examined for the possibility of their adaptation-driven emergence from processes such as cell competition and the wound-like features of the aging body. Finally, we speculate on the meaning of these interactions for the aging process and their relevance for the development of antiaging interventions.© 2023. Springer Nature America, Inc.",
-,No,20230706,epigenetics,37393564,Biological stability of DNA methylation measurements over varying intervals of time and in the presence of acute stress.,Epigenetics,"Identifying factors that influence the stability of DNA methylation measurements across biological replicates is of critical importance in basic and clinical research. Using a within-person between-group experimental design (n = 31, number of observations = 192), we report the stability of biological replicates over a variety of unique temporal scenarios, both in the absence and presence of acute psychosocial stress, and between individuals who have experienced early life adversity (ELA) and non-exposed individuals. We found that varying time intervals, acute stress, and ELA exposure influenced the stability of repeated DNA methylation measurements. In the absence of acute stress, probes were less stable as time passed; however, stress exerted a stabilizing influence on probes over longer time intervals. Compared to non-exposed individuals, ELA-exposed individuals had significantly lower probe stability immediately following acute stress. Additionally, we found that across all scenarios, probes used in most epigenetic-based algorithms for estimating epigenetic age or immune cell proportions had average or below-average stability, except for the Principal Component and DunedinPACE epigenetic ageing clocks, which were enriched for more stable probes. Finally, using highly stable probes in the absence of stress, we identified multiple probes that were hypomethylated in the presence of acute stress, regardless of ELA status. Two hypomethylated probes are located near the transcription start site of the glutathione-disulfide reductase gene (GSR), which has previously been shown to be an integral part of the stress response to environmental toxins. We discuss implications for future studies concerning the reliability and reproducibility of DNA methylation measurements.Abbreviations:DNAm - DNA methylation, CpG - 5'-cytosine-phosphate-guanine-3,' ICC - Interclass correlation coefficient, ELA - Early-life adversity, PBMCs - Peripheral blood mononuclear cells, mQTL - Methylation quantitative trait loci, TSS - Transcription start site, GSR - Glutathione-disulfide reductase gene, TSST - Trier social stress test, PC - Principal component.",
-,No,20230706,dnamage,37388854,No evidence of accelerated epigenetic aging among black heroin users: A case vs control analysis.,Addict Neurosci,"This study sought to assess the association between illicit opioid use and accelerated epigenetic aging (A.K.A. DNAm Age) among people of African ancestry who use heroin. DNA was obtained from participants with opioid use disorder (OUD) who confirmed heroin as their primary drug of choice. Clinical inventories of drug use included: the Addiction Severity Index (ASI) Drug-Composite Score (range: 0-1), and Drug Abuse Screening Test (DAST-10; range: 0-10). A control group of participants of African ancestry who did not use heroin was recruited and matched to heroin users on sex, age, socioeconomic level, and smoking status. Methylation data were assessed in an epigenetic clock to determined and compare Epigenetic Age to Chronological Age (i.e., age acceleration or deceleration). Data were obtained from 32 controls [mean age 36.3 (±7.5) years] and 64 heroin users [mean age 48.1 (±6.6) years]. The experimental group used heroin for an average of 18.1 (±10.6) years, reported use of 6.4 (±6.1) bags of heroin/day, with a mean DAST-10 score of 7.0 (±2.6) and ASI Score of 0.33 (±0.19). Mean age acceleration for heroin users [+0.56 (± 9.5) years] was significantly (p< 0.05) lower than controls [+5.19 (± 9.1) years]. This study did not find evidence that heroin use causes epigenetic age acceleration.",
-,No,20230706,pwas,37400771,Associations of circulating proteins with lipoprotein profiles: proteomic analyses from the OmniHeart randomized trial and the Atherosclerosis Risk in Communities (ARIC) Study.,Clin Proteomics,"Within healthy dietary patterns, manipulation of the proportion of macronutrient can reduce CVD risk. However, the biological pathways underlying healthy diet-disease associations are poorly understood. Using an untargeted, large-scale proteomic profiling, we aimed to (1) identify proteins mediating the association between healthy dietary patterns varying in the proportion of macronutrient and lipoproteins, and (2) validate the associations between diet-related proteins and lipoproteins in the Atherosclerosis Risk in Communities (ARIC) Study.In 140 adults from the OmniHeart trial, a randomized, cross-over, controlled feeding study with 3 intervention periods (carbohydrate-rich; protein-rich; unsaturated fat-rich dietary patterns), 4,958 proteins were quantified at the end of each diet intervention period using an aptamer assay (SomaLogic). We assessed differences in log2-transformed proteins in 3 between-diet comparisons using paired t-tests, examined the associations between diet-related proteins and lipoproteins using linear regression, and identified proteins mediating these associations using a causal mediation analysis. Levels of diet-related proteins and lipoprotein associations were validated in the ARIC study (n = 11,201) using multivariable linear regression models, adjusting for important confounders.Three between-diet comparisons identified 497 significantly different proteins (protein-rich vs. carbohydrate-rich = 18; unsaturated fat-rich vs. carbohydrate-rich = 335; protein-rich vs. unsaturated fat-rich dietary patterns = 398). Of these, 9 proteins [apolipoprotein M, afamin, collagen alpha-3(VI) chain, chitinase-3-like protein 1, inhibin beta A chain, palmitoleoyl-protein carboxylesterase NOTUM, cathelicidin antimicrobial peptide, guanylate-binding protein 2, COP9 signalosome complex subunit 7b] were positively associated with lipoproteins [high-density lipoprotein (HDL)-cholesterol (C) = 2; triglyceride = 5; non-HDL-C = 3; total cholesterol to HDL-C ratio = 1]. Another protein, sodium-coupled monocarboxylate transporter 1, was inversely associated with HDL-C and positively associated with total cholesterol to HDL-C ratio. The proportion of the association between diet and lipoproteins mediated by these 10 proteins ranged from 21 to 98%. All of the associations between diet-related proteins and lipoproteins were significant in the ARIC study, except for afamin.We identified proteins that mediate the association between healthy dietary patterns varying in macronutrients and lipoproteins in a randomized feeding study and an observational study.NCT00051350 at clinicaltrials.gov.© 2023. The Author(s).",
-,No,20230706,methods,37387182,AttOmics: attention-based architecture for diagnosis and prognosis from omics data.,Bioinformatics,"The increasing availability of high-throughput omics data allows for considering a new medicine centered on individual patients. Precision medicine relies on exploiting these high-throughput data with machine-learning models, especially the ones based on deep-learning approaches, to improve diagnosis. Due to the high-dimensional small-sample nature of omics data, current deep-learning models end up with many parameters and have to be fitted with a limited training set. Furthermore, interactions between molecular entities inside an omics profile are not patient specific but are the same for all patients.In this article, we propose AttOmics, a new deep-learning architecture based on the self-attention mechanism. First, we decompose each omics profile into a set of groups, where each group contains related features. Then, by applying the self-attention mechanism to the set of groups, we can capture the different interactions specific to a patient. The results of different experiments carried out in this article show that our model can accurately predict the phenotype of a patient with fewer parameters than deep neural networks. Visualizing the attention maps can provide new insights into the essential groups for a particular phenotype.The code and data are available at https://forge.ibisc.univ-evry.fr/abeaude/AttOmics. TCGA data can be downloaded from the Genomic Data Commons Data Portal.© The Author(s) 2023. Published by Oxford University Press.",
-,No,20230706,transgenerational,37396986,Epigenetic Inheritance and Transgenerational Environmental Justice.,Yale J Biol Med,"Many chemicals and toxicants are released into our ecosystem and environment every day, which can cause harmful effects on human populations. Agricultural compounds are used in most crop production and have been shown to cause negative health impacts, including effects on reproduction and other pathologies. Although these chemicals can be helpful for pest and weed control, the compounds indirectly impact humans. Several compounds have been banned in the European Union but continue to be used in the United States. Recent work has shown most toxicants affect transgenerational generations more than the directly exposed generations through epigenetic inheritance. While some toxicants do not impact the directly exposed generation, the later generations that are transgenerational or ancestrally exposed suffer health impacts. Due to impacts to future generations, exposure becomes an environmental justice concern. The term ""environmental justice"" denotes the application of fair strategies when resolving unjust environmental contamination. Fair treatment means that no group should bear a disproportionate share of negative environmental consequences resulting from industrial, municipal, and commercial operations. This article illustrates how research on directly exposed generations is often prioritized over studies on transgenerational generations. However, research on the latter generations suggests the need to take environmental justice concerns seriously moving forward, as future generations could be unduly shouldering harms, while not enjoying benefits of production.Copyright ©2023, Yale Journal of Biology and Medicine.",
-,No,20230706,epigenetics,36535946,A comparison of the genes and genesets identified by GWAS and EWAS of fifteen complex traits,Nat Commun,"Identifying genomic regions pertinent to complex traits is a common goal of genome-wide and epigenome-wide association studies (GWAS and EWAS). GWAS identify causal genetic variants, directly or via linkage disequilibrium, and EWAS identify variation in DNA methylation associated with a trait. While GWAS in principle will only detect variants due to causal genes, EWAS can also identify genes via confounding, or reverse causation. We systematically compare GWAS (N > 50,000) and EWAS (N > 4500) results of 15 complex traits. We evaluate if the genes or gene ontology terms flagged by GWAS and EWAS overlap, and find substantial overlap for diastolic blood pressure, (gene overlap P = 5.2 × 10-6; term overlap P = 0.001). We superimpose our empirical findings against simulated models of varying genetic and epigenetic architectures and observe that in most cases GWAS and EWAS are likely capturing distinct genesets. Our results indicate that GWAS and EWAS are capturing different aspects of the biology of complex traits.",
-,,,,,,,,
-,,20230803,,37511531,Epigenome-Wide Associations of Placental DNA Methylation and Behavioral and Emotional Difficulties in Children at 3 Years of Age.,Int J Mol Sci,"The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother-child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 (AHRR) with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (PPP1R16B), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.",
-,,20230803,,37503194,An epigenome-wide association study of child appetitive traits and DNA methylation.,bioRxiv,"Childhood appetitive traits are consistently associated with obesity risk, and yet their etiology is poorly understood. Appetitive traits are complex phenotypes which are hypothesized to be influenced by both genetic and environmental factors, as well as their interactions. Early-life epigenetic processes, such as DNA methylation (DNAm), may be involved in the developmental programming of appetite regulation in childhood. In the current study, we meta-analyzed epigenome-wide association studies (EWASs) of cord blood DNAm and early-childhood appetitive traits. Data were from two independent cohorts: the Generation R Study (n=1,086, Rotterdam, the Netherlands) and the Healthy Start study (n=236, Colorado, USA). DNAm at autosomal methylation sites in cord blood was measured using the Illumina Infinium HumanMethylation450 BeadChip. Parents reported on their child's food responsiveness, emotional undereating, satiety responsiveness and food fussiness using the Children's Eating Behaviour Questionnaire at age 4-5 years. Multiple regression models were used to examine the association of DNAm (predictor) at the individual site- and regional-level (using DMRff) with each appetitive trait (outcome), adjusting for covariates. Bonferroni-correction was applied to adjust for multiple testing. There were no associations of DNAm and any appetitive trait at the individual site-level. However, at the regional level, we identified 45 associations of DNAm with food responsiveness, 7 associations of DNAm with emotional undereating, 13 associations of DNAm with satiety responsiveness, and 9 associations of DNAm with food fussiness. This study shows that DNAm in the newborn may partially explain variation in appetitive traits expressed in early childhood and provides preliminary support for early programming of child appetitive traits through DNAm. Investigating differential DNAm associated with appetitive traits could be an important first step in identifying biological pathways underlying the development of these behaviors.",
-,,20230803,,37502923,sciMET-cap: High-throughput single-cell methylation analysis with a reduced sequencing burden.,bioRxiv,"DNA methylation is a key component of the mammalian epigenome, playing a regulatory role in development, disease, and other processes. Robust, high-throughput single-cell DNA methylation assays are now possible (sciMET); however, the genome-wide nature of DNA methylation results in a high sequencing burden per cell. Here, we leverage target enrichment with sciMET to capture sufficient information per cell for cell type assignment using substantially fewer sequence reads (sciMET-cap). Sufficient off-target coverage further enables the production of near-complete methylomes for individual cell types. We characterize sciMET-cap on human PBMCs and brain (middle frontal gyrus).",
-,,20230803,,37502922,Multi-ancestry epigenome-wide analyses identify methylated sites associated with aortic augmentation index in TOPMed MESA.,Res Sq,"Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these,ETS1andTGFB3have been previously prioritized as candidate genes. Furthermore, bothETS1andHLA-DPB1have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggestsETS1andHLA-DPB1could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.",
-,,20230803,,37501075,Genome-wide discovery of circulating cell-free DNA methylation biomarkers for colorectal cancer detection.,Clin Epigenetics,"Colorectal polyp is known a precursor of colorectal cancer (CRC) that holds an increased risk for progression to CRC. Circulating cell-free DNA (cfDNA) methylation has shown favorable performance in the detection and monitoring the malignant progression in a variety of cancers.To discover cfDNA methylation markers for the diagnosis of CRC, we first performed a genome-wide analysis between eight CRC and eight polyp tissues using the Infinium HumanMethylationEPIC BeadChip. We identified 7008 DMCs, and after filtering, we validated 39 DMCs by MethylTarget sequencing in 62 CRC and 56 polyp tissues. A panel of four CpGs (cg04486886, cg06712559, cg13539460, and cg27541454) was selected as the methylation marker in tissue by LASSO and random forest models. A diagnosis prediction model was built based on the four CpGs, and the methylation diagnosis score (md-score) can effectively discriminate tissues with CRC from polyp patients (AUROC > 0.9). Finally, the cg27541454 was confirmed hypermethylated in CRC (AUC = 0.85) in the plasma validation cohort.Our findings suggest that the md-score could robustly detect CRC from polyp tissues, and cg27541454 may be a promising candidate noninvasive biomarker for CRC early diagnosis.© 2023. The Author(s).",
-,,20230803,,37496173,The lipidomic correlates of epigenetic aging across the adult lifespan: A population-based study.,Aging Cell,"Lipid signaling is involved in longevity regulation, but which specific lipid molecular species affect human biological aging remains largely unknown. We investigated the relation between complex lipids and DNA methylation-based metrics of biological aging among 4181 participants (mean age 55.1 years (range 30.0-95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. The absolute concentration of 14 lipid classes, covering 964 molecular species and 267 fatty acid composites, was measured by Metabolon Complex Lipid Panel. DNA methylation-based metrics of biological aging (AgeAccelPheno and AgeAccelGrim) were calculated based on published algorithms. Epigenome-wide association analyses (EWAS) of biological aging-associated lipids and pathway analysis were performed to gain biological insights into the mechanisms underlying the effects of lipidomics on biological aging. We found that higher levels of molecular species belonging to neutral lipids, phosphatidylethanolamines, phosphatidylinositols, and dihydroceramides were associated with faster biological aging, whereas higher levels of lysophosphatidylcholine, hexosylceramide, and lactosylceramide species were associated with slower biological aging. Ceramide, phosphatidylcholine, and lysophosphatidylethanolamine species with odd-numbered fatty acid tail lengths were associated with slower biological aging, whereas those with even-numbered chain lengths were associated with faster biological aging. EWAS combined with functional pathway analysis revealed several complex lipids associated with biological aging as important regulators of known longevity and aging-related pathways.© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
-,,20230803,,37466420,Genome-wide analysis of DNA methylation and its relationship with serum homocysteine levels in patients with hypertension.,J Hypertens,"Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases, and elevated plasma Hcy levels could aggravate vascular injury in hypertension. Hyperhomocysteinemia can change the methylation status of global DNA and specific genes. In the present study, we aim to examine the comprehensive influence of Hcy levels on DNA methylation status in patients with hypertension.Epigenome-wide methylation profiles of the peripheral leukocyte DNA of 218 patients with hypertension were analyzed using the Illumina Infinium Methylation EPIC BeadChip. Differentially methylated positions (DMPs) associated with serum Hcy levels were identified by mixed linear regression with the adjustment of potential confounders. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to determine the potential functions of the identified DMPs. The association between the methylation level of DMPs and carotid-femoral pulse wave velocity (Cf-PWV) was also analyzed.Five DMPs at cg13169662, cg03179312, cg21976560, cg25262698, and cg09433843 showed significant association with serum Hcy levels (false discovery rate-corrected P < 0.05). An additional six CpG sites met the threshold for suggestive significance (P < 1 × 10-6), among which three DMPs (cg25781123, cg26463106, and cg06679221) were annotated to THUMPD3. Furthermore, the methylation levels of cg13169662 and cg25262698 (RPRD1A) were significantly associated with Cf-PWV.Our results suggest that Hcy could induce DNA methylation alteration in patients with hypertension. Further functional research is warranted to elucidate the concrete role of DMPs in hypertension.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.",
-,,20230803,,37464577,Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study.,J Clin Periodontol,"To investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood.We included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at Visit 4 and had available data on DNA methylation from Visit 2 or 3. DNA methylation levels were compared by periodontal disease severity and edentulism through discovery analyses and subsequent testing of individual CpGs.Our discovery analysis replicated findings from a previous study reporting a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared with no/mild periodontal disease in European American participants. Higher methylation levels in a separate region in an unknown gene (located in Chr10: 743,992-744,958) was associated with significantly higher odds of edentulism compared with no/mild periodontal disease in African American participants. In subsequent CpG testing, four CpGs in a region previously associated with periodontitis located within HOXA4 were significantly hypermethylated in severe periodontal disease compared with no/mild periodontal disease in African American participants (odds ratio per 1 SD increase in methylation level: cg11015251: 1.28 (1.02, 1.61); cg14359292: 1.24 (1.01, 1.54); cg07317062: 1.30 (1.05, 1.61); cg08657492: 1.25 (1.01, 1.55)).Our study highlights epigenetic variations in ZPF57 and HOXA4 that are significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",
-,,20230803,,37461726,Critical evaluation of the reliability of DNA methylation probes on the Illumina MethylationEPIC BeadChip microarrays for dementia research.,Res Sq,"Background DNA methylation (DNAm) has been implicated in many diseases including dementia. Array-based technologies offer a cost-effective and comprehensive approach for measuring DNAm on a genome-wide scale. However, the accuracy of DNAm measurements obtained using Illumina arrays can vary across different probes. Previous research has focused primarily on assessing the reliability of DNAm in younger subjects, and have compared duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on EPIC-EPIC comparisons. Methods We conducted a comprehensive assessment of probe reliability on the Illumina EPIC arrays using 138 duplicated blood DNAm samples from subjects older than 65 years in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. To assess the reliability of each probe, we computed intraclass correlations (ICCs) for each probe. Both the magnitude and patterns of reliability in the EPIC-EPIC comparison were assessed. Furthermore, we also investigated the impact of probe reliability on the analyses of epigenome-wide association studies (EWAS). Results Our findings revealed the reliability of probes on the EPIC arrays is higher than those of previous studies involving duplicate measurements on 450k-EPIC or 450k-450k arrays. Consistent with earlier research, we observed increased reliability in probes with substantial between-subject variances or average methylation beta values ranging from 0.2 to 0.8. Lower reliability was observed in type I probes or probes located within the promoter and CpG island regions. In addition, we found some probes can yield high ICC values despite significant disagreement in duplicate measurements, primarily due to their relatively high between-subject variance. To account for such discrepancies explicitly, we introduced a novel statistical measure called the modified ICC, which penalizes the ICC based on the half-width of the 95% confidence limits of agreement. Importantly, we found probe reliability has significant implications in various downstream analyses of EWAS, such as meta-analysis, differentially methylated regions analysis, and integrative analyses within the cross-tissue or multi-omics contexts. Conclusion We developed a valuable resource for dementia research, providing crucial reliability information for probes on the EPIC array. This resource can be utilized to identify and prioritize high-quality probes, thereby minimizing the potential for false discoveries and maximizing the potential of EWAS.",
-,,20230803,,37415231,Epigenetic marks associated with gestational diabetes mellitus across two time points during pregnancy.,Clin Epigenetics,"An adverse intrauterine or periconceptional environment, such as hyperglycemia during pregnancy, can affect the DNA methylation pattern both in mothers and their offspring. In this study, we explored the epigenetic profile in maternal peripheral blood samples through pregnancy to find potential epigenetic biomarkers for gestational diabetes mellitus (GDM), as well as candidate genes involved in GDM development. We performed an epigenome-wide association study in maternal peripheral blood samples in 32 pregnant women (16 with GDM and 16 non-GDM) at pregnancy week 24-28 and 36-38. Biochemical, anthropometric, and obstetrical variables were collected from all the participants. The main results were validated in an independent cohort with different ethnic origin (European = 307; South Asians = 165). Two hundred and seventy-two CpGs sites remained significantly different between GDM and non-GDM pregnant women across two time points during pregnancy. The significant CpG sites were related to pathways associated with type I diabetes mellitus, insulin resistance and secretion. Cg01459453 (SELP gene) was the most differentiated in the GDM group versus non-GDM (73.6 vs. 60.9, p = 1.06E-11; FDR = 7.87E-06). Three CpG sites (cg01459453, cg15329406, and cg04095097) were able to discriminate between GDM cases and controls (AUC = 1; p = 1.26E-09). Three differentially methylated positions (DMPs) were replicated in an independent cohort. To conclude, epigenetic marks during pregnancy differed between GDM cases and controls suggesting a role for these genes in GDM development. Three CpGs were able to discriminate GDM and non-GDM groups with high specificity and sensitivity, which may be biomarker candidates for diagnosis or prediction of GDM.© 2023. The Author(s).",
-,,20230803,,37405974,Contributions of neighborhood social environment and air pollution exposure to Black-White disparities in epigenetic aging.,PLoS One,"Racial disparities in many aging-related health outcomes are persistent and pervasive among older Americans, reflecting accelerated biological aging for Black Americans compared to White, known as weathering. Environmental determinants that contribute to weathering are poorly understood. Having a higher biological age, measured by DNA methylation (DNAm), than chronological age is robustly associated with worse age-related outcomes and higher social adversity. We hypothesize that individual socioeconomic status (SES), neighborhood social environment, and air pollution exposures contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm). We perform retrospective cross-sectional analyses among 2,960 non-Hispanic participants (82% White, 18% Black) in the Health and Retirement Study whose 2016 DNAm age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing DNAm age on chronological age. We observe Black individuals have significantly accelerated DNAm aging on average compared to White individuals according to GrimAge (239%) and DPoAm (238%). We implement multivariable linear regression models and threefold decomposition to identify exposures that contribute to this disparity. Exposure measures include individual-level SES, census-tract-level socioeconomic deprivation and air pollution (fine particulate matter, nitrogen dioxide, and ozone), and perceived neighborhood social and physical disorder. Race and gender are included as covariates. Regression and decomposition results show that individual-level SES is strongly associated with and accounts for a large portion of the disparity in both GrimAge and DPoAm aging. Higher neighborhood deprivation for Black participants significantly contributes to the disparity in GrimAge aging. Black participants are more vulnerable to fine particulate matter exposure for DPoAm, perhaps due to individual- and neighborhood-level SES, which may contribute to the disparity in DPoAm aging. DNAm aging may play a role in the environment ""getting under the skin"", contributing to age-related health disparities between older Black and White Americans.Copyright: © 2023 Yannatos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
-,,20230803,,37278618,Associations of four biological age markers with child development: A multi-omic analysis in the European HELIX cohort.,Elife,"While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators, to child developmental outcomes, including growth and adiposity, cognition, behavior, lung function and the onset of puberty, among European school-age children participating in the HELIX exposome cohort.The study population included up to 1173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation, and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma proteins and urinary and serum metabolites) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity, and study centre. The clock derived markers were expressed as Δ age (i.e. predicted minus chronological age).Transcriptome and immunometabolic clocks predicted chronological age well in the test set (r=0.93 andr=0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators.Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ age, smoke exposure with greater DNA methylation Δ age, and high family affluence with longer telomere length.Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p=4 e-3) and reduced inattentiveness (p=4 e-4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviors (p=0.01). Shorter telomere length was also associated with poorer externalizing behaviors (p=0.03).In children, as in adults, biological aging appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological aging. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological aging, apparent even in children.UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583).© 2023, Robinson et al.",
-,,20230803,,37364131,Antisense oligonucleotide rescue of CGG expansion-dependent FMR1 mis-splicing in fragile X syndrome restores FMRP.,Proc Natl Acad Sci U S A,"Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here, we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissues of individuals with fragile X syndrome (FXS). Surprisingly, theFMR1 (Fragile X Messenger Ribonucleoprotein 1)gene is transcribed in >70% of the FXS tissues. In allFMR1-expressing FXS tissues,FMR1RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-knownFMR1-217 RNA isoform, which is comprised ofFMR1exon 1 and a pseudo-exon in intron 1.FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissues. We show that in cells aberrantly expressing mis-splicedFMR1, antisense oligonucleotide (ASO) treatment reducesFMR1-217, rescues full-lengthFMR1RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably,FMR1gene reactivation in transcriptionally silent FXS cells using 5-aza-2'-deoxycytidine (5-AzadC), which prevents DNA methylation, increasesFMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-lengthFMR1expression and restores FMRP. These findings indicate that misregulated RNA-processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressingFMR1-217, ASO treatment may offer a therapeutic approach to mitigate the disorder.",
-,,20230803,,37414898,A prognostic risk score for development and spread of chronic pain.,Nat Med,"Chronic pain is a complex condition influenced by a combination of biological, psychological and social factors. Using data from the UK Biobank (n = 493,211), we showed that pain spreads from proximal to distal sites and developed a biopsychosocial model that predicted the number of coexisting pain sites. This data-driven model was used to identify a risk score that classified various chronic pain conditions (area under the curve (AUC) 0.70-0.88) and pain-related medical conditions (AUC 0.67-0.86). In longitudinal analyses, the risk score predicted the development of widespread chronic pain, the spreading of chronic pain across body sites and high-impact pain about 9 years later (AUC 0.68-0.78). Key risk factors included sleeplessness, feeling 'fed-up', tiredness, stressful life events and a body mass index >30. A simplified version of this score, named the risk of pain spreading, obtained similar predictive performance based on six simple questions with binarized answers. The risk of pain spreading was then validated in the Northern Finland Birth Cohort (n = 5,525) and the PREVENT-AD cohort (n = 178), obtaining comparable predictive performance. Our findings show that chronic pain conditions can be predicted from a common set of biopsychosocial factors, which can aid in tailoring research protocols, optimizing patient randomization in clinical trials and improving pain management.© 2023. The Author(s).",
-,,20230803,,37461498,Effect of Parental Adverse Childhood Experiences on Intergenerational DNA Methylation Signatures.,Res Sq,"Adverse Childhood Experiences (ACEs) are events that occur before a child turns 18 years old that may cause trauma. In this study, the effect of cumulative ACEs experienced on human maternal DNA methylation (DNAm) was estimated while accounting for interaction with domains of ACEs in prenatal peripheral blood mononuclear cell samples from the Maternal and Developmental Risks from Environmental Stressors (MADRES) pregnancy cohort. The intergenerational transmission of ACE-associated DNAm was also explored used paired maternal and neonatal cord blood samples. Replication in buccal samples was explored in the Children's Health Study (CHS). We used a four-level categorical indicator variable for ACEs exposure: none (0 ACEs), low (1-3 ACEs), moderate (4-6 ACEs), and high (> 6 ACEs). Effects of ACEs on maternal DNAm (N = 240) were estimated using linear models. To evaluate evidence for intergenerational transmission, mediation analysis was used. Analysis of maternal samples displayed some shared but mostly distinct effects of ACEs on DNAm across low, moderate, and high ACEs categories.CLCN7andPTPRN2was associated with maternal DNAm in the low ACE group and this association replicated in the CHS. ACE-associated methylation was observed in maternal and neonatal profiles in theCOMTpromoter region, with some evidence of mediation by maternalCOMTmethylation. Specific genomic loci exhibited mutually exclusive maternal ACE effects on DNAm in either maternal or neonatal population. There is some evidence for an intergenerational effect of ACEs, supported by shared DNAm signatures in theCOMTgene across maternal-neonatal paired samples.",
-,,20230803,,37430364,CimpleG: finding simple CpG methylation signatures.,Genome Biol,"DNA methylation signatures are usually based on multivariate approaches that require hundreds of sites for predictions. Here, we propose a computational framework named CimpleG for the detection of small CpG methylation signatures used for cell-type classification and deconvolution. We show that CimpleG is both time efficient and performs as well as top performing methods for cell-type classification of blood cells and other somatic cells, while basing its prediction on a single DNA methylation site per cell type. Altogether, CimpleG provides a complete computational framework for the delineation of DNAm signatures and cellular deconvolution.© 2023. The Author(s).",
-,,20230803,,37443060,Stability selection enhances feature selection and enables accurate prediction of gestational age using only five DNA methylation sites.,Clin Epigenetics,"DNA methylation (DNAm) is robustly associated with chronological age in children and adults, and gestational age (GA) in newborns. This property has enabled the development of several epigenetic clocks that can accurately predict chronological age and GA. However, the lack of overlap in predictive CpGs across different epigenetic clocks remains elusive. Our main aim was therefore to identify and characterize CpGs that are stably predictive of GA.We applied a statistical approach called 'stability selection' to DNAm data from 2138 newborns in the Norwegian Mother, Father, and Child Cohort study. Stability selection combines subsampling with variable selection to restrict the number of false discoveries in the set of selected variables. Twenty-four CpGs were identified as being stably predictive of GA. Intriguingly, only up to 10% of the CpGs in previous GA clocks were found to be stably selected. Based on these results, we used generalized additive model regression to develop a new GA clock consisting of only five CpGs, which showed a similar predictive performance as previous GA clocks (R2 = 0.674, median absolute deviation = 4.4 days). These CpGs were in or near genes and regulatory regions involved in immune responses, metabolism, and developmental processes. Furthermore, accounting for nonlinear associations improved prediction performance in preterm newborns.We present a methodological framework for feature selection that is broadly applicable to any trait that can be predicted from DNAm data. We demonstrate its utility by identifying CpGs that are highly predictive of GA and present a new and highly performant GA clock based on only five CpGs that is more amenable to a clinical setting.© 2023. The Author(s).",
-,,20230803,,37447167,Association of the DNA Methylation of Obesity-Related Genes with the Dietary Nutrient Intake in Children.,Nutrients,"The occurrence of obesity stems from both genetic and external influences. Despite thorough research and attempts to address it through various means such as dietary changes, physical activity, education, and medications, a lasting solution to this widespread problem remains elusive. Nutrients play a crucial role in various cellular processes, including the regulation of gene expression. One of the mechanisms by which nutrients can affect gene expression is through DNA methylation. This modification can alter the accessibility of DNA to transcription factors and other regulatory proteins, thereby influencing gene expression. Nutrients such as folate and vitamin B12 are involved in the one-carbon metabolism pathway, which provides the methyl groups necessary for DNA methylation. Studies have shown that the inadequate intake of these nutrients can lead to alterations in DNA methylation patterns. For this study, we aim to understand the differences in the association of the dietary intake between normal weight and overweight/obese children and between European American and African American children with the DNA methylation of the three genesNRF1,FTO, andLEPR. The research discovered a significant association between the nutritional intake of 6-10-years-old children, particularly the methyl donors present in their diet, and the methylation of theNRF1,FTO, andLEPRgenes. Additionally, the study emphasizes the significance of considering health inequalities, particularly family income and maternal education, when investigating the epigenetic impact of methyl donors in diet and gene methylation.",
-,,20230803,,37495687,Evolutionary histories of breast cancer and related clones.,Nature,"Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.© 2023. The Author(s).",
-,,20230803,,37443254,Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases.,Nat Genet,"Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
-,,20230803,,37468586,Organization of the human intestine at single-cell resolution.,Nature,"The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health1. The intesting has a length of over nine metres, along which there are differences in structure and function2. The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.© 2023. The Author(s).",
-,,20230803,,37500728,Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer.,Nat Genet,"Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.© 2023. The Author(s).",
-,,20230803,,37399400,Comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring.,Proc Natl Acad Sci U S A,"Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of thelargestcomprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop thefirstsupervised tissue deconvolution approach, a deep-learning-powered model,cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data,cfSortshowed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities ofcfSortwith two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated fromcfSortreflected the clinical outcomes of the patients. In summary, the tissue methylation atlas andcfSortenhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.",
-,,20230803,,37496025,Short-term smoking cessation leads to a universal decrease in whole blood genomic DNA methylation in patients with a smoking history.,World J Surg Oncol,"Epigenetics is involved in various human diseases. Smoking is one of the most common environmental factors causing epigenetic changes. The DNA methylation changes and mechanisms after quitting smoking have yet to be defined. The present study examined the changes in DNA methylation levels before and after short-term smoking cessation and explored the potential mechanism.Whole blood and clinical data were collected from 8 patients before and after short-term smoking cessation, DNA methylation was assessed, and differentially methylated sites were analyzed, followed by a comprehensive analysis of the differentially methylated sites with clinical data. GO/KEGG enrichment and protein-protein interaction (PPI) network analyses identified the hub genes. The differentially methylated sites between former and current smokers in GSE50660 from the GEO database were detected by GEO2R. Then, a Venn analysis was carried out using the differentially methylated sites. GO/KEGG enrichment analysis was performed on the genes corresponding to the common DNA methylation sites, the PPI network was constructed, and hub genes were predicted. The enriched genes associated with the cell cycle were selected, and the pan-cancer gene expression and clinical significance in lung cancer were analyzed based on the TCGA database.Most genes showed decreased DNA methylation levels after short-term smoking cessation; 694 upregulated methylation CpG sites and 3184 downregulated methylation CpG sites were identified. The DNA methylation levels were altered according to the clinical data (body weight, expiratory, and tobacco dependence score). Enrichment analysis, construction of the PPI network, and pan-cancer analysis suggested that smoking cessation may affect various biological processes.Smoking cessation leads to epigenetic changes, mainly decreased in the decline of most DNA methylation levels. Bioinformatics further identified the biologically relevant changes after short-term smoking cessation.© 2023. The Author(s).",
-,,20230803,,37495688,Rewiring cancer drivers to activate apoptosis.,Nature,"Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated7. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression8. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50of 1-10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
-,,20230803,,37409096,DNA methylation biomarkers distinguishing early-stage prostate cancer from benign prostatic hyperplasia.,Prostate Int,"DNA methylation markers are considered robust diagnostic features in various cancer types, as epigenetic marks are commonly altered during cancer progression. Differentiation between benign prostatic hyperplasia (BPH) and early-stage prostate cancer (PCa) is clinically difficult, relying on the information of the patient's symptoms or levels of prostate-specific antigen.A total of 42 PCa patients and 11 BPH patients were recruited. Genomic DNA was purified from tissues and used for the library preparation of the target-enriched methylome with enzymatic conversion and a Twist 85 Mbp EM-seq panel. Paired-end sequencing (150 bp) was performed using NovaSeq 6000 or NextSeq 550. After quality control, including adapter trimming and de-duplication of raw sequencing data, differential methylation patterns were analyzed between the BPH and PCa groups.We report DNA methylation patterns existing between BPH and PCa. The major finding is that broad hypermethylation occurred at genic loci in PCa tissues as compared to the BPH. Gene ontology analysis suggested that hypermethylation of genic loci involved in chromatin and transcriptional regulation is involved in cancer progression. We also compared PCa tissues with high Gleason scores to tissues with low Gleason scores. The high-Gleason PCa tissues showed hundreds of focal differentially methylated CpG sites corresponding to genes functioning in cancer cell proliferation or metastasis. This suggests that dissecting early-to-advanced-grade cancer stages requires an in-depth analysis of differential methylation at the single CpG site level.Our study reports that enzymatic methylome sequencing data can be used to distinguish PCa from BPH and advanced PCa from early-stage PCa. The stage-specific methylation patterns in this study will be valuable resources for diagnostic purposes as well as further development of liquid biopsy approaches for the early detection of PCa.© 2023 The Asian Pacific Prostate Society. Published by Elsevier B.V.",
-,,20230803,,37508326,Deep Learning Techniques with Genomic Data in Cancer Prognosis: A Comprehensive Review of the 2021-2023 Literature.,Biology (Basel),"Deep learning has brought about a significant transformation in machine learning, leading to an array of novel methodologies and consequently broadening its influence. The application of deep learning in various sectors, especially biomedical data analysis, has initiated a period filled with noteworthy scientific developments. This trend has majorly influenced cancer prognosis, where the interpretation of genomic data for survival analysis has become a central research focus. The capacity of deep learning to decode intricate patterns embedded within high-dimensional genomic data has provoked a paradigm shift in our understanding of cancer survival. Given the swift progression in this field, there is an urgent need for a comprehensive review that focuses on the most influential studies from 2021 to 2023. This review, through its careful selection and thorough exploration of dominant trends and methodologies, strives to fulfill this need. The paper aims to enhance our existing understanding of applications of deep learning in cancer survival analysis, while also highlighting promising directions for future research. This paper undertakes aims to enrich our existing grasp of the application of deep learning in cancer survival analysis, while concurrently shedding light on promising directions for future research in this vibrant and rapidly proliferating field.",
-,,,,,,,,
-,,20230810,,37550724,Global effects of identity and aging on the human sperm methylome.,Clin Epigenetics,"As the average age of fatherhood increases worldwide, so too does the need for understanding effects of aging in male germline cells. Molecular change, including epigenomic alterations, may impact offspring. Age-associated change to DNA cytosine methylation in the cytosine-guanine (CpG) context is a hallmark of aging tissues, including sperm. Prior studies have led to accurate models that predict a man's age based on specific methylation features in the DNA of sperm, but the relationship between aging and global DNA methylation in sperm remains opaque. Further clarification requires a more complete survey of the methylome with assessment of variability within and between individuals.We collected sperm methylome data in a longitudinal study of ten healthy fertile men. We used whole-genome bisulfite sequencing of samples collected 10 to 18 years apart from each donor. We found that, overall, variability between donors far exceeds age-associated variation. After controlling for donor identity, we see significant age-dependent genome-wide change to the methylome. Notably, trends of change with age depend on genomic location or annotation, with contrasting signatures that correlate with gene density and proximity to centromeres and promoter regions.We uncovered epigenetic signatures that reflect a stable process which begins in early adulthood, progressing steadily through most of the male lifespan, and warrants consideration in any future study of the aging sperm epigenome.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,,20230810,,37550674,Long-term exposure to ambient fine particulate components and leukocyte epigenome-wide DNA Methylation in older men: the Normative Aging Study.,Environ Health,"Epigenome-wide association studies of ambient fine particulate matter (PM2.5) have been reported. However, few have examined PM2.5components (PMCs) and sources or included repeated measures. The lack of high-resolution exposure measurements is the key limitation. We hypothesized that significant changes in DNA methylation might vary by PMCs and the sources.We predicted the annual average of 14 PMCs using novel high-resolution exposure models across the contiguous U.S., between 2000-2018. The resolution was 50 m × 50 m in the Greater Boston Area. We also identified PM2.5sources using positive matrix factorization. We repeatedly collected blood samples and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip in the Normative Aging Study. We then used median regression with subject-specific intercepts to estimate the associations between long-term (one-year) exposure to PMCs / PM2.5sources and DNA methylation at individual cytosine-phosphate-guanine CpG sites. Significant probes were identified by the number of independent degrees of freedom approach, using the number of principal components explaining > 95% of the variation of the DNA methylation data. We also performed regional and pathway analyses to identify significant regions and pathways.We included 669 men with 1,178 visits between 2000-2013. The subjects had a mean age of 75 years. The identified probes, regions, and pathways varied by PMCs and their sources. For example, iron was associated with 6 probes and 6 regions, whereas nitrate was associated with 15 probes and 3 regions. The identified pathways from biomass burning, coal burning, and heavy fuel oil combustion sources were associated with cancer, inflammation, and cardiovascular diseases, whereas there were no pathways associated with all traffic.Our findings showed that the effects of PM2.5on DNAm varied by its PMCs and sources.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,,20230810,,37549439,Epigenetic modifications appear in the human placenta following anxiety and depression during pregnancy.,Placenta,"The future health of the offspring can be influenced by longstanding maternal anxiety and depression disorders during pregnancy. The present study aimed to explore the effect of psychiatric disorders during pregnancy on placental epigenetics.We measured DNA methylation patterns in term-placentas of women either suffering longstanding anxiety and depression symptoms (Index group, with overt symptoms), or a healthy population (Control, none/only mild symptoms). Whole genome DNA methylation profiling was performed using the TruSeq® Methyl Capture EPIC Library Prep Kit (Illumina, San Diego, CA, USA) for library preparation and NGS technology for genomic DNA sequencing.The results of high-throughput DNA methylation analysis revealed that the Index group had differential DNA methylation at epigenome-wide significance (p < 0.05) in 226 genes in the placenta. Targeted enrichment analyses identified hypermethylation of genes associated with psychiatric disorders (BRINP1, PUM1), and ion homeostasis (COMMD1), among others. The ECM (extracellular matrix)-receptor interaction pathway was significantly dysregulated in the Index group compared to the Control. In addition, DNA methylation/mRNA integration analyses revealed that four genes with key roles in neurodevelopment and other important processes (EPB41L4B, BMPR2, KLHL18, and UBAP2) were dysregulated at both, DNA methylation and transcriptome levels in the Index group compared to Control.The presented results increase our understanding of how maternal psychiatric disorders may affect the newborn through placental differential epigenome, suggesting DNA methylation status as a biomarker when aiming to design new preventive techniques and interventions.Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.",
-,,20230810,,37546994,Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.,medRxiv,"Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at > 700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold-changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical predictor in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.",
-,,20230810,,37546290,Offspring epigenetic markers at birth related to gestational BMI predict offspring BMI-trajectories from infancy to 26 years.,Obes Sci Pract,"To date, epigenetic studies identified differential DNA methylation (DNAm) related to gestational-body mass index (BMI) in offspring at birth. This study investigated whether the identified DNAm in offspring were also associated with BMI trajectories from infancy to age 26 years.Data of 794 participants from Isle of Wight birth cohort in UK were investigated to study association between BMI trajectories and DNAm related to gestational-BMI at birth. Multinominal logistic regression models were applied to test the association between 1090 DNAm sites reported in three prior epigenome-wide association studies and BMI trajectories.DNAm site cg23089913 (NANOS1) and cg13217064 (SOX14) were associated with early persistent obesity (EPO) and delayed overweight (DOW) trajectories respectively. A higher methylation of cg23089913 showed low odds of being in EPO trajectory (OR: 0.84; 95% CI: 0.76-0.93) while higher methylation of cg13217064 resulted in 1.4-times the odds of being in DOW trajectory when compared to the normal trajectory [Correction added on 22 February 2023, after first online publication: Range of the DNAm site cg23089913 has been changed from 'lower' to 'higher' in the preceding sentence.]. In a gender-stratified analysis, the odds of developing into DOW was 1.8 times in female participants for cg13217064 while not such association was observed in males.Deviations in methylation of cg23089913 (NANOS1) and cg13217064 (SOX14) in newborns may change the risk of having excess body weight.© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.",
-,,20230810,,37542143,Identification of novel hypermethylated or hypomethylated CpG sites and genes associated with anthracycline-induced cardiomyopathy.,Sci Rep,"Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at 'CpG' sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case-control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe 'cg15939386' in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy.© 2023. Springer Nature Limited.",
-,,20230810,,37537185,Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes.,Nat Commun,"The genome-wide DNA methylation profile, or DNA methylome, is a critical component of the overall epigenomic landscape that modulates gene activities and cell fate. Single-cell DNA methylomic studies offer unprecedented resolution for detecting and profiling cell subsets based on methylomic features. However, existing single-cell methylomic technologies are based on use of tubes or well plates and these platforms are not easily scalable for handling a large number of single cells. Here we demonstrate a droplet-based microfluidic technology, Drop-BS, to construct single-cell bisulfite sequencing libraries for DNA methylome profiling. Drop-BS takes advantage of the ultrahigh throughput offered by droplet microfluidics to prepare bisulfite sequencing libraries of up to 10,000 single cells within 2 days. We apply the technology to profile mixed cell lines, mouse and human brain tissues to reveal cell type heterogeneity. Drop-BS offers a promising solution for single-cell methylomic studies requiring examination of a large cell population.© 2023. Springer Nature Limited.",
-,,20230810,,37533639,EpiMix is an integrative tool for epigenomic subtyping using DNA methylation.,Cell Rep Methods,"DNA methylation (DNAme) is a major epigenetic factor influencing gene expression with alterations leading to cancer and immunological and cardiovascular diseases. Recent technological advances have enabled genome-wide profiling of DNAme in large human cohorts. There is a need for analytical methods that can more sensitively detect differential methylation profiles present in subsets of individuals from these heterogeneous, population-level datasets. We developed an end-to-end analytical framework named ""EpiMix"" for population-level analysis of DNAme and gene expression. Compared with existing methods, EpiMix showed higher sensitivity in detecting abnormal DNAme that was present in only small patient subsets. We extended the model-based analyses of EpiMix tocis-regulatory elements within protein-coding genes, distal enhancers, and genes encoding microRNAs and long non-coding RNAs (lncRNAs). Using cell-type-specific data from two separate studies, we discover epigenetic mechanisms underlying childhood food allergy and survival-associated, methylation-driven ncRNAs in non-small cell lung cancer.© 2023 The Author(s).",
-,,20230810,,37533055,DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study.,Clin Epigenetics,"The potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (< 17 years) type 1 diabetes cohort, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (n = 368 with DNA and no CVD at baseline), both overall and separately by glycemic exposure, as measured by HbA1c at baseline (split at the median: < 8.9% and ≥ 8.9%). We also assessed whether DNAm-CVD associations were independent of established cardiometabolic risk factors, including body mass index, estimated glucose disposal rate, cholesterol, triglycerides, blood pressure, pulse rate, albumin excretion rate, and estimated glomerular filtration rate.CVD (first instance of CVD death, myocardial infarction, coronary revascularization, ischemic ECG, angina, or stroke) developed in 172 participants (46.7%) over 28 years. Overall, in Cox regression models for time to CVD, none of the 683,597 CpGs examined reached significance at a false discovery rate (FDR) ≤ 0.05. In participants with HbA1c < 8.9% (n = 180), again none reached FDR ≤ 0.05, but three were associated at the a priori nominal significance level FDR ≤ 0.10: cg07147033 in MIB2, cg12324048 (intergenic, chromosome 3), and cg15883830 (intergenic, chromosome 1). In participants with HbA1c ≥ 8.9% (n = 188), two CpGs in loci involved in calcium channel activity were significantly associated with CVD (FDR ≤ 0.05): cg21823999 in GPM6A and cg23621817 in CHRNA9; four additional CpGs were nominally associated (FDR ≤ 0.10). In participants with HbA1c ≥ 8.9%, DNAm-CVD associations were only modestly attenuated after cardiometabolic risk factor adjustment, while attenuation was greater in those with HbA1c < 8.9%. No pathways were enriched in those with HbA1c < 8.9%, while pathways for calcium channel activity and integral component of synaptic membrane were significantly enriched in those with HbA1c ≥ 8.9%.These results provide novel evidence that DNAm at loci involved in calcium channel activity and development may contribute to long-term CVD risk beyond known risk factors in type 1 diabetes, particularly in individuals with greater glycemic exposure, warranting further study.© 2023. The Author(s).",
-,,20230810,,37529779,Epigenetic associations with adolescent grey matter maturation and cognitive development.,Front Genet,"Introduction:Adolescence, a critical phase of human neurodevelopment, is marked by a tremendous reorganization of the brain and accompanied by improved cognitive performance. This development is driven in part by gene expression, which in turn is partly regulated by DNA methylation (DNAm).Methods:We collected brain imaging, cognitive assessments, and DNAm in a longitudinal cohort of approximately 200 typically developing participants, aged 9-14. This data, from three time points roughly 1 year apart, was used to explore the relationships between seven cytosine-phosphate-guanine (CpG) sites in genes highly expressed in brain tissues (GRIN2D,GABRB3,KCNC1,SLC12A9,CHD5,STXBP5, andNFASC), seven networks of grey matter (GM) volume change, and scores from seven cognitive tests.Results:The demethylation of the CpGs as well as the rates of change in DNAm were significantly related to improvements in total, crystalized, and fluid cognition scores, executive function, episodic memory, and processing speed, as well as several networks of GM volume increases and decreases that highlight typical patterns of brain maturation.Discussion:Our study provides a first look at the DNAm of genes involved in myelination, excitatory and inhibitory receptors, and connectivity, how they are related to the large-scale changes occurring in the brain structure as well as cognition during adolescence.Copyright © 2023 Jensen, Chen, Turner, Stephen, Wang, Wilson, Calhoun and Liu.",
-,,20230810,,37550624,Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases.,Clin Proteomics,"Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance.We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins.We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F).Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,,20230810,,37537391,Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development.,J Hum Genet,"Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.© 2023. The Author(s).",
-,,20230810,,37542162,Methylome-wide association study of anxiety disorders.,Mol Psychiatry,"Anxiety Disorders (ANX) such as panic disorder, generalized anxiety disorder, and phobias, are highly prevalent conditions that are moderately heritable. Evidence suggests that DNA methylation may play a role, as it is involved in critical adaptations to changing environments. Applying an enrichment-based sequencing approach covering nearly 28 million autosomal CpG sites, we conducted a methylome-wide association study (MWAS) of lifetime ANX in 1132 participants (618 cases/514 controls) from the Netherlands Study of Depression and Anxiety. Using epigenomic deconvolution, we performed MWAS for the main cell types in blood: granulocytes, T-cells, B-cells and monocytes. Cell-type specific analyses identified 280 and 82 methylome-wide significant associations (q-value < 0.1) in monocytes and granulocytes, respectively. Our top finding in monocytes was located in ZNF823 on chromosome 19 (p = 1.38 × 10-10) previously associated with schizophrenia. We observed significant overlap (p < 1 × 10-06) with the same direction of effect in monocytes (210 sites), T-cells (135 sites), and B-cells (727 sites) between this Discovery MWAS signal and a comparable replication dataset from the Great Smoky Mountains Study (N = 433). Overlapping Discovery-Replication MWAS signal was enriched for findings from published GWAS of ANX, major depression, and post-traumatic stress disorder. In monocytes, two specific sites in the FZR1 gene showed significant replication after Bonferroni correction with an additional 15 nominally replicated sites in monocytes and 4 in T-cells. FZR1 regulates neurogenesis in the hippocampus, and its knockout leads to impairments in associative fear memory and long-term potentiation in mice. In the largest and most extensive methylome-wide study of ANX, we identified replicable methylation sites located in genes of potential relevance for brain mechanisms of psychiatric conditions.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
-,,20230810,,37542161,Prenatal exposure to environmental air pollution and psychosocial stress jointly contribute to the epigenetic regulation of the serotonin transporter gene in newborns.,Mol Psychiatry,"Antenatal exposures to maternal stress and to particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5) have been independently associated with developmental outcomes in early infancy and beyond. Knowledge about their joint impact, biological mechanisms of their effects and timing-effects, is still limited. Both PM2.5and maternal stress exposure during pregnancy might result in altered patterns of DNA methylation in specific stress-related genes, such as the serotonin transporter gene (SLC6A4 DNAm), that might, in turn, influence infant development across several domains, including bio-behavioral, cognitive and socio-emotional domains. Here, we investigated the independent and interactive influence of variations in antenatal exposures to maternal pandemic-related stress (PRS) and PM2.5on SLC6A4 DNAm levels in newborns. Mother-infant dyads (N = 307) were enrolled at delivery during the COVID-19 pandemic. Infants' methylation status was assessed in 13 CpG sites within the SLC6A4 gene's region (chr17:28562750-28562958) in buccal cells at birth and women retrospectively report on PRS. PM2.5exposure throughout the entire gestation and at each gestational trimester was estimated using a spatiotemporal model based on residential address. Among several potentially confounding socio-demographic and health-related factors, infant's sex was significantly associated with infants' SLC6A4 DNAm levels, thus hierarchical regression models were adjusted for infant's sex. Higher levels of SLC6A4 DNAm at 6 CpG sites were found in newborns born to mothers reporting higher levels of antenatal PRS and greater PM2.5 exposure across gestation, while adjusting for infant's sex. These effects were especially evident when exposure to elevated PM2.5occurred during the second trimester of pregnancy. Several important brain processes (e.g., synaptogenesis and myelination) occur during mid-pregnancy, potentially making the second trimester a sensitive time window for the effects of stress-related exposures. Understanding the interplay between environmental and individual-level stressors has important implications for the improvement of mother-infant health during and after the pandemic.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
-,,20230810,,37503119,The ENCODE Uniform Analysis Pipelines.,Res Sq,"The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of theHomo sapiensandMus musculusgenomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and available via the ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL; https://openwdl.org/) is publicly available in GitHub, with images available on Dockerhub (https://hub.docker.com), enabling access to a diverse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environments via Cromwell. Access to the pipelines and data via the cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses.",
-,,20230810,,37553611,The application of long-read sequencing in clinical settings.,Hum Genomics,"Long-read DNA sequencing technologies have been rapidly evolving in recent years, and their ability to assess large and complex regions of the genome makes them ideal for clinical applications in molecular diagnosis and therapy selection, thereby providing a valuable tool for precision medicine. In the third-generation sequencing duopoly, Oxford Nanopore Technologies and Pacific Biosciences work towards increasing the accuracy, throughput, and portability of long-read sequencing methods while trying to keep costs low. These trades have made long-read sequencing an attractive tool for use in research and clinical settings. This article provides an overview of current clinical applications and limitations of long-read sequencing and explores its potential for point-of-care testing and health care in remote settings.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,,20230810,,37440569,Size matters: Fighting repeat expansion size in fragile X syndrome using antisense oligonucleotides.,Proc Natl Acad Sci U S A,NA,
-,,20230810,,37537179,Segmenting functional tissue units across human organs using community-driven development of generalizable machine learning algorithms.,Nat Commun,"The development of a reference atlas of the healthy human body requires automated image segmentation of major anatomical structures across multiple organs based on spatial bioimages generated from various sources with differences in sample preparation. We present the setup and results of the Hacking the Human Body machine learning algorithm development competition hosted by the Human Biomolecular Atlas (HuBMAP) and the Human Protein Atlas (HPA) teams on the Kaggle platform. We create a dataset containing 880 histology images with 12,901 segmented structures, engaging 1175 teams from 78 countries in community-driven, open-science development of machine learning models. Tissue variations in the dataset pose a major challenge to the teams which they overcome by using color normalization techniques and combining vision transformers with convolutional models. The best model will be productized in the HuBMAP portal to process tissue image datasets at scale in support of Human Reference Atlas construction.© 2023. Springer Nature Limited.",
-,,20230810,,37468819,"Cell 'atlases' offer unprecedented view of placenta, intestines and kidneys.",Nature,NA,
-,No,20231019,epigenetics,37650641,Widespread effects of DNA methylation and intra-motif dependencies revealed by novel transcription factor binding models.,Nucleic Acids Res,"Several studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that show a binding behaviour associated with DNA methylation. Overall, we find that the presence of CpG methylation decreases the likelihood of binding for the majority of methylation-associated TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding. We illustrate that the novel methylation-aware TF binding models allow to predict differential ChIP-seq peaks and improve the genome-wide analysis of TF binding. Our work indicates that simplistic models that neglect the effect of DNA methylation on DNA binding may lead to systematic underperformance for methylation-associated TFs.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.",
-matt,No,20231019,ctdna,37649326,Pan-cancer analysis of genome-wide methylation profiling discover type-specific markers targeting circulating free DNA for the detection of colorectal cancer.,Clin Transl Med,NA,
-,No,20231019,methods,37641110,Evaluation of the pooled sample method in Infinium MethylationEPIC BeadChip array by comparison with individual samples.,Clin Epigenetics,"The pooled sample method is used in epigenomic research and expression analysis and is a cost-effective screening approach for small amounts of DNA. Evaluation of the pooled sample method in epigenomic studies is performed using the Illumina Infinium Methylation 450K BeadChip array; however, subsequent reports on the updated 850K array are lacking. A previous study demonstrated that the methylation levels obtained from individual samples were accurately replicated using pooled samples but did not address epigenome-wide association study (EWAS) statistics. The DNA quantification method, which is important for the homogeneous mixing of DNA in the pooled sample method, has since become fluorescence-based, and additional factors need to be considered including the resolution of batch effects of microarray chips and the heterogeneity of the cellular proportions from which the DNA samples are derived. In this study, four pooled samples were created from 44 individual samples, and EWAS statistics for differentially methylated positions (DMPs) and regions (DMRs) were conducted for individual samples and compared with the statistics obtained from the pooled samples.The methylation levels could be reproduced fairly well in the pooled samples. This was the case for the entire dataset and when limited to the top 100 CpG sites, consistent with a previous study using the 450K BeadChip array. However, the statistical results of the EWAS for the DMP by individual samples were not replicated in pooled samples. Qualitative analyses highlighting methylation within an arbitrary candidate gene were replicable. Focusing on chr 20, the statistical results of EWAS for DMR from individual samples showed replicability in the pooled samples as long as they were limited to regions with a sufficient effect size.The pooled sample method replicated the methylation values well and can be used for EWAS in DMR. This method is sample amount-effective and cost-effective and can be utilized for screening by carefully understanding the effective features and disadvantages of the pooled sample method and combining it with candidate gene analyses.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,Yes,20231019,ewas,37634000,Objective and subjective measures of sleep initiation are differentially associated with DNA methylation in adolescents.,Clin Epigenetics,"The onset of puberty is associated with a shift in the circadian timing of sleep, leading to delayed sleep initiation [i.e., later sleep onset time (SOT)] due to later bedtimes and/or longer sleep onset latency (SOL). Several genome-wide association studies (GWAS) have identified genes that may be involved in the etiology of sleep phenotypes. However, circadian rhythms are also epigenetically regulated; therefore, epigenetic biomarkers may provide insight into the physiology of the pubertal sleep onset shift and the pathophysiology of prolonged or delayed sleep initiation.The gene-wide analysis indicated differential methylation within or around 1818 unique genes across the sleep initiation measurements using self-report, actigraphy (ACT), and polysomnography (PSG), while GWAS-informed analysis yielded 67 genes. Gene hits were identified for bedtime (PSG), SOL (subjective, ACT and PSG) and SOT (subjective and PSG). DNA methylation within 12 genes was associated with both subjective and PSG-measured SOL, 31 with both ACT- and PSG-measured SOL, 19 with both subjective and ACT-measured SOL, and one gene (SMG1P2) had methylation sites associated with subjective, ACT- and PSG-measured SOL.Objective and subjective sleep initiation in adolescents is associated with altered DNA methylation in genes previously identified in adult GWAS of sleep and circadian phenotypes. Additionally, our data provide evidence for a potential epigenetic link between habitual (subjective and ACT) SOL and in-lab SOT and DNA methylation in and around genes involved in circadian regulation (i.e., RASD1, RAI1), cardiometabolic disorders (i.e., FADS1, WNK1, SLC5A6), and neuropsychiatric disorders (i.e., PRR7, SDK1, FAM172A). If validated, these sites may provide valuable targets for early detection and prevention of disorders involving prolonged or delayed SOT, such as insomnia, delayed sleep phase, and their comorbidity.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,Yes,20231019,ewas,37612641,"Maternal pre-pregnancy BMI, offspring epigenome-wide DNA methylation, and childhood obesity: findings from the Boston Birth Cohort.",BMC Med,"Maternal pre-pregnancy obesity is an established risk factor for childhood obesity. Investigating epigenetic alterations induced by maternal obesity during fetal development could gain mechanistic insight into the developmental origins of childhood obesity. While obesity disproportionately affects underrepresented racial and ethnic mothers and children in the USA, few studies investigated the role of prenatal epigenetic programming in intergenerational obesity of these high-risk populations.This study included 903 mother-child pairs from the Boston Birth Cohort, a predominantly urban, low-income minority birth cohort. Mother-infant dyads were enrolled at birth and the children were followed prospectively to age 18 years. Infinium Methylation EPIC BeadChip was used to measure epigenome-wide methylation level of cord blood. We performed an epigenome-wide association study of maternal pre-pregnancy body mass index (BMI) and cord blood DNA methylation (DNAm). To quantify the degree to which cord blood DNAm mediates the maternal BMI-childhood obesity, we further investigated whether maternal BMI-associated DNAm sites impact birthweight or childhood overweight or obesity (OWO) from age 1 to age 18 and performed corresponding mediation analyses.The study sample contained 52.8% maternal pre-pregnancy OWO and 63.2% offspring OWO at age 1-18 years. Maternal BMI was associated with cord blood DNAm at 8 CpG sites (genome-wide false discovery rate [FDR] < 0.05). After accounting for the possible interplay of maternal BMI and smoking, 481 CpG sites were discovered for association with maternal BMI. Among them 123 CpGs were associated with childhood OWO, ranging from 42% decrease to 87% increase in OWO risk for each SD increase in DNAm. A total of 14 identified CpG sites showed a significant mediation effect on the maternal BMI-child OWO association (FDR < 0.05), with mediating proportion ranging from 3.99% to 25.21%. Several of these 14 CpGs were mapped to genes in association with energy balance and metabolism (AKAP7) and adulthood metabolic syndrome (CAMK2B).This prospective birth cohort study in a high-risk yet understudied US population found that maternal pre-pregnancy OWO significantly altered DNAm in newborn cord blood and provided suggestive evidence of epigenetic involvement in the intergenerational risk of obesity.© 2023. BioMed Central Ltd., part of Springer Nature.",
-sarah,Yes,20231019,ewas,37609313,Epigenome-wide association study of incident type 2 diabetes in Black and White participants from the Atherosclerosis Risk in Communities Study.,medRxiv,"DNA methylation studies of incident type 2 diabetes in US populations are limited, and to our knowledge none included individuals of African descent living in the US. We performed an epigenome-wide association analysis of blood-based methylation levels at CpG sites with incident type 2 diabetes using Cox regression in 2,091 Black and 1,029 White individuals from the Atherosclerosis Risk in Communities study. At an epigenome-wide significance threshold of 10-7, we detected 7 novel diabetes-associated CpG sites inC1orf151(cg05380846: HR= 0.89,p= 8.4 Ă— 10-12),ZNF2(cg01585592: HR= 0.88,p= 1.6 Ă— 10-9),JPH3(cg16696007: HR= 0.87,p= 7.8 Ă— 10-9),GPX6(cg02793507: HR= 0.85,p= 2.7 Ă— 10-8and cg00647063: HR= 1.20,p= 2.5 Ă— 10-8), chr17q25 (cg16865890: HR= 0.8,p= 6.9 Ă— 10-8), and chr11p15 (cg13738793: HR= 1.11,p= 7.7 Ă— 10-8). The CpG sites atC1orf151,ZNF2, JPH3andGPX6, were identified in Black adults, chr17q25 was identified in White adults, and chr11p15 was identified upon meta-analyzing the two groups. The CpG sites atJPH3andGPX6were likely associated with incident type 2 diabetes independent of BMI. All the CpG sites, except atJPH3, were likely consequences of elevated glucose at baseline. We additionally replicated known type 2 diabetes-associated CpG sites including cg19693031 atTXNIP, cg00574958 atCPT1A, cg16567056 atPLBC2, cg11024682 atSREBF1, cg08857797 atVPS25, and cg06500161 atABCG1, 3 of which were replicated in Black adults at the epigenome-wide threshold. We observed modest increase in type 2 diabetes variance explained upon addition of the significantly associated CpG sites to a Cox model that included traditional type 2 diabetes risk factors and fasting glucose (increase from 26.2% to 30.5% in Black adults; increase from 36.9% to 39.4% in White adults). We examined if groups of proximal CpG sites were associated with incident type 2 diabetes using a gene-region specific and a gene-region agnostic differentially methylated region (DMR) analysis. Our DMR analyses revealed several clusters of significant CpG sites, including a DMR consisting of a previously discovered CpG site atADCY7and promoter regions ofTP63which were differentially methylated across all race groups. This study illustrates improved discovery of CpG sites/regions by leveraging both individual CpG site and DMR analyses in an unexplored population. Our findings include genes linked to diabetes in experimental studies (e.g.,GPX6,JPH3,andTP63), and future gene-specific methylation studies could elucidate the link between genes, environment, and methylation in the pathogenesis of type 2 diabetes.",
-,Yes,20231019,ewas,37608375,Sexually dimorphic methylation patterns characterize the placenta and blood from extremely preterm newborns.,BMC Biol,"Health outcomes among children born prematurely are known to be sexually dimorphic, with male infants often more affected, yet the mechanism behind this observation is not clear. CpG methylation levels in the placenta and blood also differ by sex and are associated with adverse health outcomes. We contrasted CpG methylation levels in the placenta and neonatal blood (n = 358) from the Extremely Low Gestational Age Newborn (ELGAN) cohort based on the EPIC array, which assays over 850,000 CpG sites across the epigenome. Sex-specific epigenome-wide association analyses were conducted for the placenta and neonatal blood samples independently, and the results were compared to determine tissue-specific differences between the methylation patterns in males and females. All models were adjusted for cell type heterogeneity. Enrichment pathway analysis was performed to identify the biological functions of genes related to the sexually dimorphic CpG sites.Approximately 11,500 CpG sites were differentially methylated in relation to sex. Of these, 5949 were placenta-specific and 5361 were blood-specific, with only 233 CpG sites overlapping in both tissues. For placenta-specific CpG sites, 90% were hypermethylated in males. For blood-specific CpG sites, 95% were hypermethylated in females. In the placenta, keratinocyte differentiation biological pathways were enriched among the differentially methylated genes. No enrichment pathways were observed for blood.Distinct methylation patterns were observed between male and female children born extremely premature, and keratinocyte differentiation pathways were enriched in the placenta. These findings provide new insights into the epigenetic mechanisms underlying sexually dimorphic health outcomes among extremely premature infants.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,Yes,20231019,ewas,37598461,Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma.,EBioMedicine,"Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables.We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P < 7.94E-04) that can be explored as potential therapeutic targets.By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels.US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.",
-matt,Yes,20231019,ewas,37589453,Epigenetic signature of human immune aging in the GESTALT study.,Elife,"Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood borne immune cell types (naïve B, naïve CD4+and CD8+T cells, granulocytes, monocytes and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousands of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In-silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1β) and REST transcription factor motifs respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to transcription factor motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.",
-,Yes,20231019,ewas,37587247,"Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response.",Mol Psychiatry,"Obsessive-compulsive disorder (OCD) is a prevalent mental disorder affecting ~2-3% of the population. This disorder involves genetic and, possibly, epigenetic risk factors. The dynamic nature of epigenetics also presents a promising avenue for identifying biomarkers associated with symptom severity, clinical progression, and treatment response in OCD. We, therefore, conducted a comprehensive case-control investigation using Illumina MethylationEPIC BeadChip, encompassing 185 OCD patients and 199 controls recruited from two distinct sites in Germany. Rigorous clinical assessments were performed by trained raters employing the Structured Clinical Interview for DSM-IV (SCID-I). We performed a robust two-step epigenome-wide association study that led to the identification of 305 differentially methylated CpG positions. Next, we validated these findings by pinpointing the optimal set of CpGs that could effectively classify individuals into their respective groups. This approach identified a subset comprising 12 CpGs that overlapped with the 305 CpGs identified in our EWAS. These 12 CpGs are close to or in genes associated with the sweet-compulsive brain hypothesis which proposes that aberrant dopaminergic transmission in the striatum may impair insulin signaling sensitivity among OCD patients. We replicated three of the 12 CpGs signals from a recent independent study conducted on the Han Chinese population, underscoring also the cross-cultural relevance of our findings. In conclusion, our study further supports the involvement of epigenetic mechanisms in the pathogenesis of OCD. By elucidating the underlying molecular alterations associated with OCD, our study contributes to advancing our understanding of this complex disorder and may ultimately improve clinical outcomes for affected individuals.© 2023. The Author(s).",
-matt,No,20231019,dnamage,37563670,Introduction of a multiplex amplicon sequencing assay to quantify DNA methylation in target cytosine markers underlying four selected epigenetic clocks,Clin Epigenetics,"DNA methylation analysis has proven to be a powerful tool for age assessment. However, the implementation of epigenetic age prediction in diagnostics or routine forensic casework requires appropriate laboratory methods. In this study, we aimed to compare the performance of large-scale DNA methylation analysis protocols that show promise in terms of accuracy, throughput, multiplexing capacity, and high sensitivity.The protocols were designed to target a predefined panel of 161 genomic CG/CA sites from four known estimators of epigenetic age-related parameters, optimized and validated using artificially methylated controls or blood samples. We successfully targeted 96% of these loci using two enrichment protocols: Ion AmpliSeq™, an amplicon-based method integrated with Ion Torrent S5, and SureSelectXTMethyl-Seq, a hybridization-based method followed by MiSeq FGx sequencing. Both protocols demonstrated high accuracy and robustness. Although hybridization assays have greater multiplexing capabilities, the best overall performance was observed for the amplicon-based protocol with the lowest variability in DNA methylation at 25 ng of starting DNA, mean observed marker coverage of ~ 6.7 k reads, and accuracy of methylation quantification with a mean absolute difference between observed and expected methylation beta value of 0.054. The Ion AmpliSeq method correlated strongly with genome-scale EPIC microarray data (R = 0.91) and showed superiority in terms of methylation measurement accuracy. Method-to-method bias was accounted for by the use of linear transformation, which provided a highly accurate prediction of calendar age with a mean absolute error of less than 5 years for the VISAGE and Hannum age clocks used. The pace of aging (PoAm) and the mortality risk score (MRS) estimators included in our panel represent next-generation clocks, were found to have low to moderate correlations with the VISAGE and Hannum models (R < 0.75), and thus may capture different aspects of epigenetic aging.We propose a laboratory tool that allows the quantification of DNA methylation in cytosines underlying four different clocks, thus providing broad information on epigenetic aging while maintaining a reasonable number of CpG markers, opening the way to a wide range of applications in forensics, medicine, and healthcare.© 2023. BioMed Central Ltd., part of Springer Nature.",
-matt,No,20231019,eqtm,37563237,Expression quantitative trait methylation analysis elucidates gene regulatory effects of DNA methylation: the Framingham Heart Study.,Sci Rep,"Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p < 1E-7 where the top most significant eGenes (i.e., gene transcripts associated with a CpG) were enriched in biological pathways related to cell signaling, and for 1208 clinical traits (enrichment false discovery rate [FDR] ≤ 0.05). We also identified 246,667 significant trans CpG-transcript pairs at p < 1E-14 where the top most significant eGenes were enriched in biological pathways related to activation of the immune response, and for 1191 clinical traits (enrichment FDR ≤ 0.05). Independent and external replication of the top 1000 significant cis and trans CpG-transcript pairs was completed in the Women's Health Initiative and Jackson Heart Study cohorts. Using significant cis CpG-transcript pairs, we identified significant mediation of the association between CpG sites and cardiometabolic traits through gene expression and identified shared genetic regulation between CpGs and transcripts associated with cardiometabolic traits. In conclusion, we developed a robust and powerful resource of whole blood eQTM CpG-transcript pairs that can help inform future functional studies that seek to understand the molecular basis of disease.© 2023. Springer Nature Limited.",
-matt,No,20231019,ctdna,37500728,Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer,Nat Genet,"Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.",
-,Yes,20231019,ewas,37630812,Plasma One-Carbon Metabolism-Related Micronutrients and the Risk of Breast Cancer: Involvement of DNA Methylation.,Nutrients,"Findings of epidemiologic studies focusing on the association between one-carbon metabolism-related micronutrients and breast cancer risk, along with the involvement of DNA methylation, have been inconsistent and incomprehensive. We conducted a case-control study in China including 107 paired participants and comprehensively detected 12 plasma one-carbon metabolism-related micronutrients. Genomic DNA methylation was measured using an 850 K chip and differential methylation probes (DMPs) were identified. Multivariate logistic regression was performed to estimate the associations between plasma micronutrients and the odds of breast cancer. The mediation of selected DMPs in micronutrient breast cancer associations was examined using mediation analyses. An inverse association of plasma folate, methionine cycling-related micronutrients (methionine, S-adenosylmethionine, and S-adenosylhomocysteine), and all micronutrients in the choline metabolism and enzymatic factor groups, and a positive association of methionine cycling-related cysteine with breast cancer risk were observed. Nine micronutrients (methionine, cysteine, SAM, folate, choline, betaine, P5P, vitamins B2, and B12) were related to global or probe-specific methylation levels (p< 0.05). The selected DMPs mediated the micronutrient breast cancer associations with an average mediation proportion of 36.43%. This study depicted comprehensive associations between circulating one-carbon metabolism-related micronutrients and breast cancer risk mediated by DNA methylation.",
-,No,20231019,dnamage,37597113,Insights into ageing rates comparison across tissues from recalibrating cerebellum DNA methylation clock.,Geroscience,"DNA methylation (DNAm)-based age clocks have been studied extensively as a biomarker of human ageing and a risk factor for age-related diseases. Despite different tissues having vastly different rates of proliferation, it is still largely unknown whether they age at different rates. It was previously reported that the cerebellum ages slowly; however, this claim was drawn from a single clock using a relatively small sample size and so warrants further investigation. We collected the largest cerebellum DNAm dataset (N = 752) to date. We found the respective epigenetic ages are all severely underestimated by six representative DNAm age clocks, with the underestimation effects more pronounced in the four clocks whose training datasets do not include brain-related tissues. We identified 613 age-associated CpGs in the cerebellum, which accounts for only 14.5% of the number found in the middle temporal gyrus from the same population (N = 404). From the 613 cerebellum age-associated CpGs, we built a highly accurate age prediction model for the cerebellum named CerebellumClockspecific(Pearson correlation=0.941, MAD=3.18 years). Ageing rate comparisons based on the two tissue-specific clocks constructed on the 201 overlapping age-associated CpGs support the cerebellum has younger DNAm age. Nevertheless, we built BrainCortexClock to prove a single DNAm clock is able to unbiasedly estimate DNAm ages of both cerebellum and cerebral cortex, when they are adequately and equally represented in the training dataset. Comparing ageing rates across tissues using DNA methylation multi-tissue clocks is flawed. The large underestimation of age prediction for cerebellums by previous clocks mainly reflects the improper usage of these age clocks. There exist strong and consistent ageing effects on the cerebellar methylome, and we suggest the smaller number of age-associated CpG sites in cerebellum is largely attributed to its extremely low average cell replication rates.© 2023. The Author(s).",
-matt,No,20231019,dnamage,37609328,Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction,bioRxiv,"Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro-to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.",
-,No,20231019,dnamage,37576443,Psychological Stress and Epigenetic Aging in Older Men: The VA Normative Aging Study.,Transl Med Aging,"Psychological stress remains an important risk factor for morbidity and mortality throughout the life course. However, there have been counterintuitive findings reported in previous studies of older persons that examine the relationships of perceived psychological stress with DNA methylation-based markers of aging, which also serve as predictors of morbidity and mortality (epigenetic age/clocks). We aimed to replicate and expand findings from existing work by examining relationships of self-reported stress with nine epigenetic clocks: Hannum, Horvath, Intrinsic, Extrinsic, SkinBloodClock, PhenoAge, GrimAge, DNAm Telomere Length, and Pace of Aging. We analyzed data from 607 male participants (mean age 73.2 years) of the VA Normative Aging Study with one to two study visits from 1999 to 2007 (observations = 956). Stress was assessed via the 14-item Perceived Stress Scale (PSS). Epigenetic age was calculated from DNA methylation measured in leukocytes with the HumanMethylation450 BeadChip. In linear mixed effects models adjusted for demographic/lifestyle/health factors, a standard deviation (sd) increase in PSS was associated with Horvath (β = -0.35-years, 95%CI: -0.61, -0.09,P=0.008) and Intrinsic (β = -0.40-years, 95%CI: -0.67, -0.13,P=0.004) epigenetic age deceleration. However, in models limited to participants with the highest levels of stress (≥ 75th-percentile), Horvath (β = 2.29-years, 95%CI: 0.16, 4.41,P=0.04) and Intrinsic (β = 2.06-years, 95%CI: -0.17, 4.28,P=0.07) age acceleration associations were observed. Our results reinforce the complexity of psychological stress and epigenetic aging relationships and lay a foundation for future studies that explore longitudinal relationships with other adult stress metrics and factors that can influence stress such as resilience measures.",
-sarah,No,20231019,dnamage,37564905,Epigenetic clocks and research implications of the lack of data on whom they have been developed: a review of reported and missing sociodemographic characteristics,Environ Epigenet,"Epigenetic clocks are increasingly being used as a tool to assess the impact of a wide variety of phenotypes and exposures on healthy ageing, with a recent focus on social determinants of health. However, little attention has been paid to the sociodemographic characteristics of participants on whom these clocks have been based. Participant characteristics are important because sociodemographic and socioeconomic factors are known to be associated with both DNA methylation variation and healthy ageing. It is also well known that machine learning algorithms have the potential to exacerbate health inequities through the use of unrepresentative samples - prediction models may underperform in social groups that were poorly represented in the training data used to construct the model. To address this gap in the literature, we conducted a review of the sociodemographic characteristics of the participants whose data were used to construct 13 commonly used epigenetic clocks. We found that although some of the epigenetic clocks were created utilizing data provided by individuals from different ages, sexes/genders, and racialized groups, sociodemographic characteristics are generally poorly reported. Reported information is limited by inadequate conceptualization of the social dimensions and exposure implications of gender and racialized inequality, and socioeconomic data are infrequently reported. It is important for future work to ensure clear reporting of tangible data on the sociodemographic and socioeconomic characteristics of all the participants in the study to ensure that other researchers can make informed judgements about the appropriateness of the model for their study population.© The Author(s) 2023. Published by Oxford University Press.",
-matt,No,20231019,dnamage,37563227,Universal DNA methylation age across mammalian tissues,Nat Aging,"Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.© 2023. The Author(s).",
-matt,No,20231019,epigenetics,37660134,Epigenetic inheritance is unfaithful at intermediately methylated CpG sites.,Nat Commun,"DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform high-throughput bisulfite sequencing on clonally derived somatic cell lines to quantitatively measure methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity, and is not coordinately maintained between neighbouring sites. We determine that the probabilistic changes that occur at intermediately methylated sites are likely due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the current epigenetic inheritance model and has direct implications for both the functional relevance and general interpretability of DNA methylation as a stable epigenetic mark.© 2023. Springer Nature Limited.",
-neil,No,20231019,pqtl,37563310,Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets,Nat Immunol,"Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.© 2023. The Author(s).",
-,Yes,20231019,ewas,37587191,Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function,Commun Biol,"Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.© 2023. The Author(s).",
-matt,No,20231019,omics,37604891,Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits,Nat Commun,"We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.© 2023. Springer Nature Limited.",
-,No,20231019,epigenetics,37626340,The inactive X chromosome accumulates widespread epigenetic variability with age.,Clin Epigenetics,"Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women.We analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males (Illumina 450k methylation array) and replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variably methylated CpGs (aVMCs), whose methylation level becomes more variable with age.In females, aDMCs were relatively uncommon (n = 33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n = 987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (94%), indicating an independence of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI suggesting that they stemmed from the inactive X. In males, carrying an active copy of the X chromosome only, aDMCs (n = 316) were primarily driven by cell composition, while aVMCs replicated well (95%) but were infrequent (n = 37).Our results imply that age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,Yes,20231019,ewas,37596607,Association between acetaminophen metabolites and CYP2E1 DNA methylation level in neonate cord blood in the Boston Birth Cohort.,Clin Epigenetics,"Acetaminophen is a commonly used medication by pregnant women and is known to cross the placenta. However, little is known about the biological mechanisms that regulate acetaminophen in the developing offspring. Cytochrome 2E1 (CYP2E1) is the primary enzyme responsible for the conversion of acetaminophen to its toxic metabolite. Ex vivo studies have shown that the CYP2E1 gene expression in human fetal liver and placenta is largely controlled by DNA methylation (DNAm) at CpG sites located in the gene body of CYP2E1 at the 5' end. To date, no population studies have examined the association between acetaminophen metabolite and fetal DNAm of CYP2E1 at birth.We utilized data from the Boston Birth Cohort (BBC) which represents an urban, low-income, racially and ethnically diverse population in Boston, Massachusetts. Acetaminophen metabolites were measured in the cord plasma of newborns enrolled in BBC between 2003 and 2013 using liquid chromatography-tandem mass spectrometry. DNAm at 28 CpG sites of CYP2E1 was measured by Illumina Infinium MethylationEPIC BeadChip. We used linear regression to identify differentially methylated CpG sites and the ""DiffVar"" method to identify differences in methylation variation associated with the detection of acetaminophen, adjusting for cell heterogeneity and batch effects. The false discovery rate (FDR) was calculated to account for multiple comparisons.Among the 570 newborns included in this study, 96 (17%) had detectable acetaminophen in cord plasma. We identified 7 differentially methylated CpGs (FDR < 0.05) associated with the detection of acetaminophen and additional 4 CpGs showing a difference in the variation of methylation (FDR < 0.05). These CpGs were all located in the gene body of CYP2E1 at the 5' end and had a 3-6% lower average methylation level among participants with detectable acetaminophen compared to participants without. The CpG sites we identified overlap with previously identified DNase hypersensitivity and open chromatin regions in the ENCODE project, suggesting potential regulatory functions.In a US birth cohort, we found detection of cord biomarkers of acetaminophen was associated with DNAm level of CYP2E1 in cord blood. Our findings suggest that DNA methylation of CYP2E1 may be an important regulator of acetaminophen levels in newborns.© 2023. BioMed Central Ltd., part of Springer Nature.",
-,No,20231019,pwas,37653343,Sex differences in brain protein expression and disease.,Nat Med,"Most complex human traits differ by sex, but we have limited insight into the underlying mechanisms. Here, we investigated the influence of biological sex on protein expression and its genetic regulation in 1,277 human brain proteomes. We found that 13.2% (1,354) of brain proteins had sex-differentiated abundance and 1.5% (150) of proteins had sex-biased protein quantitative trait loci (sb-pQTLs). Among genes with sex-biased expression, we found 67% concordance between sex-differentiated protein and transcript levels; however, sex effects on the genetic regulation of expression were more evident at the protein level. Considering 24 psychiatric, neurologic and brain morphologic traits, we found that an average of 25% of their putatively causal genes had sex-differentiated protein abundance and 12 putatively causal proteins had sb-pQTLs. Furthermore, integrating sex-specific pQTLs with sex-stratified genome-wide association studies of six psychiatric and neurologic conditions, we uncovered another 23 proteins contributing to these traits in one sex but not the other. Together, these findings begin to provide insights into mechanisms underlying sex differences in brain protein expression and disease.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
-sarah,No,20231019,ml,37546907,"Equitable machine learning counteracts ancestral bias in precision medicine, improving outcomes for all.",Res Sq,"Gold standard genomic datasets severely under-represent non-European populations, leading to inequities and a limited understanding of human disease [1-8]. Therapeutics and outcomes remain hidden because we lack insights that we could gain from analyzing ancestry-unbiased genomic data. To address this significant gap, we present PhyloFrame, the first-ever machine learning method for equitable genomic precision medicine. PhyloFrame corrects for ancestral bias by integrating big data tissue-specific functional interaction networks, global population variation data, and disease-relevant transcriptomic data. Application of PhyloFrame to breast, thyroid, and uterine cancers shows marked improvements in predictive power across all ancestries, less model overfitting, and a higher likelihood of identifying known cancer-related genes. The ability to provide accurate predictions for underrepresented groups, in particular, is substantially increased. These results demonstrate how AI can mitigate ancestral bias in training data and contribute to equitable representation in medical research.",
-,No,20231019,mqtl,37628696,Polymorphisms in Glutathione S-Transferase (GST) Genes Modify the Effect of Exposure to Maternal Smoking Metabolites in Pregnancy and Offspring DNA Methylation.,Genes (Basel),"Maternal smoking in pregnancy (MSP) affects the offspring's DNA methylation (DNAm). There is a lack of knowledge regarding individual differences in susceptibility to exposure to MSP. Glutathione S-transferase (GST) genes are involved in protection against harmful oxidants such as those found in cigarette smoke. This study aimed to test whether polymorphisms inGSTgenes influence the effect of MSP on offspring DNAm. Using data from the Isle of Wight birth cohort, we assessed the association of MSP and offspring DNAm in 493 mother-child dyads (251 male, 242 female) with the effect-modifying role ofGSTgene polymorphism (at rs506008, rs574344, rs12736389, rs3768490, rs1537234, and rs1695). MSP was assessed by levels of nicotine and its downstream metabolites (cotinine, norcotinine, and hydroxycotinine) in maternal sera. In males, associations of hydroxycotinine with DNAm at cg18473733, cg25949550, cg11647108, and cg01952185 and norcotinine with DNAm at cg09935388 were modified byGSTgene polymorphisms (p-values < 0.05). In females, associations of hydroxycotinine with DNAm at cg12160087 and norcotinine with DNAm at cg18473733 were modified byGSTgene polymorphisms (p-values < 0.05). Our study emphasizes the role of genetic polymorphism inGSTgenes in DNAm's susceptibility to MSP.",
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+No,20230427,ctdna,37055640,Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.,Nature,"Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.© 2023. The Author(s).",
+No,20230427,aging,37046086,Ageing-associated changes in transcriptional elongation influence longevity,Nature,"Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.",
+No,20230427,methods,36747096,Simultaneous sequencing of genetic and epigenetic bases in DNA,Nat Biotechnol,"DNA comprises molecular information stored in genetic and epigenetic bases, both of which are vital to our understanding of biology. Most DNA sequencing approaches address either genetics or epigenetics and thus capture incomplete information. Methods widely used to detect epigenetic DNA bases fail to capture common C-to-T mutations or distinguish 5-methylcytosine from 5-hydroxymethylcytosine. We present a single base-resolution sequencing methodology that sequences complete genetics and the two most common cytosine modifications in a single workflow. DNA is copied and bases are enzymatically converted. Coupled decoding of bases across the original and copy strand provides a phased digital readout. Methods are demonstrated on human genomic DNA and cell-free DNA from a blood sample of a patient with cancer. The approach is accurate, requires low DNA input and has a simple workflow and analysis pipeline. Simultaneous, phased reading of genetic and epigenetic bases provides a more complete picture of the information stored in genomes and has applications throughout biomedicine.",
+Yes,20230525,ewas,37216580,"Impact of tobacco, alcohol, and marijuana on genome-wide DNA methylation and its relationship with hypertension.",Epigenetics,"Tobacco, alcohol, and marijuana consumption is an important public health problem because of their high use worldwide and their association with the risk of mortality and many health conditions, such as hypertension, which is the commonest risk factor for death throughout the world. A likely pathway of action of substance consumption leading to persistent hypertension is DNA methylation. Here, we evaluated the effects of tobacco, alcohol, and marijuana on DNA methylation in the same cohort (N = 3,424). Three epigenome-wide association studies (EWAS) were assessed in whole blood using the InfiniumHumanMethylationEPIC BeadChip. We also evaluated the mediation of the top CpG sites in the association between substance consumption and hypertension. Our analyses showed 2,569 CpG sites differentially methylated by alcohol drinking and 528 by tobacco smoking. We did not find significant associations with marijuana consumption after correcting for multiple comparisons. We found 61 genes overlapping between alcohol and tobacco that were enriched in biological processes involved in the nervous and cardiovascular systems. In the mediation analysis, we found 66 CpG sites that significantly mediated the effect of alcohol consumption on hypertension. The top alcohol-related CpG site (cg06690548, P-value = 5.9·10-83) mapped to SLC7A11 strongly mediated 70.5% of the effect of alcohol consumption on hypertension (P-value = 0.006). Our findings suggest that DNA methylation should be considered for new targets in hypertension prevention and management, particularly concerning alcohol consumption. Our data also encourage further research into the use of methylation in blood to study the neurological and cardiovascular effects of substance consumption.",
+Yes,20230525,ewas,37212434,Epigenetic Association Analyses and Risk Prediction of RLS.,Mov Disord,"As opposed to other neurobehavioral disorders, epigenetic analyses and biomarkers are largely missing in the case of idiopathic restless legs syndrome (RLS).Our aims were to develop a biomarker for RLS based on DNA methylation in blood and to examine DNA methylation in brain tissues for dissecting RLS pathophysiology.Methylation of blood DNA from three independent cohorts (n = 2283) and post-mortem brain DNA from two cohorts (n = 61) was assessed by Infinium EPIC 850 K BeadChip. Epigenome-wide association study (EWAS) results of individual cohorts were combined by random-effect meta-analysis. A three-stage selection procedure (discovery, n = 884; testing, n = 520; validation, n = 879) established an epigenetic risk score including 30 CpG sites. Epigenetic age was assessed by Horvath's multi-tissue clock and Shireby's cortical clock.EWAS meta-analysis revealed 149 CpG sites linked to 136 genes (P < 0.05 after Bonferroni correction) in blood and 23 CpG linked to 18 genes in brain (false discovery rate [FDR] < 5%). Gene-set analyses of blood EWAS results suggested enrichments in brain tissue types and in subunits of the kainate-selective glutamate receptor complex. Individual candidate genes of the brain EWAS could be assigned to neurodevelopmental or metabolic traits. The blood epigenetic risk score achieved an area under the curve (AUC) of 0.70 (0.67-0.73) in the validation set, comparable to analogous scores in other neurobehavioral disorders. A significant difference in biological age in blood or brain of RLS patients was not detectable.DNA methylation supports the notion of altered neurodevelopment in RLS. Epigenetic risk scores are reliably associated with RLS but require even higher accuracy to be useful as biomarkers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",
+Yes,20230525,ewas,37210443,Epigenome-wide association study of diabetic chronic kidney disease progression in the Korean population: the KNOW-CKD study.,Sci Rep,"Since the etiology of diabetic chronic kidney disease (CKD) is multifactorial, studies on DNA methylation for kidney function deterioration have rarely been performed despite the need for an epigenetic approach. Therefore, this study aimed to identify epigenetic markers associated with CKD progression based on the decline in the estimated glomerular filtration rate in diabetic CKD in Korea. An epigenome-wide association study was performed using whole blood samples from 180 CKD recruited from the KNOW-CKD cohort. Pyrosequencing was also performed on 133 CKD participants as an external replication analysis. Functional analyses, including the analysis of disease-gene networks, reactome pathways, and protein-protein interaction networks, were conducted to identify the biological mechanisms of CpG sites. A phenome-wide association study was performed to determine the associations between CpG sites and other phenotypes. Two epigenetic markers, cg10297223 on AGTR1 and cg02990553 on KRT28 indicated a potential association with diabetic CKD progression. Based on the functional analyses, other phenotypes (blood pressure and cardiac arrhythmia for AGTR1) and biological pathways (keratinization and cornified envelope for KRT28) related to CKD were also identified. This study suggests a potential association between the cg10297223 and cg02990553 and the progression of diabetic CKD in Koreans. Nevertheless, further validation is needed through additional studies.© 2023. The Author(s).",
+No,20230525,epigenetics,37205524,Combinatorial quantification of 5mC and 5hmC at individual CpG dyads and the transcriptome in single cells reveals modulators of DNA methylation maintenance fidelity.,bioRxiv,"Transmission of 5-methylcytosine (5mC) from one cell generation to the next plays a key role in regulating cellular identity in mammalian development and diseases. While recent work has shown that the activity of DNMT1, the protein responsible for the stable inheritance of 5mC from mother to daughter cells, is imprecise; it remains unclear how the fidelity of DNMT1 is tuned in different genomic and cell state contexts. Here we describe Dyad-seq, a method that combines enzymatic detection of modified cytosines with nucleobase conversion techniques to quantify the genome-wide methylation status of cytosines at the resolution of individual CpG dinucleotides. We find that the fidelity of DNMT1-mediated maintenance methylation is directly related to the local density of DNA methylation, and for genomic regions that are lowly methylated, histone modifications can dramatically alter the maintenance methylation activity. Further, to gain deeper insights into the methylation and demethylation turnover dynamics, we extended Dyad-seq to quantify all combinations of 5mC and 5-hydroxymethylcytosine (5hmC) at individual CpG dyads to show that TET proteins preferentially hydroxymethylate only one of the two 5mC sites in a symmetrically methylated CpG dyad rather than sequentially convert both 5mC to 5hmC. To understand how cell state transitions impact DNMT1-mediated maintenance methylation, we scaled the method down and combined it with the measurement of mRNA to simultaneously quantify genome-wide methylation levels, maintenance methylation fidelity and the transcriptome from the same cell (scDyad&T-seq). Applying scDyad&T-seq to mouse embryonic stem cells transitioning from serum to 2i conditions, we observe dramatic and heterogenous demethylation and the emergence of transcriptionally distinct subpopulations that are closely linked to the cell-to-cell variability in loss of DNMT1-mediated maintenance methylation activity, with regions of the genome that escape 5mC reprogramming retaining high levels of maintenance methylation fidelity. Overall, our results demonstrate that while distinct cell states can substantially impact the genome-wide activity of the DNA methylation maintenance machinery, locally there exists an intrinsic relationship between DNA methylation density, histone modifications and DNMT1-mediated maintenance methylation fidelity that is independent of cell state.",
+Yes,20230525,ewas,37204309,Environment- and epigenome-wide association study of obesity in 'Children of 1997' birth cohort.,Elife,"Increasing childhood obesity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of obesity at the onset and end of puberty in Hong Kong, the most economically developed major Chinese city.We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of obesity to systematically assess associations with body mass index (BMI) and waist-hip ratio (WHR) in Hong Kong's population-representative 'Children of 1997' birth cohort. Univariable linear regression was used to select exposures related to obesity at ~11.5 years (BMI and obesity riskn≤ 7119, WHRn= 5691) and ~17.6 years (n= 3618) at Bonferroni-corrected significance, and multivariable regression to adjust for potential confounders followed by replicated multivariable regression (n= 308) and CpG by CpG analysis (n= 286) at ~23 years. Findings were compared with evidence from published randomized controlled trials (RCTs) and Mendelian randomization (MR) studies.At ~11.5 and~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as 7 and 12 associated with WHR, respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with obesity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, and binge eating are consistent with available evidence from RCTs or MR studies. We found 17 CpGs related to BMI and 17 to WHR.These novel insights into potentially modifiable factors associated with obesity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings.This study including the follow-up survey and epigenetics testing was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction of the samples used for epigenetic testing was supported by CFS-HKU1.© 2023, Zhao, Fan et al.",
+No,20230525,MR,37202507,Investigating causality in the association between DNA methylation and type 2 diabetes using bidirectional two-sample Mendelian randomisation.,Diabetologia,"Several studies have identified associations between type 2 diabetes and DNA methylation (DNAm). However, the causal role of these associations remains unclear. This study aimed to provide evidence for a causal relationship between DNAm and type 2 diabetes.We used bidirectional two-sample Mendelian randomisation (2SMR) to evaluate causality at 58 CpG sites previously detected in a meta-analysis of epigenome-wide association studies (meta-EWAS) of prevalent type 2 diabetes in European populations. We retrieved genetic proxies for type 2 diabetes and DNAm from the largest genome-wide association study (GWAS) available. We also used data from the Avon Longitudinal Study of Parents and Children (ALSPAC, UK) when associations of interest were not available in the larger datasets. We identified 62 independent SNPs as proxies for type 2 diabetes, and 39 methylation quantitative trait loci as proxies for 30 of the 58 type 2 diabetes-related CpGs. We applied the Bonferroni correction for multiple testing and inferred causality based on p<0.001 for the type 2 diabetes to DNAm direction and p<0.002 for the opposing DNAm to type 2 diabetes direction in the 2SMR analysis.We found strong evidence of a causal effect of DNAm at cg25536676 (DHCR24) on type 2 diabetes. An increase in transformed residuals of DNAm at this site was associated with a 43% (OR 1.43, 95% CI 1.15, 1.78, p=0.001) higher risk of type 2 diabetes. We inferred a likely causal direction for the remaining CpG sites assessed. In silico analyses showed that the CpGs analysed were enriched for expression quantitative trait methylation sites (eQTMs) and for specific traits, dependent on the direction of causality predicted by the 2SMR analysis.We identified one CpG mapping to a gene related to the metabolism of lipids (DHCR24) as a novel causal biomarker for risk of type 2 diabetes. CpGs within the same gene region have previously been associated with type 2 diabetes-related traits in observational studies (BMI, waist circumference, HDL-cholesterol, insulin) and in Mendelian randomisation analyses (LDL-cholesterol). Thus, we hypothesise that our candidate CpG in DHCR24 may be a causal mediator of the association between known modifiable risk factors and type 2 diabetes. Formal causal mediation analysis should be implemented to further validate this assumption.© 2023. The Author(s).",
+No,20230525,methods,37196182,A novel principal component based method for identifying differentially methylated regions in Illumina Infinium MethylationEPIC BeadChip data.,Epigenetics,"Differentially methylated regions (DMRs) are genomic regions with methylation patterns across multiple CpG sites that are associated with a phenotype. In this study, we proposed a Principal Component (PC) based DMR analysis method for use with data generated using the Illumina Infinium MethylationEPIC BeadChip (EPIC) array. We obtained methylation residuals by regressing the M-values of CpGs within a region on covariates, extracted PCs of the residuals, and then combined association information across PCs to obtain regional significance. Simulation-based genome-wide false positive (GFP) rates and true positive rates were estimated under a variety of conditions before determining the final version of our method, which we have named DMRPC. Then, DMRPCand another DMR method, coMethDMR, were used to perform epigenome-wide analyses of several phenotypes known to have multiple associated methylation loci (age, sex, and smoking) in a discovery and a replication cohort. Among regions that were analysed by both methods, DMRPCidentified 50% more genome-wide significant age-associated DMRs than coMethDMR. The replication rate for the loci that were identified by only DMRPCwas higher than the rate for those that were identified by only coMethDMR (90% for DMRPC vs. 76% for coMethDMR). Furthermore, DMRPCidentified replicable associations in regions of moderate between-CpG correlation which are typically not analysed by coMethDMR. For the analyses of sex and smoking, the advantage of DMRPCwas less clear. In conclusion, DMRPCis a new powerful DMR discovery tool that retains power in genomic regions with moderate correlation across CpGs.",
+No,20230525,imprinting,37189164,Phenome-wide analyses identify an association between the parent-of-origin effects dependent methylome and the rate of aging in humans.,Genome Biol,"The variation in the rate at which humans age may be rooted in early events acting through the genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions enriched for genetically controlled imprinting effects (the typical type of POE) and regions influenced by environmental effects associated with parents (the atypical POE). This part of the methylome is heavily influenced by early events, making it a potential route connecting early exposures, the epigenome, and aging. We aim to test the association of POE-CpGs with early and later exposures and subsequently with health-related phenotypes and adult aging.We perform a phenome-wide association analysis for the POE-influenced methylome using GS:SFHS (Ndiscovery = 5087, Nreplication = 4450). We identify and replicate 92 POE-CpG-phenotype associations. Most of the associations are contributed by the POE-CpGs belonging to the atypical class where the most strongly enriched associations are with aging (DNAmTL acceleration), intelligence, and parental (maternal) smoking exposure phenotypes. A proportion of the atypical POE-CpGs form co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased within-module methylation connectivity with age. The atypical POE-CpGs also display high levels of methylation heterogeneity, fast information loss with age, and a strong correlation with CpGs contained within epigenetic clocks.These results identify the association between the atypical POE-influenced methylome and aging and provide new evidence for the ""early development of origin"" hypothesis for aging in humans.© 2023. The Author(s).",
+Yes,20230525,ewas,37188674,Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.,Nat Commun,"DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.© 2023. The Author(s).",
+Yes,20230525,ewas,37188670,DNA methylation markers for kidney function and progression of diabetic kidney disease.,Nat Commun,"Epigenetic markers are potential biomarkers for diabetes and related complications. Using a prospective cohort from the Hong Kong Diabetes Register, we perform two independent epigenome-wide association studies to identify methylation markers associated with baseline estimated glomerular filtration rate (eGFR) and subsequent decline in kidney function (eGFR slope), respectively, in 1,271 type 2 diabetes subjects. Here we show 40 (30 previously unidentified) and eight (all previously unidentified) CpG sites individually reach epigenome-wide significance for baseline eGFR and eGFR slope, respectively. We also develop a multisite analysis method, which selects 64 and 37 CpG sites for baseline eGFR and eGFR slope, respectively. These models are validated in an independent cohort of Native Americans with type 2 diabetes. Our identified CpG sites are near genes enriched for functional roles in kidney diseases, and some show association with renal damage. This study highlights the potential of methylation markers in risk stratification of kidney disease among type 2 diabetes individuals.© 2023. The Author(s).",
+Yes,20230525,ewas,37184252,Epigenome-wide methylation study identified 2 novel CpGs associated with T2DM risk and a network of co-methylated CpGs capable of patient's classifications.,Hum Mol Genet,"Prevention of Type 2 diabetes mellitus (T2DM) pandemic needs markers that can precisely predict the disease risk in an individual. Alterations in DNA methylations due to exposure towards environmental risk factors are widely sought markers for T2DM risk prediction. To identify such individual DNA methylation signatures and their effect on disease risk, we performed an epigenome-wide association study (EWAS) in 844 Indian individuals of Indo-European origin. We identified and validated methylation alterations at 2 novel CpG sites in MIR1287 (cg01178710), and EDN2-SCMH1 (cg04673737) genes associated with T2DM risk at the epigenome-wide-significance-level (p < 1.2x10-7). Further, we also replicated the association of 2 known CpG sites in TXNIP, and CPT1A in the Indian population. With 535 EWAS significant CpGs (p < 1.2x10-7) identified in the discovery phase samples, we created a co-methylation network using weighted correlation network analysis and identified 4 modules among the CpGs. We observed that methylation of one of the module associates with T2DM risk factors (e.g. BMI, insulin, C-peptide) and can be used as markers to segregate T2DM patients with good glycemic control (e.g. low HbA1c) and dyslipidemia (low HDL and high TG) from the other patients. Additionally, an intronic SNP (rs6503650) in the JUP gene, a member of the same module, associated with methylation at all the 14 hub CpG sites of that module as methQTL. Our network-assisted epigenome-wide association study is the first to systematically explore DNA methylation variations conferring risks to T2DM in Indians and use the identified risk CpG sites for patient segregation with different clinical outcomes. These findings can be useful for better stratification of patients to improve the clinical management and treatment effects.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+Yes,20230525,ewas,37180517,Epigenome-Wide Meta-Analysis Reveals Differential DNA Methylation Associated With Estimated Glomerular Filtration Rate Among African American Men With HIV.,Kidney Int Rep,"People with HIV (PWH) of African ancestry have faster decline of kidney function and faster progression to end-stage renal disease than PWH of European ancestry. DNA methylation have been associated with kidney function in the general population, however, their relationships are unclear for PWH of African ancestry.We performed epigenome-wide association studies (EWAS) of estimated glomerular filtration rate (eGFR) among PWH of African ancestry in 2 subsets of the Veterans Aging Cohort Study cohort (N = 885), followed by a meta-analysis to combine the results. Replication was conducted among independent African American samples without HIV.DNA methylation sites cg17944885 near Zinc Finger Family Member 788 (ZNF788) and Zinc Finger Protein 20 (ZNF20), and cg06930757 inSHANK1were significantly associated with eGFR among PWH of African ancestry (false discovery rate < 0.05). DNA methylation site cg17944885 was also associated with eGFR among different populations including African Americans without HIV.Our study attempted to address an important gap in the literature and to understand the role of DNA methylation in renal diseases in PWH of African ancestry. Replication of cg17944885 among different populations suggests there may be a common pathway for renal diseases progression among PWH and people without HIV, and across different ancestral groups. Our results suggest that genesZNF788/ZNF20andSHANK1could be involved in a pathway linking DNA methylation to renal diseases among PWH and are worth further investigation.",
+Yes,20230525,mqtl,37169753,meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans.,Nat Commun,"Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fill this critical knowledge gap by performing a large-scale cis-meQTL mapping study in 961 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We identify a total of 4,565,687 cis-acting meQTLs in 320,965 meCpGs. We find that 45% of meCpGs harbor multiple independent meQTLs, suggesting potential polygenic genetic architecture underlying methylation variation. A large percentage of the cis-meQTLs also colocalize with cis-expression QTLs (eQTLs) in the same population. Importantly, the identified cis-meQTLs explain a substantial proportion (median = 24.6%) of methylation variation. In addition, the cis-meQTL associated CpG sites mediate a substantial proportion (median = 24.9%) of SNP effects underlying gene expression. Overall, our results represent an important step toward revealing the co-regulation of methylation and gene expression, facilitating the functional interpretation of epigenetic and gene regulation underlying common diseases in African Americans.© 2023. The Author(s).",
+Yes,20230525,ewas,37145884,Gene Set Based Integrated Methylome and Transcriptome Analysis Reveals Potential Molecular Mechanisms Linking Cigarette Smoking and Related Diseases.,OMICS,"Advanced integrative analysis of DNA methylation and transcriptomics data may provide deeper insights into smoke-induced epigenetic alterations, their effects on gene expression and related biological processes, linking cigarette smoking and related diseases. We hypothesize that accumulation of DNA methylation changes in CpG sites across genomic locations of different genes might have biological significance. We tested the hypothesis by performing gene set based integrative analysis of blood DNA methylation and transcriptomics data to identify potential transcriptomic consequences of smoking via changes in DNA methylation in the Young Finns Study (YFS) participants (n = 1114, aged 34-49 years, women: 54%, men: 46%). First, we performed epigenome-wide association study (EWAS) of smoking. We then defined sets of genes based on DNA methylation status within their genomic regions, for example, sets of genes containing hyper- or hypomethylated CpG sites in their body or promoter regions. Gene set analysis was performed using transcriptomics data from the same participants. Two sets of genes, one containing 49 genes with hypomethylated CpG sites in their body region and the other containing 33 genes with hypomethylated CpG sites in their promoter region, were differentially expressed among the smokers. Genes in the two gene sets are involved in bone formation, metal ion transport, cell death, peptidyl-serine phosphorylation, and cerebral cortex development process, revealing epigenetic-transcriptomic pathways to smoking-related diseases such as osteoporosis, atherosclerosis, and cognitive impairment. These findings contribute to a deeper understanding of the pathophysiology of smoking-related diseases and may provide potential therapeutic targets.",
+Yes,20230525,ewas,37139702,DNA methylation at birth and fine motor ability in childhood: an epigenome-wide association study with replication.,Epigenetics,"Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.",
+No,20230525,dnamage,37163025,Decoding the role of transcriptomic clocks in the human prefrontal cortex.,medRxiv,"Aging is a complex process with interindividual variability, which can be measured by aging biological clocks. Aging clocks are machine-learning algorithms guided by biological information and associated with mortality risk and a wide range of health outcomes. One of these aging clocks are transcriptomic clocks, which uses gene expression data to predict biological age; however, their functional role is unknown. Here, we profiled two transcriptomic clocks (RNAAgeCalc and knowledge-based deep neural network clock) in a large dataset of human postmortem prefrontal cortex (PFC) samples. We identified that deep-learning transcriptomic clock outperforms RNAAgeCalc to predict transcriptomic age in the human PFC. We identified associations of transcriptomic clocks with psychiatric-related traits. Further, we applied system biology algorithms to identify common gene networks among both clocks and performed pathways enrichment analyses to assess its functionality and prioritize genes involved in the aging processes. Identified gene networks showed enrichment for diseases of signal transduction by growth factor receptors and second messenger pathways. We also observed enrichment of genome-wide signals of mental and physical health outcomes and identified genes previously associated with human brain aging. Our findings suggest a link between transcriptomic aging and health disorders, including psychiatric traits. Further, it reveals functional genes within the human PFC that may play an important role in aging and health risk.",
+No,20230525,dnamage,36812475,DNAmFitAge: biological age indicator incorporating physical fitness,Aging (Albany NY),"Physical fitness is a well-known correlate of health and the aging process and DNA methylation (DNAm) data can capture aging via epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance fitness in their construction. We develop blood-based DNAm biomarkers for fitness parameters gait speed (walking speed), maximum handgrip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max) which have modest correlation with fitness parameters in five large-scale validation datasets (average r between 0.16-0.48). We then use these DNAm fitness parameter biomarkers with DNAmGrimAge, a DNAm mortality risk estimate, to construct DNAmFitAge, a new biological age indicator that incorporates physical fitness. DNAmFitAge is associated with low-intermediate physical activity levels across validation datasets (p = 6.4E-13), and younger/fitter DNAmFitAge corresponds to stronger DNAm fitness parameters in both males and females. DNAmFitAge is lower (p = 0.046) and DNAmVO2max is higher (p = 0.023) in male body builders compared to controls. Physically fit people have a younger DNAmFitAge and experience better age-related outcomes: lower mortality risk (p = 7.2E-51), coronary heart disease risk (p = 2.6E-8), and increased disease-free status (p = 1.1E-7). These new DNAm biomarkers provide researchers a new method to incorporate physical fitness into epigenetic clocks.",
+No,20230525,dnamage,37209203,DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation.,Geroscience,"DNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm)-based biomarkers that reflect the individual aging process. Here, we examine the relationship between physical fitness and DNAm-based biomarkers in adults aged 33-88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO2max (� = 0.2, p = 6.4E - 4, r = 0.19, p = 1.2E - 3), Jumpmax (p = 0.11, p = 5.5E - 2, r = 0.13, p = 2.8E - 2), Gripmax (� = 0.17, p = 3.5E - 3, r = 0.16, p = 5.6E - 3), and HDL levels (� = 0.18, p = 1.95E - 3, r = 0.19, p = 1.1E - 3) are associated with better verbal short-term memory. In addition, verbal short-term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration (�: - 0.18, p = 0.0017). DNAmFitAge can distinguish high-fitness individuals from low/medium-fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high-fit males and females (1.5 and 2.0 years younger, respectively). Our research shows that regular physical exercise contributes to observable physiological and methylation differences which are beneficial to the aging process. DNAmFitAge has now emerged as a new biological marker of quality of life.© 2023. The Author(s).",
+No,20230525,pqtl,37148340,Identifying novel genes for amyotrophic lateral sclerosis by integrating human brain proteomes with genome-wide association data.,J Neurol,"Genome-Wide Association Studies (GWAS) have identified numerous risk genes for Amyotrophic Lateral Sclerosis (ALS); however, the mechanisms by which these loci confer ALS risk are uncertain. This study aims to identify novel causal proteins in the brains of patients with ALS using an integrative analytical pipeline.Using the datasets of Protein Quantitative Trait Loci (pQTL) (NpQTL1 = 376, NpQTL2 = 152), expression QTL (eQTL) (N = 452), and the largest ALS GWAS (NALS=27,205, NControls = 110,881), we performed a systematic analytical pipeline including Proteome-Wide Association Study (PWAS), Mendelian Randomization (MR), Bayesian colocalization, and Transcriptome-Wide Association Study (TWAS) to identify novel causal proteins for ALS in the brain.Using PWAS, we found that the altered protein abundance of 12 genes in the brain was associated with ALS. Three genes (SCFD1, SARM1 and CAMLG) were identified as lead causal genes for ALS with solid evidence (False discovery rate < 0.05, in MR analysis; PPH4 > 80% for Bayesian colocalization). Specifically, an increased abundance of SCFD1 and CAMLG led to an increased risk of ALS, whereas a higher abundance of SARM1 led to a decreased risk of developing ALS. TWAS showed that SCFD1 and CAMLG were related to ALS at the transcriptional level.SCFD1, CAMLG, and SARM1 exhibited robust associations and causality with ALS. The study findings provide novel clues for identifying potential therapeutic targets in ALS. Further studies are required to explore the mechanisms underlying the identified genes.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.",
+No,20230525,single-cell,37161089,Interpreting non-coding disease-associated human variants using single-cell epigenomics.,Nat Rev Genet,"Genome-wide association studies (GWAS) have linked hundreds of thousands of sequence variants in the human genome to common traits and diseases. However, translating this knowledge into a mechanistic understanding of disease-relevant biology remains challenging, largely because such variants are predominantly in non-protein-coding sequences that still lack functional annotation at cell-type resolution. Recent advances in single-cell epigenomics assays have enabled the generation of cell type-, subtype- and state-resolved maps of the epigenome in heterogeneous human tissues. These maps have facilitated cell type-specific annotation of candidate cis-regulatory elements and their gene targets in the human genome, enhancing our ability to interpret the genetic basis of common traits and diseases.© 2023. Springer Nature Limited.",
+No,20230525,cfdna,37075072,Fragmentation landscape of cell-free DNA revealed by deconvolutional analysis of end motifs.,Proc Natl Acad Sci U S A,"Cell-free DNA (cfDNA) fragmentation is nonrandom, at least partially mediated by various DNA nucleases, forming characteristic cfDNA end motifs. However, there is a paucity of tools for deciphering the relative contributions of cfDNA cleavage patterns related to underlying fragmentation factors. In this study, through non-negative matrix factorization algorithm, we used 256 5' 4-mer end motifs to identify distinct types of cfDNA cleavage patterns, referred to as ""founder"" end-motif profiles (F-profiles). F-profiles were associated with different DNA nucleases based on whether such patterns were disrupted in nuclease-knockout mouse models. Contributions of individual F-profiles in a cfDNA sample could be determined by deconvolutional analysis. We analyzed 93 murine cfDNA samples of different nuclease-deficient mice and identified six types of F-profiles. F-profiles I, II, and III were linked to deoxyribonuclease 1 like 3 (DNASE1L3), deoxyribonuclease 1 (DNASE1), and DNA fragmentation factor subunit beta (DFFB), respectively. We revealed that 42.9% of plasma cfDNA molecules were attributed to DNASE1L3-mediated fragmentation, whereas 43.4% of urinary cfDNA molecules involved DNASE1-mediated fragmentation. We further demonstrated that the relative contributions of F-profiles were useful to inform pathological states, such as autoimmune disorders and cancer. Among the six F-profiles, the use of F-profile I could inform the human patients with systemic lupus erythematosus. F-profile VI could be used to detect individuals with hepatocellular carcinoma, with an area under the receiver operating characteristic curve of 0.97. F-profile VI was more prominent in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. We proposed that this profile might be related to oxidative stress.",
+No,20230525,prediction,37127594,Early antidepressant treatment response prediction in major depression using clinical and TPH2 DNA methylation features based on machine learning approaches.,BMC Psychiatry,"To identify DNA methylation and clinical features, and to construct machine learning classifiers to assign the patients with major depressive disorder (MDD) into responders and non-responders after a 2-week treatment into responders and non-responders.Han Chinese patients (291 in total) with MDD comprised the study population. Datasets contained demographic information, environment stress factors, and the methylation levels of 38 methylated sites of tryptophan hydroxylase 2 (TPH2) genes in peripheral blood samples. Recursive Feature Elimination (RFE) was employed to select features. Five classification algorithms (logistic regression, classification and regression trees, support vector machine, logitboost and random forests) were used to establish the models. Performance metrics (AUC, F-Measure, G-Mean, accuracy, sensitivity, specificity, positive predictive value and negative predictive value) were computed with 5-fold-cross-validation. Variable importance was evaluated by random forest algorithm.RF with RFE outperformed the other models in our samples based on the demographic information and clinical features (AUC = 61.2%, 95%CI: 60.1-62.4%) / TPH2 CpGs features (AUC = 66.6%, 95%CI: 65.4-67.8%) / both clinical and TPH2 CpGs features (AUC = 72.9%, 95%CI: 71.8-74.0%).The effects of TPH2 on the early-stage antidepressant response were explored by machine learning algorithms. On the basis of the baseline depression severity and TPH2 CpG sites, machine learning approaches can enhance our ability to predict the early-stage antidepressant response. Some potentially important predictors (e.g., TPH2-10-60 (rs2129575), TPH2-2-163 (rs11178998), age of first onset, age) in early-stage treatment response could be utilized in future fundamental research, drug development and clinical practice.© 2023. The Author(s).",
+No,20230525,transgenerational,37170330,Loss of CpG island immunity to DNA methylation induced by mutation.,Epigenetics Chromatin,"The inheritance of acquired traits in mammals is a highly controversial topic in biology. Recently, Takahashi et al. (Cell 186:715-731, 2023) have reported that insertion of CpG-free DNA into a CpG island (CGI) can induce DNA methylation of the CGI and that this aberrant methylation pattern can be transmitted across generations, even after removal of the foreign DNA. These results were interpreted as evidence for transgenerational inheritance of acquired DNA methylation patterns. Here, we discuss several interpretational issues raised by this study and consider alternative explanations.© 2023. The Author(s).",
+No,20230525,methods,37161088,Beyond assembly: the increasing flexibility of single-molecule sequencing technology.,Nat Rev Genet,"The maturation of high-throughput short-read sequencing technology over the past two decades has shaped the way genomes are studied. Recently, single-molecule, long-read sequencing has emerged as an essential tool in deciphering genome structure and function, including filling gaps in the human reference genome, measuring the epigenome and characterizing splicing variants in the transcriptome. With recent technological developments, these single-molecule technologies have moved beyond genome assembly and are being used in a variety of ways, including to selectively sequence specific loci with long reads, measure chromatin state and protein-DNA binding in order to investigate the dynamics of gene regulation, and rapidly determine copy number variation. These increasingly flexible uses of single-molecule technologies highlight a young and fast-moving part of the field that is leading to a more accessible era of nucleic acid sequencing.© 2023. Springer Nature Limited.",
+No,20230525,pangenome,37165242,A draft human pangenome reference.,Nature,"Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.© 2023. The Author(s).",
+No,20230525,pangenome,37165241,Recombination between heterologous human acrocentric chromosomes.,Nature,"The short arms of the human acrocentric chromosomes 13, 14, 15, 21 and 22 (SAACs) share large homologous regions, including ribosomal DNA repeats and extended segmental duplications1,2. Although the resolution of these regions in the first complete assembly of a human genome-the Telomere-to-Telomere Consortium's CHM13 assembly (T2T-CHM13)-provided a model of their homology3, it remained unclear whether these patterns were ancestral or maintained by ongoing recombination exchange. Here we show that acrocentric chromosomes contain pseudo-homologous regions (PHRs) indicative of recombination between non-homologous sequences. Utilizing an all-to-all comparison of the human pangenome from the Human Pangenome Reference Consortium4(HPRC), we find that contigs from all of the SAACs form a community. A variation graph5constructed from centromere-spanning acrocentric contigs indicates the presence of regions in which most contigs appear nearly identical between heterologous acrocentric chromosomes in T2T-CHM13. Except on chromosome 15, we observe faster decay of linkage disequilibrium in the pseudo-homologous regions than in the corresponding short and long arms, indicating higher rates of recombination6,7. The pseudo-homologous regions include sequences that have previously been shown to lie at the breakpoint of Robertsonian translocations8, and their arrangement is compatible with crossover in inverted duplications on chromosomes 13, 14 and 21. The ubiquity of signals of recombination between heterologous acrocentric chromosomes seen in the HPRC draft pangenome suggests that these shared sequences form the basis for recurrent Robertsonian translocations, providing sequence and population-based confirmation of hypotheses first developed from cytogenetic studies 50 years ago9.© 2023. The Author(s).",
+No,20230525,genetics,37165237,Increased mutation and gene conversion within human segmental duplications.,Nature,"Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data1,2. Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions3,4. We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have 'relocated' on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences5,6.© 2023. The Author(s).",
+No,20230525,nanopore,37217507,Linear time complexity de novo long read genome assembly with GoldRush.,Nat Commun,"Current state-of-the-art de novo long read genome assemblers follow the Overlap-Layout-Consensus paradigm. While read-to-read overlap - its most costly step - was improved in modern long read genome assemblers, these tools still often require excessive RAM when assembling a typical human dataset. Our work departs from this paradigm, foregoing all-vs-all sequence alignments in favor of a dynamic data structure implemented in GoldRush, a de novo long read genome assembly algorithm with linear time complexity. We tested GoldRush on Oxford Nanopore Technologies long sequencing read datasets with different base error profiles sourced from three human cell lines, rice, and tomato. Here, we show that GoldRush achieves assembly scaffold NGA50 lengths of 18.3-22.2, 0.3 and 2.6 Mbp, for the genomes of human, rice, and tomato, respectively, and assembles each genome within a day, using at most 54.5 GB of random-access memory, demonstrating the scalability of our genome assembly paradigm and its implementation.© 2023. The Author(s).",
+No,20230525,methods,37149669,Generalising uncertainty improves accuracy and safety of deep learning analytics applied to oncology.,Sci Rep,"Uncertainty estimation is crucial for understanding the reliability of deep learning (DL) predictions, and critical for deploying DL in the clinic. Differences between training and production datasets can lead to incorrect predictions with underestimated uncertainty. To investigate this pitfall, we benchmarked one pointwise and three approximate Bayesian DL models for predicting cancer of unknown primary, using three RNA-seq datasets with 10,968 samples across 57 cancer types. Our results highlight that simple and scalable Bayesian DL significantly improves the generalisation of uncertainty estimation. Moreover, we designed a prototypical metric-the area between development and production curve (ADP), which evaluates the accuracy loss when deploying models from development to production. Using ADP, we demonstrate that Bayesian DL improves accuracy under data distributional shifts when utilising 'uncertainty thresholding'. In summary, Bayesian DL is a promising approach for generalising uncertainty, improving performance, transparency, and safety of DL models for deployment in the real world.© 2023. The Author(s).",
+No,20230525,cfdna,37138315,Single-molecule methylation profiles of cell-free DNA in cancer with nanopore sequencing.,Genome Med,"Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to 200 million reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.© 2023. The Author(s).",
+No,20230504,methods,37081487,pycoMeth: a toolbox for differential methylation testing from Nanopore methylation calls,Genome Biol,"We present pycoMeth, a toolbox to store, manage and analyze DNA methylation calls from long-read sequencing data obtained using the Oxford Nanopore Technologies sequencing platform. Building on a novel, rapid-access, read-level and reference-anchored methylation storage format MetH5, we propose efficient algorithms for haplotype aware, multi-sample consensus segmentation and differential methylation testing. We show that MetH5 is more efficient than existing solutions for storing Oxford Nanopore Technologies methylation calls, and carry out benchmarking for pycoMeth segmentation and differential methylation testing, demonstrating increased performance and sensitivity compared to existing solutions designed for short-read methylation data.",
+No,20230504,methods,37072822,The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles,Genome Biol,"A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analyzing 23 methods from the ENCODE Imputation Challenge. We find that imputation evaluations are challenging and confounded by distributional shifts from differences in data collection and processing over time, the amount of available data, and redundancy among performance measures. Our analyses suggest simple steps for overcoming these issues and promising directions for more robust research.",
+No,20230504,single-cell,37131654,Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain.,bioRxiv,"Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brain's 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq1) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH2) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq3dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brain's cellular-spatial and regulatory genome diversity.",
+Yes,20230504,ewas,37106120,Genes implicated by a methylome-wide schizophrenia study in neonatal blood show differential expression in adult brain samples.,Mol Psychiatry,"Schizophrenia is a disabling disorder involving genetic predisposition in combination with environmental influences that likely act via dynamic alterations of the epigenome and the transcriptome but its detailed pathophysiology is largely unknown. We performed cell-type specific methylome-wide association study of neonatal blood (N = 333) from individuals who later in life developed schizophrenia and controls. Suggestively significant associations (P < 1.0 × 10-6) were detected in all cell-types and in whole blood with methylome-wide significant associations in monocytes (P = 2.85 × 10-9-4.87 × 10-9), natural killer cells (P = 1.72 × 10-9-7.82 × 10-9) and B cells (P = 3.8 × 10-9). Validation of methylation findings in post-mortem brains (N = 596) from independent schizophrenia cases and controls showed significant enrichment of transcriptional differences (enrichment ratio = 1.98-3.23, P = 2.3 × 10-3-1.0 × 10-5), with specific highly significant differential expression for, for example, BDNF (t = -6.11, P = 1.90 × 10-9). In addition, expression difference in brain significantly predicted schizophrenia (multiple correlation = 0.15-0.22, P = 3.6 × 10-4-4.5 × 10-8). In summary, using a unique design combining pre-disease onset (neonatal) blood methylomic data and post-disease onset (post-mortem) brain transcriptional data, we have identified genes of likely functional relevance that are associated with schizophrenia susceptibility, rather than confounding disease associated artifacts. The identified loci may be of clinical value as a methylation-based biomarker for early detection of increased schizophrenia susceptibility.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20230504,ewas,37101222,An epigenome-wide analysis of socioeconomic position and tumor DNA methylation in breast cancer patients.,Clin Epigenetics,"Disadvantaged socioeconomic position (SEP), including lower educational attainment and household income, may influence cancer risk and outcomes. We hypothesized that DNA methylation could function as an intermediary epigenetic mechanism that internalizes and reflects the biological impact of SEP.Based on tumor DNA methylation data from the Illumina 450 K array from 694 breast cancer patients in the Women's Circle of Health Study, we conducted an epigenome-wide analysis in relation to educational attainment and household income. Functional impact of the identified CpG sites was explored in silico using data from publicly available databases.We identified 25 CpG sites associated with household income at an array-wide significance level, but none with educational attainment. Two of the top CpG sites, cg00452016 and cg01667837, were in promoter regions of NNT and GPR37, respectively, with multiple epigenetic regulatory features identified in each region. NNT is involved in β-adrenergic stress signaling and inflammatory responses, whereas GPR37 is involved in neurological and immune responses. For both loci, gene expression was inversely correlated to the levels of DNA methylation. The associations were consistent between Black and White women and did not differ by tumor estrogen receptor (ER) status.In a large breast cancer patient population, we discovered evidence of the significant biological impact of household income on the tumor DNA methylome, including genes in the β-adrenergic stress and immune response pathways. Our findings support biological effects of socioeconomic status on tumor tissues, which might be relevant to cancer development and progression.© 2023. The Author(s).",
+Yes,20230504,ewas,37093107,A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation.,Epigenetics,"Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery RateP-value <0.05). Persistent associations with DNA methylation in the peripheral blood of up to 482 children aged 4-10 y were observed for 40.7% of CpGs associated with maternal vitamin B12 and 57.1% of CpGs associated with newborn vitamin B12. Of the CpGs identified in the maternal meta-analyses, 4.6% were associated with either birth weight or gestational age in a previous work. For the newborn meta-analysis, this was the case for 14.3% of the identified CpGs. Also, of the CpGs identified in the newborn meta-analysis, 14.3% and 28.6%, respectively, were associated with childhood cognitive skills and nonverbal IQ. Of the 109 CpGs associated with maternal vitamin B12, 18.3% were associated with nearby gene expression. In this study, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood (PFDR<0.05). Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies.",
+Yes,20230504,ewas,37088033,Umbilical cord DNA methylation is associated with body mass index trajectories from birth to adolescence.,EBioMedicine,"DNA methylation (DNAm) in cord blood has been associated with various prenatal factors and birth outcomes. This study sought to fill an important knowledge gap: the link of cord DNAm with child postnatal growth trajectories from birth to age 18 years (y).Using data from a US predominantly urban, low-income, multi-ethnic birth cohort (N = 831), we first applied non-parametric methods to identify body-mass-index percentile (BMIPCT) trajectories from birth to age 18 y (the outcome); then, conducted epigenome-wide association study (EWAS) of the outcome, interrogating over 700,000 CpG sites profiled by the Illumina Infinium MethylationEPIC BeadChip. Multivariate linear regression models and likelihood ratio tests (LRT) were applied to examine the DNAm-outcome association in the overall sample and sex strata.We identified four distinct patterns of BMIPCT trajectories: normal weight (NW), Early overweight or obesity (OWO), Late OWO, and normal to very late OWO. DNAm at CpG18582997 annotated to TPGS1, CpG15241084 of TLR7, and cg24350936 of RAB31 were associated with BMIPCT at birth-to-3 y, 10 y, and 14 y, respectively (LRT FDR < 0.05 for all).In this prospective birth cohort study, we identified 4 distinct and robust patterns of growth trajectories from birth to 18 y, which were associated with variations in cord blood DNAm at genes implicated in inflammation induction pathways. These findings, if further replicated, raise the possibility that these DNAm markers along with early assessment of BMIPCT trajectories may help identify young children at high-risk for obesity later in life.Detailed in the Acknowledgements section.Copyright © 2023. Published by Elsevier B.V.",
+No,20230504,ewas,37085889,The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?,Hum Genomics,"Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian 'Clinical review of the Health of adults conceived following Assisted Reproductive Technologies' (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies ('XWASs' hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset.In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort.Genes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.© 2023. The Author(s).",
+No,20230504,mr,37085538,Role of DNA methylation in the relationship between glioma risk factors and glioma incidence: a two-step Mendelian randomization study.,Sci Rep,"Genetic evidence suggests glioma risk is altered by leukocyte telomere length, allergic disease (asthma, hay fever or eczema), alcohol consumption, childhood obesity, low-density lipoprotein cholesterol (LDLc) and triglyceride levels. DNA methylation (DNAm) variation influences many of these glioma-related traits and is an established feature of glioma. Yet the causal relationship between DNAm variation with both glioma incidence and glioma risk factors is unknown. We applied a two-step Mendelian randomization (MR) approach and several sensitivity analyses (including colocalization and Steiger filtering) to assess the association of DNAm with glioma risk factors and glioma incidence. We used data from a recently published catalogue of germline genetic variants robustly associated with DNAm variation in blood (32,851 participants) and data from a genome-wide association study of glioma risk (12,488 cases and 18,169 controls, sub-divided into 6191 glioblastoma cases and 6305 non-glioblastoma cases). MR evidence indicated that DNAm at 3 CpG sites (cg01561092, cg05926943, cg01584448) in one genomic region (HEATR3) had a putative association with glioma and glioblastoma risk (False discovery rate [FDR] < 0.05). Steiger filtering provided evidence against reverse causation. Colocalization presented evidence against genetic confounding and suggested that differential DNAm at the 3 CpG sites and glioma were driven by the same genetic variant. MR provided little evidence to suggest that DNAm acts as a mediator on the causal pathway between risk factors previously examined and glioma onset. To our knowledge, this is the first study to use MR to appraise the causal link of DNAm with glioma risk factors and glioma onset. Subsequent analyses are required to improve the robustness of our results and rule out horizontal pleiotropy.© 2023. The Author(s).",
+No,20230504,methods,37074140,Effects of Repeated Freeze and Thaw Cycles on the Genome-Wide DNA Methylation Profile of Isolated Genomic DNA.,Biopreserv Biobank,"The characterization of DNA methylation patterns to identify epigenetic markers for complex human diseases is an important and rapidly evolving part in biomedical research. DNA samples collected and stored in clinical biobanks over the past years are an important source for future epigenetic studies. Isolated gDNA is considered stable when stored at low temperatures for several years. However, the effect of multiple use and the associated repeated thawing of long-term stored DNA samples on DNA methylation patterns has not yet been investigated. In this study, we examined the influence of up to 10 freeze and thaw cycles on global DNA methylation by comparing genome-wide methylation profiles. DNA samples from 19 healthy volunteers were either frozen at -80°C or subjected to up to 10 freeze and thaw cycles. Genome-wide DNA methylation was analyzed after 0, 1, 3, 5, or 10 thaw cycles using the Illumina Infinium MethylationEPIC BeadChip. Evaluation of the global DNA methylation profile by beta-value density plots and multidimensional scaling plots revealed an expected clear participant-dependent variability, but a very low variability depending on the freeze and thaw cycles. In accordance, no significant difference in any of the methylated cytosine/guanine sites studied could be detected in the performed statistical analyses. Our results suggest that long-term frozen DNA samples are still suitable for epigenetic studies after multiple thaw cycles.",
+No,20230504,dnamage,37118759,Associations of socioeconomic disparities with buccal DNA-methylation measures of biological aging.,Clin Epigenetics,"Individuals who are socioeconomically disadvantaged are at increased risk for aging-related diseases and perform less well on tests of cognitive function. The weathering hypothesis proposes that these disparities in physical and cognitive health arise from an acceleration of biological processes of aging. Theories of how life adversity is biologically embedded identify epigenetic alterations, including DNA methylation (DNAm), as a mechanistic interface between the environment and health. Consistent with the weathering hypothesis and theories of biological embedding, recently developed DNAm algorithms have revealed profiles reflective of more advanced aging and lower cognitive function among socioeconomically-at-risk groups. These DNAm algorithms were developed using blood-DNA, but social and behavioral science research commonly collect saliva or cheek-swab DNA. This discrepancy is a potential barrier to research to elucidate mechanisms through which socioeconomic disadvantage affects aging and cognition. We therefore tested if social gradients observed in blood DNAm measures could be reproduced using buccal-cell DNA obtained from cheek swabs.We analyzed three DNAm measures of biological aging and one DNAm measure of cognitive performance, all of which showed socioeconomic gradients in previous studies: the PhenoAge and GrimAge DNAm clocks, DunedinPACE, and Epigenetic-g. We first computed blood-buccal cross-tissue correlations in n = 21 adults (GEO111165). Cross-tissue correlations were low-to-moderate (r = .25 to r = .48). We next conducted analyses of socioeconomic gradients using buccal DNAm data from SOEP-G (n = 1128, 57% female; age mean = 42 yrs, SD = 21.56, range 0-72). Associations of socioeconomic status with DNAm measures of aging were in the expected direction, but were smaller as compared to reports from blood DNAm datasets (r = - .08 to r = - .13).Our findings are consistent with the hypothesis that socioeconomic disadvantage is associated with DNAm indicators of worse physical health. However, relatively low cross-tissue correlations and attenuated effect sizes for socioeconomic gradients in buccal DNAm compared with reports from analysis of blood DNAm suggest that in order to take full advantage of buccal DNA samples, DNAm algorithms customized to buccal DNAm are needed.© 2023. The Author(s).",
+No,20230504,dnamage,37118425,Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.,Nat Aging,"The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref.10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.© 2023. The Author(s).",
+No,20230504,dnamage,37107599,"Changes in Loneliness, BDNF, and Biological Aging Predict Trajectories in a Blood-Based Epigenetic Measure of Cortical Aging: A Study of Older Black Americans.",Genes (Basel),"A recent epigenetic measure of aging has developed based on human cortex tissue. This cortical clock (CC) dramatically outperformed extant blood-based epigenetic clocks in predicting brain age and neurological degeneration. Unfortunately, measures that require brain tissue are of limited utility to investigators striving to identify everyday risk factors for dementia. The present study investigated the utility of using the CpG sites included in the CC to formulate a peripheral blood-based cortical measure of brain age (CC-Bd). To establish the utility of CC-Bd, we used growth curves with individually varying time points and longitudinal data from a sample of 694 aging African Americans. We examined whether three risk factors that have been linked to cognitive decline-loneliness, depression, and BDNFm-predicted CC-Bd after controlling for several factors, including three new-generation epigenetic clocks. Our findings showed that two clocks-DunedinPACE and PoAm-predicted CC-BD, but that increases in loneliness and BDNFm continued to be robust predictors of accelerated CC-Bd even after taking these effects into account. This suggests that CC-Bd is assessing something more than the pan-tissue epigenetic clocks but that, at least in part, brain health is also associated with the general aging of the organism.",
+No,20230504,prediction,37127563,A comparison of feature selection methodologies and learning algorithms in the development of a DNA methylation-based telomere length estimator.,BMC Bioinformatics,"The field of epigenomics holds great promise in understanding and treating disease with advances in machine learning (ML) and artificial intelligence being vitally important in this pursuit. Increasingly, research now utilises DNA methylation measures at cytosine-guanine dinucleotides (CpG) to detect disease and estimate biological traits such as aging. Given the challenge of high dimensionality of DNA methylation data, feature-selection techniques are commonly employed to reduce dimensionality and identify the most important subset of features. In this study, our aim was to test and compare a range of feature-selection methods and ML algorithms in the development of a novel DNA methylation-based telomere length (TL) estimator. We utilised both nested cross-validation and two independent test sets for the comparisons.We found that principal component analysis in advance of elastic net regression led to the overall best performing estimator when evaluated using a nested cross-validation analysis and two independent test cohorts. This approach achieved a correlation between estimated and actual TL of 0.295 (83.4% CI [0.201, 0.384]) on the EXTEND test data set. Contrastingly, the baseline model of elastic net regression with no prior feature reduction stage performed less well in general-suggesting a prior feature-selection stage may have important utility. A previously developed TL estimator, DNAmTL, achieved a correlation of 0.216 (83.4% CI [0.118, 0.310]) on the EXTEND data. Additionally, we observed that different DNA methylation-based TL estimators, which have few common CpGs, are associated with many of the same biological entities.The variance in performance across tested approaches shows that estimators are sensitive to data set heterogeneity and the development of an optimal DNA methylation-based estimator should benefit from the robust methodological approach used in this study. Moreover, our methodology which utilises a range of feature-selection approaches and ML algorithms could be applied to other biological markers and disease phenotypes, to examine their relationship with DNA methylation and predictive value.© 2023. The Author(s).",
+Yes,20230504,ewas,37120575,Prenatal phthalate exposure and cord blood DNA methylation.,Sci Rep,"Exposure to phthalates has been shown to impede the human endocrine system, resulting in deleterious effects on pregnant women and their children. Phthalates modify DNA methylation patterns in infant cord blood. We examined the association between prenatal phthalate exposure and DNA methylation patterns in cord blood in a Korean birth cohort. Phthalate levels were measured in 274 maternal urine samples obtained during late pregnancy and 102 neonatal urine samples obtained at birth, and DNA methylation levels were measured in cord blood samples. For each infant in the cohort, associations between CpG methylation and both maternal and neonate phthalate levels were analyzed using linear mixed models. The results were combined with those from a meta-analysis of the levels of phthalates in maternal and neonatal urine samples, which were also analyzed for MEOHP, MEHHP, MnBP, and DEHP. This meta-analysis revealed significant associations between the methylation levels of CpG sites near the CHN2 and CUL3 genes, which were also associated with MEOHP and MnBP in neonatal urine. When the data were stratified by the sex of the infant, MnBP concentration was found to be associated with one CpG site near the OR2A2 and MEGF11 genes in female infants. In contrast, the concentrations of the three maternal phthalates showed no significant association with CpG site methylation. Furthermore, the data identified distinct differentially methylated regions in maternal and neonatal urine samples following exposure to phthalates. The CpGs with methylation levels that were positively associated with phthalate levels (particularly MEOHP and MnBP) were found to be enriched genes and related pathways. These results indicate that prenatal phthalate exposure is significantly associated with DNA methylation at multiple CpG sites. These alterations in DNA methylation may serve as biomarkers of maternal exposure to phthalates in infants and are potential candidates for investigating the mechanisms by which phthalates impact maternal and neonatal health.© 2023. The Author(s).",
+No,20230504,dnamage,37076473,Multi-omic underpinnings of epigenetic aging and human longevity.,Nat Commun,"Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
+No,20230504,single-cell,37085594,Single-cell genomics meets human genetics.,Nat Rev Genet,"Single-cell genomic technologies are revealing the cellular composition, identities and states in tissues at unprecedented resolution. They have now scaled to the point that it is possible to query samples at the population level, across thousands of individuals. Combining single-cell information with genotype data at this scale provides opportunities to link genetic variation to the cellular processes underpinning key aspects of human biology and disease. This strategy has potential implications for disease diagnosis, risk prediction and development of therapeutic solutions. But, effectively integrating large-scale single-cell genomic data, genetic variation and additional phenotypic data will require advances in data generation and analysis methods. As single-cell genetics begins to emerge as a field in its own right, we review its current state and the challenges and opportunities ahead.© 2023. Springer Nature Limited.",
+No,20230504,prediction,37117793,Development and validation of DNA methylation scores in two European cohorts augment 10-year risk prediction of type 2 diabetes.,Nat Aging,"Type 2 diabetes mellitus (T2D) presents a major health and economic burden that could be alleviated with improved early prediction and intervention. While standard risk factors have shown good predictive performance, we show that the use of blood-based DNA methylation information leads to a significant improvement in the prediction of 10-year T2D incidence risk. Previous studies have been largely constrained by linear assumptions, the use of cytosine-guanine pairs one-at-a-time and binary outcomes. We present a flexible approach (via an R package, MethylPipeR) based on a range of linear and tree-ensemble models that incorporate time-to-event data for prediction. Using the Generation Scotland cohort (training set ncases = 374, ncontrols = 9,461; test set ncases = 252, ncontrols = 4,526) our best-performing model (area under the receiver operating characteristic curve (AUC) = 0.872, area under the precision-recall curve (PRAUC) = 0.302) showed notable improvement in 10-year onset prediction beyond standard risk factors (AUC = 0.839, precision-recall AUC = 0.227). Replication was observed in the German-based KORA study (n = 1,451, ncases = 142, P = 1.6 × 10-5).© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20230504,single-cell,37034737,A single-nucleus transcriptome-wide association study implicates novel genes in depression pathogenesis.,medRxiv,"Depression is a common psychiatric illness and global public health problem. However, our limited understanding of the biological basis of depression has hindered the development of novel treatments and interventions.To identify new candidate genes for therapeutic development, we examined single-nucleus RNA sequencing (snucRNAseq) data from the dorsolateral prefrontal cortex (N=424) in relation to ante-mortem depressive symptoms. To complement these direct analyses, we also used genome- wide association study (GWAS) results for depression (N=500,199) along with genetic tools for inferring the expression of 22,159 genes in 7 cell types and 55 cell subtypes to perform transcriptome-wide association studies (TWAS) of depression followed by Mendelian randomization (MR).Our single-nucleus TWAS analysis identified 71 causal genes in depression that have a role in specific neocortical cell subtypes; 59 of 71 genes were novel compared to previous studies. Depression TWAS genes showed a cell type specific pattern, with the greatest enrichment being in both excitatory and inhibitory neurons as well as astrocytes. Gene expression in different neuron subtypes have different directions of effect on depression risk. Compared to lower genetically correlated traits (e.g. body mass index) with depression, higher correlated traits (e.g., neuroticism) have more common TWAS genes with depression. In parallel, we performed differential gene expression analysis in relation to depression in 55 cortical cell subtypes, and we found that genes such asANKRD36,MADD,TAOK3,SCAIandCHUKare associated with depression in specific cell subtypes.These two sets of analyses illustrate the utility of large snucRNAseq data to uncover both genes whose expression is altered in specific cell subtypes in the context of depression and to enhance the interpretation of well-powered GWAS so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.",
+No,20230504,eqtl,37076491,Mapping genomic regulation of kidney disease and traits through high-resolution and interpretable eQTLs.,Nat Commun,"Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). Efforts to maximize their accuracy are ongoing. Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5371 GLOM and 9787 TUBE genes with at least one variant significantly associated with expression (eGene) by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an ""integrative prior"" for Bayesian statistical fine-mapping. The use of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of variants in credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS of two kidney traits, (3) an increased number of variants colocalized with the GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants. A subset of variants and genes were validated experimentally in vitro and using a Drosophila nephrocyte model. More broadly, this study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses.© 2023. The Author(s).",
+No,20230504,gwas,37120605,Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.,Nat Commun,"Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.© 2023. The Author(s).",
+No,20230504,omics,37117186,A precision environmental health approach to prevention of human disease.,Nat Commun,"Human health is determined by the interaction of our environment with the genome, epigenome, and microbiome, which shape the transcriptomic, proteomic, and metabolomic landscape of cells and tissues. Precision environmental health is an emerging field leveraging environmental and system-level ('omic) data to understand underlying environmental causes of disease, identify biomarkers of exposure and response, and develop new prevention and intervention strategies. In this article we provide real-life illustrations of the utility of precision environmental health approaches, identify current challenges in the field, and outline new opportunities to promote health through a precision environmental health framework.© 2023. The Author(s).",
+No,20230504,omics,37082508,Multi-omic integration via similarity network fusion to detect molecular subtypes of ageing.,Brain Commun,"Molecular subtyping of brain tissue provides insights into the heterogeneity of common neurodegenerative conditions, such as Alzheimer's disease. However, existing subtyping studies have mostly focused on single data modalities and only those individuals with severe cognitive impairment. To address these gaps, we applied similarity network fusion, a method capable of integrating multiple high-dimensional multi-omic data modalities simultaneously, to an elderly sample spanning the full spectrum of cognitive ageing trajectories. We analyzed human frontal cortex brain samples characterized by five omic modalities: bulk RNA sequencing (18 629 genes), DNA methylation (53 932 CpG sites), histone acetylation (26 384 peaks), proteomics (7737 proteins) and metabolomics (654 metabolites). Similarity network fusion followed by spectral clustering was used for subtype detection, and subtype numbers were determined by Eigen-gap and rotation cost statistics. Normalized mutual information determined the relative contribution of each modality to the fused network. Subtypes were characterized by associations with 13 age-related neuropathologies and cognitive decline. Fusion of all five data modalities (n= 111) yielded two subtypes (nS1= 53,nS2= 58), which were nominally associated with diffuse amyloid plaques; however, this effect was not significant after correction for multiple testing. Histone acetylation (normalized mutual information = 0.38), DNA methylation (normalized mutual information = 0.18) and RNA abundance (normalized mutual information = 0.15) contributed most strongly to this network. Secondary analysis integrating only these three modalities in a larger subsample (n= 513) indicated support for both three- and five-subtype solutions, which had significant overlap, but showed varying degrees of internal stability and external validity. One subtype showed marked cognitive decline, which remained significant even after correcting for tests across both three- and five-subtype solutions (pBonf= 5.9 × 10-3). Comparison to single-modality subtypes demonstrated that the three-modal subtypes were able to uniquely capture cognitive variability. Comprehensive sensitivity analyses explored influences of sample size and cluster number parameters. We identified highly integrative molecular subtypes of ageing derived from multiple high dimensional, multi-omic data modalities simultaneously. Fusing RNA abundance, DNA methylation, and histone acetylation measures generated subtypes that were associated with cognitive decline. This work highlights the potential value and challenges of multi-omic integration in unsupervised subtyping of post-mortem brain.© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.",
+No,20230504,methods,37066421,The ENCODE Uniform Analysis Pipelines.,bioRxiv,"The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of theHomo sapiensandMus musculusgenomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and availableviathe ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL; https://openwdl.org/ ) is publicly available in GitHub, with images available on Dockerhub ( https://hub.docker.com ), enabling access to a diverse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environmentsviaCromwell. Access to the pipelines and dataviathe cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses.Database URL:https://www.encodeproject.org/.",
+No,20230504,pqtl,37085628,Proteome-wide Mendelian randomization reveals the causal effects of immune-related plasma proteins on psychiatric disorders.,Hum Genet,"Immune dysregulation has been consistently reported in psychiatric disorders, however, the causes and mechanisms underlying immune dysregulation in psychiatric disorders remain largely unclear. Here we conduct a Mendelian randomization study by integrating plasma proteome and GWASs of schizophrenia, bipolar disorder and depression. The primate-specific immune-related protein BTN3A3 showed the most significant associations with all three psychiatric disorders. In addition, other immune-related proteins, including AIF1, FOXO3, IRF3, CFHR4, IGLON5, FKBP2, and PI3, also showed significant associations with psychiatric disorders. Our study showed that a proportion of psychiatric risk variants may contribute to disease risk by regulating immune-related plasma proteins, providing direct evidence that connect the genetic risk of psychiatric disorders to immune system.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",
+No,20230629,methods,37369639,E-value: a superior alternative to P-value and its adjustments in DNA methylation studies.,Brief Bioinform,"DNA methylation plays a crucial role in transcriptional regulation. Reduced representation bisulfite sequencing (RRBS) is a technique of increasing use for analyzing genome-wide methylation profiles. Many computational tools such as Metilene, MethylKit, BiSeq and DMRfinder have been developed to use RRBS data for the detection of the differentially methylated regions (DMRs) potentially involved in epigenetic regulations of gene expression. For DMR detection tools, as for countless other medical applications, P-values and their adjustments are among the most standard reporting statistics used to assess the statistical significance of biological findings. However, P-values are coming under increasing criticism relating to their questionable accuracy and relatively high levels of false positive or negative indications. Here, we propose a method to calculate E-values, as likelihood ratios falling into the null hypothesis over the entire parameter space, for DMR detection in RRBS data. We also provide the R package 'metevalue' as a user-friendly interface to implement E-value calculations into various DMR detection tools. To evaluate the performance of E-values, we generated various RRBS benchmarking datasets using our simulator 'RRBSsim' with eight samples in each experimental group. Our comprehensive benchmarking analyses showed that using E-values not only significantly improved accuracy, area under ROC curve and power, over that of P-values or adjusted P-values, but also reduced false discovery rates and type I errors. In applications using real RRBS data of CRL rats and a clinical trial on low-salt diet, the use of E-values detected biologically more relevant DMRs and also improved the negative association between DNA methylation and gene expression.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
+No,20230629,transgenerational,37365578,Associations between DNA methylation and gene regulation depend on chromatin accessibility during transgenerational plasticity.,BMC Biol,"Epigenetic processes are proposed to be a mechanism regulating gene expression during phenotypic plasticity. However, environmentally induced changes in DNA methylation exhibit little-to-no association with differential gene expression in metazoans at a transcriptome-wide level. It remains unexplored whether associations between environmentally induced differential methylation and expression are contingent upon other epigenomic processes such as chromatin accessibility. We quantified methylation and gene expression in larvae of the purple sea urchin Strongylocentrotus purpuratus exposed to different ecologically relevant conditions during gametogenesis (maternal conditioning) and modeled changes in gene expression and splicing resulting from maternal conditioning as functions of differential methylation, incorporating covariates for genomic features and chromatin accessibility. We detected significant interactions between differential methylation, chromatin accessibility, and genic feature type associated with differential expression and splicing.Differential gene body methylation had significantly stronger effects on expression among genes with poorly accessible transcriptional start sites while baseline transcript abundance influenced the direction of this effect. Transcriptional responses to maternal conditioning were 4-13 × more likely when accounting for interactions between methylation and chromatin accessibility, demonstrating that the relationship between differential methylation and gene regulation is partially explained by chromatin state.DNA methylation likely possesses multiple associations with gene regulation during transgenerational plasticity in S. purpuratus and potentially other metazoans, but its effects are dependent on chromatin accessibility and underlying genic features.© 2023. The Author(s).",
+Yes,20230629,ewas,37341931,NSAIDs use history: impact on the genome-wide DNA methylation profile and possible mechanisms of action.,Clin Exp Med,"NSAIDs inhibit cyclooxygenase, but their role in aging and other diseases is not well understood. Our group previously showed the potential benefit of NSAIDs in decreasing the risk of delirium and mortality. Concurrently, epigenetics signals have also been associated with delirium. Therefore, we sought to find differentially methylated genes and biological pathways related to exposure with NSAIDs by comparing the genome-wide DNA methylation profiles of patients with and without a history of NSAIDs use.Whole blood samples were collected from 171 patients at the University of Iowa Hospital and Clinics from November 2017 to March 2020. History of NSAIDs use was assessed through a word-search function in the subjects' electronic medical records. DNA was extracted from the blood samples, processed with bisulfite conversion, and analyzed using Illumina's EPIC array. The analysis of top differentially methylated CpG sites and subsequent enrichment analysis were conducted using an established pipeline using R statistical software.Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) showed several biological pathways relevant to NSAIDs' function. The identified GO terms included ""arachidonic acid metabolic process,"" while KEGG results included ""linoleic acid metabolism,"" ""cellular senescence,"" and ""circadian rhythm."" Nonetheless, none of the top GO and KEGG pathways and the top differentially methylated CpG sites reached statistical significance.Our results suggest a potential role of epigenetics in the mechanisms of the action of NSAIDs. However, the results should be viewed with caution as exploratory and hypothesis-generating given the lack of statistically significant findings.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.",
+No,20230629,methods,37337720,Calculating detection limits and uncertainty of reference-based deconvolution of whole-blood DNA methylation data.,Epigenomics,"DNA methylation (DNAm)-based cell mixture deconvolution (CMD) has become a quintessential part of epigenome-wide association studies where DNAm is profiled in heterogeneous tissue types. Despite being introduced over a decade ago, detection limits, which represent the smallest fraction of a cell type in a mixed biospecimen that can be reliably detected, have yet to be determined in the context of DNAm-based CMD. Moreover, there has been little attention given to approaches for quantifying the uncertainty associated with DNAm-based CMD. Here, analytical frameworks for determining both cell-specific limits of detection and quantification of uncertainty associated with DNAm-based CMD are described. This work may contribute to improved rigor, reproducibility and replicability of epigenome-wide association studies involving CMD.",
+Yes,20230629,ewas,37330044,Epigenetic Intergenerational Transmission: Mothers' Adverse Childhood Experiences and DNA Methylation.,J Am Acad Child Adolesc Psychiatry,"Individual differences in risk for mental disorders over the lifespan are shaped by forces acting before the individual is born-in utero, but likely even earlier, during the mother's own childhood. The environmental epigenetics hypothesis proposes that sustained effects of environmental conditions on gene expression are mediated by epigenetic mechanisms. Recent human studies have shown that adversities in childhood are correlated with DNA methylation (DNAm) in adulthood. In the current study, we tested the following pre-registered hypotheses: Mothers' adverse childhood experiences (ACEs) are correlated with DNAm in peripheral blood during pregnancy (hypothesis 1) and in cord blood samples from newborn infants (hypothesis 2), and women's depression and anxiety symptoms during pregnancy mediate the association between mothers' ACE exposure and prenatal/neonatal DNA methylation (hypothesis 3).Data were from the Avon Longitudinal Study of Parents and Children Accessible Resource for Integrated Epigenomic Studies substudy. Women provided retrospective self-reports during pregnancy of ACE exposure. We conducted an epigenome-wide association study testing whether mothers' ACE exposure, cumulative score (0-10), was associated with DNAm in maternal antenatal blood and infant cord blood in more than 450,000 CpG (point on DNA sequence where Cytosine and Guanine base pairs are linked by a phosphate, where methylation usually occurs) sites on the Illumina 450K BeadChip. Analyses for cord blood were separated by infant sex, a pre-registered analysis.Hypothesis 1: In 896 mother-infant pairs with available methylation and ACE exposure data, there were no significant associations between mothers' ACE score and DNAm from antenatal peripheral blood, after controlling for covariates. Hypothesis 2: In infant cord blood, there were 5 CpG sites significantly differentially methylated in relation to mothers' ACEs (false discovery rate [FDR] < .05), but only in male offspring. Effect sizes were medium, with partial eta squared values ranging from 0.060 to 0.078. CpG sites were in genes related to mitochondrial function and neuronal development in the cerebellum. Hypothesis 3: There was no mediation by maternal anxiety/depression symptoms found between mothers' ACEs score and DNAm in the significant CpG sites in male cord blood. Mediation was not tested in antenatal peripheral blood, because no direct association between mothers' ACE score and antenatal peripheral blood was found.Our results show that mothers' ACE exposure is associated with DNAm in male offspring, supporting the notion that DNAm could be a marker of intergenerational biological embedding of mothers' childhood adversity.Epigenetic Intergenerational Transmission: Mothers' Adverse Childhood Experiences and DNA Methylation; https://doi.org/10.1016/j.jaac.2020.03.008.Copyright © 2023. Published by Elsevier Inc.",
+Yes,20230629,ewas,37327798,Association between the timing of childhood adversity and epigenetic patterns across childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort.,Lancet Child Adolesc Health,"Childhood adversity is a potent determinant of health across development and is associated with altered DNA methylation signatures, which might be more common in children exposed during sensitive periods in development. However, it remains unclear whether adversity has persistent epigenetic associations across childhood and adolescence. We aimed to examine the relationship between time-varying adversity (defined through sensitive period, accumulation of risk, and recency life course hypotheses) and genome-wide DNA methylation, measured three times from birth to adolescence, using data from a prospective, longitudinal cohort study.We first investigated the relationship between the timing of exposure to childhood adversity between birth and 11 years and blood DNA methylation at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study. Our analytic sample included ALSPAC participants with DNA methylation data and complete childhood adversity data between birth and 11 years. We analysed seven types of adversity (caregiver physical or emotional abuse, sexual or physical abuse [by anyone], maternal psychopathology, one-adult households, family instability, financial hardship, and neighbourhood disadvantage) reported by mothers five to eight times between birth and 11 years. We used the structured life course modelling approach (SLCMA) to identify time-varying associations between childhood adversity and adolescent DNA methylation. Top loci were identified using an R2threshold of 0·035 (ie, ≥3·5% of DNA methylation variance explained by adversity). We attempted to replicate these associations using data from the Raine Study and Future of Families and Child Wellbeing Study (FFCWS). We also assessed the persistence of adversity-DNA methylation associations we previously identified from age 7 blood DNA methylation into adolescence and the influence of adversity on DNA methylation trajectories from ages 0-15 years.Of 13 988 children in the ALSPAC cohort, 609-665 children (311-337 [50-51%] boys and 298-332 [49-50%] girls) had complete data available for at least one of the seven childhood adversities and DNA methylation at 15 years. Exposure to adversity was associated with differences in DNA methylation at 15 years for 41 loci (R2≥0·035). Sensitive periods were the most often selected life course hypothesis by the SLCMA. 20 (49%) of 41 loci were associated with adversities occurring between age 3 and 5 years. Exposure to one-adult households was associated with differences in DNA methylation at 20 [49%] of 41 loci, exposure to financial hardship was associated with changes at nine (22%) loci, and physical or sexual abuse was associated with changes at four (10%) loci. We replicated the direction of associations for 18 (90%) of 20 loci associated with exposure to one-adult household using adolescent blood DNA methylation from the Raine Study and 18 (64%) of 28 loci using saliva DNA methylation from the FFCWS. The directions of effects for 11 one-adult household loci were replicated in both cohorts. Differences in DNA methylation at 15 years were not present at 7 years and differences identified at 7 years were no longer apparent by 15 years. We also identified six distinct DNA methylation trajectories from these patterns of stability and persistence.These findings highlight the time-varying effect of childhood adversity on DNA methylation profiles across development, which might link exposure to adversity to potential adverse health outcomes in children and adolescents. If replicated, these epigenetic signatures could ultimately serve as biological indicators or early warning signs of initiated disease processes, helping identify people at greater risk for the adverse health consequences of childhood adversity.Canadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.Copyright © 2023 Elsevier Ltd. All rights reserved.",
+No,20230629,dnamage,37306997,Association of Adverse Childhood Experiences With Accelerated Epigenetic Aging in Midlife.,JAMA Netw Open,"Adverse childhood experiences (ACEs) are associated with the risk of poorer health, and identifying molecular mechanisms may lay the foundation for health promotion in people with ACEs.To investigate the associations of ACEs with changes in epigenetic age acceleration (EAA), a biomarker associated with various health outcomes in middle-aged adults, in a population with balanced race and sex demographics.Data for this cohort study were from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants in CARDIA underwent 8 follow-up exams from baseline (year 0 [Y0]; 1985-1986) to Y30 (2015-2016), and participant blood DNA methylation information was obtained at Y15 (2000-2001) and Y20 (2005-2006). Individuals from Y15 and Y20 with available DNA methylation data and complete variables for ACEs and covariates were included. Data were analyzed from September 2021 to August 2022.Participant ACEs (general negligence, emotional negligence, physical violence, physical negligence, household substance abuse, verbal and emotional abuse, and household dysfunction) were obtained at Y15.The primary outcome consisted of results from 5 DNA methylation-based EAA measurements known to be associated with biological aging and long-term health: intrinsic EAA (IEAA), extrinsic EAA (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), measured at Y15 and Y20. Linear regression and generalized estimating equations were used to assess associations of the burden of ACEs (≥4 vs <4 ACEs) with EAA adjusting for demographics, health-related behaviors, and early life and adult socioeconomic status.A total of 895 participants for Y15 (mean [SD] age, 40.4 [3.5] years; 450 males [50.3%] and 445 females [49.7%]; 319 Black [35.6%] and 576 White [64.4%]) and 867 participants for Y20 (mean [SD] age, 45.4 [3.5] years; 432 males [49.8%] and 435 females [50.2%]; 306 Black [35.3%] and 561 White [64.7%]) were included after excluding participants with missing data. There were 185 participants with (20.7%) vs 710 participants without (79.3%) 4 or more ACEs at Y15 and 179 participants with (20.6%) vs 688 participants without (79.4%) 4 or more ACEs at Y20. Having 4 or more ACEs was positively associated with EAA in years at Y15 (EEAA: β = 0.60 years; 95% CI, 0.18-1.02 years; PhenoAA: β = 0.62 years; 95% CI = 0.13-1.11 years; GrimAA: β = 0.71 years; 95% CI, 0.42-1.00 years; DunedinPACE: β = 0.01; 95% CI, 0.01-0.02) and Y20 (IEAA: β = 0.41 years; 95% CI, 0.05-0.77 years; EEAA: β = 1.05 years; 95% CI, 0.66-1.44 years; PhenoAA: β = 0.57 years; 95% CI, 0.08-1.05 years; GrimAA: β = 0.57 years; 95% CI, 0.28-0.87 years; DunedinPACE: β = 0.01; 95% CI, 0.01-0.02) after adjusting for demographics, health-related behaviors, and socioeconomic status.In this cohort study, ACEs were associated with EAA among middle-aged adults after controlling for demographics, behavior, and socioeconomic status. These findings of the associations between early life experience and the biological aging process in midlife may contribute to health promotion in a life course perspective.",
+Yes,20230629,EWAS,37300821,Prenatal maternal stress is associated with site-specific and age acceleration changes in maternal and newborn DNA methylation.,Epigenetics,"Prenatal maternal stress has a negative impact on child health but the mechanisms through which maternal stress affects child health are unclear. Epigenetic variation, such as DNA methylation, is a likely mechanistic candidate as DNA methylation is sensitive to environmental insults and can regulate long-term changes in gene expression. We recruited 155 mother-newborn dyads in the Democratic Republic of Congo to investigate the effects of maternal stress on DNA methylation in mothers and newborns. We used four measures of maternal stress to capture a range of stressful experiences: general trauma, sexual trauma, war trauma, and chronic stress. We identified differentially methylated positions (DMPs) associated with general trauma, sexual trauma, and war trauma in both mothers and newborns. No DMPs were associated with chronic stress. Sexual trauma was positively associated with epigenetic age acceleration across several epigenetic clocks in mothers. General trauma and war trauma were positively associated with newborn epigenetic age acceleration using the extrinsic epigenetic age clock. We tested the top DMPs for enrichment of DNase I hypersensitive sites (DHS) and found no enrichment in mothers. In newborns, top DMPs associated with war trauma were enriched for DHS in embryonic and foetal cell types. Finally, one of the top DMPs associated with war trauma in newborns also predicted birthweight, completing the cycle from maternal stress to DNA methylation to newborn health outcome. Our results indicate that maternal stress is associated with site-specific changes in DNAm and epigenetic age acceleration in both mothers and newborns.",
+No,20230629,omics,37326626,Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation.,Elife,"Obesity is a major risk factor for cardiovascular disease, stroke, and type 2 diabetes (T2D). Excessive accumulation of fat in the abdomen further increases T2D risk. Abdominal obesity is measured by calculating the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI), a trait with a significant genetic inheritance. Genetic loci associated with WHRadjBMI identified in genome-wide association studies are predicted to act through adipose tissues, but many of the exact molecular mechanisms underlying fat distribution and its consequences for T2D risk are poorly understood. Further, mechanisms that uncouple the genetic inheritance of abdominal obesity from T2D risk have not yet been described. Here we utilize multi-omic data to predict mechanisms of action at loci associated with discordant effects on abdominal obesity and T2D risk. We find six genetic signals in five loci associated with protection from T2D but also with increased abdominal obesity. We predict the tissues of action at these discordant loci and the likely effector Genes (eGenes) at three discordant loci, from which we predict significant involvement of adipose biology. We then evaluate the relationship between adipose gene expression of eGenes with adipogenesis, obesity, and diabetic physiological phenotypes. By integrating these analyses with prior literature, we propose models that resolve the discordant associations at two of the five loci. While experimental validation is required to validate predictions, these hypotheses provide potential mechanisms underlying T2D risk stratification within abdominal obesity.© 2023, Aberra et al.",
+No,20230629,omics,37365616,Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage.,Genome Biol,"The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage.Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are supported as putatively causal. We then prioritize 153 of these genomic regions using additional colocalization analyses. Our genome-wide findings are supported by existing knowledge (animal models for MANBA, DACH1, SH3YL1, INHBB), exceed the underlying GWAS signals (28 region-trait combinations without significant GWAS hit), identify independent gene/protein-trait associations within the same genomic region (INHBC, SPRYD4), nominate tissues underlying the associations (tubule expression of NRBP1), and distinguish markers of kidney filtration from those with a role in creatinine and cystatin C metabolism. Furthermore, we follow up on members of the TGF-beta superfamily of proteins and find a prognostic value of INHBC for kidney disease progression even after adjustment for measured glomerular filtration rate (GFR).In summary, this study combines multimodal, genome-wide association studies to generate a catalog of putatively causal target genes and proteins relevant to kidney function and damage which can guide follow-up studies in physiology, basic science, and clinical medicine.© 2023. The Author(s).",
+No,20230629,cancer,37344596,Y chromosome loss in cancer drives growth by evasion of adaptive immunity.,Nature,"Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers1-6, but its clinical and biological significance is unknown. Here, using genomic and transcriptomic studies, we report that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells as well as those with targeted deletion of Y chromosome by CRISPR-Cas9. Y-positive (Y+) and Y-negative (Y-) tumours grew similarly in vitro, whereas Y-tumours were more aggressive than Y+tumours in immune-competent hosts in a T cell-dependent manner. High-dimensional flow cytometric analyses demonstrated that Y-tumours promote striking dysfunction or exhaustion of CD8+T cells in the tumour microenvironment. These findings were validated using single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Of note, compared with Y+tumours, Y-tumours exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. This work provides insights into the basic biology of LOY mutation and potential biomarkers for improving cancer immunotherapy.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20230629,ctdna,37330511,Early detection and stratification of lung cancer aided by a cost-effective assay targeting circulating tumor DNA (ctDNA) methylation.,Respir Res,"Detection of lung cancer at earlier stage can greatly improve patient survival. We aim to develop, validate, and implement a cost-effective ctDNA-methylation-based plasma test to aid lung cancer early detection.Case-control studies were designed to select the most relevant markers to lung cancer. Patients with lung cancer or benign lung disease and healthy individuals were recruited from different clinical centers. A multi-locus qPCR assay, LunaCAM, was developed for lung cancer alertness by ctDNA methylation. Two LunaCAM models were built for screening (-S) or diagnostic aid (-D) to favor sensitivity or specificity, respectively. The performance of the models was validated for different intended uses in clinics.Profiling DNA methylation on 429 plasma samples including 209 lung cancer, 123 benign diseases and 97 healthy participants identified the top markers that detected lung cancer from benign diseases and healthy with an AUC of 0.85 and 0.95, respectively. The most effective methylation markers were verified individually in 40 tissues and 169 plasma samples to develop LunaCAM assay. Two models corresponding to different intended uses were trained with 513 plasma samples, and validated with an independent collection of 172 plasma samples. In validation, LunaCAM-S model achieved an AUC of 0.90 (95% CI: 0.88-0.94) between lung cancer and healthy individuals, whereas LunaCAM-D model stratified lung cancer from benign pulmonary diseases with an AUC of 0.81 (95% CI: 0.78-0.86). When implemented sequentially in the validation set, LunaCAM-S enables to identify 58 patients of lung cancer (90.6% sensitivity), followed by LunaCAM-D to remove 20 patients with no evidence of cancer (83.3% specificity). LunaCAM-D significantly outperformed the blood test of carcinoembryonic antigen (CEA), and the combined model can further improve the predictive power for lung cancer to an overall AUC of 0.86.We developed two different models by ctDNA methylation assay to sensitively detect early-stage lung cancer or specifically classify lung benign diseases. Implemented at different clinical settings, LunaCAM models has a potential to provide a facile and inexpensive avenue for early screening and diagnostic aids for lung cancer.© 2023. The Author(s).",
+No,20230629,tandem repeats,37307504,Genome-wide identification of tandem repeats associated with splicing variation across 49 tissues in humans.,Genome Res,"Tandem repeats (TRs) are one of the largest sources of polymorphism, and their length is associated with gene regulation. Although previous studies reported several tandem repeats regulating gene splicing incis(spl-TRs), no large-scale study has been conducted. In this study, we established a genome-wide catalog of 9537 spl-TRs with a total of 58,290 significant TR-splicing associations across 49 tissues (false discovery rate 5%) by using Genotype-Tissue expression (GTex) Project data. Regression models explaining splicing variation by using spl-TRs and other flanking variants suggest that at least some of the spl-TRs directly modulate splicing. In our catalog, two spl-TRs are known loci for repeat expansion diseases, spinocerebellar ataxia 6 (SCA6) and 12 (SCA12). Splicing alterations by these spl-TRs were compatible with those observed in SCA6 and SCA12. Thus, our comprehensive spl-TR catalog may help elucidate the pathomechanism of genetic diseases.© 2023 Hamanaka et al.; Published by Cold Spring Harbor Laboratory Press.",
+No,20230629,circadian rhythm,37262074,The circadian clock is disrupted in pancreatic cancer.,PLoS Genet,"Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.Copyright: © 2023 Schwartz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+Yes,20230706,ewas,37405801,No association between war-related trauma or PTSD symptom severity and epigenome-wide DNA methylation in Burundian refugees.,Eur J Psychotraumatol,"Background:War-related trauma is associated with varying posttraumatic stress disorder (PTSD) prevalence rates in refugees. In PTSD development, differential DNA methylation (DNAm) levels associated with trauma exposure might be involved in risk versus resilience processes. Studies investigating DNAm profiles related to trauma exposure and PTSD among refugees remain sparse.Objective:The present epigenome-wide association study investigated associations between war-related trauma, PTSD, and altered DNAm patterns in Burundian refugee families with 110 children and their 207 female and male caregivers.Method:War-related trauma load and PTSD symptom severity were assessed in structured clinical interviews with standardised instruments. Epigenome-wide DNAm levels were quantified from buccal epithelia using the Illumina EPIC beadchip.Results:Controlling for biological confounders, no significant epigenome-wide DNAm alterations associated with trauma exposure or PTSD were identified in children or caregivers (FDRs > .05). Co-methylated positions derived as modules from weighted gene correlation network analyses were not significantly associated with either war-related trauma experience in children or caregivers or with PTSD.Conclusions:These results do not provide evidence for altered DNAm patterns associated with exposure to war-related trauma or PTSD.",
+Yes,20230706,ewas,37398583,Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans.,Front Psychiatry,"The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown.To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans.Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDRq-value <0.05), including cg13301722 on chromosome 7, which lies between the genesSLC4A2andCDK5; cg04724646 inPDE3A; and cg04999352 inRARRES3.cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans.Taken together, the present findings suggest thatSLC4A2,CDK5,PDE3A, andRARRES3may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples.Copyright © 2023 Kimbrel, Garrett, Evans, Mellows, Dennis, Hair, Hauser, the VA Mid-Atlantic MIRECC Workgroup, Ashley-Koch and Beckham.",
+Yes,20230706,ewas,37394087,Epigenome-wide association study identifies Vogt-Koyanagi-Harada disease-associated DNA methylation loci in Chinese.,Exp Eye Res,"DNA methylation is one of the important epigenetic mechanisms for modulating gene expression. By performing a genome-wide methylation association analysis of whole peripheral blood from 60 Vogt-Koyanagi-Harada disease (VKH) patients and 60 healthy controls, we depicted the global DNA methylation status of VKH disease. Further pyrosequencing validation in 160 patients and 159 controls identified 3 aberrant CpG sites in HLA gene regions including cg04026937 and cg18052547 (located in HLA-DRB1 region), and cg13778567 (HLA-DQA1). We also identified 9 aberrant CpG sites in non-HLA gene regions including cg13979407, cg21075643, cg24290586, cg10135747 and cg22707857 (BTNL2), cg22155039 (NOTCH4), cg02605387 (TNXB), cg06255004 (AGPAT2) and cg18855195 (RIBC2). Increased mRNA levels of BTNL2, NOTCH4 and TNXB were identified in VKH patients when compared with healthy controls, consistent with the hypomethylated CpG status in these gene regions. Moreover, seven aberrantly methylated CpG sites may serve as a diagnostic marker for VKH disease (AUC = 84.95%, 95%CI: 79.49%-90.41%).Copyright © 2023 Elsevier Ltd. All rights reserved.",
+Yes,20230706,ewas,37393498,Sixteen-Year Longitudinal Evaluation of Blood-Based DNA Methylation Biomarkers for Early Prediction of Alzheimer's Disease.,J Alzheimers Dis,"DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer's disease (AD) prediction.Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers.EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10-16 years), and post-AD-onset time-points.EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (ps: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOEɛ4-carriership (OR = 1.38 per 1 SD DNAm score increase versus OR = 13.58 for ɛ4-allele carriage; AUCs = 77.2% versus 87.0%). Literature review showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.",
+Yes,20230706,ewas,37393279,DNA methylation is differentially associated with glycemic outcomes by different types of weight-loss interventions: an epigenome-wide association study.,Clin Epigenetics,"Alterations in DNA methylation (DNAm) have been reported to be a mechanism by which bariatric surgeries resulted in considerable metabolic improvements. Previous studies have mostly focused on change in DNAm following weight-loss interventions, yet whether DNAm prior to intervention can explain the variability in glycemic outcomes has not been investigated. Here, we aim to examine whether baseline DNAm is differentially associated with glycemic outcomes induced by different types of weight-loss interventions.Participants were 75 adults with severe obesity who underwent non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) or Roux-en-Y gastric bypass (RYGB) (n = 25 each). Changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) were measured at 1-year after intervention. DNAm was quantified by Illumina 450 K arrays in baseline peripheral blood DNA. Epigenome-wide association studies were performed to identify CpG probes that modify the effects of different weight-loss interventions on glycemic outcomes, i.e., changes in FPG and HbA1c, by including an interaction term between types of intervention and DNAm. Models were adjusted for weight loss and baseline clinical factors.Baseline DNAm levels at 3216 and 117 CpGs were differentially associated with changes in FPG and HbA1c, respectively, when comparing RYGB versus IMI. Of these, 79 CpGs were significant for both FPG and HbA1c. The identified genes are enriched in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation. Additionally, DNAm at 6 CpGs was differentially associated with changes in HbA1c when comparing RYGB versus BAND.Baseline DNAm is differentially associated with glycemic outcomes in response to different types of weight-loss interventions, independent of weight loss and other clinical factors. Such findings provided initial evidence that baseline DNAm levels may serve as potential biomarkers predictive of differential glycemic outcomes in response to different types of weight-loss interventions.© 2023. The Author(s).",
+Yes,20230706,ewas,37356726,DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes.,Diabetes Res Clin Pract,"Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newly-diagnosed individuals with type 2 diabetes.We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for � 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin's effects on HbA1c.Metformin-associated alterations in DNA methylation partially mediates metformin's antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes.Copyright © 2023. Published by Elsevier B.V.",
+No,20230706,dnamage,37386259,"The meaning of adaptation in aging: insights from cellular senescence, epigenetic clocks and stem cell alterations.",Nat Aging,"With recent rapid progress in research on aging, there is increasing evidence that many features commonly considered to be mechanisms or drivers of aging in fact represent adaptations. Here, we examine several such features, including cellular senescence, epigenetic aging and stem cell alterations. We draw a distinction between the causes and consequences of aging and define short-term consequences as 'responses' and long-term ones as 'adaptations'. We also discuss 'damaging adaptations', which despite having beneficial effects in the short term, lead to exacerbation of the initial insult and acceleration of aging. Features commonly recognized as 'basic mechanisms of the aging process' are critically examined for the possibility of their adaptation-driven emergence from processes such as cell competition and the wound-like features of the aging body. Finally, we speculate on the meaning of these interactions for the aging process and their relevance for the development of antiaging interventions.© 2023. Springer Nature America, Inc.",
+No,20230706,epigenetics,37393564,Biological stability of DNA methylation measurements over varying intervals of time and in the presence of acute stress.,Epigenetics,"Identifying factors that influence the stability of DNA methylation measurements across biological replicates is of critical importance in basic and clinical research. Using a within-person between-group experimental design (n = 31, number of observations = 192), we report the stability of biological replicates over a variety of unique temporal scenarios, both in the absence and presence of acute psychosocial stress, and between individuals who have experienced early life adversity (ELA) and non-exposed individuals. We found that varying time intervals, acute stress, and ELA exposure influenced the stability of repeated DNA methylation measurements. In the absence of acute stress, probes were less stable as time passed; however, stress exerted a stabilizing influence on probes over longer time intervals. Compared to non-exposed individuals, ELA-exposed individuals had significantly lower probe stability immediately following acute stress. Additionally, we found that across all scenarios, probes used in most epigenetic-based algorithms for estimating epigenetic age or immune cell proportions had average or below-average stability, except for the Principal Component and DunedinPACE epigenetic ageing clocks, which were enriched for more stable probes. Finally, using highly stable probes in the absence of stress, we identified multiple probes that were hypomethylated in the presence of acute stress, regardless of ELA status. Two hypomethylated probes are located near the transcription start site of the glutathione-disulfide reductase gene (GSR), which has previously been shown to be an integral part of the stress response to environmental toxins. We discuss implications for future studies concerning the reliability and reproducibility of DNA methylation measurements.Abbreviations:DNAm - DNA methylation, CpG - 5'-cytosine-phosphate-guanine-3,' ICC - Interclass correlation coefficient, ELA - Early-life adversity, PBMCs - Peripheral blood mononuclear cells, mQTL - Methylation quantitative trait loci, TSS - Transcription start site, GSR - Glutathione-disulfide reductase gene, TSST - Trier social stress test, PC - Principal component.",
+No,20230706,dnamage,37388854,No evidence of accelerated epigenetic aging among black heroin users: A case vs control analysis.,Addict Neurosci,"This study sought to assess the association between illicit opioid use and accelerated epigenetic aging (A.K.A. DNAm Age) among people of African ancestry who use heroin. DNA was obtained from participants with opioid use disorder (OUD) who confirmed heroin as their primary drug of choice. Clinical inventories of drug use included: the Addiction Severity Index (ASI) Drug-Composite Score (range: 0-1), and Drug Abuse Screening Test (DAST-10; range: 0-10). A control group of participants of African ancestry who did not use heroin was recruited and matched to heroin users on sex, age, socioeconomic level, and smoking status. Methylation data were assessed in an epigenetic clock to determined and compare Epigenetic Age to Chronological Age (i.e., age acceleration or deceleration). Data were obtained from 32 controls [mean age 36.3 (±7.5) years] and 64 heroin users [mean age 48.1 (±6.6) years]. The experimental group used heroin for an average of 18.1 (±10.6) years, reported use of 6.4 (±6.1) bags of heroin/day, with a mean DAST-10 score of 7.0 (±2.6) and ASI Score of 0.33 (±0.19). Mean age acceleration for heroin users [+0.56 (± 9.5) years] was significantly (p< 0.05) lower than controls [+5.19 (± 9.1) years]. This study did not find evidence that heroin use causes epigenetic age acceleration.",
+No,20230706,pwas,37400771,Associations of circulating proteins with lipoprotein profiles: proteomic analyses from the OmniHeart randomized trial and the Atherosclerosis Risk in Communities (ARIC) Study.,Clin Proteomics,"Within healthy dietary patterns, manipulation of the proportion of macronutrient can reduce CVD risk. However, the biological pathways underlying healthy diet-disease associations are poorly understood. Using an untargeted, large-scale proteomic profiling, we aimed to (1) identify proteins mediating the association between healthy dietary patterns varying in the proportion of macronutrient and lipoproteins, and (2) validate the associations between diet-related proteins and lipoproteins in the Atherosclerosis Risk in Communities (ARIC) Study.In 140 adults from the OmniHeart trial, a randomized, cross-over, controlled feeding study with 3 intervention periods (carbohydrate-rich; protein-rich; unsaturated fat-rich dietary patterns), 4,958 proteins were quantified at the end of each diet intervention period using an aptamer assay (SomaLogic). We assessed differences in log2-transformed proteins in 3 between-diet comparisons using paired t-tests, examined the associations between diet-related proteins and lipoproteins using linear regression, and identified proteins mediating these associations using a causal mediation analysis. Levels of diet-related proteins and lipoprotein associations were validated in the ARIC study (n = 11,201) using multivariable linear regression models, adjusting for important confounders.Three between-diet comparisons identified 497 significantly different proteins (protein-rich vs. carbohydrate-rich = 18; unsaturated fat-rich vs. carbohydrate-rich = 335; protein-rich vs. unsaturated fat-rich dietary patterns = 398). Of these, 9 proteins [apolipoprotein M, afamin, collagen alpha-3(VI) chain, chitinase-3-like protein 1, inhibin beta A chain, palmitoleoyl-protein carboxylesterase NOTUM, cathelicidin antimicrobial peptide, guanylate-binding protein 2, COP9 signalosome complex subunit 7b] were positively associated with lipoproteins [high-density lipoprotein (HDL)-cholesterol (C) = 2; triglyceride = 5; non-HDL-C = 3; total cholesterol to HDL-C ratio = 1]. Another protein, sodium-coupled monocarboxylate transporter 1, was inversely associated with HDL-C and positively associated with total cholesterol to HDL-C ratio. The proportion of the association between diet and lipoproteins mediated by these 10 proteins ranged from 21 to 98%. All of the associations between diet-related proteins and lipoproteins were significant in the ARIC study, except for afamin.We identified proteins that mediate the association between healthy dietary patterns varying in macronutrients and lipoproteins in a randomized feeding study and an observational study.NCT00051350 at clinicaltrials.gov.© 2023. The Author(s).",
+No,20230706,methods,37387182,AttOmics: attention-based architecture for diagnosis and prognosis from omics data.,Bioinformatics,"The increasing availability of high-throughput omics data allows for considering a new medicine centered on individual patients. Precision medicine relies on exploiting these high-throughput data with machine-learning models, especially the ones based on deep-learning approaches, to improve diagnosis. Due to the high-dimensional small-sample nature of omics data, current deep-learning models end up with many parameters and have to be fitted with a limited training set. Furthermore, interactions between molecular entities inside an omics profile are not patient specific but are the same for all patients.In this article, we propose AttOmics, a new deep-learning architecture based on the self-attention mechanism. First, we decompose each omics profile into a set of groups, where each group contains related features. Then, by applying the self-attention mechanism to the set of groups, we can capture the different interactions specific to a patient. The results of different experiments carried out in this article show that our model can accurately predict the phenotype of a patient with fewer parameters than deep neural networks. Visualizing the attention maps can provide new insights into the essential groups for a particular phenotype.The code and data are available at https://forge.ibisc.univ-evry.fr/abeaude/AttOmics. TCGA data can be downloaded from the Genomic Data Commons Data Portal.© The Author(s) 2023. Published by Oxford University Press.",
+No,20230706,transgenerational,37396986,Epigenetic Inheritance and Transgenerational Environmental Justice.,Yale J Biol Med,"Many chemicals and toxicants are released into our ecosystem and environment every day, which can cause harmful effects on human populations. Agricultural compounds are used in most crop production and have been shown to cause negative health impacts, including effects on reproduction and other pathologies. Although these chemicals can be helpful for pest and weed control, the compounds indirectly impact humans. Several compounds have been banned in the European Union but continue to be used in the United States. Recent work has shown most toxicants affect transgenerational generations more than the directly exposed generations through epigenetic inheritance. While some toxicants do not impact the directly exposed generation, the later generations that are transgenerational or ancestrally exposed suffer health impacts. Due to impacts to future generations, exposure becomes an environmental justice concern. The term ""environmental justice"" denotes the application of fair strategies when resolving unjust environmental contamination. Fair treatment means that no group should bear a disproportionate share of negative environmental consequences resulting from industrial, municipal, and commercial operations. This article illustrates how research on directly exposed generations is often prioritized over studies on transgenerational generations. However, research on the latter generations suggests the need to take environmental justice concerns seriously moving forward, as future generations could be unduly shouldering harms, while not enjoying benefits of production.Copyright ©2023, Yale Journal of Biology and Medicine.",
+No,20230706,epigenetics,36535946,A comparison of the genes and genesets identified by GWAS and EWAS of fifteen complex traits,Nat Commun,"Identifying genomic regions pertinent to complex traits is a common goal of genome-wide and epigenome-wide association studies (GWAS and EWAS). GWAS identify causal genetic variants, directly or via linkage disequilibrium, and EWAS identify variation in DNA methylation associated with a trait. While GWAS in principle will only detect variants due to causal genes, EWAS can also identify genes via confounding, or reverse causation. We systematically compare GWAS (N > 50,000) and EWAS (N > 4500) results of 15 complex traits. We evaluate if the genes or gene ontology terms flagged by GWAS and EWAS overlap, and find substantial overlap for diastolic blood pressure, (gene overlap P = 5.2 × 10-6; term overlap P = 0.001). We superimpose our empirical findings against simulated models of varying genetic and epigenetic architectures and observe that in most cases GWAS and EWAS are likely capturing distinct genesets. Our results indicate that GWAS and EWAS are capturing different aspects of the biology of complex traits.",
+,20230803,,37511531,Epigenome-Wide Associations of Placental DNA Methylation and Behavioral and Emotional Difficulties in Children at 3 Years of Age.,Int J Mol Sci,"The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother-child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 (AHRR) with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (PPP1R16B), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.",
+,20230803,,37503194,An epigenome-wide association study of child appetitive traits and DNA methylation.,bioRxiv,"Childhood appetitive traits are consistently associated with obesity risk, and yet their etiology is poorly understood. Appetitive traits are complex phenotypes which are hypothesized to be influenced by both genetic and environmental factors, as well as their interactions. Early-life epigenetic processes, such as DNA methylation (DNAm), may be involved in the developmental programming of appetite regulation in childhood. In the current study, we meta-analyzed epigenome-wide association studies (EWASs) of cord blood DNAm and early-childhood appetitive traits. Data were from two independent cohorts: the Generation R Study (n=1,086, Rotterdam, the Netherlands) and the Healthy Start study (n=236, Colorado, USA). DNAm at autosomal methylation sites in cord blood was measured using the Illumina Infinium HumanMethylation450 BeadChip. Parents reported on their child's food responsiveness, emotional undereating, satiety responsiveness and food fussiness using the Children's Eating Behaviour Questionnaire at age 4-5 years. Multiple regression models were used to examine the association of DNAm (predictor) at the individual site- and regional-level (using DMRff) with each appetitive trait (outcome), adjusting for covariates. Bonferroni-correction was applied to adjust for multiple testing. There were no associations of DNAm and any appetitive trait at the individual site-level. However, at the regional level, we identified 45 associations of DNAm with food responsiveness, 7 associations of DNAm with emotional undereating, 13 associations of DNAm with satiety responsiveness, and 9 associations of DNAm with food fussiness. This study shows that DNAm in the newborn may partially explain variation in appetitive traits expressed in early childhood and provides preliminary support for early programming of child appetitive traits through DNAm. Investigating differential DNAm associated with appetitive traits could be an important first step in identifying biological pathways underlying the development of these behaviors.",
+,20230803,,37502923,sciMET-cap: High-throughput single-cell methylation analysis with a reduced sequencing burden.,bioRxiv,"DNA methylation is a key component of the mammalian epigenome, playing a regulatory role in development, disease, and other processes. Robust, high-throughput single-cell DNA methylation assays are now possible (sciMET); however, the genome-wide nature of DNA methylation results in a high sequencing burden per cell. Here, we leverage target enrichment with sciMET to capture sufficient information per cell for cell type assignment using substantially fewer sequence reads (sciMET-cap). Sufficient off-target coverage further enables the production of near-complete methylomes for individual cell types. We characterize sciMET-cap on human PBMCs and brain (middle frontal gyrus).",
+,20230803,,37502922,Multi-ancestry epigenome-wide analyses identify methylated sites associated with aortic augmentation index in TOPMed MESA.,Res Sq,"Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these,ETS1andTGFB3have been previously prioritized as candidate genes. Furthermore, bothETS1andHLA-DPB1have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggestsETS1andHLA-DPB1could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.",
+,20230803,,37501075,Genome-wide discovery of circulating cell-free DNA methylation biomarkers for colorectal cancer detection.,Clin Epigenetics,"Colorectal polyp is known a precursor of colorectal cancer (CRC) that holds an increased risk for progression to CRC. Circulating cell-free DNA (cfDNA) methylation has shown favorable performance in the detection and monitoring the malignant progression in a variety of cancers.To discover cfDNA methylation markers for the diagnosis of CRC, we first performed a genome-wide analysis between eight CRC and eight polyp tissues using the Infinium HumanMethylationEPIC BeadChip. We identified 7008 DMCs, and after filtering, we validated 39 DMCs by MethylTarget sequencing in 62 CRC and 56 polyp tissues. A panel of four CpGs (cg04486886, cg06712559, cg13539460, and cg27541454) was selected as the methylation marker in tissue by LASSO and random forest models. A diagnosis prediction model was built based on the four CpGs, and the methylation diagnosis score (md-score) can effectively discriminate tissues with CRC from polyp patients (AUROC > 0.9). Finally, the cg27541454 was confirmed hypermethylated in CRC (AUC = 0.85) in the plasma validation cohort.Our findings suggest that the md-score could robustly detect CRC from polyp tissues, and cg27541454 may be a promising candidate noninvasive biomarker for CRC early diagnosis.© 2023. The Author(s).",
+,20230803,,37496173,The lipidomic correlates of epigenetic aging across the adult lifespan: A population-based study.,Aging Cell,"Lipid signaling is involved in longevity regulation, but which specific lipid molecular species affect human biological aging remains largely unknown. We investigated the relation between complex lipids and DNA methylation-based metrics of biological aging among 4181 participants (mean age 55.1 years (range 30.0-95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. The absolute concentration of 14 lipid classes, covering 964 molecular species and 267 fatty acid composites, was measured by Metabolon Complex Lipid Panel. DNA methylation-based metrics of biological aging (AgeAccelPheno and AgeAccelGrim) were calculated based on published algorithms. Epigenome-wide association analyses (EWAS) of biological aging-associated lipids and pathway analysis were performed to gain biological insights into the mechanisms underlying the effects of lipidomics on biological aging. We found that higher levels of molecular species belonging to neutral lipids, phosphatidylethanolamines, phosphatidylinositols, and dihydroceramides were associated with faster biological aging, whereas higher levels of lysophosphatidylcholine, hexosylceramide, and lactosylceramide species were associated with slower biological aging. Ceramide, phosphatidylcholine, and lysophosphatidylethanolamine species with odd-numbered fatty acid tail lengths were associated with slower biological aging, whereas those with even-numbered chain lengths were associated with faster biological aging. EWAS combined with functional pathway analysis revealed several complex lipids associated with biological aging as important regulators of known longevity and aging-related pathways.© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
+,20230803,,37466420,Genome-wide analysis of DNA methylation and its relationship with serum homocysteine levels in patients with hypertension.,J Hypertens,"Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases, and elevated plasma Hcy levels could aggravate vascular injury in hypertension. Hyperhomocysteinemia can change the methylation status of global DNA and specific genes. In the present study, we aim to examine the comprehensive influence of Hcy levels on DNA methylation status in patients with hypertension.Epigenome-wide methylation profiles of the peripheral leukocyte DNA of 218 patients with hypertension were analyzed using the Illumina Infinium Methylation EPIC BeadChip. Differentially methylated positions (DMPs) associated with serum Hcy levels were identified by mixed linear regression with the adjustment of potential confounders. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to determine the potential functions of the identified DMPs. The association between the methylation level of DMPs and carotid-femoral pulse wave velocity (Cf-PWV) was also analyzed.Five DMPs at cg13169662, cg03179312, cg21976560, cg25262698, and cg09433843 showed significant association with serum Hcy levels (false discovery rate-corrected P < 0.05). An additional six CpG sites met the threshold for suggestive significance (P < 1 × 10-6), among which three DMPs (cg25781123, cg26463106, and cg06679221) were annotated to THUMPD3. Furthermore, the methylation levels of cg13169662 and cg25262698 (RPRD1A) were significantly associated with Cf-PWV.Our results suggest that Hcy could induce DNA methylation alteration in patients with hypertension. Further functional research is warranted to elucidate the concrete role of DMPs in hypertension.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.",
+,20230803,,37464577,Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study.,J Clin Periodontol,"To investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood.We included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at Visit 4 and had available data on DNA methylation from Visit 2 or 3. DNA methylation levels were compared by periodontal disease severity and edentulism through discovery analyses and subsequent testing of individual CpGs.Our discovery analysis replicated findings from a previous study reporting a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared with no/mild periodontal disease in European American participants. Higher methylation levels in a separate region in an unknown gene (located in Chr10: 743,992-744,958) was associated with significantly higher odds of edentulism compared with no/mild periodontal disease in African American participants. In subsequent CpG testing, four CpGs in a region previously associated with periodontitis located within HOXA4 were significantly hypermethylated in severe periodontal disease compared with no/mild periodontal disease in African American participants (odds ratio per 1 SD increase in methylation level: cg11015251: 1.28 (1.02, 1.61); cg14359292: 1.24 (1.01, 1.54); cg07317062: 1.30 (1.05, 1.61); cg08657492: 1.25 (1.01, 1.55)).Our study highlights epigenetic variations in ZPF57 and HOXA4 that are significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",
+,20230803,,37461726,Critical evaluation of the reliability of DNA methylation probes on the Illumina MethylationEPIC BeadChip microarrays for dementia research.,Res Sq,"Background DNA methylation (DNAm) has been implicated in many diseases including dementia. Array-based technologies offer a cost-effective and comprehensive approach for measuring DNAm on a genome-wide scale. However, the accuracy of DNAm measurements obtained using Illumina arrays can vary across different probes. Previous research has focused primarily on assessing the reliability of DNAm in younger subjects, and have compared duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on EPIC-EPIC comparisons. Methods We conducted a comprehensive assessment of probe reliability on the Illumina EPIC arrays using 138 duplicated blood DNAm samples from subjects older than 65 years in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. To assess the reliability of each probe, we computed intraclass correlations (ICCs) for each probe. Both the magnitude and patterns of reliability in the EPIC-EPIC comparison were assessed. Furthermore, we also investigated the impact of probe reliability on the analyses of epigenome-wide association studies (EWAS). Results Our findings revealed the reliability of probes on the EPIC arrays is higher than those of previous studies involving duplicate measurements on 450k-EPIC or 450k-450k arrays. Consistent with earlier research, we observed increased reliability in probes with substantial between-subject variances or average methylation beta values ranging from 0.2 to 0.8. Lower reliability was observed in type I probes or probes located within the promoter and CpG island regions. In addition, we found some probes can yield high ICC values despite significant disagreement in duplicate measurements, primarily due to their relatively high between-subject variance. To account for such discrepancies explicitly, we introduced a novel statistical measure called the modified ICC, which penalizes the ICC based on the half-width of the 95% confidence limits of agreement. Importantly, we found probe reliability has significant implications in various downstream analyses of EWAS, such as meta-analysis, differentially methylated regions analysis, and integrative analyses within the cross-tissue or multi-omics contexts. Conclusion We developed a valuable resource for dementia research, providing crucial reliability information for probes on the EPIC array. This resource can be utilized to identify and prioritize high-quality probes, thereby minimizing the potential for false discoveries and maximizing the potential of EWAS.",
+,20230803,,37415231,Epigenetic marks associated with gestational diabetes mellitus across two time points during pregnancy.,Clin Epigenetics,"An adverse intrauterine or periconceptional environment, such as hyperglycemia during pregnancy, can affect the DNA methylation pattern both in mothers and their offspring. In this study, we explored the epigenetic profile in maternal peripheral blood samples through pregnancy to find potential epigenetic biomarkers for gestational diabetes mellitus (GDM), as well as candidate genes involved in GDM development. We performed an epigenome-wide association study in maternal peripheral blood samples in 32 pregnant women (16 with GDM and 16 non-GDM) at pregnancy week 24-28 and 36-38. Biochemical, anthropometric, and obstetrical variables were collected from all the participants. The main results were validated in an independent cohort with different ethnic origin (European = 307; South Asians = 165). Two hundred and seventy-two CpGs sites remained significantly different between GDM and non-GDM pregnant women across two time points during pregnancy. The significant CpG sites were related to pathways associated with type I diabetes mellitus, insulin resistance and secretion. Cg01459453 (SELP gene) was the most differentiated in the GDM group versus non-GDM (73.6 vs. 60.9, p = 1.06E-11; FDR = 7.87E-06). Three CpG sites (cg01459453, cg15329406, and cg04095097) were able to discriminate between GDM cases and controls (AUC = 1; p = 1.26E-09). Three differentially methylated positions (DMPs) were replicated in an independent cohort. To conclude, epigenetic marks during pregnancy differed between GDM cases and controls suggesting a role for these genes in GDM development. Three CpGs were able to discriminate GDM and non-GDM groups with high specificity and sensitivity, which may be biomarker candidates for diagnosis or prediction of GDM.© 2023. The Author(s).",
+,20230803,,37405974,Contributions of neighborhood social environment and air pollution exposure to Black-White disparities in epigenetic aging.,PLoS One,"Racial disparities in many aging-related health outcomes are persistent and pervasive among older Americans, reflecting accelerated biological aging for Black Americans compared to White, known as weathering. Environmental determinants that contribute to weathering are poorly understood. Having a higher biological age, measured by DNA methylation (DNAm), than chronological age is robustly associated with worse age-related outcomes and higher social adversity. We hypothesize that individual socioeconomic status (SES), neighborhood social environment, and air pollution exposures contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm). We perform retrospective cross-sectional analyses among 2,960 non-Hispanic participants (82% White, 18% Black) in the Health and Retirement Study whose 2016 DNAm age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing DNAm age on chronological age. We observe Black individuals have significantly accelerated DNAm aging on average compared to White individuals according to GrimAge (239%) and DPoAm (238%). We implement multivariable linear regression models and threefold decomposition to identify exposures that contribute to this disparity. Exposure measures include individual-level SES, census-tract-level socioeconomic deprivation and air pollution (fine particulate matter, nitrogen dioxide, and ozone), and perceived neighborhood social and physical disorder. Race and gender are included as covariates. Regression and decomposition results show that individual-level SES is strongly associated with and accounts for a large portion of the disparity in both GrimAge and DPoAm aging. Higher neighborhood deprivation for Black participants significantly contributes to the disparity in GrimAge aging. Black participants are more vulnerable to fine particulate matter exposure for DPoAm, perhaps due to individual- and neighborhood-level SES, which may contribute to the disparity in DPoAm aging. DNAm aging may play a role in the environment ""getting under the skin"", contributing to age-related health disparities between older Black and White Americans.Copyright: © 2023 Yannatos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+,20230803,,37278618,Associations of four biological age markers with child development: A multi-omic analysis in the European HELIX cohort.,Elife,"While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators, to child developmental outcomes, including growth and adiposity, cognition, behavior, lung function and the onset of puberty, among European school-age children participating in the HELIX exposome cohort.The study population included up to 1173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation, and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma proteins and urinary and serum metabolites) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity, and study centre. The clock derived markers were expressed as Δ age (i.e. predicted minus chronological age).Transcriptome and immunometabolic clocks predicted chronological age well in the test set (r=0.93 andr=0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators.Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ age, smoke exposure with greater DNA methylation Δ age, and high family affluence with longer telomere length.Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p=4 e-3) and reduced inattentiveness (p=4 e-4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviors (p=0.01). Shorter telomere length was also associated with poorer externalizing behaviors (p=0.03).In children, as in adults, biological aging appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological aging. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological aging, apparent even in children.UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583).© 2023, Robinson et al.",
+,20230803,,37364131,Antisense oligonucleotide rescue of CGG expansion-dependent FMR1 mis-splicing in fragile X syndrome restores FMRP.,Proc Natl Acad Sci U S A,"Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here, we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissues of individuals with fragile X syndrome (FXS). Surprisingly, theFMR1 (Fragile X Messenger Ribonucleoprotein 1)gene is transcribed in >70% of the FXS tissues. In allFMR1-expressing FXS tissues,FMR1RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-knownFMR1-217 RNA isoform, which is comprised ofFMR1exon 1 and a pseudo-exon in intron 1.FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissues. We show that in cells aberrantly expressing mis-splicedFMR1, antisense oligonucleotide (ASO) treatment reducesFMR1-217, rescues full-lengthFMR1RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably,FMR1gene reactivation in transcriptionally silent FXS cells using 5-aza-2'-deoxycytidine (5-AzadC), which prevents DNA methylation, increasesFMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-lengthFMR1expression and restores FMRP. These findings indicate that misregulated RNA-processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressingFMR1-217, ASO treatment may offer a therapeutic approach to mitigate the disorder.",
+,20230803,,37414898,A prognostic risk score for development and spread of chronic pain.,Nat Med,"Chronic pain is a complex condition influenced by a combination of biological, psychological and social factors. Using data from the UK Biobank (n = 493,211), we showed that pain spreads from proximal to distal sites and developed a biopsychosocial model that predicted the number of coexisting pain sites. This data-driven model was used to identify a risk score that classified various chronic pain conditions (area under the curve (AUC) 0.70-0.88) and pain-related medical conditions (AUC 0.67-0.86). In longitudinal analyses, the risk score predicted the development of widespread chronic pain, the spreading of chronic pain across body sites and high-impact pain about 9 years later (AUC 0.68-0.78). Key risk factors included sleeplessness, feeling 'fed-up', tiredness, stressful life events and a body mass index >30. A simplified version of this score, named the risk of pain spreading, obtained similar predictive performance based on six simple questions with binarized answers. The risk of pain spreading was then validated in the Northern Finland Birth Cohort (n = 5,525) and the PREVENT-AD cohort (n = 178), obtaining comparable predictive performance. Our findings show that chronic pain conditions can be predicted from a common set of biopsychosocial factors, which can aid in tailoring research protocols, optimizing patient randomization in clinical trials and improving pain management.© 2023. The Author(s).",
+,20230803,,37461498,Effect of Parental Adverse Childhood Experiences on Intergenerational DNA Methylation Signatures.,Res Sq,"Adverse Childhood Experiences (ACEs) are events that occur before a child turns 18 years old that may cause trauma. In this study, the effect of cumulative ACEs experienced on human maternal DNA methylation (DNAm) was estimated while accounting for interaction with domains of ACEs in prenatal peripheral blood mononuclear cell samples from the Maternal and Developmental Risks from Environmental Stressors (MADRES) pregnancy cohort. The intergenerational transmission of ACE-associated DNAm was also explored used paired maternal and neonatal cord blood samples. Replication in buccal samples was explored in the Children's Health Study (CHS). We used a four-level categorical indicator variable for ACEs exposure: none (0 ACEs), low (1-3 ACEs), moderate (4-6 ACEs), and high (> 6 ACEs). Effects of ACEs on maternal DNAm (N = 240) were estimated using linear models. To evaluate evidence for intergenerational transmission, mediation analysis was used. Analysis of maternal samples displayed some shared but mostly distinct effects of ACEs on DNAm across low, moderate, and high ACEs categories.CLCN7andPTPRN2was associated with maternal DNAm in the low ACE group and this association replicated in the CHS. ACE-associated methylation was observed in maternal and neonatal profiles in theCOMTpromoter region, with some evidence of mediation by maternalCOMTmethylation. Specific genomic loci exhibited mutually exclusive maternal ACE effects on DNAm in either maternal or neonatal population. There is some evidence for an intergenerational effect of ACEs, supported by shared DNAm signatures in theCOMTgene across maternal-neonatal paired samples.",
+,20230803,,37430364,CimpleG: finding simple CpG methylation signatures.,Genome Biol,"DNA methylation signatures are usually based on multivariate approaches that require hundreds of sites for predictions. Here, we propose a computational framework named CimpleG for the detection of small CpG methylation signatures used for cell-type classification and deconvolution. We show that CimpleG is both time efficient and performs as well as top performing methods for cell-type classification of blood cells and other somatic cells, while basing its prediction on a single DNA methylation site per cell type. Altogether, CimpleG provides a complete computational framework for the delineation of DNAm signatures and cellular deconvolution.© 2023. The Author(s).",
+,20230803,,37443060,Stability selection enhances feature selection and enables accurate prediction of gestational age using only five DNA methylation sites.,Clin Epigenetics,"DNA methylation (DNAm) is robustly associated with chronological age in children and adults, and gestational age (GA) in newborns. This property has enabled the development of several epigenetic clocks that can accurately predict chronological age and GA. However, the lack of overlap in predictive CpGs across different epigenetic clocks remains elusive. Our main aim was therefore to identify and characterize CpGs that are stably predictive of GA.We applied a statistical approach called 'stability selection' to DNAm data from 2138 newborns in the Norwegian Mother, Father, and Child Cohort study. Stability selection combines subsampling with variable selection to restrict the number of false discoveries in the set of selected variables. Twenty-four CpGs were identified as being stably predictive of GA. Intriguingly, only up to 10% of the CpGs in previous GA clocks were found to be stably selected. Based on these results, we used generalized additive model regression to develop a new GA clock consisting of only five CpGs, which showed a similar predictive performance as previous GA clocks (R2 = 0.674, median absolute deviation = 4.4 days). These CpGs were in or near genes and regulatory regions involved in immune responses, metabolism, and developmental processes. Furthermore, accounting for nonlinear associations improved prediction performance in preterm newborns.We present a methodological framework for feature selection that is broadly applicable to any trait that can be predicted from DNAm data. We demonstrate its utility by identifying CpGs that are highly predictive of GA and present a new and highly performant GA clock based on only five CpGs that is more amenable to a clinical setting.© 2023. The Author(s).",
+,20230803,,37447167,Association of the DNA Methylation of Obesity-Related Genes with the Dietary Nutrient Intake in Children.,Nutrients,"The occurrence of obesity stems from both genetic and external influences. Despite thorough research and attempts to address it through various means such as dietary changes, physical activity, education, and medications, a lasting solution to this widespread problem remains elusive. Nutrients play a crucial role in various cellular processes, including the regulation of gene expression. One of the mechanisms by which nutrients can affect gene expression is through DNA methylation. This modification can alter the accessibility of DNA to transcription factors and other regulatory proteins, thereby influencing gene expression. Nutrients such as folate and vitamin B12 are involved in the one-carbon metabolism pathway, which provides the methyl groups necessary for DNA methylation. Studies have shown that the inadequate intake of these nutrients can lead to alterations in DNA methylation patterns. For this study, we aim to understand the differences in the association of the dietary intake between normal weight and overweight/obese children and between European American and African American children with the DNA methylation of the three genesNRF1,FTO, andLEPR. The research discovered a significant association between the nutritional intake of 6-10-years-old children, particularly the methyl donors present in their diet, and the methylation of theNRF1,FTO, andLEPRgenes. Additionally, the study emphasizes the significance of considering health inequalities, particularly family income and maternal education, when investigating the epigenetic impact of methyl donors in diet and gene methylation.",
+,20230803,,37495687,Evolutionary histories of breast cancer and related clones.,Nature,"Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.© 2023. The Author(s).",
+,20230803,,37443254,Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases.,Nat Genet,"Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+,20230803,,37468586,Organization of the human intestine at single-cell resolution.,Nature,"The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health1. The intesting has a length of over nine metres, along which there are differences in structure and function2. The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.© 2023. The Author(s).",
+,20230803,,37500728,Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer.,Nat Genet,"Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.© 2023. The Author(s).",
+,20230803,,37399400,Comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring.,Proc Natl Acad Sci U S A,"Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of thelargestcomprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop thefirstsupervised tissue deconvolution approach, a deep-learning-powered model,cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data,cfSortshowed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities ofcfSortwith two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated fromcfSortreflected the clinical outcomes of the patients. In summary, the tissue methylation atlas andcfSortenhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.",
+,20230803,,37496025,Short-term smoking cessation leads to a universal decrease in whole blood genomic DNA methylation in patients with a smoking history.,World J Surg Oncol,"Epigenetics is involved in various human diseases. Smoking is one of the most common environmental factors causing epigenetic changes. The DNA methylation changes and mechanisms after quitting smoking have yet to be defined. The present study examined the changes in DNA methylation levels before and after short-term smoking cessation and explored the potential mechanism.Whole blood and clinical data were collected from 8 patients before and after short-term smoking cessation, DNA methylation was assessed, and differentially methylated sites were analyzed, followed by a comprehensive analysis of the differentially methylated sites with clinical data. GO/KEGG enrichment and protein-protein interaction (PPI) network analyses identified the hub genes. The differentially methylated sites between former and current smokers in GSE50660 from the GEO database were detected by GEO2R. Then, a Venn analysis was carried out using the differentially methylated sites. GO/KEGG enrichment analysis was performed on the genes corresponding to the common DNA methylation sites, the PPI network was constructed, and hub genes were predicted. The enriched genes associated with the cell cycle were selected, and the pan-cancer gene expression and clinical significance in lung cancer were analyzed based on the TCGA database.Most genes showed decreased DNA methylation levels after short-term smoking cessation; 694 upregulated methylation CpG sites and 3184 downregulated methylation CpG sites were identified. The DNA methylation levels were altered according to the clinical data (body weight, expiratory, and tobacco dependence score). Enrichment analysis, construction of the PPI network, and pan-cancer analysis suggested that smoking cessation may affect various biological processes.Smoking cessation leads to epigenetic changes, mainly decreased in the decline of most DNA methylation levels. Bioinformatics further identified the biologically relevant changes after short-term smoking cessation.© 2023. The Author(s).",
+,20230803,,37495688,Rewiring cancer drivers to activate apoptosis.,Nature,"Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated7. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression8. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50of 1-10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+,20230803,,37409096,DNA methylation biomarkers distinguishing early-stage prostate cancer from benign prostatic hyperplasia.,Prostate Int,"DNA methylation markers are considered robust diagnostic features in various cancer types, as epigenetic marks are commonly altered during cancer progression. Differentiation between benign prostatic hyperplasia (BPH) and early-stage prostate cancer (PCa) is clinically difficult, relying on the information of the patient's symptoms or levels of prostate-specific antigen.A total of 42 PCa patients and 11 BPH patients were recruited. Genomic DNA was purified from tissues and used for the library preparation of the target-enriched methylome with enzymatic conversion and a Twist 85 Mbp EM-seq panel. Paired-end sequencing (150 bp) was performed using NovaSeq 6000 or NextSeq 550. After quality control, including adapter trimming and de-duplication of raw sequencing data, differential methylation patterns were analyzed between the BPH and PCa groups.We report DNA methylation patterns existing between BPH and PCa. The major finding is that broad hypermethylation occurred at genic loci in PCa tissues as compared to the BPH. Gene ontology analysis suggested that hypermethylation of genic loci involved in chromatin and transcriptional regulation is involved in cancer progression. We also compared PCa tissues with high Gleason scores to tissues with low Gleason scores. The high-Gleason PCa tissues showed hundreds of focal differentially methylated CpG sites corresponding to genes functioning in cancer cell proliferation or metastasis. This suggests that dissecting early-to-advanced-grade cancer stages requires an in-depth analysis of differential methylation at the single CpG site level.Our study reports that enzymatic methylome sequencing data can be used to distinguish PCa from BPH and advanced PCa from early-stage PCa. The stage-specific methylation patterns in this study will be valuable resources for diagnostic purposes as well as further development of liquid biopsy approaches for the early detection of PCa.© 2023 The Asian Pacific Prostate Society. Published by Elsevier B.V.",
+,20230803,,37508326,Deep Learning Techniques with Genomic Data in Cancer Prognosis: A Comprehensive Review of the 2021-2023 Literature.,Biology (Basel),"Deep learning has brought about a significant transformation in machine learning, leading to an array of novel methodologies and consequently broadening its influence. The application of deep learning in various sectors, especially biomedical data analysis, has initiated a period filled with noteworthy scientific developments. This trend has majorly influenced cancer prognosis, where the interpretation of genomic data for survival analysis has become a central research focus. The capacity of deep learning to decode intricate patterns embedded within high-dimensional genomic data has provoked a paradigm shift in our understanding of cancer survival. Given the swift progression in this field, there is an urgent need for a comprehensive review that focuses on the most influential studies from 2021 to 2023. This review, through its careful selection and thorough exploration of dominant trends and methodologies, strives to fulfill this need. The paper aims to enhance our existing understanding of applications of deep learning in cancer survival analysis, while also highlighting promising directions for future research. This paper undertakes aims to enrich our existing grasp of the application of deep learning in cancer survival analysis, while concurrently shedding light on promising directions for future research in this vibrant and rapidly proliferating field.",
+,20230810,,37550724,Global effects of identity and aging on the human sperm methylome.,Clin Epigenetics,"As the average age of fatherhood increases worldwide, so too does the need for understanding effects of aging in male germline cells. Molecular change, including epigenomic alterations, may impact offspring. Age-associated change to DNA cytosine methylation in the cytosine-guanine (CpG) context is a hallmark of aging tissues, including sperm. Prior studies have led to accurate models that predict a man's age based on specific methylation features in the DNA of sperm, but the relationship between aging and global DNA methylation in sperm remains opaque. Further clarification requires a more complete survey of the methylome with assessment of variability within and between individuals.We collected sperm methylome data in a longitudinal study of ten healthy fertile men. We used whole-genome bisulfite sequencing of samples collected 10 to 18 years apart from each donor. We found that, overall, variability between donors far exceeds age-associated variation. After controlling for donor identity, we see significant age-dependent genome-wide change to the methylome. Notably, trends of change with age depend on genomic location or annotation, with contrasting signatures that correlate with gene density and proximity to centromeres and promoter regions.We uncovered epigenetic signatures that reflect a stable process which begins in early adulthood, progressing steadily through most of the male lifespan, and warrants consideration in any future study of the aging sperm epigenome.© 2023. BioMed Central Ltd., part of Springer Nature.",
+,20230810,,37550674,Long-term exposure to ambient fine particulate components and leukocyte epigenome-wide DNA Methylation in older men: the Normative Aging Study.,Environ Health,"Epigenome-wide association studies of ambient fine particulate matter (PM2.5) have been reported. However, few have examined PM2.5components (PMCs) and sources or included repeated measures. The lack of high-resolution exposure measurements is the key limitation. We hypothesized that significant changes in DNA methylation might vary by PMCs and the sources.We predicted the annual average of 14 PMCs using novel high-resolution exposure models across the contiguous U.S., between 2000-2018. The resolution was 50 m × 50 m in the Greater Boston Area. We also identified PM2.5sources using positive matrix factorization. We repeatedly collected blood samples and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip in the Normative Aging Study. We then used median regression with subject-specific intercepts to estimate the associations between long-term (one-year) exposure to PMCs / PM2.5sources and DNA methylation at individual cytosine-phosphate-guanine CpG sites. Significant probes were identified by the number of independent degrees of freedom approach, using the number of principal components explaining > 95% of the variation of the DNA methylation data. We also performed regional and pathway analyses to identify significant regions and pathways.We included 669 men with 1,178 visits between 2000-2013. The subjects had a mean age of 75 years. The identified probes, regions, and pathways varied by PMCs and their sources. For example, iron was associated with 6 probes and 6 regions, whereas nitrate was associated with 15 probes and 3 regions. The identified pathways from biomass burning, coal burning, and heavy fuel oil combustion sources were associated with cancer, inflammation, and cardiovascular diseases, whereas there were no pathways associated with all traffic.Our findings showed that the effects of PM2.5on DNAm varied by its PMCs and sources.© 2023. BioMed Central Ltd., part of Springer Nature.",
+,20230810,,37549439,Epigenetic modifications appear in the human placenta following anxiety and depression during pregnancy.,Placenta,"The future health of the offspring can be influenced by longstanding maternal anxiety and depression disorders during pregnancy. The present study aimed to explore the effect of psychiatric disorders during pregnancy on placental epigenetics.We measured DNA methylation patterns in term-placentas of women either suffering longstanding anxiety and depression symptoms (Index group, with overt symptoms), or a healthy population (Control, none/only mild symptoms). Whole genome DNA methylation profiling was performed using the TruSeq® Methyl Capture EPIC Library Prep Kit (Illumina, San Diego, CA, USA) for library preparation and NGS technology for genomic DNA sequencing.The results of high-throughput DNA methylation analysis revealed that the Index group had differential DNA methylation at epigenome-wide significance (p < 0.05) in 226 genes in the placenta. Targeted enrichment analyses identified hypermethylation of genes associated with psychiatric disorders (BRINP1, PUM1), and ion homeostasis (COMMD1), among others. The ECM (extracellular matrix)-receptor interaction pathway was significantly dysregulated in the Index group compared to the Control. In addition, DNA methylation/mRNA integration analyses revealed that four genes with key roles in neurodevelopment and other important processes (EPB41L4B, BMPR2, KLHL18, and UBAP2) were dysregulated at both, DNA methylation and transcriptome levels in the Index group compared to Control.The presented results increase our understanding of how maternal psychiatric disorders may affect the newborn through placental differential epigenome, suggesting DNA methylation status as a biomarker when aiming to design new preventive techniques and interventions.Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.",
+,20230810,,37546994,Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.,medRxiv,"Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at > 700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold-changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical predictor in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.",
+,20230810,,37546290,Offspring epigenetic markers at birth related to gestational BMI predict offspring BMI-trajectories from infancy to 26 years.,Obes Sci Pract,"To date, epigenetic studies identified differential DNA methylation (DNAm) related to gestational-body mass index (BMI) in offspring at birth. This study investigated whether the identified DNAm in offspring were also associated with BMI trajectories from infancy to age 26 years.Data of 794 participants from Isle of Wight birth cohort in UK were investigated to study association between BMI trajectories and DNAm related to gestational-BMI at birth. Multinominal logistic regression models were applied to test the association between 1090 DNAm sites reported in three prior epigenome-wide association studies and BMI trajectories.DNAm site cg23089913 (NANOS1) and cg13217064 (SOX14) were associated with early persistent obesity (EPO) and delayed overweight (DOW) trajectories respectively. A higher methylation of cg23089913 showed low odds of being in EPO trajectory (OR: 0.84; 95% CI: 0.76-0.93) while higher methylation of cg13217064 resulted in 1.4-times the odds of being in DOW trajectory when compared to the normal trajectory [Correction added on 22 February 2023, after first online publication: Range of the DNAm site cg23089913 has been changed from 'lower' to 'higher' in the preceding sentence.]. In a gender-stratified analysis, the odds of developing into DOW was 1.8 times in female participants for cg13217064 while not such association was observed in males.Deviations in methylation of cg23089913 (NANOS1) and cg13217064 (SOX14) in newborns may change the risk of having excess body weight.© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.",
+,20230810,,37542143,Identification of novel hypermethylated or hypomethylated CpG sites and genes associated with anthracycline-induced cardiomyopathy.,Sci Rep,"Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at 'CpG' sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case-control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe 'cg15939386' in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy.© 2023. Springer Nature Limited.",
+,20230810,,37537185,Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes.,Nat Commun,"The genome-wide DNA methylation profile, or DNA methylome, is a critical component of the overall epigenomic landscape that modulates gene activities and cell fate. Single-cell DNA methylomic studies offer unprecedented resolution for detecting and profiling cell subsets based on methylomic features. However, existing single-cell methylomic technologies are based on use of tubes or well plates and these platforms are not easily scalable for handling a large number of single cells. Here we demonstrate a droplet-based microfluidic technology, Drop-BS, to construct single-cell bisulfite sequencing libraries for DNA methylome profiling. Drop-BS takes advantage of the ultrahigh throughput offered by droplet microfluidics to prepare bisulfite sequencing libraries of up to 10,000 single cells within 2 days. We apply the technology to profile mixed cell lines, mouse and human brain tissues to reveal cell type heterogeneity. Drop-BS offers a promising solution for single-cell methylomic studies requiring examination of a large cell population.© 2023. Springer Nature Limited.",
+,20230810,,37533639,EpiMix is an integrative tool for epigenomic subtyping using DNA methylation.,Cell Rep Methods,"DNA methylation (DNAme) is a major epigenetic factor influencing gene expression with alterations leading to cancer and immunological and cardiovascular diseases. Recent technological advances have enabled genome-wide profiling of DNAme in large human cohorts. There is a need for analytical methods that can more sensitively detect differential methylation profiles present in subsets of individuals from these heterogeneous, population-level datasets. We developed an end-to-end analytical framework named ""EpiMix"" for population-level analysis of DNAme and gene expression. Compared with existing methods, EpiMix showed higher sensitivity in detecting abnormal DNAme that was present in only small patient subsets. We extended the model-based analyses of EpiMix tocis-regulatory elements within protein-coding genes, distal enhancers, and genes encoding microRNAs and long non-coding RNAs (lncRNAs). Using cell-type-specific data from two separate studies, we discover epigenetic mechanisms underlying childhood food allergy and survival-associated, methylation-driven ncRNAs in non-small cell lung cancer.© 2023 The Author(s).",
+,20230810,,37533055,DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study.,Clin Epigenetics,"The potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (< 17 years) type 1 diabetes cohort, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (n = 368 with DNA and no CVD at baseline), both overall and separately by glycemic exposure, as measured by HbA1c at baseline (split at the median: < 8.9% and ≥ 8.9%). We also assessed whether DNAm-CVD associations were independent of established cardiometabolic risk factors, including body mass index, estimated glucose disposal rate, cholesterol, triglycerides, blood pressure, pulse rate, albumin excretion rate, and estimated glomerular filtration rate.CVD (first instance of CVD death, myocardial infarction, coronary revascularization, ischemic ECG, angina, or stroke) developed in 172 participants (46.7%) over 28 years. Overall, in Cox regression models for time to CVD, none of the 683,597 CpGs examined reached significance at a false discovery rate (FDR) ≤ 0.05. In participants with HbA1c < 8.9% (n = 180), again none reached FDR ≤ 0.05, but three were associated at the a priori nominal significance level FDR ≤ 0.10: cg07147033 in MIB2, cg12324048 (intergenic, chromosome 3), and cg15883830 (intergenic, chromosome 1). In participants with HbA1c ≥ 8.9% (n = 188), two CpGs in loci involved in calcium channel activity were significantly associated with CVD (FDR ≤ 0.05): cg21823999 in GPM6A and cg23621817 in CHRNA9; four additional CpGs were nominally associated (FDR ≤ 0.10). In participants with HbA1c ≥ 8.9%, DNAm-CVD associations were only modestly attenuated after cardiometabolic risk factor adjustment, while attenuation was greater in those with HbA1c < 8.9%. No pathways were enriched in those with HbA1c < 8.9%, while pathways for calcium channel activity and integral component of synaptic membrane were significantly enriched in those with HbA1c ≥ 8.9%.These results provide novel evidence that DNAm at loci involved in calcium channel activity and development may contribute to long-term CVD risk beyond known risk factors in type 1 diabetes, particularly in individuals with greater glycemic exposure, warranting further study.© 2023. The Author(s).",
+,20230810,,37529779,Epigenetic associations with adolescent grey matter maturation and cognitive development.,Front Genet,"Introduction:Adolescence, a critical phase of human neurodevelopment, is marked by a tremendous reorganization of the brain and accompanied by improved cognitive performance. This development is driven in part by gene expression, which in turn is partly regulated by DNA methylation (DNAm).Methods:We collected brain imaging, cognitive assessments, and DNAm in a longitudinal cohort of approximately 200 typically developing participants, aged 9-14. This data, from three time points roughly 1 year apart, was used to explore the relationships between seven cytosine-phosphate-guanine (CpG) sites in genes highly expressed in brain tissues (GRIN2D,GABRB3,KCNC1,SLC12A9,CHD5,STXBP5, andNFASC), seven networks of grey matter (GM) volume change, and scores from seven cognitive tests.Results:The demethylation of the CpGs as well as the rates of change in DNAm were significantly related to improvements in total, crystalized, and fluid cognition scores, executive function, episodic memory, and processing speed, as well as several networks of GM volume increases and decreases that highlight typical patterns of brain maturation.Discussion:Our study provides a first look at the DNAm of genes involved in myelination, excitatory and inhibitory receptors, and connectivity, how they are related to the large-scale changes occurring in the brain structure as well as cognition during adolescence.Copyright © 2023 Jensen, Chen, Turner, Stephen, Wang, Wilson, Calhoun and Liu.",
+,20230810,,37550624,Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases.,Clin Proteomics,"Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance.We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins.We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F).Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.© 2023. BioMed Central Ltd., part of Springer Nature.",
+,20230810,,37537391,Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development.,J Hum Genet,"Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.© 2023. The Author(s).",
+,20230810,,37542162,Methylome-wide association study of anxiety disorders.,Mol Psychiatry,"Anxiety Disorders (ANX) such as panic disorder, generalized anxiety disorder, and phobias, are highly prevalent conditions that are moderately heritable. Evidence suggests that DNA methylation may play a role, as it is involved in critical adaptations to changing environments. Applying an enrichment-based sequencing approach covering nearly 28 million autosomal CpG sites, we conducted a methylome-wide association study (MWAS) of lifetime ANX in 1132 participants (618 cases/514 controls) from the Netherlands Study of Depression and Anxiety. Using epigenomic deconvolution, we performed MWAS for the main cell types in blood: granulocytes, T-cells, B-cells and monocytes. Cell-type specific analyses identified 280 and 82 methylome-wide significant associations (q-value < 0.1) in monocytes and granulocytes, respectively. Our top finding in monocytes was located in ZNF823 on chromosome 19 (p = 1.38 × 10-10) previously associated with schizophrenia. We observed significant overlap (p < 1 × 10-06) with the same direction of effect in monocytes (210 sites), T-cells (135 sites), and B-cells (727 sites) between this Discovery MWAS signal and a comparable replication dataset from the Great Smoky Mountains Study (N = 433). Overlapping Discovery-Replication MWAS signal was enriched for findings from published GWAS of ANX, major depression, and post-traumatic stress disorder. In monocytes, two specific sites in the FZR1 gene showed significant replication after Bonferroni correction with an additional 15 nominally replicated sites in monocytes and 4 in T-cells. FZR1 regulates neurogenesis in the hippocampus, and its knockout leads to impairments in associative fear memory and long-term potentiation in mice. In the largest and most extensive methylome-wide study of ANX, we identified replicable methylation sites located in genes of potential relevance for brain mechanisms of psychiatric conditions.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+,20230810,,37542161,Prenatal exposure to environmental air pollution and psychosocial stress jointly contribute to the epigenetic regulation of the serotonin transporter gene in newborns.,Mol Psychiatry,"Antenatal exposures to maternal stress and to particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5) have been independently associated with developmental outcomes in early infancy and beyond. Knowledge about their joint impact, biological mechanisms of their effects and timing-effects, is still limited. Both PM2.5and maternal stress exposure during pregnancy might result in altered patterns of DNA methylation in specific stress-related genes, such as the serotonin transporter gene (SLC6A4 DNAm), that might, in turn, influence infant development across several domains, including bio-behavioral, cognitive and socio-emotional domains. Here, we investigated the independent and interactive influence of variations in antenatal exposures to maternal pandemic-related stress (PRS) and PM2.5on SLC6A4 DNAm levels in newborns. Mother-infant dyads (N = 307) were enrolled at delivery during the COVID-19 pandemic. Infants' methylation status was assessed in 13 CpG sites within the SLC6A4 gene's region (chr17:28562750-28562958) in buccal cells at birth and women retrospectively report on PRS. PM2.5exposure throughout the entire gestation and at each gestational trimester was estimated using a spatiotemporal model based on residential address. Among several potentially confounding socio-demographic and health-related factors, infant's sex was significantly associated with infants' SLC6A4 DNAm levels, thus hierarchical regression models were adjusted for infant's sex. Higher levels of SLC6A4 DNAm at 6 CpG sites were found in newborns born to mothers reporting higher levels of antenatal PRS and greater PM2.5 exposure across gestation, while adjusting for infant's sex. These effects were especially evident when exposure to elevated PM2.5occurred during the second trimester of pregnancy. Several important brain processes (e.g., synaptogenesis and myelination) occur during mid-pregnancy, potentially making the second trimester a sensitive time window for the effects of stress-related exposures. Understanding the interplay between environmental and individual-level stressors has important implications for the improvement of mother-infant health during and after the pandemic.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+,20230810,,37503119,The ENCODE Uniform Analysis Pipelines.,Res Sq,"The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of theHomo sapiensandMus musculusgenomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and available via the ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL; https://openwdl.org/) is publicly available in GitHub, with images available on Dockerhub (https://hub.docker.com), enabling access to a diverse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environments via Cromwell. Access to the pipelines and data via the cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses.",
+,20230810,,37553611,The application of long-read sequencing in clinical settings.,Hum Genomics,"Long-read DNA sequencing technologies have been rapidly evolving in recent years, and their ability to assess large and complex regions of the genome makes them ideal for clinical applications in molecular diagnosis and therapy selection, thereby providing a valuable tool for precision medicine. In the third-generation sequencing duopoly, Oxford Nanopore Technologies and Pacific Biosciences work towards increasing the accuracy, throughput, and portability of long-read sequencing methods while trying to keep costs low. These trades have made long-read sequencing an attractive tool for use in research and clinical settings. This article provides an overview of current clinical applications and limitations of long-read sequencing and explores its potential for point-of-care testing and health care in remote settings.© 2023. BioMed Central Ltd., part of Springer Nature.",
+,20230810,,37440569,Size matters: Fighting repeat expansion size in fragile X syndrome using antisense oligonucleotides.,Proc Natl Acad Sci U S A,NA,
+,20230810,,37537179,Segmenting functional tissue units across human organs using community-driven development of generalizable machine learning algorithms.,Nat Commun,"The development of a reference atlas of the healthy human body requires automated image segmentation of major anatomical structures across multiple organs based on spatial bioimages generated from various sources with differences in sample preparation. We present the setup and results of the Hacking the Human Body machine learning algorithm development competition hosted by the Human Biomolecular Atlas (HuBMAP) and the Human Protein Atlas (HPA) teams on the Kaggle platform. We create a dataset containing 880 histology images with 12,901 segmented structures, engaging 1175 teams from 78 countries in community-driven, open-science development of machine learning models. Tissue variations in the dataset pose a major challenge to the teams which they overcome by using color normalization techniques and combining vision transformers with convolutional models. The best model will be productized in the HuBMAP portal to process tissue image datasets at scale in support of Human Reference Atlas construction.© 2023. Springer Nature Limited.",
+,20230810,,37468819,"Cell 'atlases' offer unprecedented view of placenta, intestines and kidneys.",Nature,NA,
+No,20231019,epigenetics,37650641,Widespread effects of DNA methylation and intra-motif dependencies revealed by novel transcription factor binding models.,Nucleic Acids Res,"Several studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that show a binding behaviour associated with DNA methylation. Overall, we find that the presence of CpG methylation decreases the likelihood of binding for the majority of methylation-associated TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding. We illustrate that the novel methylation-aware TF binding models allow to predict differential ChIP-seq peaks and improve the genome-wide analysis of TF binding. Our work indicates that simplistic models that neglect the effect of DNA methylation on DNA binding may lead to systematic underperformance for methylation-associated TFs.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.",
+No,20231019,ctdna,37649326,Pan-cancer analysis of genome-wide methylation profiling discover type-specific markers targeting circulating free DNA for the detection of colorectal cancer.,Clin Transl Med,NA,
+No,20231019,methods,37641110,Evaluation of the pooled sample method in Infinium MethylationEPIC BeadChip array by comparison with individual samples.,Clin Epigenetics,"The pooled sample method is used in epigenomic research and expression analysis and is a cost-effective screening approach for small amounts of DNA. Evaluation of the pooled sample method in epigenomic studies is performed using the Illumina Infinium Methylation 450K BeadChip array; however, subsequent reports on the updated 850K array are lacking. A previous study demonstrated that the methylation levels obtained from individual samples were accurately replicated using pooled samples but did not address epigenome-wide association study (EWAS) statistics. The DNA quantification method, which is important for the homogeneous mixing of DNA in the pooled sample method, has since become fluorescence-based, and additional factors need to be considered including the resolution of batch effects of microarray chips and the heterogeneity of the cellular proportions from which the DNA samples are derived. In this study, four pooled samples were created from 44 individual samples, and EWAS statistics for differentially methylated positions (DMPs) and regions (DMRs) were conducted for individual samples and compared with the statistics obtained from the pooled samples.The methylation levels could be reproduced fairly well in the pooled samples. This was the case for the entire dataset and when limited to the top 100 CpG sites, consistent with a previous study using the 450K BeadChip array. However, the statistical results of the EWAS for the DMP by individual samples were not replicated in pooled samples. Qualitative analyses highlighting methylation within an arbitrary candidate gene were replicable. Focusing on chr 20, the statistical results of EWAS for DMR from individual samples showed replicability in the pooled samples as long as they were limited to regions with a sufficient effect size.The pooled sample method replicated the methylation values well and can be used for EWAS in DMR. This method is sample amount-effective and cost-effective and can be utilized for screening by carefully understanding the effective features and disadvantages of the pooled sample method and combining it with candidate gene analyses.© 2023. BioMed Central Ltd., part of Springer Nature.",
+Yes,20231019,ewas,37634000,Objective and subjective measures of sleep initiation are differentially associated with DNA methylation in adolescents.,Clin Epigenetics,"The onset of puberty is associated with a shift in the circadian timing of sleep, leading to delayed sleep initiation [i.e., later sleep onset time (SOT)] due to later bedtimes and/or longer sleep onset latency (SOL). Several genome-wide association studies (GWAS) have identified genes that may be involved in the etiology of sleep phenotypes. However, circadian rhythms are also epigenetically regulated; therefore, epigenetic biomarkers may provide insight into the physiology of the pubertal sleep onset shift and the pathophysiology of prolonged or delayed sleep initiation.The gene-wide analysis indicated differential methylation within or around 1818 unique genes across the sleep initiation measurements using self-report, actigraphy (ACT), and polysomnography (PSG), while GWAS-informed analysis yielded 67 genes. Gene hits were identified for bedtime (PSG), SOL (subjective, ACT and PSG) and SOT (subjective and PSG). DNA methylation within 12 genes was associated with both subjective and PSG-measured SOL, 31 with both ACT- and PSG-measured SOL, 19 with both subjective and ACT-measured SOL, and one gene (SMG1P2) had methylation sites associated with subjective, ACT- and PSG-measured SOL.Objective and subjective sleep initiation in adolescents is associated with altered DNA methylation in genes previously identified in adult GWAS of sleep and circadian phenotypes. Additionally, our data provide evidence for a potential epigenetic link between habitual (subjective and ACT) SOL and in-lab SOT and DNA methylation in and around genes involved in circadian regulation (i.e., RASD1, RAI1), cardiometabolic disorders (i.e., FADS1, WNK1, SLC5A6), and neuropsychiatric disorders (i.e., PRR7, SDK1, FAM172A). If validated, these sites may provide valuable targets for early detection and prevention of disorders involving prolonged or delayed SOT, such as insomnia, delayed sleep phase, and their comorbidity.© 2023. BioMed Central Ltd., part of Springer Nature.",
+Yes,20231019,ewas,37612641,"Maternal pre-pregnancy BMI, offspring epigenome-wide DNA methylation, and childhood obesity: findings from the Boston Birth Cohort.",BMC Med,"Maternal pre-pregnancy obesity is an established risk factor for childhood obesity. Investigating epigenetic alterations induced by maternal obesity during fetal development could gain mechanistic insight into the developmental origins of childhood obesity. While obesity disproportionately affects underrepresented racial and ethnic mothers and children in the USA, few studies investigated the role of prenatal epigenetic programming in intergenerational obesity of these high-risk populations.This study included 903 mother-child pairs from the Boston Birth Cohort, a predominantly urban, low-income minority birth cohort. Mother-infant dyads were enrolled at birth and the children were followed prospectively to age 18 years. Infinium Methylation EPIC BeadChip was used to measure epigenome-wide methylation level of cord blood. We performed an epigenome-wide association study of maternal pre-pregnancy body mass index (BMI) and cord blood DNA methylation (DNAm). To quantify the degree to which cord blood DNAm mediates the maternal BMI-childhood obesity, we further investigated whether maternal BMI-associated DNAm sites impact birthweight or childhood overweight or obesity (OWO) from age 1 to age 18 and performed corresponding mediation analyses.The study sample contained 52.8% maternal pre-pregnancy OWO and 63.2% offspring OWO at age 1-18 years. Maternal BMI was associated with cord blood DNAm at 8 CpG sites (genome-wide false discovery rate [FDR] < 0.05). After accounting for the possible interplay of maternal BMI and smoking, 481 CpG sites were discovered for association with maternal BMI. Among them 123 CpGs were associated with childhood OWO, ranging from 42% decrease to 87% increase in OWO risk for each SD increase in DNAm. A total of 14 identified CpG sites showed a significant mediation effect on the maternal BMI-child OWO association (FDR < 0.05), with mediating proportion ranging from 3.99% to 25.21%. Several of these 14 CpGs were mapped to genes in association with energy balance and metabolism (AKAP7) and adulthood metabolic syndrome (CAMK2B).This prospective birth cohort study in a high-risk yet understudied US population found that maternal pre-pregnancy OWO significantly altered DNAm in newborn cord blood and provided suggestive evidence of epigenetic involvement in the intergenerational risk of obesity.© 2023. BioMed Central Ltd., part of Springer Nature.",
+Yes,20231019,ewas,37609313,Epigenome-wide association study of incident type 2 diabetes in Black and White participants from the Atherosclerosis Risk in Communities Study.,medRxiv,"DNA methylation studies of incident type 2 diabetes in US populations are limited, and to our knowledge none included individuals of African descent living in the US. We performed an epigenome-wide association analysis of blood-based methylation levels at CpG sites with incident type 2 diabetes using Cox regression in 2,091 Black and 1,029 White individuals from the Atherosclerosis Risk in Communities study. At an epigenome-wide significance threshold of 10-7, we detected 7 novel diabetes-associated CpG sites inC1orf151(cg05380846: HR= 0.89,p= 8.4 Ă— 10-12),ZNF2(cg01585592: HR= 0.88,p= 1.6 Ă— 10-9),JPH3(cg16696007: HR= 0.87,p= 7.8 Ă— 10-9),GPX6(cg02793507: HR= 0.85,p= 2.7 Ă— 10-8and cg00647063: HR= 1.20,p= 2.5 Ă— 10-8), chr17q25 (cg16865890: HR= 0.8,p= 6.9 Ă— 10-8), and chr11p15 (cg13738793: HR= 1.11,p= 7.7 Ă— 10-8). The CpG sites atC1orf151,ZNF2, JPH3andGPX6, were identified in Black adults, chr17q25 was identified in White adults, and chr11p15 was identified upon meta-analyzing the two groups. The CpG sites atJPH3andGPX6were likely associated with incident type 2 diabetes independent of BMI. All the CpG sites, except atJPH3, were likely consequences of elevated glucose at baseline. We additionally replicated known type 2 diabetes-associated CpG sites including cg19693031 atTXNIP, cg00574958 atCPT1A, cg16567056 atPLBC2, cg11024682 atSREBF1, cg08857797 atVPS25, and cg06500161 atABCG1, 3 of which were replicated in Black adults at the epigenome-wide threshold. We observed modest increase in type 2 diabetes variance explained upon addition of the significantly associated CpG sites to a Cox model that included traditional type 2 diabetes risk factors and fasting glucose (increase from 26.2% to 30.5% in Black adults; increase from 36.9% to 39.4% in White adults). We examined if groups of proximal CpG sites were associated with incident type 2 diabetes using a gene-region specific and a gene-region agnostic differentially methylated region (DMR) analysis. Our DMR analyses revealed several clusters of significant CpG sites, including a DMR consisting of a previously discovered CpG site atADCY7and promoter regions ofTP63which were differentially methylated across all race groups. This study illustrates improved discovery of CpG sites/regions by leveraging both individual CpG site and DMR analyses in an unexplored population. Our findings include genes linked to diabetes in experimental studies (e.g.,GPX6,JPH3,andTP63), and future gene-specific methylation studies could elucidate the link between genes, environment, and methylation in the pathogenesis of type 2 diabetes.",
+Yes,20231019,ewas,37608375,Sexually dimorphic methylation patterns characterize the placenta and blood from extremely preterm newborns.,BMC Biol,"Health outcomes among children born prematurely are known to be sexually dimorphic, with male infants often more affected, yet the mechanism behind this observation is not clear. CpG methylation levels in the placenta and blood also differ by sex and are associated with adverse health outcomes. We contrasted CpG methylation levels in the placenta and neonatal blood (n = 358) from the Extremely Low Gestational Age Newborn (ELGAN) cohort based on the EPIC array, which assays over 850,000 CpG sites across the epigenome. Sex-specific epigenome-wide association analyses were conducted for the placenta and neonatal blood samples independently, and the results were compared to determine tissue-specific differences between the methylation patterns in males and females. All models were adjusted for cell type heterogeneity. Enrichment pathway analysis was performed to identify the biological functions of genes related to the sexually dimorphic CpG sites.Approximately 11,500 CpG sites were differentially methylated in relation to sex. Of these, 5949 were placenta-specific and 5361 were blood-specific, with only 233 CpG sites overlapping in both tissues. For placenta-specific CpG sites, 90% were hypermethylated in males. For blood-specific CpG sites, 95% were hypermethylated in females. In the placenta, keratinocyte differentiation biological pathways were enriched among the differentially methylated genes. No enrichment pathways were observed for blood.Distinct methylation patterns were observed between male and female children born extremely premature, and keratinocyte differentiation pathways were enriched in the placenta. These findings provide new insights into the epigenetic mechanisms underlying sexually dimorphic health outcomes among extremely premature infants.© 2023. BioMed Central Ltd., part of Springer Nature.",
+Yes,20231019,ewas,37598461,Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma.,EBioMedicine,"Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables.We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P < 7.94E-04) that can be explored as potential therapeutic targets.By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels.US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.",
+Yes,20231019,ewas,37589453,Epigenetic signature of human immune aging in the GESTALT study.,Elife,"Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood borne immune cell types (naïve B, naïve CD4+and CD8+T cells, granulocytes, monocytes and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousands of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In-silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1β) and REST transcription factor motifs respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to transcription factor motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.",
+Yes,20231019,ewas,37587247,"Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response.",Mol Psychiatry,"Obsessive-compulsive disorder (OCD) is a prevalent mental disorder affecting ~2-3% of the population. This disorder involves genetic and, possibly, epigenetic risk factors. The dynamic nature of epigenetics also presents a promising avenue for identifying biomarkers associated with symptom severity, clinical progression, and treatment response in OCD. We, therefore, conducted a comprehensive case-control investigation using Illumina MethylationEPIC BeadChip, encompassing 185 OCD patients and 199 controls recruited from two distinct sites in Germany. Rigorous clinical assessments were performed by trained raters employing the Structured Clinical Interview for DSM-IV (SCID-I). We performed a robust two-step epigenome-wide association study that led to the identification of 305 differentially methylated CpG positions. Next, we validated these findings by pinpointing the optimal set of CpGs that could effectively classify individuals into their respective groups. This approach identified a subset comprising 12 CpGs that overlapped with the 305 CpGs identified in our EWAS. These 12 CpGs are close to or in genes associated with the sweet-compulsive brain hypothesis which proposes that aberrant dopaminergic transmission in the striatum may impair insulin signaling sensitivity among OCD patients. We replicated three of the 12 CpGs signals from a recent independent study conducted on the Han Chinese population, underscoring also the cross-cultural relevance of our findings. In conclusion, our study further supports the involvement of epigenetic mechanisms in the pathogenesis of OCD. By elucidating the underlying molecular alterations associated with OCD, our study contributes to advancing our understanding of this complex disorder and may ultimately improve clinical outcomes for affected individuals.© 2023. The Author(s).",
+No,20231019,dnamage,37563670,Introduction of a multiplex amplicon sequencing assay to quantify DNA methylation in target cytosine markers underlying four selected epigenetic clocks,Clin Epigenetics,"DNA methylation analysis has proven to be a powerful tool for age assessment. However, the implementation of epigenetic age prediction in diagnostics or routine forensic casework requires appropriate laboratory methods. In this study, we aimed to compare the performance of large-scale DNA methylation analysis protocols that show promise in terms of accuracy, throughput, multiplexing capacity, and high sensitivity.The protocols were designed to target a predefined panel of 161 genomic CG/CA sites from four known estimators of epigenetic age-related parameters, optimized and validated using artificially methylated controls or blood samples. We successfully targeted 96% of these loci using two enrichment protocols: Ion AmpliSeq™, an amplicon-based method integrated with Ion Torrent S5, and SureSelectXTMethyl-Seq, a hybridization-based method followed by MiSeq FGx sequencing. Both protocols demonstrated high accuracy and robustness. Although hybridization assays have greater multiplexing capabilities, the best overall performance was observed for the amplicon-based protocol with the lowest variability in DNA methylation at 25 ng of starting DNA, mean observed marker coverage of ~ 6.7 k reads, and accuracy of methylation quantification with a mean absolute difference between observed and expected methylation beta value of 0.054. The Ion AmpliSeq method correlated strongly with genome-scale EPIC microarray data (R = 0.91) and showed superiority in terms of methylation measurement accuracy. Method-to-method bias was accounted for by the use of linear transformation, which provided a highly accurate prediction of calendar age with a mean absolute error of less than 5 years for the VISAGE and Hannum age clocks used. The pace of aging (PoAm) and the mortality risk score (MRS) estimators included in our panel represent next-generation clocks, were found to have low to moderate correlations with the VISAGE and Hannum models (R < 0.75), and thus may capture different aspects of epigenetic aging.We propose a laboratory tool that allows the quantification of DNA methylation in cytosines underlying four different clocks, thus providing broad information on epigenetic aging while maintaining a reasonable number of CpG markers, opening the way to a wide range of applications in forensics, medicine, and healthcare.© 2023. BioMed Central Ltd., part of Springer Nature.",
+No,20231019,eqtm,37563237,Expression quantitative trait methylation analysis elucidates gene regulatory effects of DNA methylation: the Framingham Heart Study.,Sci Rep,"Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p < 1E-7 where the top most significant eGenes (i.e., gene transcripts associated with a CpG) were enriched in biological pathways related to cell signaling, and for 1208 clinical traits (enrichment false discovery rate [FDR] ≤ 0.05). We also identified 246,667 significant trans CpG-transcript pairs at p < 1E-14 where the top most significant eGenes were enriched in biological pathways related to activation of the immune response, and for 1191 clinical traits (enrichment FDR ≤ 0.05). Independent and external replication of the top 1000 significant cis and trans CpG-transcript pairs was completed in the Women's Health Initiative and Jackson Heart Study cohorts. Using significant cis CpG-transcript pairs, we identified significant mediation of the association between CpG sites and cardiometabolic traits through gene expression and identified shared genetic regulation between CpGs and transcripts associated with cardiometabolic traits. In conclusion, we developed a robust and powerful resource of whole blood eQTM CpG-transcript pairs that can help inform future functional studies that seek to understand the molecular basis of disease.© 2023. Springer Nature Limited.",
+No,20231019,ctdna,37500728,Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer,Nat Genet,"Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.",
+Yes,20231019,ewas,37630812,Plasma One-Carbon Metabolism-Related Micronutrients and the Risk of Breast Cancer: Involvement of DNA Methylation.,Nutrients,"Findings of epidemiologic studies focusing on the association between one-carbon metabolism-related micronutrients and breast cancer risk, along with the involvement of DNA methylation, have been inconsistent and incomprehensive. We conducted a case-control study in China including 107 paired participants and comprehensively detected 12 plasma one-carbon metabolism-related micronutrients. Genomic DNA methylation was measured using an 850 K chip and differential methylation probes (DMPs) were identified. Multivariate logistic regression was performed to estimate the associations between plasma micronutrients and the odds of breast cancer. The mediation of selected DMPs in micronutrient breast cancer associations was examined using mediation analyses. An inverse association of plasma folate, methionine cycling-related micronutrients (methionine, S-adenosylmethionine, and S-adenosylhomocysteine), and all micronutrients in the choline metabolism and enzymatic factor groups, and a positive association of methionine cycling-related cysteine with breast cancer risk were observed. Nine micronutrients (methionine, cysteine, SAM, folate, choline, betaine, P5P, vitamins B2, and B12) were related to global or probe-specific methylation levels (p< 0.05). The selected DMPs mediated the micronutrient breast cancer associations with an average mediation proportion of 36.43%. This study depicted comprehensive associations between circulating one-carbon metabolism-related micronutrients and breast cancer risk mediated by DNA methylation.",
+No,20231019,dnamage,37597113,Insights into ageing rates comparison across tissues from recalibrating cerebellum DNA methylation clock.,Geroscience,"DNA methylation (DNAm)-based age clocks have been studied extensively as a biomarker of human ageing and a risk factor for age-related diseases. Despite different tissues having vastly different rates of proliferation, it is still largely unknown whether they age at different rates. It was previously reported that the cerebellum ages slowly; however, this claim was drawn from a single clock using a relatively small sample size and so warrants further investigation. We collected the largest cerebellum DNAm dataset (N = 752) to date. We found the respective epigenetic ages are all severely underestimated by six representative DNAm age clocks, with the underestimation effects more pronounced in the four clocks whose training datasets do not include brain-related tissues. We identified 613 age-associated CpGs in the cerebellum, which accounts for only 14.5% of the number found in the middle temporal gyrus from the same population (N = 404). From the 613 cerebellum age-associated CpGs, we built a highly accurate age prediction model for the cerebellum named CerebellumClockspecific(Pearson correlation=0.941, MAD=3.18 years). Ageing rate comparisons based on the two tissue-specific clocks constructed on the 201 overlapping age-associated CpGs support the cerebellum has younger DNAm age. Nevertheless, we built BrainCortexClock to prove a single DNAm clock is able to unbiasedly estimate DNAm ages of both cerebellum and cerebral cortex, when they are adequately and equally represented in the training dataset. Comparing ageing rates across tissues using DNA methylation multi-tissue clocks is flawed. The large underestimation of age prediction for cerebellums by previous clocks mainly reflects the improper usage of these age clocks. There exist strong and consistent ageing effects on the cerebellar methylome, and we suggest the smaller number of age-associated CpG sites in cerebellum is largely attributed to its extremely low average cell replication rates.© 2023. The Author(s).",
+No,20231019,dnamage,37609328,Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction,bioRxiv,"Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro-to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.",
+No,20231019,dnamage,37576443,Psychological Stress and Epigenetic Aging in Older Men: The VA Normative Aging Study.,Transl Med Aging,"Psychological stress remains an important risk factor for morbidity and mortality throughout the life course. However, there have been counterintuitive findings reported in previous studies of older persons that examine the relationships of perceived psychological stress with DNA methylation-based markers of aging, which also serve as predictors of morbidity and mortality (epigenetic age/clocks). We aimed to replicate and expand findings from existing work by examining relationships of self-reported stress with nine epigenetic clocks: Hannum, Horvath, Intrinsic, Extrinsic, SkinBloodClock, PhenoAge, GrimAge, DNAm Telomere Length, and Pace of Aging. We analyzed data from 607 male participants (mean age 73.2 years) of the VA Normative Aging Study with one to two study visits from 1999 to 2007 (observations = 956). Stress was assessed via the 14-item Perceived Stress Scale (PSS). Epigenetic age was calculated from DNA methylation measured in leukocytes with the HumanMethylation450 BeadChip. In linear mixed effects models adjusted for demographic/lifestyle/health factors, a standard deviation (sd) increase in PSS was associated with Horvath (β = -0.35-years, 95%CI: -0.61, -0.09,P=0.008) and Intrinsic (β = -0.40-years, 95%CI: -0.67, -0.13,P=0.004) epigenetic age deceleration. However, in models limited to participants with the highest levels of stress (≥ 75th-percentile), Horvath (β = 2.29-years, 95%CI: 0.16, 4.41,P=0.04) and Intrinsic (β = 2.06-years, 95%CI: -0.17, 4.28,P=0.07) age acceleration associations were observed. Our results reinforce the complexity of psychological stress and epigenetic aging relationships and lay a foundation for future studies that explore longitudinal relationships with other adult stress metrics and factors that can influence stress such as resilience measures.",
+No,20231019,dnamage,37564905,Epigenetic clocks and research implications of the lack of data on whom they have been developed: a review of reported and missing sociodemographic characteristics,Environ Epigenet,"Epigenetic clocks are increasingly being used as a tool to assess the impact of a wide variety of phenotypes and exposures on healthy ageing, with a recent focus on social determinants of health. However, little attention has been paid to the sociodemographic characteristics of participants on whom these clocks have been based. Participant characteristics are important because sociodemographic and socioeconomic factors are known to be associated with both DNA methylation variation and healthy ageing. It is also well known that machine learning algorithms have the potential to exacerbate health inequities through the use of unrepresentative samples - prediction models may underperform in social groups that were poorly represented in the training data used to construct the model. To address this gap in the literature, we conducted a review of the sociodemographic characteristics of the participants whose data were used to construct 13 commonly used epigenetic clocks. We found that although some of the epigenetic clocks were created utilizing data provided by individuals from different ages, sexes/genders, and racialized groups, sociodemographic characteristics are generally poorly reported. Reported information is limited by inadequate conceptualization of the social dimensions and exposure implications of gender and racialized inequality, and socioeconomic data are infrequently reported. It is important for future work to ensure clear reporting of tangible data on the sociodemographic and socioeconomic characteristics of all the participants in the study to ensure that other researchers can make informed judgements about the appropriateness of the model for their study population.© The Author(s) 2023. Published by Oxford University Press.",
+No,20231019,dnamage,37563227,Universal DNA methylation age across mammalian tissues,Nat Aging,"Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.© 2023. The Author(s).",
+No,20231019,epigenetics,37660134,Epigenetic inheritance is unfaithful at intermediately methylated CpG sites.,Nat Commun,"DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform high-throughput bisulfite sequencing on clonally derived somatic cell lines to quantitatively measure methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity, and is not coordinately maintained between neighbouring sites. We determine that the probabilistic changes that occur at intermediately methylated sites are likely due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the current epigenetic inheritance model and has direct implications for both the functional relevance and general interpretability of DNA methylation as a stable epigenetic mark.© 2023. Springer Nature Limited.",
+No,20231019,pqtl,37563310,Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets,Nat Immunol,"Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.© 2023. The Author(s).",
+Yes,20231019,ewas,37587191,Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function,Commun Biol,"Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.© 2023. The Author(s).",
+No,20231019,omics,37604891,Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits,Nat Commun,"We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.© 2023. Springer Nature Limited.",
+No,20231019,epigenetics,37626340,The inactive X chromosome accumulates widespread epigenetic variability with age.,Clin Epigenetics,"Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women.We analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males (Illumina 450k methylation array) and replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variably methylated CpGs (aVMCs), whose methylation level becomes more variable with age.In females, aDMCs were relatively uncommon (n = 33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n = 987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (94%), indicating an independence of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI suggesting that they stemmed from the inactive X. In males, carrying an active copy of the X chromosome only, aDMCs (n = 316) were primarily driven by cell composition, while aVMCs replicated well (95%) but were infrequent (n = 37).Our results imply that age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.© 2023. BioMed Central Ltd., part of Springer Nature.",
+Yes,20231019,ewas,37596607,Association between acetaminophen metabolites and CYP2E1 DNA methylation level in neonate cord blood in the Boston Birth Cohort.,Clin Epigenetics,"Acetaminophen is a commonly used medication by pregnant women and is known to cross the placenta. However, little is known about the biological mechanisms that regulate acetaminophen in the developing offspring. Cytochrome 2E1 (CYP2E1) is the primary enzyme responsible for the conversion of acetaminophen to its toxic metabolite. Ex vivo studies have shown that the CYP2E1 gene expression in human fetal liver and placenta is largely controlled by DNA methylation (DNAm) at CpG sites located in the gene body of CYP2E1 at the 5' end. To date, no population studies have examined the association between acetaminophen metabolite and fetal DNAm of CYP2E1 at birth.We utilized data from the Boston Birth Cohort (BBC) which represents an urban, low-income, racially and ethnically diverse population in Boston, Massachusetts. Acetaminophen metabolites were measured in the cord plasma of newborns enrolled in BBC between 2003 and 2013 using liquid chromatography-tandem mass spectrometry. DNAm at 28 CpG sites of CYP2E1 was measured by Illumina Infinium MethylationEPIC BeadChip. We used linear regression to identify differentially methylated CpG sites and the ""DiffVar"" method to identify differences in methylation variation associated with the detection of acetaminophen, adjusting for cell heterogeneity and batch effects. The false discovery rate (FDR) was calculated to account for multiple comparisons.Among the 570 newborns included in this study, 96 (17%) had detectable acetaminophen in cord plasma. We identified 7 differentially methylated CpGs (FDR < 0.05) associated with the detection of acetaminophen and additional 4 CpGs showing a difference in the variation of methylation (FDR < 0.05). These CpGs were all located in the gene body of CYP2E1 at the 5' end and had a 3-6% lower average methylation level among participants with detectable acetaminophen compared to participants without. The CpG sites we identified overlap with previously identified DNase hypersensitivity and open chromatin regions in the ENCODE project, suggesting potential regulatory functions.In a US birth cohort, we found detection of cord biomarkers of acetaminophen was associated with DNAm level of CYP2E1 in cord blood. Our findings suggest that DNA methylation of CYP2E1 may be an important regulator of acetaminophen levels in newborns.© 2023. BioMed Central Ltd., part of Springer Nature.",
+No,20231019,pwas,37653343,Sex differences in brain protein expression and disease.,Nat Med,"Most complex human traits differ by sex, but we have limited insight into the underlying mechanisms. Here, we investigated the influence of biological sex on protein expression and its genetic regulation in 1,277 human brain proteomes. We found that 13.2% (1,354) of brain proteins had sex-differentiated abundance and 1.5% (150) of proteins had sex-biased protein quantitative trait loci (sb-pQTLs). Among genes with sex-biased expression, we found 67% concordance between sex-differentiated protein and transcript levels; however, sex effects on the genetic regulation of expression were more evident at the protein level. Considering 24 psychiatric, neurologic and brain morphologic traits, we found that an average of 25% of their putatively causal genes had sex-differentiated protein abundance and 12 putatively causal proteins had sb-pQTLs. Furthermore, integrating sex-specific pQTLs with sex-stratified genome-wide association studies of six psychiatric and neurologic conditions, we uncovered another 23 proteins contributing to these traits in one sex but not the other. Together, these findings begin to provide insights into mechanisms underlying sex differences in brain protein expression and disease.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
+No,20231019,ml,37546907,"Equitable machine learning counteracts ancestral bias in precision medicine, improving outcomes for all.",Res Sq,"Gold standard genomic datasets severely under-represent non-European populations, leading to inequities and a limited understanding of human disease [1-8]. Therapeutics and outcomes remain hidden because we lack insights that we could gain from analyzing ancestry-unbiased genomic data. To address this significant gap, we present PhyloFrame, the first-ever machine learning method for equitable genomic precision medicine. PhyloFrame corrects for ancestral bias by integrating big data tissue-specific functional interaction networks, global population variation data, and disease-relevant transcriptomic data. Application of PhyloFrame to breast, thyroid, and uterine cancers shows marked improvements in predictive power across all ancestries, less model overfitting, and a higher likelihood of identifying known cancer-related genes. The ability to provide accurate predictions for underrepresented groups, in particular, is substantially increased. These results demonstrate how AI can mitigate ancestral bias in training data and contribute to equitable representation in medical research.",
+No,20231019,mqtl,37628696,Polymorphisms in Glutathione S-Transferase (GST) Genes Modify the Effect of Exposure to Maternal Smoking Metabolites in Pregnancy and Offspring DNA Methylation.,Genes (Basel),"Maternal smoking in pregnancy (MSP) affects the offspring's DNA methylation (DNAm). There is a lack of knowledge regarding individual differences in susceptibility to exposure to MSP. Glutathione S-transferase (GST) genes are involved in protection against harmful oxidants such as those found in cigarette smoke. This study aimed to test whether polymorphisms inGSTgenes influence the effect of MSP on offspring DNAm. Using data from the Isle of Wight birth cohort, we assessed the association of MSP and offspring DNAm in 493 mother-child dyads (251 male, 242 female) with the effect-modifying role ofGSTgene polymorphism (at rs506008, rs574344, rs12736389, rs3768490, rs1537234, and rs1695). MSP was assessed by levels of nicotine and its downstream metabolites (cotinine, norcotinine, and hydroxycotinine) in maternal sera. In males, associations of hydroxycotinine with DNAm at cg18473733, cg25949550, cg11647108, and cg01952185 and norcotinine with DNAm at cg09935388 were modified byGSTgene polymorphisms (p-values < 0.05). In females, associations of hydroxycotinine with DNAm at cg12160087 and norcotinine with DNAm at cg18473733 were modified byGSTgene polymorphisms (p-values < 0.05). Our study emphasizes the role of genetic polymorphism inGSTgenes in DNAm's susceptibility to MSP.",
+No,20231026,epigenetics,37640946,Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects,Nat Biotechnol,"Oxidative modification of 5-methylcytosine (5mC) by ten-eleven translocation (TET) DNA dioxygenases generates 5-hydroxymethylcytosine (5hmC), the most abundant form of oxidized 5mC. Existing single-cell bisulfite sequencing methods cannot resolve 5mC and 5hmC, leaving the cell-type-specific regulatory mechanisms of TET and 5hmC largely unknown. Here, we present joint single-nucleus (hydroxy)methylcytosine sequencing (Joint-snhmC-seq), a scalable and quantitative approach that simultaneously profiles 5hmC and true 5mC in single cells by harnessing differential deaminase activity of APOBEC3A toward 5mC and chemically protected 5hmC. Joint-snhmC-seq profiling of single nuclei from mouse brains reveals an unprecedented level of epigenetic heterogeneity of both 5hmC and true 5mC at single-cell resolution. We show that cell-type-specific profiles of 5hmC or true 5mC improve multimodal single-cell data integration, enable accurate identification of neuronal subtypes and uncover context-specific regulatory effects on cell-type-specific genes by TET enzymes.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20231026,dnamage,37622096,Calibrating epigenetic clocks with training data error.,Evol Appl,"Animal age data are valuable for management of wildlife populations. Yet, for most species, there is no practical method for determining the age of unknown individuals. However, epigenetic clocks, a molecular-based method, are capable of age prediction by sampling specific tissue types and measuring DNA methylation levels at specific loci. Developing an epigenetic clock requires a large number of samples from animals of known ages. For most species, there are no individuals whose exact ages are known, making epigenetic clock calibration inaccurate or impossible. For many epigenetic clocks, calibration samples with inaccurate age estimates introduce a degree of error to epigenetic clock calibration. In this study, we investigated how much error in the training data set of an epigenetic clock can be tolerated before it resulted in an unacceptable increase in error for age prediction. Using four publicly available data sets, we artificially increased the training data age error by iterations of 1% and then tested the model against an independent set of known ages. A small effect size increase (Cohen's d >0.2) was detected when the error in age was higher than 22%. The effect size increased linearly with age error. This threshold was independent of sample size. Downstream applications for age data may have a more important role in deciding how much error can be tolerated for age prediction. If highly precise age estimates are required, then it may be futile to embark on the development of an epigenetic clock when there is no accurately aged calibration population to work with. However, for other problems, such as determining the relative age order of pairs of individuals, a lower-quality calibration data set may be adequate.© 2023 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.",
+No,20231026,prediction,37620601,Multiparameter prediction of myeloid neoplasia risk.,Nat Genet,"The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis. By analyzing differences between 'pre-MN' and controls, we develop and validate Cox regression models quantifying the risk of progression to each myeloid neoplasm subtype. We construct 'MN-predict', a web application that generates time-dependent predictions with the input of basic blood tests and genetic data. Our study demonstrates that many individuals that develop myeloid neoplasms can be identified years in advance and provides a framework for disease-specific prognostication that will be of substantial use to researchers and physicians.© 2023. The Author(s).",
+No,20231026,prediction,37606673,Evaluation of Large-Scale Proteomics for Prediction of Cardiovascular Events.,JAMA,"Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk factors and polygenic risk scores, is uncertain.To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations.The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals.Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling.Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death.In the primary event population test set (4018 individuals [59.0% women]; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 [95% CI, 0.007 to 0.038]). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 [95% CI, 0.002 to 0.028]). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 [95% CI, 0.011 to 0.042]). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population.A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination.",
+No,20231026,epigenetics,37580596,In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis,Nat Genet,"Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis.© 2023. The Author(s).",
+No,20231026,screening,37608214,Early detection of lung cancer using artificial intelligence-enhanced optical nanosensing of chromatin alterations in field carcinogenesis.,Sci Rep,"Supranucleosomal chromatin structure, including chromatin domain conformation, is involved in the regulation of gene expression and its dysregulation has been associated with carcinogenesis. Prior studies have shown that cells in the buccal mucosa carry a molecular signature of lung cancer among the cigarette-smoking population, the phenomenon known as field carcinogenesis or field of injury. Thus, we hypothesized that chromatin structural changes in buccal mucosa can be predictive of lung cancer. However, the small size of the chromatin chain (approximately 20 nm) folded into chromatin packing domains, themselves typically below 300 nm in diameter, preclude the detection of alterations in intradomain chromatin conformation using diffraction-limited optical microscopy. In this study, we developed an optical spectroscopic statistical nanosensing technique to detect chromatin packing domain changes in buccal mucosa as a lung cancer biomarker: chromatin-sensitive partial wave spectroscopic microscopy (csPWS). Artificial intelligence (AI) was applied to csPWS measurements of chromatin alterations to enhance diagnostic performance. Our AI-enhanced buccal csPWS nanocytology of 179 patients at two clinical sites distinguished Stage-I lung cancer versus cancer-free controls with an area under the ROC curve (AUC) of 0.92 ± 0.06 for Site 1 (in-state location) and 0.82 ± 0.11 for Site 2 (out-of-state location).© 2023. Springer Nature Limited.",
+No,20231026,methods,37582783,Cross-platform comparisons for targeted bisulfite sequencing of MGISEQ-2000 and NovaSeq6000.,Clin Epigenetics,"An accurate and reproducible next-generation sequencing platform is essential to identify malignancy-related abnormal DNA methylation changes and translate them into clinical applications including cancer detection, prognosis, and surveillance. However, high-quality DNA methylation sequencing has been challenging because poor sequence diversity of the bisulfite-converted libraries severely impairs sequencing quality and yield. In this study, we tested MGISEQ-2000 Sequencer's capability of DNA methylation sequencing with a published non-invasive pancreatic cancer detection assay, using NovaSeq6000 as the benchmark.We sequenced a series of synthetic cell-free DNA (cfDNA) samples with different tumor fractions and found MGISEQ-2000 yielded data with similar quality as NovaSeq6000. The methylation levels measured by MGISEQ-2000 demonstrated high consistency with NovaSeq6000. Moreover, MGISEQ-2000 showed a comparable analytic sensitivity with NovaSeq6000, suggesting its potential for clinical detection. As to evaluate the clinical performance of MGISEQ-2000, we sequenced 24 clinical samples and predicted the pathology of the samples with a clinical diagnosis model, PDACatch classifier. The clinical model performance of MGISEQ-2000's data was highly consistent with that of NovaSeq6000's data, with the area under the curve of 1. We also tested the model's robustness with MGISEQ-2000's data when reducing the sequencing depth. The results showed that MGISEQ-2000's data showed matching robustness of the PDACatch classifier with NovaSeq6000's data.Taken together, MGISEQ-2000 demonstrated similar data quality, consistency of the methylation levels, comparable analytic sensitivity, and matching clinical performance, supporting its application in future non-invasive early cancer detection investigations by detecting distinct methylation patterns of cfDNAs.© 2023. BioMed Central Ltd., part of Springer Nature.",
+No,20231026,methods,37590228,The specious art of single-cell genomics.,PLoS Comput Biol,"Dimensionality reduction is standard practice for filtering noise and identifying relevant features in large-scale data analyses. In biology, single-cell genomics studies typically begin with reduction to 2 or 3 dimensions to produce ""all-in-one"" visuals of the data that are amenable to the human eye, and these are subsequently used for qualitative and quantitative exploratory analysis. However, there is little theoretical support for this practice, and we show that extreme dimension reduction, from hundreds or thousands of dimensions to 2, inevitably induces significant distortion of high-dimensional datasets. We therefore examine the practical implications of low-dimensional embedding of single-cell data and find that extensive distortions and inconsistent practices make such embeddings counter-productive for exploratory, biological analyses. In lieu of this, we discuss alternative approaches for conducting targeted embedding and feature exploration to enable hypothesis-driven biological discovery.Copyright: © 2023 Chari, Pachter. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+No,20231026,genetics,37612512,The complete sequence of a human Y chromosome.,Nature,"The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure that includes long palindromes, tandem repeats and segmental duplications1-3. As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished4,5. Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference, showing the complete ampliconic structures of gene families TSPY, DAZ and RBMY; 41 additional protein-coding genes, mostly from the TSPY family; and an alternating pattern of human satellite 1 and 3 blocks in the heterochromatic Yq12 region. We have combined T2T-Y with a previous assembly of the CHM13 genome4and mapped available population variation, clinical variants and functional genomics data to produce a complete and comprehensive reference sequence for all 24 human chromosomes.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
+No,20231026,genetics,37612510,Assembly of 43 human Y chromosomes reveals extensive complexity and variation,Nature,"The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date1and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes2. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established1boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.",
+No,20231026,epigenetics,37639434,Prediction of DNA Methylation based on Multi-dimensional feature encoding and double convolutional fully connected convolutional neural network.,PLoS Comput Biol,"DNA methylation takes on critical significance to the regulation of gene expression by affecting the stability of DNA and changing the structure of chromosomes. DNA methylation modification sites should be identified, which lays a solid basis for gaining more insights into their biological functions. Existing machine learning-based methods of predicting DNA methylation have not fully exploited the hidden multidimensional information in DNA gene sequences, such that the prediction accuracy of models is significantly limited. Besides, most models have been built in terms of a single methylation type. To address the above-mentioned issues, a deep learning-based method was proposed in this study for DNA methylation site prediction, termed the MEDCNN model. The MEDCNN model is capable of extracting feature information from gene sequences in three dimensions (i.e., positional information, biological information, and chemical information). Moreover, the proposed method employs a convolutional neural network model with double convolutional layers and double fully connected layers while iteratively updating the gradient descent algorithm using the cross-entropy loss function to increase the prediction accuracy of the model. Besides, the MEDCNN model can predict different types of DNA methylation sites. As indicated by the experimental results,the deep learning method based on coding from multiple dimensions outperformed single coding methods, and the MEDCNN model was highly applicable and outperformed existing models in predicting DNA methylation between different species. As revealed by the above-described findings, the MEDCNN model can be effective in predicting DNA methylation sites.Copyright: © 2023 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
+No,20231026,genetics,37612393,From target discovery to clinical drug development with human genetics,Nature,"The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.© 2023. Springer Nature Limited.",
+No,20231026,pqtl,37563310,Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets,Nat Immunol,"Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-? in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.",
+No,20231026,prediction,37640858,Cell-free DNA methylome analysis for early preeclampsia prediction.,Nat Med,"Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis in the prevention of PE, pregnancies at risk of PE must be identified early-in the first trimester. To identify at-risk pregnancies we profiled methylomes of plasma-derived, cell-free DNA from 498 pregnant women, of whom about one-third developed early-onset PE. We detected DNA methylation differences between control and PE pregnancies that enabled risk stratification at PE diagnosis but also presymptomatically, at around 12 weeks of gestation (range 9-14 weeks). The first-trimester risk prediction model was validated in an external cohort collected from two centers (area under the curve (AUC) = 0.75) and integrated with routinely available maternal risk factors (AUC = 0.85). The combined risk score correctly predicted 72% of patients with early-onset PE at 80% specificity. These preliminary results suggest that cell-free DNA methylation profiling is a promising tool for presymptomatic PE risk assessment, and has the potential to improve treatment and follow-up in the obstetric clinic.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
+No,20231026,mtdna,37620817,Association of mitochondrial DNA copy number with chronic kidney disease in older adults.,BMC Geriatr,"Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of chronic kidney disease (CKD). Estimation of mitochondrial DNA copy number (mtDNA-CN) is considered a convenient method for representing mitochondrial function in large samples. However, no study has investigated the association between mtDNA-CN and CKD in older adults with the highest prevalence. The objective is to examine cross-sectional and prospective associations between mtDNA-CN values and CKD risk in older adults to determine whether mtDNA-CN represents a novel potential biomarker for the recognition of CKD risk.In a Chinese community-based cohort of over 65-year-olds, we included 14,467 participants (52.6% females). CKD was defined by eGFR < 60 mL/min/1.73 m2or ICD-10 codes (patients = 3831 (26.5%)). Participants had peripheral blood levels of mtDNA-CN calculated from probe intensities of the Axiom CAS Array.The risk of CKD prevalence decreased with mtDNA-CN per 1-SD increment, independent of established risk factors for older CKD (odds ratio [OR] per SD 0.90, 95% confidence interval [CI] 0.86, 0.93, P < 0.001), and has comparable strength of association with these established risk factors. Furthermore, the progression of kidney function was stratified according to the worsening of eGFR categories. The risk of kidney function progression to a more severe stage gradually decreased as the mtDNA-CN increased (P trend < 0.001). Non-CKD participants in the highest quartile of mtDNA-CN had a lower risk of developing CKD compared to the lowest quartile within 2 years of follow-up, reducing the risk of CKD by 36% (95% CI 0.42, 0.97; P = 0.037).Based on the analysis of the largest sample to date investigating the association between mtDNA-CN and CKD in older adults, higher levels of mtDNA-CN were found to be associated with a lower risk of CKD, suggesting that a reduced level of mtDNA-CN is a potential risk factor for CKD.© 2023. BioMed Central Ltd., part of Springer Nature.",
+No,20231026,dnamage,37592018,Pan-mammalian methylation clocks reveal evolutionarily conserved aging effects.,Nat Aging,,
+No,20231026,h3k27ac,35301427,Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose,Mol Psychiatry,"Opioid use disorder is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. Opioid overdose, the most severe outcome of opioid use disorder, remains the leading cause of accidental death in the United States. We interrogated the effects of opioid overdose on the brain using ChIP-seq to quantify patterns of H3K27 acetylation in dorsolateral prefrontal cortical neurons isolated from 51 opioid-overdose cases and 51 accidental death controls. Among opioid cases, we observed global hypoacetylation and identified 388 putative enhancers consistently depleted for H3K27ac. Machine learning on H3K27ac patterns predicted case-control status with high accuracy. We focused on case-specific regulatory alterations, revealing 81,399 hypoacetylation events, uncovering vast inter-patient heterogeneity. We developed a strategy to decode this heterogeneity based on convergence analysis, which leveraged promoter-capture Hi-C to identify five genes over-burdened by alterations in their regulatory network or ""plexus"": ASTN2, KCNMA1, DUSP4, GABBR2, ENOX1. These convergent loci are enriched for opioid use disorder risk genes and heritability for generalized anxiety, number of sexual partners, and years of education. Overall, our multi-pronged approach uncovers neurobiological aspects of opioid use disorder and captures genetic and environmental factors perpetuating the opioid epidemic.",
+No,20231026,prostate,37628978,"Prostate Cancer: Genetics, Epigenetics and the Need for Immunological Biomarkers.",Int J Mol Sci,"Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocyte-derived and TAM-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer.",
+No,20231026,prediction,37664631,REFINED-CNN framework for survival prediction with high-dimensional features.,iScience,"Robust and accurate survival prediction of clinical trials using high-throughput genomics data is a fundamental challenge in pharmacogenomics. Current machine learning tools often provide limited predictive performance and model interpretation in these settings. In the present study, we extend the application of REFINED-CNN from regression tasks to making survival predictions, by mapping high-dimensional RNA sequencing data into REFINED images which are conducive to CNN modeling. We show that the REFINED-CNN survival model can be easily adapted to new tasks of a similar nature (e.g., predicting on new cancer types) using transfer learning with a low number of patients. Furthermore, the model can also be interpreted both locally and globally through risk score back propagation that quantifies each feature (e.g., gene) importance in survival prediction task for the patient or cancer type of interest.© 2023 The Author(s).",
+No,20231026,prediction,37379494,A circulating panel of circRNA biomarkers for the noninvasive and early detection of pancreatic ductal adenocarcinoma,Gastroenterology,"Background & aims: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. Delayed manifestation of symptoms and the lack of specific diagnostic markers lead to diagnosing PDAC patients at advanced stages. This study aimed to develop a circular RNA (circRNA)-based biomarker panel to facilitate noninvasive and early detection of PDAC.
+
+Methods: We performed a systematic genomewide discovery of circRNAs overexpressed in patients with PDAC. Subsequently, we performed validation of the candidate markers in the primary tumors from PDAC patients, followed by their translation into a plasma-based liquid biopsy assay by analyzing two independent clinical cohorts of PDAC patients and non-disease controls. We assessed the performance of our circRNA-panel in conjunction with the plasma levels of CA19-9 for the early detection of PDAC.
+
+Results: We initially identified a panel of 10 circRNA candidates during the discovery phase. Subsequently, the panel was reduced to 5 circRNAs in the liquid biopsy-based assay, which robustly identified patients with PDAC and distinguished between early (stage I/II)- and late-stage (stage III/IV) disease. The AUCs of this diagnostic panel for the detection of early-stage PDAC were 0.83 and 0.81 in the training and validation cohorts, respectively. Moreover, when we combined this panel with CA19-9 levels, the diagnostic performance for identifying, PDAC patients improved remarkably (AUC, 0.94) in the validation cohort patients. Furthermore, our circRNA panel could also efficiently identify PDAC patients (AUC, 0.85) who were otherwise deemed clinically CA19-9-negative (<37 U/ml).
+
+Conclusions: We developed a circRNA-based biomarker panel with a robust noninvasive diagnostic potential for identifying patients with early-stage PDAC.",
+No,20231026,prediction,37164005,"Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort",J Clin Oncol,"Purpose: To investigate the utility of integrating a panel of circulating protein biomarkers in combination with a risk model on the basis of subject characteristics to identify individuals at high risk of harboring a lethal lung cancer.
+
+Methods: Data from an established logistic regression model that combines four-marker protein panel (4MP) together with the Prostate, Lung, Colorectal, and Ovarian (PLCO) risk model (PLCOm2012) assayed in prediagnostic sera from 552 lung cancer cases and 2,193 noncases from the PLCO cohort were used in this study. Of the 552 lung cancer cases, 387 (70%) died of lung cancer. Cumulative incidence of lung cancer death and subdistributional and cause-specific hazard ratios (HRs) were calculated on the basis of 4MP + PLCOm2012 risk scores at a predefined 1.0% and 1.7% 6-year risk thresholds, which correspond to the current and former US Preventive Services Task Force screening criteria, respectively.
+
+Results: When considering cases diagnosed within 1 year of blood draw and all noncases, the area under receiver operation characteristics curve estimate of the 4MP + PLCOm2012 model for risk prediction of lung cancer death was 0.88 (95% CI, 0.86 to 0.90). The cumulative incidence of lung cancer death was statistically significantly higher in individuals with 4MP + PLCOm2012 scores above the 1.0% 6-year risk threshold (modified ?2, 166.27; P < .0001). Corresponding subdistributional and lung cancer death-specific HRs for test-positive cases were 9.88 (95% CI, 6.44 to 15.18) and 10.65 (95% CI, 6.93 to 16.37), respectively.
+
+Conclusion: The blood-based biomarker panel in combination with PLCOm2012 identifies individuals at high risk of a lethal lung cancer.",
+No,20231026,genetics,37839499,"Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the ""omnigenic"" sparse effector hypothesis of complex trait genetics",Am J Hum Genet,"The ""omnigenic"" hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated through trans-effects on expression of a relatively sparse set of effector (""core"") genes. We tested this hypothesis in a study of 4,964 cases of type 1 diabetes (T1D) and 7,497 controls by using summary statistics to calculate aggregated (excluding the HLA region) trans-scores for gene expression in blood. From associations of T1D with aggregated trans-scores, nine putative core genes were identified, of which three-STAT1, CTLA4 and FOXP3-are genes in which variants cause monogenic forms of autoimmune diabetes. Seven of these genes affect the activity of regulatory T cells, and two are involved in immune responses to microbial lipids. Four T1D-associated genomic regions could be identified as master regulators via trans-effects on gene expression. These results support the sparse effector hypothesis and reshape our understanding of the genetic architecture of T1D.",
+No,20231026,prediction,36902312,Combinatorial Blood Platelets-Derived circRNA and mRNA Signature for Early-Stage Lung Cancer Detection,Int J Mol Sci,"Despite the diversity of liquid biopsy transcriptomic repertoire, numerous studies often exploit only a single RNA type signature for diagnostic biomarker potential. This frequently results in insufficient sensitivity and specificity necessary to reach diagnostic utility. Combinatorial biomarker approaches may offer a more reliable diagnosis. Here, we investigated the synergistic contributions of circRNA and mRNA signatures derived from blood platelets as biomarkers for lung cancer detection. We developed a comprehensive bioinformatics pipeline permitting an analysis of platelet-circRNA and mRNA derived from non-cancer individuals and lung cancer patients. An optimal selected signature is then used to generate the predictive classification model using machine learning algorithm. Using an individual signature of 21 circRNA and 28 mRNA, the predictive models reached an area under the curve (AUC) of 0.88 and 0.81, respectively. Importantly, combinatorial analysis including both types of RNAs resulted in an 8-target signature (6 mRNA and 2 circRNA), enhancing the differentiation of lung cancer from controls (AUC of 0.92). Additionally, we identified five biomarkers potentially specific for early-stage detection of lung cancer. Our proof-of-concept study presents the first multi-analyte-based approach for the analysis of platelets-derived biomarkers, providing a potential combinatorial diagnostic signature for lung cancer detection.",
+,,,,,,,
+,,,10.1101/2023.03.31.23287853,,,,
diff --git a/data/presented.txt b/data/presented.txt
index b98f455..2664c3a 100644
--- a/data/presented.txt
+++ b/data/presented.txt
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diff --git a/docs/presentations/20231026/candidates.csv b/docs/presentations/20231026/candidates.csv
index a667408..ffe1515 100644
--- a/docs/presentations/20231026/candidates.csv
+++ b/docs/presentations/20231026/candidates.csv
@@ -1,318 +1,20 @@
 keep,pmid,title,source,abstract
-,37630778,"The Microbiome, Epigenome, and Diet in Adults with Obesity during Behavioral Weight Loss.",Nutrients,"Obesity has been linked to the gut microbiome, epigenome, and diet, yet these factors have not been studied together during obesity treatment. Our objective was to evaluate associations among gut microbiota (MB), DNA methylation (DNAme), and diet prior to and during a behavioral weight loss intervention. Adults (n= 47, age 40.9 ± 9.7 years, body mass index (BMI) 33.5 ± 4.5 kg/m2, 77% female) with data collected at baseline (BL) and 3 months (3 m) were included. Fecal MB was assessed via 16S sequencing and whole blood DNAme via the Infinium EPIC array. Food group and nutrient intakes and Healthy Eating Index (HEI) scores were calculated from 7-day diet records. Linear models were used to test for the effect of taxa relative abundance on DNAme and diet cross-sectionally at each time point, adjusting for confounders and a false discovery rate of 5%. Mean weight loss was 6.2 ± 3.9% at 3 m. At BL, one MB taxon,Ruminiclostridium, was associated with DNAme of the genesCOL20A1(r = 0.651,p= 0.029),COL18A1(r = 0.578,p= 0.044), andNT5E(r = 0.365,p= 0.043). At 3 m, there were 14 unique MB:DNAme associations, such asAkkermansiawith DNAme ofGUSB(r = -0.585,p= 0.003),CRYL1(r = -0.419,p= 0.007),C9(r = -0.439,p= 0.019), andGMDS(r = -0.559,p= 0.046). Among taxa associated with DNAme, no significant relationships were seen with dietary intakes of relevant nutrients, food groups, or HEI scores. Our findings indicate that microbes linked to mucin degradation, short-chain fatty acid production, and body weight are associated with DNAme of phenotypically relevant genes. These relationships offer an initial understanding of the possible routes by which alterations in gut MB may influence metabolism during weight loss."
-,37629043,Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease.,Int J Mol Sci,"Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD is strongly correlated with obesity; however, it has been extensively reported among lean/nonobese individuals in recent years. Although lean patients demonstrate a lower prevalence of diabetes mellitus, central obesity, dyslipidemia, hypertension, and metabolic syndrome, a percentage of these patients may develop steatohepatitis, advanced liver fibrosis, and cardiovascular disease, and have increased all-cause mortality. The pathophysiological mechanisms of lean NAFLD remain vague. Studies have reported that lean NAFLD demonstrates a close association with environmental factors, genetic predisposition, and epigenetic modifications. In this review, we aim to discuss and summarize the epigenetic mechanisms involved in lean NAFLD and to introduce the interaction between epigenetic patterns and genetic or non genetic factors. Several epigenetic mechanisms have been implicated in the regulation of lean NAFLD. These include DNA methylation, histone modifications, and noncoding-RNA-mediated gene regulation. Epigenetics is an area of special interest in the setting of lean NAFLD as it could provide new insights into the therapeutic options and noninvasive biomarkers that target this under-recognized and challenging disorder."
-,37626900,The Transcription Factor HOXA5: Novel Insights into Metabolic Diseases and Adipose Tissue Dysfunction.,Cells,"The transcription factorHOXA5, from theHOXgene family, has long been studied due to its critical role in physiological activities in normal cells, such as organ development and body patterning, and pathological activities in cancer cells. Nonetheless, recent evidence supports the hypothesis of a role forHOXA5in metabolic diseases, particularly in obesity and type 2 diabetes (T2D). In line with the current opinion that adipocyte and adipose tissue (AT) dysfunction belong to the group of primary defects in obesity, linking this condition to an increased risk of insulin resistance (IR) and T2D, theHOXA5gene has been shown to regulate adipocyte function and AT remodeling both in humans and mice. Epigenetics adds complexity toHOXA5gene regulation in metabolic diseases. Indeed, epigenetic mechanisms, specifically DNA methylation, influence the dynamicHOXA5expression profile. In human AT, the DNA methylation profile at theHOXA5gene is associated with hypertrophic obesity and an increased risk of developing T2D. Thus, an inappropriateHOXA5gene expression may be a mechanism causing or maintaining an impaired AT function in obesity and potentially linking obesity to its associated disorders. In this review, we integrate the current evidence about the involvement ofHOXA5in regulating AT function, as well as its association with the pathogenesis of obesity and T2D. We also summarize the current knowledge on the role of DNA methylation in controllingHOXA5expression. Moreover, considering the susceptibility of epigenetic changes to reversal through targeted interventions, we discuss the potential therapeutic value of targetingHOXA5DNA methylation changes in the treatment of metabolic diseases."
-,37604969,Micronutrients in early life and offspring metabolic health programming: a promising target for preventing non-communicable diseases.,Eur J Clin Nutr,"Chronic non-communicable diseases are the leading cause of morbidity and mortality worldwide. Developing and implementing effective preventive strategies is the best way to ensure the overall metabolic health status of the population and to counter the global burden of non-communicable diseases. Predisposition to obesity and other non-communicable diseases is due to a combination of genetic and environmental factors throughout life, but the early environment, particularly the environment during the fetal period and the early years of life, is crucial in determining metabolic health, hence the concept of 'fetal programming'. The origins of this causal link between environmental factors and disease lie in epigenetic mechanisms. Among the environmental factors, diet plays a crucial role in this process. Substantial evidence documented the key role of macronutrients in the programming of metabolic diseases early in life. Recently, the effect of maternal micronutrient intake on offspring metabolic health in later life emerged. The purpose of this narrative review is to bring to light available evidence in the literature on the effect of maternal micronutrient status on offspring metabolic health and underlying epigenetic mechanisms that drive this link to highlight its potential role in the prevention of non-communicable diseases.© 2023. The Author(s), under exclusive licence to Springer Nature Limited."
-,37591977,NA,NA,"Obesity is a chronic, multifactorial disease which is linked to a number of adverse endocrinological and metabolic conditions. Currently, bariatric surgery is one of the most effective treatments for individuals diagnosed with severe obesity. However, the current indications for bariatric surgery are based on inadequate metrics (i.e., BMI) which do not account for the complexity of the disease, nor the heterogeneity among the patient population. Moreover, there is a lack of understanding with respect to the biological underpinnings that influence successful and sustained weight loss post-bariatric surgery. Studies have implicated age and pre-surgery body weight as two factors that are associated with favorable patient outcomes. Still, there is an urgent medical need to identify other potential factors that could improve the specificity of candidate selection and better inform the treatment plan of patients with obesity. In this report, we present and describe the cohort of the DECON pilot project, a multicenter study which aims to identify predictive biomarkers of successful weight loss after bariatric surgery.© 2023. Springer Nature Limited."
-,37560311,"Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease.",Front Endocrinol (Lausanne),"The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.Copyright © 2023 Masse and Lu."
-,37663891,Nourishing the brain on deep space missions: nutritional psychiatry in promoting resilience.,Front Neural Circuits,"The grueling psychological demands of a journey into deep space coupled with ever-increasing distances away from home pose a unique problem: how can we best take advantage of the benefits of fresh foods in a place that has none? Here, we consider the biggest challenges associated with our current spaceflight food system, highlight the importance of supporting optimal brain health on missions into deep space, and discuss evidence about food components that impact brain health. We propose a future food system that leverages the gut microbiota that can be individually tailored to best support the brain and mental health of crews on deep space long-duration missions. Working toward this goal, we will also be making investments in sustainable means to nourish the crew that remains here on spaceship Earth.Copyright © 2023 Pathare, Fayet-Moore, Fogarty, Jacka, Strandwitz, Strangman and Donoviel."
-,37624890,NA,NA,"The next steps of deep space exploration are manned missions to Moon and Mars. For safe space missions for crew members, it is important to understand the impact of space flight on the immune system. We studied the effects of 21 days dry immersion (DI) exposure on the transcriptomes of T cells isolated from blood samples of eight healthy volunteers. Samples were collected 7 days before DI, at day 7, 14, and 21 during DI, and 7 days after DI. RNA sequencing of CD3+T cells revealed transcriptional alterations across all time points, with most changes occurring 14 days after DI exposure. At day 21, T cells showed evidence of adaptation with a transcriptional profile resembling that of 7 days before DI. At 7 days after DI, T cells again changed their transcriptional profile. These data suggest that T cells adapt by rewiring their transcriptomes in response to simulated weightlessness and that remodeling cues persist when reexposed to normal gravity."
-,37597101,Demethylation of CDKN2A in systemic lupus erythematosus and rheumatoid arthritis: a blood biomarker for diagnosis and assessment of disease activity.,Clin Rheumatol,"Considering the phenotypic and serological heterogeneity of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), significant challenges may intervene with the precise diagnosis. In this regard, numerous studies have shown that changes in DNA methylation levels can be used to distinguish between healthy individuals and those with SLE and RA, as well as to predict disease activity and prognosis.In the current study, we evaluated quantitative methylation level of CDKN2A promoter in peripheral blood mononuclear cells (PBMCs) of SLE and RA patients, and healthy controls by methylation-quantification of endonuclease-resistant DNA (MethyQESD), a bisulfite conversion-independent method.Our findings revealed an excessive hypomethylation of CDKN2A in SLE and RA patients compared to healthy individuals (P < 0.001). Besides, by determining efficient cutoff value, the specificity of CDKN2A for correct diagnosis of healthy subjects was measured to be 77.30% and the sensitivity for SLE and RA diagnosis were 81.33%, and 72%, respectively. Furthermore, CDKN2A methylation level was shown to be positively associated with C3 and C4 levels and negatively associated with anti‑dsDNA concentration (P < 0.001). Moreover, a statistically significant difference in the DNA methylation levels of CDKN2A promoter was identified between SLE cases with age of ≤ 18 and patients with > 18 years of age (P = 0.025).Our findings demonstrated that CDKN2A methylation levels in PBMCs of SLE and RA patients could be used as a promising diagnostic biomarker. The significant association between hypomethylation of CDKN2A promoter and disease activity factors in SLE patients, is suggesting that CDKN2A hypomethylation could be used as an alternative biomarker for assessment of disease activity. Key Points • Several studies have reported increased expression of CDKN2A in SLE and RA suggesting that it may be involved in the pathogenesis of these disorders. • CDKN2A hypomethylation has been implicated in different autoimmune diseases. • Our findings demonstrated that CDKN2A methylation levels in PBMCs of SLE and RA patients could be used as a promising diagnostic and prognostic biomarker.© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR)."
-,37669926,NA,NA,"Cell lines are valuable resources as model for human biology and translational medicine. It is thus important to explore the concordance between the expression in various cell lines vis-à-vis human native and disease tissues. In this study, we investigate the expression of all human protein-coding genes in more than 1,000 human cell lines representing 27 cancer types by a genome-wide transcriptomics analysis. The cell line gene expression is compared with the corresponding profiles in various tissues, organs, single-cell types and cancers. Here, we present the expression for each cell line and give guidance for the most appropriate cell line for a given experimental study. In addition, we explore the cancer-related pathway and cytokine activity of the cell lines to aid human biology studies and drug development projects. All data are presented in an open access cell line section of the Human Protein Atlas to facilitate the exploration of all human protein-coding genes across these cell lines.© 2023. Springer Nature Limited."
-,37659057,NA,NA,"Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.© 2023. The Author(s)."
-,37660055,TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition.,Nat Commun,"The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a 'closed' state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that 'opens' the active site for substrate acetylation. Importantly, genetic mutations that lead to p300/CBP TAZ2 truncations are found in human cancers, and cells with TAZ2 truncations are vulnerable to histone deacetylase inhibitors. Our study reveals a function of the TAZ2 domain in HAT autoinhibitory regulation and provides a potential therapeutic strategy for the treatment of cancers harboring p300/CBP TAZ2 truncations.© 2023. Springer Nature Limited."
-,37647391,TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis.,Sci Adv,"TERT reactivation occurs frequently in human malignancies, especially advanced cancers. However, in vivo functions of TERT reactivation in cancer progression and the underlying mechanism are not fully understood. In this study, we expressed TERT and/or active BRAF (BRAFV600E) specifically in mouse thyroid epithelium. WhileBRAFV600E alone induced papillary thyroid cancer (PTC), coexpression ofBRAFV600E and TERT resulted in poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome analysis revealed that tumors from mice coexpressingBRAFV600E and TERT were highly heterogeneous, and cell dedifferentiation was positively correlated with ribosomal biogenesis. Mechanistically, TERT boosted ribosomal RNA (rRNA) expression and protein synthesis by interacting with multiple proteins involved in ribosomal biogenesis. Furthermore, we found that CX-5461, an rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation of thyroid cancer. Thus, TERT promotes thyroid cancer progression by inducing cancer cell dedifferentiation, and ribosome inhibition represents a potential strategy to treat TERT-reactivated cancers."
-,37645963,Multi-omic stratification of the missense variant cysteinome.,bioRxiv,"Cancer genomes are rife with genetic variants; one key outcome of this variation is gain-of-cysteine, which is the most frequently acquired amino acid due to missense variants in COSMIC. Acquired cysteines are both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all acquired cysteines remain uncharacterized. Here, we pair cysteine chemoproteomics-a technique that enables proteome-wide pinpointing of functional, redox sensitive, and potentially druggable residues-with genomics to reveal the hidden landscape of cysteine acquisition. For both cancer and healthy genomes, we find that cysteine acquisition is a ubiquitous consequence of genetic variation that is further elevated in the context of decreased DNA repair. Our chemoproteogenomics platform integrates chemoproteomic, whole exome, and RNA-seq data, with a customized 2-stage false discovery rate (FDR) error controlled proteomic search, further enhanced with a user-friendly FragPipe interface. Integration of CADD predictions of deleteriousness revealed marked enrichment for likely damaging variants that result in acquisition of cysteine. By deploying chemoproteogenomics across eleven cell lines, we identify 116 gain-of-cysteines, of which 10 were liganded by electrophilic druglike molecules. Reference cysteines proximal to missense variants were also found to be pervasive, 791 in total, supporting heretofore untapped opportunities for proteoform-specific chemical probe development campaigns. As chemoproteogenomics is further distinguished by sample-matched combinatorial variant databases and compatible with redox proteomics and small molecule screening, we expect widespread utility in guiding proteoform-specific biology and therapeutic discovery."
-,37629096,"Construction and Validation of a Reliable Disulfidptosis-Related LncRNAs Signature of the Subtype, Prognostic, and Immune Landscape in Colon Cancer.",Int J Mol Sci,"Disulfidptosis, a novel form of regulated cell death (RCD) associated with metabolism, represents a promising intervention target in cancer therapy. While abnormal lncRNA expression is associated with colon cancer development, the prognostic potential and biological characteristics of disulfidptosis-related lncRNAs (DRLs) remain unclear. Consequently, the research aimed to discover a novel indication of DRLs with significant prognostic implications, and to investigate their possible molecular role in the advancement of colon cancer. Here, we acquired RNA-seq data, pertinent clinical data, and genomic mutations of colon adenocarcinoma (COAD) from the TCGA database, and then DRLs were determined through Pearson correlation analysis. A total of 434 COAD patients were divided in to three subgroups through clustering analysis based on DRLs. By utilizing univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate Cox regression analysis, we ultimately created a prognostic model consisting of four DRLs (AC007728.3, AP003555.1, ATP2B1.AS1, and NSMCE1.DT), and an external database was used to validate the prognostic features of the risk model. According to the Kaplan-Meier curve analysis, patients in the low-risk group exhibited a considerably superior survival time in comparison to those in the high-risk group. Enrichment analysis revealed a significant association between metabolic processes and the genes that were differentially expressed in the high- and low-risk groups. Additionally, significant differences in the tumor immune microenvironment landscape were observed, specifically pertaining to immune cells, function, and checkpoints. High-risk patients exhibited a low likelihood of immune evasion, as indicated by the Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Patients who exhibit both a high risk and high Tumor Mutational Burden (TMB) experience the least amount of time for survival, whereas those belonging to the low-risk and low-TMB category demonstrate the most favorable prognosis. In addition, the risk groups determined by the 4-DRLs signature displayed distinct drug sensitivities. Finally, we confirmed the levels of expression for four DRLs through rt-qPCR in both tissue samples from colon cancer patients and cell lines. Taken together, the first 4-DRLs-based signature we proposed may serve for a hopeful instrument for forecasting the prognosis, immune landscape, and therapeutic responses in colon cancer patients, thereby facilitating optimal clinical decision-making."
-,37627150,Luciferase Expressing Preclinical Model Systems Representing the Different Molecular Subtypes of Colorectal Cancer.,Cancers (Basel),"Colorectal cancer (CRC) is a heterogeneous disease. More insight into the biological diversity of CRC is needed to improve therapeutic outcomes. Established CRC cell lines are frequently used and were shown to be representative models of the main subtypes of CRC at the genomic and transcriptomic level. In the present work, we established stable, luciferase expressing derivatives from 10 well-established CRC cell lines, generated spheroids and subcutaneous xenograft tumors in nude mice, and performed comparative characterization of these model systems. Transcriptomic analyses revealed the close relation of cell lines with their derived spheroids and xenograft tumors. The preclinical model systems clustered with patient tumor samples when compared to normal tissue thereby confirming that cell-line-based tumor models retain specific characteristics of primary tumors. Xenografts showed different differentiation patterns and bioluminescence imaging revealed metastatic spread to the lungs. In addition, the models were classified according to the CMS classification system, with further sub-classification according to the recently identified two intrinsic epithelial tumor cell states of CRC, iCMS2 and iCMS3. The combined data showed that regarding primary tumor characteristics, 3D-spheroid cultures resemble xenografts more closely than 2D-cultured cells do. Furthermore, we set up a bioluminescence-based spheroid cytotoxicity assay in order to be able to perform dose-response relationship studies in analogy to typical monolayer assays. Applying the established assay, we studied the efficacy of oxaliplatin. Seven of the ten used cell lines showed a significant reduction in the response to oxaliplatin in the 3D-spheroid model compared to the 2D-monolayer model. Therapy studies in selected xenograft models confirmed the response or lack of response to oxaliplatin treatment. Analyses of differentially expressed genes in these models identified CAV1 as a possible marker of oxaliplatin resistance. In conclusion, we established a combined 2D/3D, in vitro/in vivo model system representing the heterogeneity of CRC, which can be used in preclinical research applications."
-,37620409,Synthetic viability induces resistance to immune checkpoint inhibitors in cancer cells.,Br J Cancer,"Immune checkpoint inhibitors (ICI) have revolutionized the treatment for multiple cancers. However, most of patients encounter resistance. Synthetic viability (SV) between genes could induce resistance. In this study, we established SV signature to predict the efficacy of ICI treatment for melanoma.We collected features and predicted SV gene pairs by random forest classifier. This work prioritized SV gene pairs based on CRISPR/Cas9 screens. SV gene pairs signature were constructed to predict the response to ICI for melanoma patients.This study predicted robust SV gene pairs based on 14 features. Filtered by CRISPR/Cas9 screens, we identified 1,861 SV gene pairs, which were also related with prognosis across multiple cancer types. Next, we constructed the six SV pairs signature to predict resistance to ICI for melanoma patients. This study applied the six SV pairs signature to divide melanoma patients into high-risk and low-risk. High-risk melanoma patients were associated with worse response after ICI treatment. Immune landscape analysis revealed that high-risk melanoma patients had lower natural killer cells and CD8+T cells infiltration.In summary, the 14 features classifier accurately predicted robust SV gene pairs for cancer. The six SV pairs signature could predict resistance to ICI.© 2023. The Author(s)."
-,37612728,Partial gene suppression improves identification of cancer vulnerabilities when CRISPR-Cas9 knockout is pan-lethal.,Genome Biol,"Hundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency Map, to identify gene dependencies-genes whose loss of function reduces cell viability or fitness. Recently, large-scale screening efforts have shifted from RNAi to CRISPR-Cas9, due to superior efficacy and specificity. However, many effective oncology drugs only partially inhibit their protein targets, leading us to question whether partial suppression of genes using RNAi could reveal cancer vulnerabilities that are missed by complete knockout using CRISPR-Cas9. Here, we compare CRISPR-Cas9 and RNAi dependency profiles of genes across approximately 400 matched cancer cell lines.We find that CRISPR screens accurately identify more gene dependencies per cell line, but the majority of each cell line's dependencies are part of a set of 1867 genes that are shared dependencies across the entire collection (pan-lethals). While RNAi knockdown of about 30% of these genes is also pan-lethal, approximately 50% have selective dependency patterns across cell lines, suggesting they could still be cancer vulnerabilities. The accuracy of the unique RNAi selectivity is supported by associations to multi-omics profiles, drug sensitivity, and other expected co-dependencies.Incorporating RNAi data for genes that are pan-lethal knockouts facilitates the discovery of a wider range of gene targets than could be detected using the CRISPR dataset alone. This can aid in the interpretation of contrasting results obtained from CRISPR and RNAi screens and reinforce the importance of partial gene suppression methods in building a cancer dependency map.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37591722,A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance.,Life Sci Alliance,"Cancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later disease stages. Depletion of folylpolyglutamate synthetase (FPGS), which normally promotes intracellular accumulation and activity of natural folates and methotrexate, is linked to methotrexate and 5-fluorouracil resistance and its association with relapse illustrates the need for improved intervention strategies. Here, we describe a novel antifolate (C1) that, like methotrexate, potently inhibits dihydrofolate reductase and downstream one-carbon metabolism. Contrary to methotrexate, C1 displays optimal efficacy in FPGS-deficient contexts, due to decreased competition with intracellular folates for interaction with dihydrofolate reductase. We show that FPGS-deficient patient-derived CRC organoids display enhanced sensitivity to C1, whereas FPGS-high CRC organoids are more sensitive to methotrexate. Our results argue that polyglutamylation-independent antifolates can be applied to exert selective pressure on FPGS-deficient cells during chemotherapy, using a vulnerability created by polyglutamylation deficiency.© 2023 van der Krift et al."
-,37578979,Deconvolution of cancer cell states by the XDec-SM method.,PLoS Comput Biol,"Proper characterization of cancer cell states within the tumor microenvironment is a key to accurately identifying matching experimental models and the development of precision therapies. To reconstruct this information from bulk RNA-seq profiles, we developed the XDec Simplex Mapping (XDec-SM) reference-optional deconvolution method that maps tumors and the states of constituent cells onto a biologically interpretable low-dimensional space. The method identifies gene sets informative for deconvolution from relevant single-cell profiling data when such profiles are available. When applied to breast tumors in The Cancer Genome Atlas (TCGA), XDec-SM infers the identity of constituent cell types and their proportions. XDec-SM also infers cancer cells states within individual tumors that associate with DNA methylation patterns, driver somatic mutations, pathway activation and metabolic coupling between stromal and breast cancer cells. By projecting tumors, cancer cell lines, and PDX models onto the same map, we identify in vitro and in vivo models with matching cancer cell states. Map position is also predictive of therapy response, thus opening the prospects for precision therapy informed by experiments in model systems matched to tumors in vivo by cancer cell state.Copyright: © 2023 Murillo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37578973,NA,NA,"Although children and adolescents with acute lymphoblastic leukaemia (ALL) have high survival rates, approximately 15-20% of patients relapse. Risk of relapse is routinely estimated at diagnosis by biological factors, including flow cytometry data. This high-dimensional data is typically manually assessed by projecting it onto a subset of biomarkers. Cell density and ""empty spaces"" in 2D projections of the data, i.e. regions devoid of cells, are then used for qualitative assessment. Here, we use topological data analysis (TDA), which quantifies shapes, including empty spaces, in data, to analyse pre-treatment ALL datasets with known patient outcomes. We combine these fully unsupervised analyses with Machine Learning (ML) to identify significant shape characteristics and demonstrate that they accurately predict risk of relapse, particularly for patients previously classified as 'low risk'. We independently confirm the predictive power of CD10, CD20, CD38, and CD45 as biomarkers for ALL diagnosis. Based on our analyses, we propose three increasingly detailed prognostic pipelines for analysing flow cytometry data from ALL patients depending on technical and technological availability: 1. Visual inspection of specific biological features in biparametric projections of the data; 2. Computation of quantitative topological descriptors of such projections; 3. A combined analysis, using TDA and ML, in the four-parameter space defined by CD10, CD20, CD38 and CD45. Our analyses readily extend to other haematological malignancies.Copyright: © 2023 Chulián et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37577299,Overexpression of MRPL19 in predicting poor prognosis and promoting the development of lung adenocarcinoma.,Transl Lung Cancer Res,"Mitochondrial ribosomal protein L19 (MRPL19) is a member of the mitochondrial ribosomal protein (MRP) family. MRPs have a role in the progression of many cancers. However, the role ofMRPL19in lung adenocarcinoma (LUAD) is yet unknown.The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, real-time polymerase chain reaction, and immunohistochemistry (IHC) were used to assessMRPL19expression and clinical relevance. Gene Expression Profiling Interactive Analysis (GEPIA) and the online Kaplan-Meier (KM) Plotter database were used to determine the prognostic significance. Through use of LinkedOmics, genes that were coexpressed withMRPL19and its regulators were identified. The biological roles ofMRPL19were investigated through R-implemented packages and RNA interference. The Tumor Immune Estimation Resource (TIMER) was employed to assess the connection betweenMRPL19expression and infiltrated immune cells in LUAD.MRPL19expression in LUAD was upregulated and was correlated with lymph node metastasis, differentiation level, and tumor status.MRPL19was prognostic and associated with poor prognosis. Functional network analysis revealed thatMRPL19may be associated with the cell cycle, cell adhesion molecules, spliceosome, and T-helper cell differentiation and was regulated by several microRNA and the E2F family. The gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network indicated thatMRPL19was correlated with cancer proliferation signaling pathways. The immune infiltration analysis revealed a correlation betweenMRPL19expression and the extent of B cells, CD4+T cells, and dendritic cells' infiltration in LUAD. Additionally,MRPL19knockdown in LUAD cells substantially reduced cell growth, migration, and invasion of malignant cells.The poor prognosis and immunological infiltration in LUAD were significantly associated withMRPL19, which may have pro-oncogenic effects on the disease.2023 Translational Lung Cancer Research. All rights reserved."
-,37572177,Tumoral P2Y(2) receptor modulates tumor growth and host anti-tumor immune responses in a syngeneic murine model of oral cancer.,Purinergic Signal,"Head and neck squamous cell carcinomas (HNSCCs) are a heterogenous group of tumors and among the top 10 most common cancers and they arise from the epithelial tissues of the mucosal surfaces of the oral cavity, oropharynx, and larynx. Aberrant purinergic signaling has been associated with various cancer types. Here, we studied the role of the P2Y2purinergic receptor (P2Y2R) in the context of oral cancer. We utilized bioinformatics analysis of deposited datasets to examine purinome gene expression in HNSCC tumors and cells lines and functionally characterized nucleotide-induced P2 receptor signaling in human FaDu and Cal27 and murine MOC2 oral cancer cell lines. Utilizing tumorigenesis assays with wild-type or P2ry2 knockout MOC2 cells we evaluated the role of P2Y2Rs in tumor growth and the host anti-tumor immune responses. Our data demonstrate that human and murine oral cancer cell lines express numerous P2 receptors, with the P2Y2R being highly expressed. Using syngeneic tumor grafts in wild-type mice, we observed that MOC2 tumors expressing P2Y2R were larger than P2Y2R-/-tumors. Wild-type MOC2 tumors contained a lower population of tumor-infiltrating CD11b+F4/80+macrophages and CD3+ cells, which were revealed to be CD3+CD4+IFNγ+T cells, compared to P2Y2R-/-tumors. These results were mirrored when utilizing P2Y2R-/-mice, indicating that the changes in MOC2 tumor growth and to the host anti-tumor immune response were independent of host derived P2Y2Rs. Results suggest that targeted suppression of the P2Y2R in HNSCC cells in vivo, rather than systemic P2Y2R antagonism, may be a more effective treatment strategy for HNSCCs.© 2023. The Author(s), under exclusive licence to Springer Nature B.V."
-,37569676,Investigating the Role of FoxP3 in Renal Cell Carcinoma Metastasis with BAP1 or SEDT2 Mutation.,Int J Mol Sci,"Forkhead box protein P3 (FoxP3) primarily functions as the master regulator in regulatory T cells (Tregs) differentiation, but its high level of expression has also been found in tumor cells recently. The aim of our study was to clarify the role ofFoxP3in renal cell carcinoma (RCC) progression and metastasis. We verified theFoxP3characteristic clinicopathological data from The Cancer Genome Atlas (TCGA) database using bioinformatics tools. Meanwhile, RNA sequencing was performed to determine theFoxP3biofunction in RCC progression. Our results showed that high expression ofFoxP3was found inBAP1- orSETD2-mutant patients with RCC, and a higherFoxP3expression was related to worse prognosis. However, there was no statistically significant relationship between theFoxP3IHC score and RCC malignant progression owning to the limited number of patients in our tissue microarray. Using in vitroFoxP3loss-of-function assays, we verified that silencingFoxP3in 786-O and ACHN cells could inhibit the cell migration/invasion capability, which was consistent with the data from RNA sequencing in 786-O cells and from the TCGA datasets. Using an in vivo nude mice orthotopic kidney cancer model, we found that silencingFoxP3could inhibit tumor growth. In conclusion, our study demonstrated thatBAP1orSEDT2mutation could lead to higher expression ofFoxP3in RCC patients, andFoxP3could eventually stimulate RCC cells' invasion and metastasis, which might indicate thatFoxP3could function as a potential oncogene in RCC progression."
-,37564101,Comparative transcriptome characterization of esophageal squamous cell carcinoma and adenocarcinoma.,Comput Struct Biotechnol J,"Esophageal cancers are primarily categorized as esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). While various (epi) genomic alterations associated with tumor development in ESCC and EAC have been documented, a comprehensive comparison of the transcriptomes in these two cancer subtypes remains lacking.We collected 551 gene expression profiles from publicly available sources, including normal, ESCC, and EAC tissues or cell lines. Subsequently, we conducted a systematic analysis to compare the transcriptomes of these samples at various levels, including gene expression, promoter activity, alternative splicing (AS), alternative polyadenylation (APA), and gene fusion.Seven distinct cluster gene expression patterns were identified among the differentially expressed genes in normal, ESCC, and EAC tissues. These patterns were enriched in the PI3K-Akt signaling pathway and the activation of extracellular matrix organization and exhibited repression of epidermal development. Notably, we observed additional genes or unique expression levels enriched in these shared pathways and biological processes related to tumor development and immune activation. In addition to the differentially expressed genes, there was an enrichment of lncRNA co-expression networks and downregulation of promoter activity associated with the repression of epidermal development in both ESCC and EAC. This indicates a common feature between these two cancer subtypes. Furthermore, differential AS and APA patterns in ESCC and EAC appear to partially affect the expression of host genes associated with bacterial or viral infections in these subtypes. No gene fusions were observed between ESCC and EAC, thus highlighting the distinct molecular mechanisms underlying these two cancer subtypes.We conducted a comprehensive comparison of ESCC and EAC transcriptomes and uncovered shared and distinct transcriptomic signatures at multiple levels. These findings suggest that ESCC and EAC may exhibit common and unique mechanisms involved in tumorigenesis.© 2023 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology."
-,37558831,NA,NA,"Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analyse 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detect the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constitutes drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduces anticipated associations, and in addition, we find that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.© 2023. Springer Nature Limited."
-,37554444,The SWI/SNF complex member SMARCB1 supports lineage fidelity in kidney cancer.,iScience,"Lineage switching can induce therapy resistance in cancer. Yet, how lineage fidelity is maintained and how it can be lost remain poorly understood. Here, we have used CRISPR-Cas9-based genetic screening to demonstrate that loss of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, can confer an advantage to clear cell renal cell carcinoma (ccRCC) cells upon inhibition of the renal lineage factor PAX8. Lineage factor inhibition-resistant ccRCC cells formed tumors with morphological features, but not molecular markers, of neuroendocrine differentiation. SMARCB1 inactivation led to large-scale loss of kidney-specific epigenetic programs and restoration of proliferative capacity through the adoption of new dependencies on factors that represent rare essential genes across different cancers. We further developed an analytical approach to systematically characterize lineage fidelity using large-scale CRISPR-Cas9 data. An understanding of the rules that govern lineage switching could aid the development of more durable lineage factor-targeted and other cancer therapies.© 2023 The Author(s)."
-,37546802,Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.,bioRxiv,"The chromatin-associated protein WDR5 is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the ""WIN"" site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoetic stem cell expansion. Our discovery and interrogation of small molecule WIN site inhibitors, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anti-cancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad translational choke, induction of a DNA damage response, and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anti-cancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies."
-,37544034,APE1 promotes radiation resistance against radiation-induced pyroptosis by inhibiting the STING pathway in lung adenocarcinoma.,Transl Oncol,"Mammalian apurinic/apyrimidinic endonuclease 1 (APE1, APEX1) is a multifunctional enzyme that maintains cellular homeostasis. It is involved in the base excision repair (BER) pathway and plays a key role in radiation-induced DNA damage response. However, the relationship between APE1-driven radiation resistance and pyroptosis in lung adenocarcinoma (LUAD) cells and the underlying molecular mechanisms remain unclear. We found that APE1 was significantly upregulated in LUAD tissues compared to para-carcinoma tissues and promoted the proliferation and invasion of LUAD cells in vitro and in vivo. Mechanistically, APE1 inhibited pyroptosis by inactivating the interferon gene stimulator (STING) pathway via direct interaction with AIM2 and DDX41, as detected by RNA-seq and co-immunoprecipitation. APE1 protects LUAD cells against radiation-induced damage and induces radio-resistance by targeting the STING pathway. It can induce pyroptosis and is negatively regulated by interactions with AIM2 and DDX41. Therefore, APE1 inhibitors should be considered to enhance the radiosensitivity of LUAD cells and improve patient prognosis and therapeutic outcomes. Thus, APE1 play a role in the tumor immune microenvironment and in tumor immunotherapy.Copyright © 2023. Published by Elsevier Inc."
-,37523146,High-Throughput Drug Screening of Primary Tumor Cells Identifies Therapeutic Strategies for Treating Children with High-Risk Cancer.,Cancer Res,"For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed in vitro screening of 125 patient-derived samples against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in NTRK, BRAF, and ALK and responses to matching targeted drugs. The in vitro results were further validated in patient-derived xenograft models in vivo and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers.Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers.©2023 The Authors; Published by the American Association for Cancer Research."
-,37488358,Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.,Nat Struct Mol Biol,"Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2, wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal deletions that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic disruption or dTAG-mediated degradation, we show that targeting HDAC2 suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2-NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders that could leverage HDAC1/2 synthetic lethality to target NuRD vulnerabilities. Altogether, we identify HDAC1/2 collateral synthetic lethality as a potential therapeutic target and reveal an unexplored mechanism for targeting NuRD-associated cancer dependencies.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
-,37487008,Single-cell transcriptomics reveals the drivers and therapeutic targets of lymph node metastasis in lung adenocarcinoma.,Aging (Albany NY),"Lymph node metastasis (LNM) is usually the most common metastatic pathway in lung adenocarcinoma (LUAD) and is associated with a poorer prognosis and higher possibility of recurrence. Therefore, discovering the drivers and therapeutic targets of LNM is important for early and non-invasive detection of patients with a high risk of LNM and guiding individualized therapy. Various cell constitutions of the primary tumor and lymph node microenvironment was characterized based on scRNA-seq data. The copy number variation (CNV) analysis was performed to probe clonal structures and origins of metastatic lymph nodes, and found 6q loss and 20q gain may drive LNM in LUAD. Then a LNM-related cell subset, named Scissor+ cells, was identified using the Scissor algorithm. And cell-cell communication network among Scissor+ cells and microenvironment was further analyzed. Besides, a pro-LNM signature was subsequently constructed based on 27 genes using pseudotime trajectory analysis and gene set variation analysis. The pro-LNM signature showed a significant correlation withNstage and a good predictive ability of LUAD survival. At last, we identified that erastin and gefitinib could potentially inhibit LNM by targeting Scissor+ cells based on the drug sensitivity data of the cancer cell lines, which provided new insights for LUAD therapy."
-,37577627,KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster.,bioRxiv,"Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous,de novotruncating mutations inLysine(K) acetyltransferase 6A(KAT6A). ARTHS is clinically heterogeneous and characterized by several common features including intellectual disability, developmental and speech delay, hypotonia and affects multiple organ systems.KAT6Ais highly expressed in early development and plays a key role in cell-type specific differentiation. KAT6A is the enzymatic core of a histone-acetylation protein complex, however the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n=8) and control (n=14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused byKAT6Amutations. We identified differential chromatin accessibility within the promoter or gene body of 23%(14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posteriorHOXCgene cluster (HOXC10,HOXC11,HOXC-AS3, HOXC-AS2, HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles ofKAT6Ain a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types."
-,37627316,NA,NA,"Intracranial and extracranial large-artery atherosclerosis (LAA) are a main cause of ischemic stroke. Biomarkers may aid in the diagnosis of LAA and help to stratify patients' risk of stroke. We performed a narrative review of the literature, mainly published in the last five years, with the aim of identifying biomarkers associated either with intracranial or extracranial LAA in humans. Several potential biomarkers of LAA, mainly related to lipidic pathways and inflammation, have been studied. Diagnostic biomarkers of LAA were evaluated by measuring biomarkers levels in patients with LAA stroke and other stroke etiologies. Some biomarkers were associated with the functional prognosis of LAA stroke patients. Increased levels of IL-6 and sLOX-1 were associated with a risk of progression of carotid atherosclerotic disease. Findings support the notion that the immune system plays a central role in the pathogenesis of LAA. Overall, in most studies, results were not externally validated. In the future, biomarkers could be useful for the selection of patients for clinical trials. To adopt these biomarkers in clinical practice, we will need robust multicentric studies proving their reproducibility and a clear practical applicability for their use."
-,37575906,"Association of gut microbiota, plasma and fecal metabolite profiles with intellectual development in school-age children.",Transl Pediatr,"Little is known about how the gut microbiota and metabolic profiles are related to cognitive outcomes in young children until now. It was hypothesized that the gut microbiota, the plasma and fecal metabolites significantly correlated with intelligence quotient (IQ) in school-age children in current study.This cross-sectional study enrolled 452 children aged 6-9 years old. IQ was measured using the Wechsler Intelligence Scale for Children-Fourth Edition. Fecal microbiota, plasma and fecal metabolites were analyzed using 16S rRNA amplicon sequencing and targeted metabolomic technologies, respectively.Restricted maximum likelihood (REML) analyses showed that microbiota composition and fecal metabolites were associated with neither subscale nor full-scale IQ (P: 0.059-0.500). However, plasma metabolites were significantly correlated with the processing speed (P=0.008). In multiple regression analysis after adjusting for confounders and multiple test correction, benzoic acid, azelaic acid, adipic acid, suberic acid and malonic acid selected by the multivariate methods with unbiased variable selection were positively associated with processing speed index (PSI) [Pfalse discovery rate (FDR): 0.006-0.024], whereas pyruvic acid was negatively associated with the PSI and full-scale IQ (PFDR: 0.014-0.030).In normal school-age children, certain plasma metabolites concentrations but not the gut microbiota composition nor fecal metabolites are correlated with intelligence.2023 Translational Pediatrics. All rights reserved."
-,37601094,Post-translational modifications and protein quality control of mitochondrial channels and transporters.,Front Cell Dev Biol,"Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.Copyright © 2023 Kadam, Jadiya and Tomar."
-,37591949,NA,NA,"LINE-1s are the major clade of retrotransposons with autonomous retrotransposition activity. Despite the potential genotoxicity, LINE-1s are highly activated in early embryos. Here we show that a subset of young LINE-1s, L1Md_Ts, are marked by the RNA polymerase II elongation factor ELL3, and function as enhancers in mouse embryonic stem cells. ELL3 depletion dislodges the DNA hydroxymethylase TET1 and the co-repressor SIN3A from L1Md_Ts, but increases the enrichment of the Bromodomain protein BRD4, leading to loss of 5hmC, gain of H3K27ac, and upregulation of the L1Md_T nearby genes. Specifically, ELL3 occupies and represses the L1Md_T-based enhancer located within Akt3, which encodes a key regulator of AKT pathway. ELL3 is required for proper ERK activation and efficient shutdown of naïve pluripotency through inhibiting Akt3 during naïve-primed transition. Our study reveals that the enhancer function of a subset of young LINE-1s controlled by ELL3 in transcription regulation and mouse early embryo development.© 2023. The Author(s), under exclusive licence to Springer Nature Limited."
-,37645713,Dissecting tumor transcriptional heterogeneity from single-cell RNA-seq data by generalized binary covariance decomposition.,bioRxiv,"Profiling tumors with single-cell RNA sequencing (scRNA-seq) has the potential to identify recurrent patterns of transcription variation related to cancer progression, and so produce new therapeutically-relevant insights. However, the presence of strong inter-tumor heterogeneity often obscures more subtle patterns that are shared across tumors, some of which may characterize clinically-relevant disease subtypes. Here we introduce a new statistical method to address this problem. We show that this method can help decompose transcriptional heterogeneity into interpretable components - including patient-specific, dataset-specific and shared components relevant to disease subtypes - and that, in the presence of strong inter-tumor heterogeneity, our method can produce more interpretable results than existing widely-used methods. Applied to data from three studies on pancreatic cancer adenocarcinoma (PDAC), our method produces a refined characterization of existing tumor subtypes (e.g. classical vs basal), and identifies a new gene expression program (GEP) that is prognostic of poor survival independent of established prognostic factors such as tumor stage and subtype. The new GEP is enriched for genes involved in a variety of stress responses, and suggests a potentially important role for the integrated stress response in PDAC development and prognosis."
-,37645043,Modeling and interpretation of single-cell proteogenomic data.,ArXiv,"Biological functions stem from coordinated interactions among proteins, nucleic acids and small molecules. Mass spectrometry technologies for reliable, high throughput single-cell proteomics will add a new modality to genomics and enable data-driven modeling of the molecular mechanisms coordinating proteins and nucleic acids at single-cell resolution. This promising potential requires estimating the reliability of measurements and computational analysis so that models can distinguish biological regulation from technical artifacts. We discuss approaches for developing both abstract and mechanistic models that aim to biologically interpret the measured differences across modalities. Mechanistic models of direct molecular interactions will provide generalizable and predictive representations of biological systems."
-,37639146,NA,NA,"The advance of single-cell RNA-sequencing technologies in the past years has enabled unprecedented insights into the complexity and heterogeneity of microglial cell states in the homeostatic and diseased brain. This includes rather complex proteomic, metabolomic, morphological, transcriptomic, and epigenetic adaptations to external stimuli and challenges resulting in a novel concept of core microglia properties and functions. To uncover the regulatory programs facilitating the rapid transcriptomic adaptation in response to changes in the local microenvironment, the accessibility of gene bodies and gene regulatory elements can be assessed. Here, we describe the application of a previously published method for simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq) on microglia nuclei isolated from frozen mouse brain tissue.© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature."
-,37600970,NA,NA,"Important quantities of biological data can today be acquired to characterize cell types and states, from various sources and using a wide diversity of methods, providing scientists with more and more information to answer challenging biological questions. Unfortunately, working with this amount of data comes at the price of ever-increasing data complexity. This is caused by the multiplication of data types and batch effects, which hinders the joint usage of all available data within common analyses. Data integration describes a set of tasks geared towards embedding several datasets of different origins or modalities into a joint representation that can then be used to carry out downstream analyses. In the last decade, dozens of methods have been proposed to tackle the different facets of the data integration problem, relying on various paradigms. This review introduces the most common data types encountered in computational biology and provides systematic definitions of the data integration problems. We then present how machine learning innovations were leveraged to build effective data integration algorithms, that are widely used today by computational biologists. We discuss the current state of data integration and important pitfalls to consider when working with data integration tools. We eventually detail a set of challenges the field will have to overcome in the coming years.Copyright © 2023 Fouché and Zinovyev."
-,37577383,Dissecting the brain with spatially resolved multi-omics.,J Pharm Anal,"Recent studies have highlighted spatially resolved multi-omics technologies, including spatial genomics, transcriptomics, proteomics, and metabolomics, as powerful tools to decipher the spatial heterogeneity of the brain. Here, we focus on two major approaches in spatial transcriptomics (next-generation sequencing-based technologies and image-based technologies), and mass spectrometry imaging technologies used in spatial proteomics and spatial metabolomics. Furthermore, we discuss their applications in neuroscience, including building the brain atlas, uncovering gene expression patterns of neurons for special behaviors, deciphering the molecular basis of neuronal communication, and providing a more comprehensive explanation of the molecular mechanisms underlying central nervous system disorders. However, further efforts are still needed toward the integrative application of multi-omics technologies, including the real-time spatial multi-omics analysis in living cells, the detailed gene profile in a whole-brain view, and the combination of functional verification.© 2023 The Author(s)."
-,37566049,"A Review of Single-Cell RNA-Seq Annotation, Integration, and Cell-Cell Communication.",Cells,"Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for investigating cellular biology at an unprecedented resolution, enabling the characterization of cellular heterogeneity, identification of rare but significant cell types, and exploration of cell-cell communications and interactions. Its broad applications span both basic and clinical research domains. In this comprehensive review, we survey the current landscape of scRNA-seq analysis methods and tools, focusing on count modeling, cell-type annotation, data integration, including spatial transcriptomics, and the inference of cell-cell communication. We review the challenges encountered in scRNA-seq analysis, including issues of sparsity or low expression, reliability of cell annotation, and assumptions in data integration, and discuss the potential impact of suboptimal clustering and differential expression analysis tools on downstream analyses, particularly in identifying cell subpopulations. Finally, we discuss recent advancements and future directions for enhancing scRNA-seq analysis. Specifically, we highlight the development of novel tools for annotating single-cell data, integrating and interpreting multimodal datasets covering transcriptomics, epigenomics, and proteomics, and inferring cellular communication networks. By elucidating the latest progress and innovation, we provide a comprehensive overview of the rapidly advancing field of scRNA-seq analysis."
-,37547002,Batch-Corrected Distance Mitigates Temporal and Spatial Variability for Clustering and Visualization of Single-Cell Gene Expression Data.,Res Sq,"Clustering and visualization are essential parts of single-cell gene expression data analysis. The Euclidean distance used in most distance-based methods is not optimal. The batch effect, i.e., the variability among samples gathered from different times, tissues, and patients, introduces large between-group distance and obscures the true identities of cells. To solve this problem, we introduce Batch-Corrected Distance (BCD), a metric using temporal/spatial locality of the batch effect to control for such factors. We validate BCD on simulated data as well as applied it to a mouse retina development dataset and a lung dataset. We also found the utility of our approach in understanding the progression of the Coronavirus Disease 2019 (COVID-19). BCD achieves more accurate clusters and better visualizations than state-of-the-art batch correction methods on longitudinal datasets. BCD can be directly integrated with most clustering and visualization methods to enable more scientific findings."
-,37535039,"Single-cell multiomic understanding of HIV-1 reservoir at epigenetic, transcriptional, and protein levels.",Curr Opin HIV AIDS,"The success of HIV-1 eradication strategies relies on in-depth understanding of HIV-1-infected cells. However, HIV-1-infected cells are extremely heterogeneous and rare. Single-cell multiomic approaches resolve the heterogeneity and rarity of HIV-1-infected cells.Advancement in single-cell multiomic approaches enabled HIV-1 reservoir profiling across the epigenetic (ATAC-seq), transcriptional (RNA-seq), and protein levels (CITE-seq). Using HIV-1 RNA as a surrogate, ECCITE-seq identified enrichment of HIV-1-infected cells in clonally expanded cytotoxic CD4+ T cells. Using HIV-1 DNA PCR-activated microfluidic sorting, FIND-seq captured the bulk transcriptome of HIV-1 DNA+ cells. Using targeted HIV-1 DNA amplification, PheP-seq identified surface protein expression of intact versus defective HIV-1-infected cells. Using ATAC-seq to identify HIV-1 DNA, ASAP-seq captured transcription factor activity and surface protein expression of HIV-1 DNA+ cells. Combining HIV-1 mapping by ATAC-seq and HIV-1 RNA mapping by RNA-seq, DOGMA-seq captured the epigenetic, transcriptional, and surface protein expression of latent and transcriptionally active HIV-1-infected cells. To identify reproducible biological insights and authentic HIV-1-infected cells and avoid false-positive discovery of artifacts, we reviewed current practices of single-cell multiomic experimental design and bioinformatic analysis.Single-cell multiomic approaches may identify innovative mechanisms of HIV-1 persistence, nominate therapeutic strategies, and accelerate discoveries.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved."
-,37615906,CTLA-4 and ovarian cancer residual tumors: the dark side of debulking surgery.,Hum Cell,NA
-,37585411,Membrane metalloendopeptidase (MME) is positively correlated with systemic lupus erythematosus and may inhibit the occurrence of breast cancer.,PLoS One,"Patients with systemic lupus erythematosus (SLE) have a lower risk of breast cancer (BRCA) than the general population. In this study, we explored the underlying molecular mechanism that is dysregulated in both diseases.Weighted gene coexpression network analysis (WGCNA) was executed with the SLE and BRCA datasets from the Gene Expression Omnibus (GEO) website and identified the potential role of membrane metalloendopeptidase (MME) in both diseases. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of related proteins and miRNAs were performed to investigate the potential molecular pathways.WGCNA revealed that MME was positively related to SLE but negatively related to BRCA. In BRCA, MME expression was significantly decreased in tumor tissues, especially in luminal B and infiltrating ductal carcinoma subtypes. Receiver operating characteristic (ROC) analysis identified MME as a valuable diagnostic biomarker of BRCA, with an area under the curve (AUC) value equal to 0.984 (95% confidence interval = 0.976-0.992). KEGG enrichment analysis suggested that MME-related proteins and targeted miRNAs may reduce the incidence of BRCA in SLE patients via the PI3K/AKT/FOXO signaling pathway. Low MME expression was associated with favorable relapse-free survival (RFS) but no other clinical outcomes and may contribute to resistance to chemotherapy in BRCA, with an AUC equal to 0.527 (P value < 0.05).In summary, MME expression was significantly decreased in BRCA but positively correlated with SLE, and it might reduce the incidence of BRCA in SLE patients via the PI3K/AKT/FOXO signaling pathway.Copyright: © 2023 Ding et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37627276,A Comparison of Cell-Cell Interaction Prediction Tools Based on scRNA-seq Data.,Biomolecules,"Computational prediction of cell-cell interactions (CCIs) is becoming increasingly important for understanding disease development and progression. We present a benchmark study of available CCI prediction tools based on single-cell RNA sequencing (scRNA-seq) data. By comparing prediction outputs with a manually curated gold standard for idiopathic pulmonary fibrosis (IPF), we evaluated prediction performance and processing time of several CCI prediction tools, including CCInx, CellChat, CellPhoneDB, iTALK, NATMI, scMLnet, SingleCellSignalR, and an ensemble of tools. According to our results, CellPhoneDB and NATMI are the best performer CCI prediction tools, among the ones analyzed, when we define a CCI as a source-target-ligand-receptor tetrad. In addition, we recommend specific tools according to different types of research projects and discuss the possible future paths in the field."
-,37575241,Prognostic value and immune landscapes of TERT promoter methylation in triple negative breast cancer.,Front Immunol,"Treatment options for patients with triple-negative breast cancer (TNBC) remain limited to mainstay therapies owing to a lack of efficacious therapeutic targets. Accordingly, there is an urgent need to discover and identify novel molecular targets for the treatment and diagnosis of this disease. In this study, we analyzed the correlation of telomerase reverse transcriptase (TERT) methylation status with TERT expression, prognosis, and immune infiltration in TNBC and identified the role of TERT methylation in the regulation TNBC prognosis and immunotherapy.Data relating to the transcriptome, clinicopathological characteristics and methylation of TNBC patients were obtained from The Cancer Genome Atlas (TCGA) database. TERT expression levels and differential methylation sites (DMSs) were detected. The correlations between TERT expression and DMSs were calculated. Kaplan-Meier curves was plotted to analyze the relationship between the survival of TNBC patients and the DMSs. The correlations of DMSs and TERT expression with several immunological characteristics of immune microenvironment (immune cell infiltration, immunomodulators, immune-related biological pathways, and immune checkpoints) were assessed. The results were validated using 40 TNBC patients from Sun Yat-sen University Cancer Center (SYSUCC).Six DMSs were identified. Among them, four sites (cg11625005, cg07380026, cg17166338, and cg26006951) were within the TERT promoter, in which two sites (cg07380026 and cg26006951) were significantly related to the prognosis of patients with TNBC. Further validation using 40 TNBC samples from SYSUCC showed that the high methylation of the cg26006951 CpG site was associated with poor survival prognosis (P=0.0022). TERT expression was significantly correlated with pathological N stage and clinical stage, and cg07380026 were significantly associated with pathological T and N stages in the TCGA cohort. Moreover, the methylation site cg26006951, cg07380026 and TERT expression were significantly correlated with immune cell infiltration, common immunomodulators, and the level of the immune checkpoint receptor lymphocyte activation gene 3 (LAG-3) in TNBC patients.TERT promotertypermethylation plays an important role in TERT expression regulation and tumor microenvironment in TNBC. It is associated with overall survival and LAG-3 expression. TERT promoter hypermethylation may be a potential molecular biomarker for predicting response to the TERT inhibitors and immune checkpoint inhibitors in TNBC.Copyright © 2023 Lin, Huang, Zhu, Jiang, Guo, Xia, Chen, Guo, Deng and Lin."
-,37527019,USNAP: fast unique dense region detection and its application to lung cancer.,Bioinformatics,"Many real-world problems can be modeled as annotated graphs. Scalable graph algorithms that extract actionable information from such data are in demand since these graphs are large, varying in topology, and have diverse node/edge annotations. When these graphs change over time they create dynamic graphs, and open the possibility to find patterns across different time points. In this article, we introduce a scalable algorithm that finds unique dense regions across time points in dynamic graphs. Such algorithms have applications in many different areas, including the biological, financial, and social domains.There are three important contributions to this manuscript. First, we designed a scalable algorithm, USNAP, to effectively identify dense subgraphs that are unique to a time stamp given a dynamic graph. Importantly, USNAP provides a lower bound of the density measure in each step of the greedy algorithm. Second, insights and understanding obtained from validating USNAP on real data show its effectiveness. While USNAP is domain independent, we applied it to four non-small cell lung cancer gene expression datasets. Stages in non-small cell lung cancer were modeled as dynamic graphs, and input to USNAP. Pathway enrichment analyses and comprehensive interpretations from literature show that USNAP identified biologically relevant mechanisms for different stages of cancer progression. Third, USNAP is scalable, and has a time complexity of O(m+mc log nc+nc log nc), where m is the number of edges, and n is the number of vertices in the dynamic graph; mc is the number of edges, and nc is the number of vertices in the collapsed graph.The code of USNAP is available at https://www.cs.utoronto.ca/~juris/data/USNAP22.© The Author(s) 2023. Published by Oxford University Press."
-,37607190,Inferring gene regulatory networks using transcriptional profiles as dynamical attractors.,PLoS Comput Biol,"Genetic regulatory networks (GRNs) regulate the flow of genetic information from the genome to expressed messenger RNAs (mRNAs) and thus are critical to controlling the phenotypic characteristics of cells. Numerous methods exist for profiling mRNA transcript levels and identifying protein-DNA binding interactions at the genome-wide scale. These enable researchers to determine the structure and output of transcriptional regulatory networks, but uncovering the complete structure and regulatory logic of GRNs remains a challenge. The field of GRN inference aims to meet this challenge using computational modeling to derive the structure and logic of GRNs from experimental data and to encode this knowledge in Boolean networks, Bayesian networks, ordinary differential equation (ODE) models, or other modeling frameworks. However, most existing models do not incorporate dynamic transcriptional data since it has historically been less widely available in comparison to ""static"" transcriptional data. We report the development of an evolutionary algorithm-based ODE modeling approach (named EA) that integrates kinetic transcription data and the theory of attractor matching to infer GRN architecture and regulatory logic. Our method outperformed six leading GRN inference methods, none of which incorporate kinetic transcriptional data, in predicting regulatory connections among TFs when applied to a small-scale engineered synthetic GRN in Saccharomyces cerevisiae. Moreover, we demonstrate the potential of our method to predict unknown transcriptional profiles that would be produced upon genetic perturbation of the GRN governing a two-state cellular phenotypic switch in Candida albicans. We established an iterative refinement strategy to facilitate candidate selection for experimentation; the experimental results in turn provide validation or improvement for the model. In this way, our GRN inference approach can expedite the development of a sophisticated mathematical model that can accurately describe the structure and dynamics of the in vivo GRN.Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37614425,NA,NA,"Asthma is a complex disease, often with evident genetic predisposition; for example, the single-nucleotide polymorphism (SNP) rs7130588 was significantly associated with asthma by genome-wide association study (GWAS). Analysis of 1000 Genomes Project data suggests that there is another SNP, rs6592645, in complete linkage disequilibrium with rs7130588 and should present the same signal in GWAS. However, the causal SNP and the mechanism for the association between rs7130588 and asthma remain to be elucidated. In the presents study, results from dual-luciferase assays indicated that the A/G alleles of rs7130588 failed to present significantly different reporter gene expression. By contrast, A allele of rs6592645 presented a significant increase in relative luciferase activity than G allele, thus suggesting that rs6592645 may be a causal SNP. Using chromosome conformation capture, the enhancer region containing rs6592645 was observed to interact with promoter region of leucine-rich repeat-containing 32 (LRRC32). Gene expression quantification suggested thatLRRC32expression is significantly increased in lung tissue of patients with asthma and is dependent on the genotype of this locus, thus verifying thatLRRC32may be involved in asthma onset and that rs6592645 can regulateLRRC32expression. Through chromatin immunoprecipitation, transcription factor 3 (TCF3) was identified to bind to rs6592645 surrounding region and the interaction between TCF3 and rs6592645 surrounding region was investigated. Results from the present study may improve our understanding of the mechanism by which the genetic variation in this locus might influence asthma susceptibility.Copyright © 2020, Spandidos Publications."
-,37669931,Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia.,Nat Commun,"Preeclampsia (PE) is the leading cause of maternal and fetal mortality globally and may trigger dementia later in life in mothers and their offspring. However, the etiological drivers remain elusive. Cis P-tau is an early etiological driver and blood biomarker in pre-clinical Alzheimer's and after vascular or traumatic brain injury, which can be targeted by stereo-specific antibody, with clinical trials ongoing. Here we find significant cis P-tau in the placenta and serum of PE patients, and in primary human trophoblasts exposed to hypoxia or sera from PE patients due to Pin1 inactivation. Depletion of cis P-tau from PE patient sera by the antibody prevents their ability to disrupt trophoblast invasion and endovascular activity and to cause the PE-like pathological and clinical features in pregnant humanized tau mice. Our studies uncover that cis P-tau is a central circulating etiological driver and its stereo-specific antibody is valuable for early PE diagnosis and treatment.© 2023. Springer Nature Limited."
-,37667186,NA,NA,"A relevant part of the genetic architecture of complex traits is still unknown; despite the discovery of many disease-associated common variants. Polygenic risk score (PRS) models are based on the evaluation of the additive effects attributable to common variants and have been successfully implemented to assess the genetic susceptibility for many phenotypes. In contrast, burden tests are often used to identify an enrichment of rare deleterious variants in specific genes. Both kinds of genetic contributions are typically analyzed independently. Many studies suggest that complex phenotypes are influenced by both low effect common variants and high effect rare deleterious variants. The aim of this paper is to integrate the effect of both common and rare functional variants for a more comprehensive genetic risk modeling.We developed a framework combining gene-based scores based on the enrichment of rare functionally relevant variants with genome-wide PRS based on common variants for association analysis and prediction models. We applied our framework on UK Biobank dataset with genotyping and exome data and considered 28 blood biomarkers levels as target phenotypes. For each biomarker, an association analysis was performed on full cohort using gene-based scores (GBS). The cohort was then split into 3 subsets for PRS construction and feature selection, predictive model training, and independent evaluation, respectively. Prediction models were generated including either PRS, GBS or both (combined).Association analyses of the cohort were able to detect significant genes that were previously known to be associated with different biomarkers. Interestingly, the analyses also revealed heterogeneous effect sizes and directionality highlighting the complexity of the blood biomarkers regulation. However, the combined models for many biomarkers show little or no improvement in prediction accuracy compared to the PRS models.This study shows that rare variants play an important role in the genetic architecture of complex multifactorial traits such as blood biomarkers. However, while rare deleterious variants play a strong role at an individual level, our results indicate that classical common variant based PRS might be more informative to predict the genetic susceptibility at the population level.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37644440,NA,NA,"Understanding the impact of gene interactions on disease phenotypes is increasingly recognised as a crucial aspect of genetic disease research. This trend is reflected by the growing amount of clinical research on oligogenic diseases, where disease manifestations are influenced by combinations of variants on a few specific genes. Although statistical machine-learning methods have been developed to identify relevant genetic variant or gene combinations associated with oligogenic diseases, they rely on abstract features and black-box models, posing challenges to interpretability for medical experts and impeding their ability to comprehend and validate predictions. In this work, we present a novel, interpretable predictive approach based on a knowledge graph that not only provides accurate predictions of disease-causing gene interactions but also offers explanations for these results.We introduce BOCK, a knowledge graph constructed to explore disease-causing genetic interactions, integrating curated information on oligogenic diseases from clinical cases with relevant biomedical networks and ontologies. Using this graph, we developed a novel predictive framework based on heterogenous paths connecting gene pairs. This method trains an interpretable decision set model that not only accurately predicts pathogenic gene interactions, but also unveils the patterns associated with these diseases. A unique aspect of our approach is its ability to offer, along with each positive prediction, explanations in the form of subgraphs, revealing the specific entities and relationships that led to each pathogenic prediction.Our method, built with interpretability in mind, leverages heterogenous path information in knowledge graphs to predict pathogenic gene interactions and generate meaningful explanations. This not only broadens our understanding of the molecular mechanisms underlying oligogenic diseases, but also presents a novel application of knowledge graphs in creating more transparent and insightful predictors for genetic research.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37577666,"GEGenetic regulatory effects in response to a high cholesterol, high fat diet in baboons.",bioRxiv,"Disease-associated loci discovered through genome-wide association studies (GWAS) are primarily located in non-coding regions with putative regulatory effects on gene expression1. Steady-state, standard expression quantitative trait loci (eQTLs) explain only a limited portion of GWAS signals2-6, while eQTLs involved in gene-by-environment (GxE) interactions have rarely been characterized in humans due to experimental challenges. Here, we characterized gene-by-diet effects in a baboon model system. By analyzing three tissue types obtained from 99 captive baboons, we identify hundreds of diet-responsive eQTLs with high tissue specificity. Diet-responsive eQTLs exhibit genomic localization and genic features that are distinct from steady-state eQTLs. Furthermore, the human orthologs of genes associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context-responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. Our results highlight the dynamic complexity of genetic regulatory effects and the potential of eQTLs with disease-relevant GxE interactions in enhancing the understanding of GWAS signals for human complex disease using the baboon model."
-,37554308,Functional genomics in stem cell models: considerations and applications.,Front Cell Dev Biol,"Protocols to differentiate human pluripotent stem cells have advanced in terms of cell type specificity and tissue-level complexity over the past 2 decades, which has facilitated human disease modeling in the most relevant cell types. The ability to generate induced PSCs (iPSCs) from patients further enables the study of disease mutations in an appropriate cellular context to reveal the mechanisms that underlie disease etiology and progression. As iPSC-derived disease models have improved in robustness and scale, they have also been adopted more widely for use in drug screens to discover new therapies and therapeutic targets. Advancement in genome editing technologies, in particular the discovery of CRISPR-Cas9, has further allowed for rapid development of iPSCs containing disease-causing mutations. CRISPR-Cas9 technologies have now evolved beyond creating single gene edits, aided by the fusion of inhibitory (CRISPRi) or activation (CRISPRa) domains to a catalytically dead Cas9 protein, enabling inhibition or activation of endogenous gene loci. These tools have been used in CRISPR knockout, CRISPRi, or CRISPRa screens to identify genetic modifiers that synergize or antagonize with disease mutations in a systematic and unbiased manner, resulting in identification of disease mechanisms and discovery of new therapeutic targets to accelerate drug discovery research. However, many technical challenges remain when applying large-scale functional genomics approaches to differentiated PSC populations. Here we review current technologies in the field of iPSC disease modeling and CRISPR-based functional genomics screens and practical considerations for implementation across a range of modalities, applications, and disease areas, as well as explore CRISPR screens that have been performed in iPSC models to-date and the insights and therapies these screens have produced.Copyright © 2023 Shevade, Peddada, Mader and Przybyla."
-,37478860,Platform-agnostic CellNet enables cross-study analysis of cell fate engineering protocols.,Stem Cell Reports,"Optimization of cell engineering protocols requires standard, comprehensive quality metrics. We previously developed CellNet, a computational tool to quantitatively assess the transcriptional fidelity of engineered cells compared with their natural counterparts, based on bulk-derived expression profiles. However, this platform and others were limited in their ability to compare data from different sources, and no current tool makes it easy to compare new protocols with existing state-of-the-art protocols in a standardized manner. Here, we utilized our prior application of the top-scoring pair transformation to build a computational platform, platform-agnostic CellNet (PACNet), to address both shortcomings. To demonstrate the utility of PACNet, we applied it to thousands of samples from over 100 studies that describe dozens of protocols designed to produce seven distinct cell types. We performed an in-depth examination of hepatocyte and cardiomyocyte protocols to identify the best-performing methods, characterize the extent of intra-protocol and inter-lab variation, and identify common off-target signatures, including a surprising neural/neuroendocrine signature in primary liver-derived organoids. We have made PACNet available as an easy-to-use web application, allowing users to assess their protocols relative to our database of reference engineered samples, and as open-source, extensible code.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved."
-,37592093,Integrative analysis of GWAS and transcriptomics data reveal key genes for non-small lung cancer.,Med Oncol,"Lung cancer is one of the world's most common and deadly cancers. The two main types of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). More than 85% of lung cancers are NSCLC. Genetic factors play a significant role in the risk of NSCLC. Growing studies focus on studying risk factors at the molecular level. The aim of the study is to build a pipeline to integrate Genome-wide association analysis (GWAS) and transcriptomics data with machine learning to effectively identify genetic risk factors of NSCLC. GWAS datasets and GWAS summary data were downloaded from GWAS catalog, which include lung carcinoma genetic variants among the European population. Then, with the GWAS summary, data functional analysis of significant SNPs was performed using a webserver called FUMAGWAS. The transcriptomics data of NSCLC and non-NSCLC people were used to build a machine learning model to identify the key genes that help predict the NSCLC. The top up-regulation and down-regulation genes were identified by the BART cancer webserver, and the mechanistic roles of the genes were validated by literature review. By performing integrative analysis of GWAS and transcriptomics analysis using machine learning, we identified multiple SNPs and genes that related to NSCLC. The computational pipeline may facilitate the biomarker discovery for NSCLC and other diseases.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature."
-,37640946,NA,NA,"Oxidative modification of 5-methylcytosine (5mC) by ten-eleven translocation (TET) DNA dioxygenases generates 5-hydroxymethylcytosine (5hmC), the most abundant form of oxidized 5mC. Existing single-cell bisulfite sequencing methods cannot resolve 5mC and 5hmC, leaving the cell-type-specific regulatory mechanisms of TET and 5hmC largely unknown. Here, we present joint single-nucleus (hydroxy)methylcytosine sequencing (Joint-snhmC-seq), a scalable and quantitative approach that simultaneously profiles 5hmC and true 5mC in single cells by harnessing differential deaminase activity of APOBEC3A toward 5mC and chemically protected 5hmC. Joint-snhmC-seq profiling of single nuclei from mouse brains reveals an unprecedented level of epigenetic heterogeneity of both 5hmC and true 5mC at single-cell resolution. We show that cell-type-specific profiles of 5hmC or true 5mC improve multimodal single-cell data integration, enable accurate identification of neuronal subtypes and uncover context-specific regulatory effects on cell-type-specific genes by TET enzymes.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
-,37580628,Simultaneous profiling of chromatin architecture and transcription in single cells.,Nat Struct Mol Biol,"The three-dimensional structure of chromatin plays a crucial role in development and disease, both of which are associated with transcriptional changes. However, given the heterogeneity in single-cell chromatin architecture and transcription, the regulatory relationship between the three-dimensional chromatin structure and gene expression is difficult to explain based on bulk cell populations. Here we develop a single-cell, multimodal, omics method allowing the simultaneous detection of chromatin architecture and messenger RNA expression by sequencing (single-cell transcriptome sequencing (scCARE-seq)). Applying scCARE-seq to examine chromatin architecture and transcription from 2i to serum single mouse embryonic stem cells, we observe improved separation of cell clusters compared with single-cell chromatin conformation capture. In addition, after defining the cell-cycle phase of each cell through chromatin architecture extracted by scCARE-seq, we find that periodic changes in chromatin architecture occur in parallel with transcription during the cell cycle. These findings highlight the potential of scCARE-seq to facilitate comprehensive analyses that may boost our understanding of chromatin architecture and transcription in the same single cell.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
-,37569258,Effects of DNA Methylation on Gene Expression and Phenotypic Traits in Cattle: A Review.,Int J Mol Sci,"Gene expression in cells is determined by the epigenetic state of chromatin. Therefore, the study of epigenetic changes is very important to understand the regulatory mechanism of genes at the molecular, cellular, tissue and organ levels. DNA methylation is one of the most studied epigenetic modifications, which plays an important role in maintaining genome stability and ensuring normal growth and development. Studies have shown that methylation levels in bovine primordial germ cells, the rearrangement of methylation during embryonic development and abnormal methylation during placental development are all closely related to their reproductive processes. In addition, the application of bovine male sterility and assisted reproductive technology is also related to DNA methylation. This review introduces the principle, development of detection methods and application conditions of DNA methylation, with emphasis on the relationship between DNA methylation dynamics and bovine spermatogenesis, embryonic development, disease resistance and muscle and fat development, in order to provide theoretical basis for the application of DNA methylation in cattle breeding in the future."
-,37568653,Precision Medicine: Disease Subtyping and Tailored Treatment.,Cancers (Basel),"The genomics-based concept of precision medicine began to emerge following the completion of the Human Genome Project. In contrast to evidence-based medicine, precision medicine will allow doctors and scientists to tailor the treatment of different subpopulations of patients who differ in their susceptibility to specific diseases or responsiveness to specific therapies. The current precision medicine model was proposed to precisely classify patients into subgroups sharing a common biological basis of diseases for more effective tailored treatment to achieve improved outcomes. Precision medicine has become a term that symbolizes the new age of medicine. In this review, we examine the history, development, and future perspective of precision medicine. We also discuss the concepts, principles, tools, and applications of precision medicine and related fields. In our view, for precision medicine to work, two essential objectives need to be achieved. First, diseases need to be classified into various subtypes. Second, targeted therapies must be available for each specific disease subtype. Therefore, we focused this review on the progress in meeting these two objectives."
-,37546900,Concurrent profiling of multiscale 3D genome organization and gene expression in single mammalian cells.,bioRxiv,"The organization of mammalian genomes within the nucleus features a complex, multiscale three-dimensional (3D) architecture. The functional significance of these 3D genome features, however, remains largely elusive due to limited single-cell technologies that can concurrently profile genome organization and transcriptional activities. Here, we report GAGE-seq, a highly scalable, robust single-cell co-assay that simultaneously measures 3D genome structure and transcriptome within the same cell. Employing GAGE-seq on mouse brain cortex and human bone marrow CD34+ cells, we comprehensively characterized the intricate relationships between 3D genome and gene expression. We found that these multiscale 3D genome features collectively inform cell type-specific gene expressions, hence contributing to defining cell identity at the single-cell level. Integration of GAGE-seq data with spatial transcriptomic data revealedin situvariations of the 3D genome in mouse cortex. Moreover, our observations of lineage commitment in normal human hematopoiesis unveiled notable discordant changes between 3D genome organization and gene expression, underscoring a complex, temporal interplay at the single-cell level that is more nuanced than previously appreciated. Together, GAGE-seq provides a powerful, cost-effective approach for interrogating genome structure and gene expression relationships at the single-cell level across diverse biological contexts."
-,37559897,Design of a gradient-rheotaxis microfluidic chip for sorting of high-quality Sperm with progressive motility.,iScience,"Assisted reproductive technology (ART) is an important invention for the treatment of human infertility, and the isolation of high-quality sperm with progressive motility is one of the most critical steps that eventually affect the fertilization rate. Conventional sperm separation approaches include the swim-up method and density gradient centrifugation. However, the quality of isolated sperm obtained from both approaches can still be improved by improving sorted sperm motility, minimizing the DNA fragmentation rate, and removing abnormal phenotypes. Here, we report a Progressive Sperm Sorting Chip (PSSC) for high-quality sperm isolation. Based on the rheotaxis behavior of sperm, a gradient flow field is created in the chip for progressive sperm sorting. Clinical experiment results for 10 volunteers showed that greater than 90% of isolated sperm exhibit high motility (> 25 μm/s), high linearity (0.8), and a very low DNA fragmentation rate (< 5%). In addition, the whole process is label and chemical free. These features aid in gentle sperm sorting to obtain healthy sperm. This device uniquely enables the selection of high-quality sperm with progressive motility and might be clinically applied for infertility treatment in the near future.© 2023 The Authors."
-,37663760,"Characteristics of Autophagy-Related Genes, Diagnostic Models, and Their Correlation with Immune Infiltration in Keratoconus.",J Inflamm Res,"Keratoconus (KTCN) is one of the most common degenerative keratopathies, significantly affecting vision and even leading to blindness. This study identifies potential biomarkers of KTCN based on the characterization of autophagy-related genes (ARGs) and the construction of a diagnostic model; and explores their relevance to immune infiltrating cells in KTCN.Gene Expression Omnibus (GEO) data were downloaded and ARGs were acquired from GeneCards and Molecular Signatures Database (MSigDB). Autophagy-related differential expression genes (ARDEGs) were discovered through the integration of differentially expressed genes (DEGs) with ARGs, while hub genes of KTCN were discovered by protein-protein interaction (PPI) network analysis. The probable biological roles of these hub ARDEGs were examined using functional enrichment analysis, and a KTCN diagnostic model was generated using the least absolute shrinkage and selection operator (LASSO) regression analysis. We also employed the CIBERSORTx and ssGSEA algorithms to identify potential regulatory pathways to compare the abundance of immune cell infiltrates and their association with hub genes. Finally, the hub gene expression levels were confirmed using validation datasets as well as blood samples from KTCN and healthy individuals.In this study, we identified 12 hub ARDEGs, of which 9 genes were substantially distinct between KTCN patients and normal groups. The LASSO risk score was used to generate the nomogram, and the calibration curve evaluated the model's effective diagnostic performance (C index of 0.961). Patients with KTCN had greater percentages of M2 Macrophages and Gamma delta T cells, according to CIBERSORTx and ssGSEA. The outcomes of the bioinformatics analysis were supported by the DDIT3 and BINP3 expression levels in KTCN patients and healthy controls, according to the qRT-PCR data.Five biomarkers (CFTR, PLIN2, DDIT3, BAG3, and BNIP3) and diagnostic models offer fresh perspectives on identifying and managing KTCN.© 2023 Liu et al."
-,37662825,Identification of cancer stemness and M2 macrophage-associated biomarkers in lung adenocarcinoma.,Heliyon,"Cancer stemness and M2 macrophages are intimately linked to the prognosis of lung adenocarcinoma (LUAD). For this reason, this investigation sought to identify the key genes relevant to cancer stemness and M2 macrophages, explore the relationship between these genes and clinical characteristics, and determine the potential mechanism.LUAD transcriptomic data was analyzed from The Cancer Genome Atlas (TCGA) as well as the Gene Expression Omnibus databases. Differential expression analysis was performed to discern abnormally expressed genes between LUAD and control samples in TCGA cohort. The Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was applied to determine varyingly infiltrated immune cells in LUAD compared with the control samples in TCGA cohort. Weighted correlation network analysis (WGCNA) was performed to identify genes associated with mRNA expression-based stemness index (mRNAsi) and M2 macrophages. Least absolute shrinkage and selection operator (LASSO), RandomForest (RF) and support vector machine-recursive feature elimination (SVM-RFE) machine learning methods were conducted to detect gene signatures. Global survival evaluation (Kaplan-Meier curve) was applied to investigate the relationship between gene signatures and the survival time of LUAD patients. Receiver operating characteristic (ROC) curves were produced to define biomarkers relevant to diagnosis. Gene Set Enrichment Analysis (GSEA) was performed to probe the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to diagnostic biomarkers. The public single-cell dataset of LUAD (GSE123902) was used to investigate the expression differences of diagnostic biomarkers in various cell types in LUAD. Real-time quantitative PCR (qRT-PCR) was performed to confirm key genes in lung adenocarcinoma cells.A total of 5,410 differentialy expressed genes (DEGs) as well as 15 differentially infiltrated immune cells were identified between LUAD and control sepcimens in TCGA cohort. Thirty-seven DEGs were associated with both M2 macrophages and mRNAsi according to the WGCNA analysis. Sixteen common gene signatures were obtained using three diverse algorithms. CBFA2T3, DENND3 and FCAMR were correlated to overall and disease-free survival of LUAD patients. ROC curves revealed that CBFA2T3 and DENND3 expression accurately classified LUAD and control samples. The results of single cell related analysis showed that two diagnostic biomarkers expressions were differed between the different tissue sources in M2-like macrophages. QRT-PCR demonstrated the mRNA expressions of CBFA2T3 and DENND3 were upregulated in lung adenocarcinoma cells A549 and H2122.Our study identified CBFA2T3 and DENND3 as key genes associated with mRNAsi and M2 macrophages in LUAD and investigated the potential molecular mechanisms underlying this relationship.© 2023 Published by Elsevier Ltd."
-,37661250,A hypoxia- and lactate metabolism-related gene signature to predict prognosis of sepsis: discovery and validation in independent cohorts.,Eur J Med Res,"High throughput gene expression profiling is a valuable tool in providing insight into the molecular mechanism of human diseases. Hypoxia- and lactate metabolism-related genes (HLMRGs) are fundamentally dysregulated in sepsis and have great predictive potential. Therefore, we attempted to build an HLMRG signature to predict the prognosis of patients with sepsis.Three publicly available transcriptomic profiles of peripheral blood mononuclear cells from patients with sepsis (GSE65682, E-MTAB-4421 and E-MTAB-4451, total n = 850) were included in this study. An HLMRG signature was created by employing Cox regression and least absolute shrinkage and selection operator estimation. The CIBERSORT method was used to analyze the abundances of 22 immune cell subtypes based on transcriptomic data. Metascape was used to investigate pathways related to the HLMRG signature.We developed a prognostic signature based on five HLMRGs (ERO1L, SIAH2, TGFA, TGFBI, and THBS1). This classifier successfully discriminated patients with disparate 28-day mortality in the discovery cohort (GSE65682, n = 479), and consistent results were observed in the validation cohort (E-MTAB-4421 plus E-MTAB-4451, n = 371). Estimation of immune infiltration revealed significant associations between the risk score and a subset of immune cells. Enrichment analysis revealed that pathways related to antimicrobial immune responses, leukocyte activation, and cell adhesion and migration were significantly associated with the HLMRG signature.Identification of a prognostic signature suggests the critical role of hypoxia and lactate metabolism in the pathophysiology of sepsis. The HLMRG signature can be used as an efficient tool for the risk stratification of patients with sepsis.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37575252,Unveiling efferocytosis-related signatures through the integration of single-cell analysis and machine learning: a predictive framework for prognosis and immunotherapy response in hepatocellular carcinoma.,Front Immunol,"Hepatocellular carcinoma (HCC) represents a prominent gastrointestinal malignancy with a grim clinical outlook. In this regard, the discovery of novel early biomarkers holds substantial promise for ameliorating HCC-associated mortality. Efferocytosis, a vital immunological process, assumes a central position in the elimination of apoptotic cells. However, comprehensive investigations exploring the role of efferocytosis-related genes (EFRGs) in HCC are sparse, and their regulatory influence on HCC immunotherapy and targeted drug interventions remain poorly understood.RNA sequencing data and clinical characteristics of HCC patients were acquired from the TCGA database. To identify prognostically significant genes in HCC, we performed the limma package and conducted univariate Cox regression analysis. Subsequently, machine learning algorithms were employed to identify hub genes. To assess the immunological landscape of different HCC subtypes, we employed the CIBERSORT algorithm. Furthermore, single-cell RNA sequencing (scRNA-seq) was utilized to investigate the expression levels of ERFGs in immune cells and to explore intercellular communication within HCC tissues. The migratory capacity of HCC cells was evaluated using CCK-8 assays, while drug sensitivity prediction reliability was determined through wound-healing assays.We have successfully identified a set of nine genes, termed EFRGs, that hold significant potential for the establishment of a hepatocellular carcinoma-specific prognostic model. Furthermore, leveraging the individual risk scores derived from this model, we were able to stratify patients into two distinct risk groups, unveiling notable disparities in terms of immune infiltration patterns and response to immunotherapy. Notably, the model's capacity to accurately predict drug responses was substantiated through comprehensive experimental investigations, encompassing wound-healing assay, and CCK8 experiments conducted on the HepG2 and Huh7 cell lines.We constructed an EFRGs model that serves as valuable tools for prognostic assessment and decision-making support in the context of immunotherapy and chemotherapy.Copyright © 2023 Liu, Li, Zhang, Hu and Li."
-,37555866,Identification of hepatocellular carcinoma-related subtypes and development of a prognostic model: a study based on ferritinophagy-related genes.,Discov Oncol,"Hepatocellular carcinoma still has a high incidence and mortality rate worldwide, and further research is needed to investigate its occurrence and development mechanisms in depth in order to identify new therapeutic targets. Ferritinophagy is a type of autophagy and a key factor in ferroptosis that could influence tumor onset and progression. Although, the potential role of ferritinophagy-related genes (FRGs) in liver hepatocellular carcinoma (LIHC) is unknown.Single-cell RNA sequencing (scRNA-seq) data of LIHC were obtained from the Gene Expression Omnibus (GEO) dataset. In addition, transcriptome and clinical follow-up outcome data of individuals with LIHC were extracted from the The Cancer Genome Atlas (TCGA) dataset. FRGs were collected through the GeneCards database. Differential cell subpopulations were distinguished, and differentially expressed FRGs (DEFRGs) were obtained. Differential expression of FRGs and prognosis were observed according to the TCGA database. An FRG-related risk model was constructed to predict patient prognosis by absolute shrinkage and selection operator (LASSO) and COX regression analyses, and its prognosis predictive power was validated. Ultimately, the association between risk score and tumor microenvironment (TME), immune cell infiltration, immune checkpoints, drug sensitivity, and tumor mutation burden (TMB) was analyzed. We also used quantitative reverse transcription polymerase chain reaction (qRT-PCR) to validate the expression of key genes in normal liver cells and liver cancer cells.We ultimately identified 8 cell types, and 7 differentially expressed FRGs genes (ZFP36, NCOA4, FTH1, FTL, TNF, PCBP1, CYB561A3) were found among immune cells, and we found that Monocytes and Macrophages were closely related to FRGs genes. Subsequently, COX regression analysis showed that patients with high expression of FTH1, FTL, and PCBP1 had significantly worse prognosis than those with low expression, and our survival prediction model, constructed based on age, stage, and risk score, showed better prognostic prediction ability. Our risk model based on 3 FRGs genes ultimately revealed significant differences between high-risk and low-risk groups in terms of immune infiltration and immune checkpoint correlation, drug sensitivity, and somatic mutation risk. Finally, we validated the key prognostic genes FTH1, FTL, using qRT-PCR, and found that the expression of FTH1 and FTL was significantly higher in various liver cancer cells than in normal liver cells. At the same time, immunohistochemistry showed that the expression of FTH1, FTL in tumor tissues was significantly higher than that in para-tumor tissues.This study identifies a considerable impact of FRGs on immunity and prognosis in individuals with LIHC. The collective findings of this research provide new ideas for personalized treatment of LIHC and a more targeted therapy approach for individuals with LIHC to improve their prognosis.© 2023. Springer Science+Business Media, LLC."
-,37460696,H3K36 methylation is a reprogramming barrier.,Nat Cell Biol,NA
-,37596691,GTM-decon: guided-topic modeling of single-cell transcriptomes enables sub-cell-type and disease-subtype deconvolution of bulk transcriptomes.,Genome Biol,"Cell-type composition is an important indicator of health. We present Guided Topic Model for deconvolution (GTM-decon) to automatically infer cell-type-specific gene topic distributions from single-cell RNA-seq data for deconvolving bulk transcriptomes. GTM-decon performs competitively on deconvolving simulated and real bulk data compared with the state-of-the-art methods. Moreover, as demonstrated in deconvolving disease transcriptomes, GTM-decon can infer multiple cell-type-specific gene topic distributions per cell type, which captures sub-cell-type variations. GTM-decon can also use phenotype labels from single-cell or bulk data to infer phenotype-specific gene distributions. In a nested-guided design, GTM-decon identified cell-type-specific differentially expressed genes from bulk breast cancer transcriptomes.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37556306,Invited Perspective: Opportunities and Obstacles of Longitudinal Data in Pregnancy to Quantify Mechanisms and Understand Etiology.,Environ Health Perspect,NA
-,37610690,Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer.,Cell Oncol (Dordr),"PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research.The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments.We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission.Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.© 2023. Springer Nature Switzerland AG."
-,37645746,Genetic evidence for serum amyloid P component as a drug target for treatment of neurodegenerative disorders.,medRxiv,"The direct causes of neurodegeneration underlying Alzheimer's disease (AD) and many other dementias, are not known. Here we identify serum amyloid P component (SAP), a constitutive plasma protein normally excluded from the brain, as a potential drug target. After meta-analysis of three genome-wide association studies, comprising 44,288 participants,cis-Mendelian randomization showed that genes responsible for higher plasma SAP values are significantly associated with AD, Lewy body dementia and plasma tau concentration. These genetic findings are consistent with experimental evidence of SAP neurotoxicity and the strong, independent association of neocortex SAP content with dementia at death. Depletion of SAP from the blood and from the brain, as is provided by the safe, well tolerated, experimental drug, miridesap, may therefore contribute to treatment of neurodegeneration."
-,37626771,Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington's Disease: Mechanisms and Potential Therapeutics.,Biomedicines,"Brain-derived neurotrophic factor (BDNF) is a major neurotrophin whose loss or interruption is well established to have numerous intersections with the pathogenesis of progressive neurological disorders. There is perhaps no greater example of disease pathogenesis resulting from the dysregulation of BDNF signaling than Huntington's disease (HD)-an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive impairments associated with basal ganglia dysfunction and the ultimate death of striatal projection neurons. Investigation of the collection of mechanisms leading to BDNF loss in HD highlights this neurotrophin's importance to neuronal viability and calls attention to opportunities for therapeutic interventions. Using electronic database searches of existing and forthcoming research, we constructed a literature review with the overarching goal of exploring the diverse set of molecular events that trigger BDNF dysregulation within HD. We highlighted research that investigated these major mechanisms in preclinical models of HD and connected these studies to those evaluating similar endpoints in human HD subjects. We also included a special focus on the growing body of literature detailing key transcriptomic and epigenetic alterations that affect BDNF abundance in HD. Finally, we offer critical evaluation of proposed neurotrophin-directed therapies and assessed clinical trials seeking to correct BDNF expression in HD individuals."
-,37668029,[Association between maternal gestational diabetes mellitus and the risk of autism spectrum disorder in offspring].,Zhongguo Dang Dai Er Ke Za Zhi,"To explore the association between maternal gestational diabetes mellitus (GDM) exposure and the development of autism spectrum disorder (ASD) in offspring.A case-control study was conducted, recruiting 221 children with ASD and 400 healthy children as controls. Questionnaires and interviews were used to collect information on general characteristics of the children, socio-economic characteristics of the family, maternal pregnancy history, and maternal disease exposure during pregnancy. Multivariate logistic regression analysis was used to investigate the association between maternal GDM exposure and the development of ASD in offspring. The potential interaction between offspring gender and maternal GDM exposure on the development of ASD in offspring was explored.The proportion of maternal GDM was significantly higher in the ASD group compared to the control group (16.3% vs 9.4%,P=0.014). After adjusting for variables such as gender, gestational age, mode of delivery, parity, and maternal education level, maternal GDM exposure was a risk factor for ASD in offspring (OR=2.18, 95%CI: 1.04-4.54,P=0.038). On the basis of adjusting the above variables, after further adjusting the variables including prenatal intake of multivitamins, folic acid intake in the first three months of pregnancy, and assisted reproduction the result trend did not change, but no statistical significance was observed (OR=1.94, 95%CI: 0.74-5.11,P=0.183). There was an interaction between maternal GDM exposure and offspring gender on the development of ASD in offspring (P<0.001). Gender stratified analysis showed that only in male offspring of mothers with GDM, the risk of ASD was significantly increased (OR=3.67, 95%CI: 1.16-11.65,P=0.027).Maternal GDM exposure might increase the risk of ASD in offspring. There is an interaction between GDM exposure and offspring gender in the development of ASD in offspring."
-,37577575,MousiPLIER: A Mouse Pathway-Level Information Extractor Model.,bioRxiv,"High throughput gene expression profiling is a powerful approach to generate hypotheses on the underlying causes of biological function and disease. Yet this approach is limited by its ability to infer underlying biological pathways and burden of testing tens of thousands of individual genes. Machine learning models that incorporate prior biological knowledge are necessary to extract meaningful pathways and generate rational hypothesis from the vast amount of gene expression data generated to date. We adopted an unsupervised machine learning method, Pathway-level information extractor (PLIER), to train the first mouse PLIER model on 190,111 mouse brain RNA-sequencing samples, the greatest amount of training data ever used by PLIER. mousiPLER converted gene expression data into a latent variables that align to known pathway or cell maker gene sets, substantially reducing data dimensionality and improving interpretability. To determine the utility of mousiPLIER, we applied it to a mouse brain aging study of microglia and astrocyte transcriptomic profiling. We found a specific set of latent variables that are significantly associated with aging, including one latent variable (LV41) corresponding to striatal signal. We next performed k-means clustering on the training data to identify studies that respond strongly to LV41, finding that the variable is relevant to striatum and aging across the scientific literature. Finally, we built a web server ( http://mousiplier.greenelab.com/ ) for users to easily explore the learned latent variables. Taken together this study provides proof of concept that mousiPLIER can uncover meaningful biological processes in mouse transcriptomic studies.Analysis of RNA-sequencing data commonly generates differential expression of individual genes across conditions. However, genes are regulated in complex networks, not as individual entities. Machine learning models that incorporate prior biological information are a powerful tool to analyze human gene expression. However, such models are lacking for mouse despite the vast number of mouse RNA-seq datasets. We trained a mouse pathway-level information extractor model (mousiPLIER). The model reduced the data dimensionality from over 10,000 genes to 196 latent variables that map to prior pathway and cell marker gene sets. We demonstrated the utility of mousiPLIER by applying it to mouse brain aging data and developed a web server to facilitate the use of the model by the scientific community."
-,37606762,Radiomics-guided prognostic assessment of early-stage hepatocellular carcinoma recurrence post-radical resection.,J Cancer Res Clin Oncol,"The prognosis of early-stage hepatocellular carcinoma (HCC) patients after radical resection has received widespread attention, but reliable prediction methods are lacking. Radiomics derived from enhanced computed tomography (CT) imaging offers a potential avenue for practical prognostication in HCC patients.We recruited early-stage HCC patients undergoing radical resection. Statistical analyses were performed to identify clinicopathological and radiomic features linked to recurrence. Clinical, radiomic, and combined models (incorporating clinicopathological and radiomic features) were built using four algorithms. The performance of these models was scrutinized via fivefold cross-validation, with evaluation metrics including the area under the curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE) being calculated and compared. Ultimately, an integrated nomogram was devised by combining independent clinicopathological predictors with the Radscore.From January 2016 through December 2020, HCC recurrence was observed in 167 cases (64.5%), with a median time to recurrence of 26.7 months following initial resection. Combined models outperformed those solely relying on clinicopathological or radiomic features. Notably, among the combined models, those employing support vector machine (SVM) algorithms exhibited the most promising predictive outcomes (AUC: 0.840 (95% Confidence interval (CI): [0.696, 0.984]), ACC: 0.805, SEN: 0.849, SPE: 0.733). Hepatitis B infection, tumour size > 5 cm, and alpha-fetoprotein (AFP) > 400 ng/mL were identified as independent recurrence predictors and were subsequently amalgamated with the Radscore to create a visually intuitive nomogram, delivering robust and reliable predictive performance.Machine learning models amalgamating clinicopathological and radiomic features provide a valuable tool for clinicians to predict postoperative HCC recurrence, thereby informing early preventative strategies.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature."
-,37526884,NA,NA,"α-Synucleinopathies are a group of neurodegenerative disorders characterized by alterations in α-synuclein (α-syn), a protein associated with membrane phospholipids, whose precise function in normal cells is still unknown. These kinds of diseases are caused by multiple factors, but the regulation of the α-syn gene is believed to play a central role in the pathology of these disorders; therefore, the α-syn gene is one of the most studied genes. α-Synucleinopathies are complex disorders that derive from the interaction between genetic and environmental factors. Here, we offer an update on the landscape of the epigenetic regulation of α-syn gene expression that has been linked with α-synucleinopathies. We also delve into the reciprocal influence between epigenetic modifications and other factors related to these disorders, such as posttranslational modifications, microbiota participation, interactions with lipids, neuroinflammation and oxidative stress, to promote α-syn aggregation by acting on the transcription and/or translation of the α-syn gene.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature."
-,37620297,Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons.,Nat Commun,"Axon regeneration of dorsal root ganglia (DRG) neurons after peripheral axotomy involves reconfiguration of gene regulatory circuits to establish regenerative gene programs. However, the underlying mechanisms remain unclear. Here, through an unbiased survey, we show that the binding motif of Bmal1, a central transcription factor of the circadian clock, is enriched in differentially hydroxymethylated regions (DhMRs) of mouse DRG after peripheral lesion. By applying conditional deletion of Bmal1 in neurons, in vitro and in vivo neurite outgrowth assays, as well as transcriptomic profiling, we demonstrate that Bmal1 inhibits axon regeneration, in part through a functional link with the epigenetic factor Tet3. Mechanistically, we reveal that Bmal1 acts as a gatekeeper of neuroepigenetic responses to axonal injury by limiting Tet3 expression and restricting 5hmC modifications. Bmal1-regulated genes not only concern axon growth, but also stress responses and energy homeostasis. Furthermore, we uncover an epigenetic rhythm of diurnal oscillation of Tet3 and 5hmC levels in DRG neurons, corresponding to time-of-day effect on axon growth potential. Collectively, our studies demonstrate that targeting Bmal1 enhances axon regeneration.© 2023. Springer Nature Limited."
-,37652985,Profiling of repetitive RNA sequences in the blood plasma of patients with cancer.,Nat Biomed Eng,"Liquid biopsies provide a means for the profiling of cell-free RNAs secreted by cells throughout the body. Although well-annotated coding and non-coding transcripts in blood are readily detectable and can serve as biomarkers of disease, the overall diagnostic utility of the cell-free transcriptome remains unclear. Here we show that RNAs derived from transposable elements and other repeat elements are enriched in the cell-free transcriptome of patients with cancer, and that they serve as signatures for the accurate classification of the disease. We used repeat-element-aware liquid-biopsy technology and single-molecule nanopore sequencing to profile the cell-free transcriptome in plasma from patients with cancer and to examine millions of genomic features comprising all annotated genes and repeat elements throughout the genome. By aggregating individual repeat elements to the subfamily level, we found that samples with pancreatic cancer are enriched with specific Alu subfamilies, whereas other cancers have their own characteristic cell-free RNA profile. Our findings show that repetitive RNA sequences are abundant in blood and can be used as disease-specific diagnostic biomarkers.© 2023. The Author(s)."
-,37463106,SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.,Cell Rep,"Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8+T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC.Published by Elsevier Inc."
-,37612524,M6A-mediated-upregulation of lncRNA BLACAT3 promotes bladder cancer angiogenesis and hematogenous metastasis through YBX3 nuclear shuttling and enhancing NCF2 transcription.,Oncogene,"Lymphatic metastasis is recognized as the leading manner of metastasis in bladder cancer (BLCa), but hematogenous metastasis accounts for a majority of cancer-associated deaths. The past two decades have witnessed tremendous attention in long non-coding RNAs (lncRNAs), which are a new hope for the development of targeted drug therapy for metastatic cancers; however, the underlying mechanism of lncRNAs involved in BLCa hematogenous metastasis remains to be elucidated. Here, we identified BLCa-associated transcript 3 (BLACAT3), a lncRNA, which was aberrantly upregulated in BLCa and corelated with poor prognosis of patients with muscle-invasive bladder cancer. Methodologically, m6A epitranscriptomic microarray, RNA sequencing and mass spectrometry (MS) were used to screen the key molecules of the regulatory axis. Functional assays, animal models and clinical samples were used to explore the roles of BLACAT3 in BLCa in vitro and in vivo. Mechanistically, m6A modification contributes to BLACAT3 upregulation by stabilizing RNA structure. BLACAT3 recruits YBX3 to shuttle into the nucleus, synergistically enhances NCF2 transcription, and promotes BLCa angiogenesis and hematogenous metastasis by activating downstream NF-κB signaling. Our findings will develop prognosis prediction tools for BLCa patients and discover novel therapeutic biological targets for metastatic BLCa.© 2023. The Author(s)."
-,37571393,Underlying Mechanisms of Brain Aging and Neurodegenerative Diseases as Potential Targets for Preventive or Therapeutic Strategies Using Phytochemicals.,Nutrients,"During aging, several tissues and biological systems undergo a progressive decline in function, leading to age-associated diseases such as neurodegenerative, inflammatory, metabolic, and cardiovascular diseases and cancer. In this review, we focus on the molecular underpinning of senescence and neurodegeneration related to age-associated brain diseases, in particular, Alzheimer's and Parkinson's diseases, along with introducing nutrients or phytochemicals that modulate age-associated molecular dysfunctions, potentially offering preventive or therapeutic benefits. Based on current knowledge, the dysregulation of microglia genes and neuroinflammation, telomere attrition, neuronal stem cell degradation, vascular system dysfunction, reactive oxygen species, loss of chromosome X inactivation in females, and gut microbiome dysbiosis have been seen to play pivotal roles in neurodegeneration in an interactive manner. There are several phytochemicals (e.g., curcumin, EGCG, fucoidan, galangin, astin C, apigenin, resveratrol, phytic acid, acacetin, daucosterol, silibinin, sulforaphane, withaferin A, and betulinic acid) that modulate the dysfunction of one or several key genes (e.g., TREM2, C3, C3aR1, TNFA, NF-kb, TGFB1&2, SIRT1&6, HMGB1, and STING) affected in the aged brain. Although phytochemicals have shown promise in slowing down the progression of age-related brain diseases, more studies to identify their efficacy, alone or in combinations, in preclinical systems can help to design novel nutritional strategies for the management of neurodegenerative diseases in humans."
-,37622096,Calibrating epigenetic clocks with training data error.,Evol Appl,"Animal age data are valuable for management of wildlife populations. Yet, for most species, there is no practical method for determining the age of unknown individuals. However, epigenetic clocks, a molecular-based method, are capable of age prediction by sampling specific tissue types and measuring DNA methylation levels at specific loci. Developing an epigenetic clock requires a large number of samples from animals of known ages. For most species, there are no individuals whose exact ages are known, making epigenetic clock calibration inaccurate or impossible. For many epigenetic clocks, calibration samples with inaccurate age estimates introduce a degree of error to epigenetic clock calibration. In this study, we investigated how much error in the training data set of an epigenetic clock can be tolerated before it resulted in an unacceptable increase in error for age prediction. Using four publicly available data sets, we artificially increased the training data age error by iterations of 1% and then tested the model against an independent set of known ages. A small effect size increase (Cohen's d >0.2) was detected when the error in age was higher than 22%. The effect size increased linearly with age error. This threshold was independent of sample size. Downstream applications for age data may have a more important role in deciding how much error can be tolerated for age prediction. If highly precise age estimates are required, then it may be futile to embark on the development of an epigenetic clock when there is no accurately aged calibration population to work with. However, for other problems, such as determining the relative age order of pairs of individuals, a lower-quality calibration data set may be adequate.© 2023 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd."
-,37614226,CRISPR interference to evaluate modifiers of C9ORF72-mediated toxicity in FTD.,Front Cell Dev Biol,"Treatments for neurodegenerative disease, including Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS), remain rather limited, underscoring the need for greater mechanistic insight and disease-relevant models. Our ability to develop novel disease models of genetic risk factors, disease modifiers, and other FTD/ALS-relevant targets is impeded by the significant amount of time and capital required to develop conventional knockout and transgenic mice. To overcome these limitations, we have generated a novel CRISPRi interference (CRISPRi) knockin mouse. CRISPRi uses a catalytically dead form of Cas9, fused to a transcriptional repressor to knockdown protein expression, following the introduction of single guide RNA against the gene of interest. To validate the utility of this model we have selected the TAR DNA binding protein (TDP-43) splicing target, stathmin-2 (STMN2).STMN2RNA is downregulated in FTD/ALS due to loss of TDP-43 activity and STMN2 loss is suggested to play a role in ALS pathogenesis. The involvement of STMN2 loss of function in FTD has yet to be determined. We find that STMN2 protein levels in familial FTD cases are significantly reduced compared to controls, supporting that STMN2 depletion may be involved in the pathogenesis of FTD. Here, we provide proof-of-concept that we can simultaneously knock down Stmn2 and express the expanded repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene, successfully replicating features of C9-associated pathology. Of interest, depletion of Stmn2 had no effect on expression or deposition of dipeptide repeat proteins (DPRs), but significantly decreased the number of phosphorylated Tdp-43 (pTdp-43) inclusions. We submit that our novel CRISPRi mouse provides a versatile and rapid method to silence gene expressionin vivoand propose this model will be useful to understand gene function in isolation or in the context of other neurodegenerative disease models.Copyright © 2023 Pickles, Zanetti Alepuz, Koike, Yue, Tong, Liu, Zhou, Jansen-West, Daughrity, Song, DeTure, Oskarsson, Graff-Radford, Boeve, Petersen, Josephs, Dickson, Ward, Dong, Prudencio, Cook and Petrucelli."
-,37640903,NA,NA,"An abnormal chromosome number, or aneuploidy, underlies developmental disorders and is a common feature of cancer, with different cancer types exhibiting distinct patterns of chromosomal gains and losses. To understand how specific aneuploidies emerge in certain tissues and how they contribute to disease development, various methods have been developed to alter the karyotype of mammalian cells and mice. In this review, we provide an overview of both classic and novel strategies for inducing or selecting specific chromosomal gains and losses in human and murine cell systems. We highlight how these customized aneuploidy models helped expanding our knowledge of the consequences of specific aneuploidies to (cancer) cell physiology.© 2023. The Author(s)."
-,37628880,NA,NA,"JAK2V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN).JAK2mutations are also frequent in clonal hematopoiesis of indeterminate potential (CHIP) in otherwise ""healthy"" individuals. However, the period between mutation acquisition and MPN diagnosis (known as latency) varies widely between individuals, withJAK2mutations detectable several decades before diagnosis and even from birth in some individuals. Here, we will review the current evidence on the biological factors, such as additional mutations and chronic inflammation, which influence clonal expansion and may determine why someJAK2-mutated individuals will progress to an overt neoplasm during their lifetime while others will not. We will also introduce several germline variants that predispose individuals to CHIP (as well as MPN) identified from genome-wide association studies. Finally, we will explore possible mutation screening or interventions that could help to minimize MPN-associated cardiovascular complications or even delay malignant progression."
-,37620601,Multiparameter prediction of myeloid neoplasia risk.,Nat Genet,"The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis. By analyzing differences between 'pre-MN' and controls, we develop and validate Cox regression models quantifying the risk of progression to each myeloid neoplasm subtype. We construct 'MN-predict', a web application that generates time-dependent predictions with the input of basic blood tests and genetic data. Our study demonstrates that many individuals that develop myeloid neoplasms can be identified years in advance and provides a framework for disease-specific prognostication that will be of substantial use to researchers and physicians.© 2023. The Author(s)."
-,37600859,Genetic Predisposition to Clonal Hematopoiesis.,Hemasphere,NA
-,37575386,Development of a Mouse Model of Hematopoietic Loss of Y Chromosome.,Bio Protoc,"This protocol describes the generation of chimeric mice in which the Y chromosome is deleted from a proportion of blood cells. This model recapitulates the phenomenon of hematopoietic mosaic loss of Y chromosome (mLOY), which is frequently observed in the blood of aged men. To construct mice with hematopoietic Y chromosome loss, lineage-negative cells are isolated from the bone marrow of ROSA26-Cas9 knock-in mice. These cells are transduced with a lentivirus vector encoding a guide RNA (gRNA) that targets multiple repeats of the Y chromosome centromere, effectively removing the Y chromosome. These cells are then transplanted into lethally irradiated wildtype C57BL6 mice. Control gRNAs are designed to target either no specific region or the fourth intron ofActingene. Transduced cells are tracked by measuring the fraction of blood cells expressing the virally encoded reporter gene tRFP. This model represents a clinically relevant model of hematopoietic mosaic loss of Y chromosome, which can be used to study the impact of mLOY on various age-related diseases. Graphical overview.©Copyright : © 2023 The Authors; This is an open access article under the CC BY-NC license."
-,37465995,NA,NA,"Mosaic loss of chromosome Y (LOY) is associated with cardiovascular and neurodegenerative diseases in men, and genetic predisposition to LOY is associated with poor poststroke outcome. We, therefore, tested the hypothesis that LOY itself is associated with functional outcome after ischemic stroke.The study comprised male patients with ischemic stroke from the cohort studies SAHLSIS2 (Sahlgrenska Academy Study on Ischemic Stroke Phase 2; n=588) and LSR (Lund Stroke Register; n=735). We used binary logistic regression to analyze associations between LOY, determined by DNA microarray intensity data, and poor 3-month functional outcome (modified Rankin Scale score, >2) in each cohort separately and combined. Patients who received recanalization therapy were excluded from sensitivity analyses.LOY was associated with about 2.5-fold increased risk of poor outcome in univariable analyses (P<0.001). This association withstood separate adjustment for stroke severity and diabetes in both cohorts but not age. In sensitivity analyses restricted to the nonrecanalization group (n=987 in the combined cohort), the association was significant also after separate adjustment for age (odds ratio, 1.6 [95% CI, 1.1-2.4]) and when additionally adjusting for stroke severity and diabetes (odds ratio, 1.6 [95% CI, 1.1-2.5]).We observed an association between LOY and poor outcome after ischemic stroke in patients not receiving recanalization therapy. Future studies on LOY and other somatic genetic alterations in larger stroke cohorts are warranted."
-,37576439,Investigating the Relationship Between Body Shape and Life History Traits in Toothed Whales: Can Body Shape Predict Fast-Slow Life Histories?,Evol Biol,"A widespread pattern in vertebrate life-history evolution is for species to evolve towards either fast or slow life histories; however, the underlying causes of this pattern remain unclear. Toothed whales (Odontoceti) are a diverse group with a range of body sizes and life histories, making them an ideal model to investigate potential drivers of this dichotomy. Using ancestral reconstruction, we identified that certain groups of odontocetes evolved more-streamlined, presumably faster, body shapes around the same time that killer whales (Orcinus orca) evolved into whale predators approximately 1 Mya during the Pleistocene. This suggests that the evolution of a streamlined body shape may have been an adaptation to escape killer whale predation, leading to longer life-history events. To test this hypothesis, we performed a cluster analysis of odontocete whales and confirmed the dual pattern of life-history traits, with one group referred to as 'reproducers' characterized by early age of maturity, short gestation, short interbirth interval, and short lifespan, and the other group referred to as 'bet-hedgers' exhibiting the opposite pattern. However, we found that life history grouping was relatively unrelated to whale shape (i.e., more streamlined or less streamlined). Therefore, we incorporated principal component results into mixed effects models, and the model results indicated that body shape was positively related to neonate length (a measure of investment in progeny), but not significantly related to the temporal life-history traits. Thus, whale body shape is not a sufficient explanation for the evolution of fast-slow life histories in odontocete whales.The online version contains supplementary material available at 10.1007/s11692-023-09605-4.© Crown 2023."
-,37576596,Organoids: opportunities and challenges of cancer therapy.,Front Cell Dev Biol,"Organoids are a class of multicellular structures with the capability of self-organizing and the characteristic of original tissues, they are generated from stem cells in 3D culturein vitro. Organoids can mimic the occurrence and progression of original tissues and widely used in disease models in recent years. The ability of tumor organoids to retain characteristic of original tumors make them unique for tumorigenesis and cancer therapy. However, the history of organoid development and the application of organoid technology in cancer therapy are not well understood. In this paper, we reviewed the history of organoids development, the culture methods of tumor organoids establishing and the applications of organoids in cancer research for better understanding the process of tumor development and providing better strategies for cancer therapy. The standardization of organoids cultivation facilitated the large-scale production of tumor organoids. Moreover, it was found that combination of tumor organoids and other cells such as immune cells, fibroblasts and nervous cells would better mimic the microenvironment of tumor progression. This might be important developing directions for tumor organoids in the future.Copyright © 2023 Jiang, Oyang, Peng, Liu, Xu, Wu, Tan, Yang, Han, Lin, Xia, Peng, Tang, Luo, Su, Shi, Zhou and Liao."
-,37567918,Chimeric antibody targeting unique epitope on onco-mucin16 reduces tumor burden in pancreatic and lung malignancies.,NPJ Precis Oncol,"Aberrantly expressed onco-mucin 16 (MUC16) and its post-cleavage generated surface tethered carboxy-terminal (MUC16-Cter) domain are strongly associated with poor prognosis and lethality of pancreatic (PC) and non-small cell lung cancer (NSCLC). To date, most anti-MUC16 antibodies are directed towards the extracellular domain of MUC16 (CA125), which is usually cleaved and shed in the circulation hence obscuring antibody accessibility to the cancer cells. Herein, we establish the utility of targeting a post-cleavage generated, surface-tethered oncogenic MUC16 carboxy-terminal (MUC16-Cter) domain by using a novel chimeric antibody in human IgG1 format, ch5E6, whose epitope expression directly correlates with disease severity in both cancers. ch5E6 binds and interferes with MUC16-associated oncogenesis, suppresses the downstream signaling pFAK(Y397)/p-p70S6K(T389)/N-cadherin axis and exert antiproliferative effects in cancer cells, 3D organoids, and tumor xenografts of both PC and NSCLC. The robust clinical correlations observed between MUC16 and N-cadherin in patient tumors and metastatic samples imply ch5E6 potential in targeting a complex and significantly occurring phenomenon of epithelial to mesenchymal transition (EMT) associated with disease aggressiveness. Our study supports evaluating ch5E6 with standard-of-care drugs, to potentially augment treatment outcomes in malignancies inflicted with MUC16-associated poor prognosis.© 2023. Nature Publishing Group UK."
-,37606673,Evaluation of Large-Scale Proteomics for Prediction of Cardiovascular Events.,JAMA,"Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk factors and polygenic risk scores, is uncertain.To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations.The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals.Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling.Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death.In the primary event population test set (4018 individuals [59.0% women]; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 [95% CI, 0.007 to 0.038]). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 [95% CI, 0.002 to 0.028]). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 [95% CI, 0.011 to 0.042]). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population.A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination."
-,37626895,Loss of the Novel Myelin Protein CMTM5 in Multiple Sclerosis Lesions and Its Involvement in Oligodendroglial Stress Responses.,Cells,"This study comprehensively addresses the involvement of the protein CKLF-like Marvel transmembrane domain-containing family member 5 (CMTM5) in the context of demyelination and cytodegenerative autoimmune diseases, particularly multiple Sclerosis (MS). An observed reduction in CMTM5 expression in post-mortem MS lesions prompted further investigations in both in vitro and in vivo animal models. In the cuprizone animal model, we detected a decrease in CMTM5 expression in oligodendrocytes that is absent in other members of the CMTM protein family. Our findings also confirm these results in the experimental autoimmune encephalomyelitis (EAE) model with decreased CMTM5 expression in both cerebellum and spinal cord white matter. We also examined the effects of aCmtm5knockdown in vitro in the oligodendroglial Oli-neu mouse cell line using the CRISPR interference technique. Interestingly, we found no effects on cell response to thapsigargin-induced endoplasmic reticulum (ER) stress as determined byAtf4activity, an indicator of cellular stress responses. Overall, these results substantiate previous findings suggesting that CMTM5, rather than contributing to myelin biogenesis, is involved in maintaining axonal integrity. Our study further demonstrates that the knockdown ofCmtm5in vitro does not modulate oligodendroglial responses to ER stress. These results warrant further investigation into the functional role of CMTM5 during axonal degeneration in the context of demyelinating conditions."
-,37621717,Retinal astrocyte morphology predicts integration of vascular and neuronal architecture.,Front Neurosci,"Astrocytes are important regulators of blood flow and play a key role in the response to injury and disease in the central nervous system (CNS). Despite having an understanding that structural changes to these cells have consequences for local neurovascular physiology, individual astrocyte morphology remains largely unexplored in the retina. Here, we used MORF3 mice to capture full membranous morphology for over fifteen hundred individual astrocytes in the mouse retina, a highly metabolically active component of the CNS. We demonstrate that retinal astrocytes have been misrepresented as stellate in morphology due to marker use like GFAP and S100β which underestimates cell complexity. We also find that astrocytes contain recurring morphological motifs which are predictive of the underlying neurovascular architecture of the inner retina and suggestive of function. These motifs predict fine sampling and integration of retinal ganglion cell electrical activity with consequences for blood flow regulation. Additionally, our data shows that astrocytes participate in neurovascular interactions to a much greater degree than currently reported. 100% of cells contact the vasculature through one of three mutually exclusive classes of connections. Similarly, 100% of cells contact some neuronal element, be it an RGC axon or soma. Finally, we report that astrocyte morphology depends on retinal eccentricity, with cells appearing compressed near the nerve head and in the periphery. These results reveal a large degree of astrocyte morphological complexity that informs their contribution to neurovascular coupling in the retina.Copyright © 2023 Holden, Wareham and Calkins."
-,37558878,NA,NA,"Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.© 2023. The Author(s), under exclusive licence to Springer Nature Limited."
-,37467333,Secretomics reveals gelatinase substrates at the blood-brain barrier that are implicated in astroglial barrier function.,Sci Adv,"The gelatinases, matrix metalloproteinase 2 (MMP-2) and MMP-9, are key for leukocyte penetration of the brain parenchymal border in neuroinflammation and the functional integrity of this barrier; however, it is unclear which MMP substrates are involved. Using a tailored, sensitive, label-free mass spectrometry-based secretome approach, not previously applied to nonimmune cells, we identified 119 MMP-9 and 21 MMP-2 potential substrates at the cell surface of primary astrocytes, including known substrates (β-dystroglycan) and a broad spectrum of previously unknown MMP-dependent events involved in cell-cell and cell-matrix interactions. Using neuroinflammation as a model of assessing compromised astroglial barrier function, a selection of the potential MMP substrates were confirmed in vivo and verified in human samples, including vascular cell adhesion molecule-1 and neuronal cell adhesion molecule. We provide a unique resource of potential MMP-2/MMP-9 substrates specific for the astroglia barrier. Our data support a role for the gelatinases in the formation and maintenance of this barrier but also in astrocyte-neuron interactions."
-,37630850,NA,NA,"Aging is characterized by alterations in the inflammatory microenvironment, which is tightly regulated by a complex network of inflammatory mediators. Excessive calorie consumption contributes to age- and lifestyle-associated diseases like obesity, type 2 diabetes, cardiovascular disorders, and cancer, while limited nutrient availability may lead to systemic health-promoting adaptations. Geroprotective effects of short-term caloric restriction (CR) can beneficially regulate innate immune receptors and interferon signaling in the liver of aged mice, but how CR impacts the hepatic release of immunomodulatory mediators like cytokines and lipid mediators (LM) is elusive. Here, we investigated the impact of aging on the inflammatory microenvironment in the liver and its linkage to calorie consumption. The livers of female young and aged C57BL/6JRj mice, as well as of aged mice after caloric restriction (CR) up to 28 days, with and without subsequent re-feeding (2 days), were evaluated. Surprisingly, despite differences in the hepatic proteome of young and old mice, aging did not promote a pro-inflammatory environment in the liver, but it reduced lipoxygenase-mediated formation of LM from polyunsaturated fatty acids without affecting the expression of the involved lipoxygenases and related oxygenases. Moreover, CR failed to ameliorate the secretion of pro-inflammatory cytokines but shifted the LM production to the formation of monohydroxylated LM with inflammation-resolving features. Unexpectedly, re-feeding after CR even further decreased the inflammatory response as LM species were markedly downregulated. Our findings raise the question of how short-term CR is indeed beneficial as a nutritional intervention for healthy elderly subjects and further stress the necessity to address tissue-specific inflammatory states."
-,37608128,Reconstructing the immunosenescence core pathway reveals global characteristics in pan-cancer.,Cancer Immunol Immunother,"Immunosenescence has been demonstrated to play an important role in tumor progression. However, there is lacking comprehensive analyses of immunosenescence-related pathways. Meanwhile, the sex disparities of immunosenescence in cancer are still poorly understood. In this study, we analyzed the multi-omics data of 12,836 tumor samples, including genomics, transcriptomics, epigenomics, proteomics, and metabolomics. We systematically identified immunosenescence pathways that were disordered across cancer types. The mutations and copy number variations of immunosenescence pathways were found to be more active in pan-cancer. We reconstructed the immunosenescence core pathways (ISC-pathways) to improve the ability of prognostic stratification in 33 cancer types. We also found the head and neck squamous carcinoma (HNSC) contained abundant sex-specific immunosenescence features and showed sex differences in survival. We found that OSI-027 was a potential sex-specific drug in HNSC tumors, which tended to be more effective in male HNSC by targeting the MTOR gene in the PI3K-Akt signaling pathway. In conclusion, our study provided a systematic understanding of immunosenescence pathways and revealed the global characteristics of immunosenescence in pan-cancer. We highlighted MTOR gene could be a powerful immunosenescence biomarker of HNSC that helps to develop sex-specific immunosenescence drugs.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature."
-,37604983,The sex gap in bladder cancer survival - a missing link in bladder cancer care?,Nat Rev Urol,"The differences in bladder cancer outcomes between the sexes has again been highlighted. Uncommon among cancers, bladder cancer outcomes are notably worse for women than for men. Furthermore, bladder cancer is three to four times more common among men than among women. Factors that might explain these sex differences include understanding the importance of haematuria as a symptom of bladder cancer by both clinicians and patients, the resultant delays in diagnosis and referral of women with haematuria, and health-care access. Notably, these factors seem to have geographical variation and are not consistent across all health-care systems. Likewise, data relating to sex-specific treatment responses for patients with non-muscle-invasive or muscle-invasive bladder cancer are inconsistent. The influence of differences in the microbiome, bladder wall thickness and urine dwell times remain to be elucidated. The interplay of hormone signalling, gene expression, immunology and the tumour microenvironment remains complex but probably underpins the sexual dimorphism in disease incidence and stage and histology at presentation. The contribution of these biological phenomena to sex-specific outcome differences is probable, albeit potentially treatment-specific, and further understanding is required. Notwithstanding these aspects, we identify opportunities to harness biological differences to improve treatment outcomes, as well as areas of fundamental and translational research to pursue. At the level of policy and health-care delivery, improvements can be made across the domains of patient awareness, clinician education, referral pathways and guideline-based care. Together, we aim to highlight opportunities to close the sex gap in bladder cancer outcomes.© 2023. Springer Nature Limited."
-,37666996,Inflammation across tissues: can shared cell biology help design smarter trials?,Nat Rev Rheumatol,"Immune-mediated inflammatory diseases (IMIDs) are responsible for substantial global disease burden and associated health-care costs. Traditional models of research and service delivery silo their management within organ-based medical disciplines. Very often patients with disease in one organ have comorbid involvement in another, suggesting shared pathogenic pathways. Moreover, different IMIDs are often treated with the same drugs (including glucocorticoids, immunoregulators and biologics). Unlocking the cellular basis of these diseases remains a major challenge, leading us to ask why, if these diseases have so much in common, they are not investigated in a common manner. A tissue-based, cellular understanding of inflammation might pave the way for cross-disease, cross-discipline basket trials (testing one drug across two or more diseases) to reduce the risk of failure of early-phase drug development in IMIDs. This new approach will enable rapid assessment of the efficacy of new therapeutic agents in cross-disease translational research in humans.© 2023. Springer Nature Limited."
-,37659974,Single-cell RNA sequencing technology in human spermatogenesis: Progresses and perspectives.,Mol Cell Biochem,"Spermatogenesis, a key part of the spermiation process, is regulated by a combination of key cells, such as primordial germ cells, spermatogonial stem cells, and somatic cells, such as Sertoli cells. Abnormal spermatogenesis can lead to azoospermia, testicular tumors, and other diseases related to male infertility. The application of single-cell RNA sequencing (scRNA-seq) technology in male reproduction is gradually increasing with its unique insight into deep mining and analysis. The data cover different periods of neonatal, prepubertal, pubertal, and adult stages. Different types of male infertility diseases including obstructive and non-obstructive azoospermia (NOA), Klinefelter Syndrome (KS), Sertoli Cell Only Syndrome (SCOS), and testicular tumors are also covered. We briefly review the principles and application of scRNA-seq and summarize the research results and application directions in spermatogenesis in different periods and pathological states. Moreover, we discuss the challenges of applying this technology in male reproduction and the prospects of combining it with other technologies.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature."
-,37629071,CXCR4 Expressed by Tumor-Infiltrating B Cells in Gastric Cancer Related to Survival in the Tumor Microenvironment: An Analysis Combining Single-Cell RNA Sequencing with Bulk RNA Sequencing.,Int J Mol Sci,"According to the World Health Organization (WHO), gastric cancer (GC) is the fourth leading cause of tumor-related mortality globally and one of the most prevalent malignant tumors. To better understand the role of tumor-infiltrating B cells (TIBs) in GC, this work used single-cell RNA sequencing (scRNA-Seq) and bulk RNA sequencing (bulk RNA-Seq) data to identify candidate hub genes. Both scRNA-Seq and bulk RNA-Seq data for stomach adenocarcinoma (STAD) were obtained from the GEO and TCGA databases, respectively. Using scRNA-seq data, the FindNeighbors and FindClusters tools were used to group the cells into distinct groups. Immune cell clusters were sought in the massive RNA-seq expression matrix using the single-sample gene set enrichment analysis (ssGSEA). The expression profiles were used in Weighted Gene Coexpression Network Analysis (WGCNA) to build TCGA's gene coexpression networks. Next, univariate Cox regression, LASSO regression, and Kaplan-Meier analyses were used to identify hub genes in scRNA-seq data from sequential B-cell analyses. Finally, we examined the correlation between the hub genes and TIBs utilizing the TISIDB database. We confirmed the immune-related markers in clinical validation samples using reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). 15 cell clusters were classified in the scRNA-seq database. According to the WGCNA findings, the green module is most associated with cancer and B cells. The intersection of 12 genes in two separate datasets (scRNA and bulk) was attained for further analysis. However, survival studies revealed that increasedC-X-C motif chemokine receptor 4(CXCR4) expression was linked to worse overall survival.CXCR4expression is correlated with active, immature, and memory B cells in STAD were identified. Finally, RT-PCR and IHC assays verified that in GC,CXCR4is overexpressed, and its expression level correlates with TIBs. We used scRNA-Seq and bulk RNA-Seq to study STAD's cellular composition. We found thatCXCR4is highly expressed by TIBs in GC, suggesting that it may serve as a hub gene for these cells and a starting point for future research into the molecular mechanisms by which these immune cells gain access to tumors and potentially identify therapeutic targets."
-,37627192,"Advancing Breast Cancer Heterogeneity Analysis: Insights from Genomics, Transcriptomics and Proteomics at Bulk and Single-Cell Levels.",Cancers (Basel),"Breast cancer continues to pose a significant healthcare challenge worldwide for its inherent molecular heterogeneity. This review offers an in-depth assessment of the molecular profiling undertaken to understand this heterogeneity, focusing on multi-omics strategies applied both in traditional bulk and single-cell levels. Genomic investigations have profoundly informed our comprehension of breast cancer, enabling its categorization into six intrinsic molecular subtypes. Beyond genomics, transcriptomics has rendered deeper insights into the gene expression landscape of breast cancer cells. It has also facilitated the formulation of more precise predictive and prognostic models, thereby enriching the field of personalized medicine in breast cancer. The comparison between traditional and single-cell transcriptomics has identified unique gene expression patterns and facilitated the understanding of cell-to-cell variability. Proteomics provides further insights into breast cancer subtypes by illuminating intricate protein expression patterns and their post-translational modifications. The adoption of single-cell proteomics has been instrumental in this regard, revealing the complex dynamics of protein regulation and interaction. Despite these advancements, this review underscores the need for a holistic integration of multiple 'omics' strategies to fully decipher breast cancer heterogeneity. Such integration not only ensures a comprehensive understanding of breast cancer's molecular complexities, but also promotes the development of personalized treatment strategies."
-,37609075,Immune cell type signature discovery and random forest classification for analysis of single cell gene expression datasets.,Front Immunol,"Robust immune cell gene expression signatures are central to the analysis of single cell studies. Nearly all known sets of immune cell signatures have been derived by making use of only single gene expression datasets. Utilizing the power of multiple integrated datasets could lead to high-quality immune cell signatures which could be used as superior inputs to machine learning-based cell type classification approaches.We established a novel workflow for the discovery of immune cell type signatures based primarily on gene-versus-gene expression similarity. It leverages multiple datasets, here seven single cell expression datasets from six different cancer types and resulted in eleven immune cell type-specific gene expression signatures. We used these to train random forest classifiers for immune cell type assignment for single-cell RNA-seq datasets. We obtained similar or better prediction results compared to commonly used methods for cell type assignment in independent benchmarking datasets. Our gene signature set yields higher prediction scores than other published immune cell type gene sets in random forest-based cell type classification. We further demonstrate how our approach helps to avoid bias in downstream statistical analyses by re-analysis of a published IFN stimulation experiment.We demonstrated the quality of our immune cell signatures and their strong performance in a random forest-based cell typing approach. We argue that classifying cells based on our comparably slim sets of genes accompanied by a random forest-based approach not only matches or outperforms widely used published approaches. It also facilitates unbiased downstream statistical analyses of differential gene expression between cell types for significantly more genes compared to previous cell classification algorithms.Copyright © 2023 Aybey, Zhao, Brors and Staub."
-,37603589,STREAK: A supervised cell surface receptor abundance estimation strategy for single cell RNA-sequencing data using feature selection and thresholded gene set scoring.,PLoS Comput Biol,"The accurate estimation of cell surface receptor abundance for single cell transcriptomics data is important for the tasks of cell type and phenotype categorization and cell-cell interaction quantification. We previously developed an unsupervised receptor abundance estimation technique named SPECK (Surface Protein abundance Estimation using CKmeans-based clustered thresholding) to address the challenges associated with accurate abundance estimation. In that paper, we concluded that SPECK results in improved concordance with Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) data relative to comparative unsupervised abundance estimation techniques using only single-cell RNA-sequencing (scRNA-seq) data. In this paper, we outline a new supervised receptor abundance estimation method called STREAK (gene Set Testing-based Receptor abundance Estimation using Adjusted distances and cKmeans thresholding) that leverages associations learned from joint scRNA-seq/CITE-seq training data and a thresholded gene set scoring mechanism to estimate receptor abundance for scRNA-seq target data. We evaluate STREAK relative to both unsupervised and supervised receptor abundance estimation techniques using two evaluation approaches on six joint scRNA-seq/CITE-seq datasets that represent four human and mouse tissue types. We conclude that STREAK outperforms other abundance estimation strategies and provides a more biologically interpretable and transparent statistical model.Copyright: © 2023 Javaid, Frost. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37498558,Sub-Cluster Identification through Semi-Supervised Optimization of Rare-Cell Silhouettes (SCISSORS) in single-cell RNA-sequencing.,Bioinformatics,"Single-cell RNA-sequencing (scRNA-seq) has enabled the molecular profiling of thousands to millions of cells simultaneously in biologically heterogenous samples. Currently, the common practice in scRNA-seq is to determine cell type labels through unsupervised clustering and the examination of cluster-specific genes. However, even small differences in analysis and parameter choosing can greatly alter clustering results and thus impose great influence on which cell types are identified. Existing methods largely focus on determining the optimal number of robust clusters, which can be problematic for identifying cells of extremely low abundance due to their subtle contributions toward overall patterns of gene expression.Here, we present a carefully designed framework, SCISSORS, which accurately profiles subclusters within broad cluster(s) for the identification of rare cell types in scRNA-seq data. SCISSORS employs silhouette scoring for the estimation of heterogeneity of clusters and reveals rare cells in heterogenous clusters by a multi-step semi-supervised reclustering process. Additionally, SCISSORS provides a method for the identification of marker genes of high specificity to the cell type. SCISSORS is wrapped around the popular Seurat R package and can be easily integrated into existing Seurat pipelines.SCISSORS, including source code and vignettes, are freely available at https://github.com/jr-leary7/SCISSORS.© The Author(s) 2023. Published by Oxford University Press."
-,37580137,What Is the Role of Ferroptosis in Neurodegeneration?,Neurology,NA
-,37569389,Mitochondrial Dysfunction Associated with mtDNA in Metabolic Syndrome and Obesity.,Int J Mol Sci,"Metabolic syndrome (MetS) is a precursor to the major health diseases associated with high mortality in industrialized countries: cardiovascular disease and diabetes. An important component of the pathogenesis of the metabolic syndrome is mitochondrial dysfunction, which is associated with tissue hypoxia, disruption of mitochondrial integrity, increased production of reactive oxygen species, and a decrease in ATP, leading to a chronic inflammatory state that affects tissues and organ systems. The mitochondrial AAA + protease Lon (Lonp1) has a broad spectrum of activities. In addition to its classical function (degradation of misfolded or damaged proteins), enzymatic activity (proteolysis, chaperone activity, mitochondrial DNA (mtDNA)binding) has been demonstrated. At the same time, the spectrum of Lonp1 activity extends to the regulation of cellular processes inside mitochondria, as well as outside mitochondria (nuclear localization). This mitochondrial protease with enzymatic activity may be a promising molecular target for the development of targeted therapy for MetS and its components. The aim of this review is to elucidate the role of mtDNA in the pathogenesis of metabolic syndrome and its components as a key component of mitochondrial dysfunction and to describe the promising and little-studied AAA + LonP1 protease as a potential target in metabolic disorders."
-,37658169,Mapping epigenetic modifications by sequencing technologies.,Cell Death Differ,"The ""epigenetics"" concept was first described in 1942. Thus far, chemical modifications on histones, DNA, and RNA have emerged as three important building blocks of epigenetic modifications. Many epigenetic modifications have been intensively studied and found to be involved in most essential biological processes as well as human diseases, including cancer. Precisely and quantitatively mapping over 100 [1], 17 [2], and 160 [3] different known types of epigenetic modifications in histone, DNA, and RNA is the key to understanding the role of epigenetic modifications in gene regulation in diverse biological processes. With the rapid development of sequencing technologies, scientists are able to detect specific epigenetic modifications with various quantitative, high-resolution, whole-genome/transcriptome approaches. Here, we summarize recent advances in epigenetic modification sequencing technologies, focusing on major histone, DNA, and RNA modifications in mammalian cells.© 2023. The Author(s)."
-,37621707,Colocalization of corneal resistance factor GWAS loci with GTEx e/sQTLs highlights plausible candidate causal genes for keratoconus postnatal corneal stroma weakening.,Front Genet,"Background:Genome-wide association studies (GWAS) for corneal resistance factor (CRF) have identified 100s of loci and proved useful to uncover genetic determinants for keratoconus, a corneal ectasia of early-adulthood onset and common indication of corneal transplantation. In the current absence of studies to probe the impact of candidate causal variants in the cornea, we aimed to fill some of this knowledge gap by leveraging tissue-shared genetic effects.Methods:181 CRF signals were examined for evidence of colocalization with genetic signals affecting steady-state gene transcription and splicing in adult, non-eye, tissues of the Genotype-Tissue Expression (GTEx) project. Expression of candidate causal genes thus nominated was evaluated in single cell transcriptomes from adult cornea, limbus and conjunctiva. Fine-mapping and colocalization of CRF and keratoconus GWAS signals was also deployed to support their sharing causal variants.Results and discussion:26.5% of CRF causal signals colocalized with GTEx v8 signals and nominated genes enriched in genes with high and specific expression in corneal stromal cells amongst tissues examined. Enrichment analyses carried out with nearest genes to all 181 CRF GWAS signals indicated that stromal cells of the limbus could be susceptible to signals that did not colocalize with GTEx's. These cells might not be well represented in GTEx and/or the genetic associations might have context specific effects. The causal signals shared with GTEx provide new insights into mediation of CRF genetic effects, including modulation of splicing events. Functionally relevant roles for several implicated genes' products in providing tensile strength, mechano-sensing and signaling make the corresponding genes and regulatory variants prime candidates to be validated and their roles and effects across tissues elucidated. Colocalization of CRF and keratoconus GWAS signals strengthened support for shared causal variants but also highlighted many ways into which likely true shared signals could be missed when using readily available GWAS summary statistics.Copyright © 2023 Jiang, Boutin and Vitart."
-,37604982,Bioinformatics in urology - molecular characterization of pathophysiology and response to treatment.,Nat Rev Urol,"The application of bioinformatics has revolutionized the practice of medicine in the past 20 years. From early studies that uncovered subtypes of cancer to broad efforts spearheaded by the Cancer Genome Atlas initiative, the use of bioinformatics strategies to analyse high-dimensional data has provided unprecedented insights into the molecular basis of disease. In addition to the identification of disease subtypes - which enables risk stratification - informatics analysis has facilitated the identification of novel risk factors and drivers of disease, biomarkers of progression and treatment response, as well as possibilities for drug repurposing or repositioning; moreover, bioinformatics has guided research towards precision and personalized medicine. Implementation of specific computational approaches such as artificial intelligence, machine learning and molecular subtyping has yet to become widespread in urology clinical practice for reasons of cost, disruption of clinical workflow and need for prospective validation of informatics approaches in independent patient cohorts. Solving these challenges might accelerate routine integration of bioinformatics into clinical settings.© 2023. Springer Nature Limited."
-,37667220,TET2 inhibits the proliferation and metastasis of lung adenocarcinoma cells via activation of the cGAS-STING signalling pathway.,BMC Cancer,"Effective identification and development of new molecular methods for the diagnosis, treatment and prognosis of lung adenocarcinoma (LUAD) remains an urgent clinical need. DNA methylation patterns at cytosine bases in the genome are closely related to gene expression, and abnormal DNA methylation is frequently observed in various cancers. The ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) and promote locus-specific DNA methylation reversal. This study aimed to explore the role of the TET2 protein and its downstream effector, 5-hmC/5-mC DNA modification, in LUAD progression.The expression of TET2 was analysed by real-time PCR, Western blotting and immunohistochemistry. The 5-hmC DNA content was determined by a colorimetric kit. Activation of the cGAS-STING signalling pathway was evaluated by Western blotting. CCK-8, wound healing and Transwell assays were performed to evaluate the effect of TET2 on cell proliferation, migration and invasion abilities. A xenograft model was used to analyse the effect of TET2 on the tumorigenic ability of A549 cells.TET2 overexpression decreased proliferation and metastasis of A549 and H1975 cells in vitro and in vivo. However, TET2 knockdown dramatically enhanced the proliferation, migration and invasion of A549 and H1975 cells. Mechanistically, activation of the cGAS-STING signalling pathway is critical for the TET2-mediated suppression of LUAD cell tumorigenesis and metastasis.In this study, we demonstrate a tumour suppressor role of TET2 in LUAD, providing new potential molecular therapeutic targets and clinical therapies for patients with non-small cell lung cancer.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37580596,NA,NA,"Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis.© 2023. The Author(s)."
-,37657044,Comprehensive analysis of the prognostic values and immune implication of ESYT3 in lung adenocarcinoma.,Medicine (Baltimore),"Few studies have reported the association between ESYT3 and tumors. The purpose of this study was to investigate the molecular features and potential roles of ESYT3 in lung adenocarcinoma (LUAD). In the present study, GEPIA, UALCAN, TCGA databases, and KM Plotter were primarily used to study ESYT3 mRNA expression profiles and prognostic values in patients with LUAD. Then we evaluated co-expressed genes of ESYT3 by cBioPortal online tools and performed enrichment analysis using Metascape. Moreover, the relationship between ESYT3 and immune infiltrating cells was explored via TIMER2, and MethSurv database was used to conduct methylation analysis. We found ESYT3 was downregulated in LUAD tissues based on TCGA and GEPIA databases. Low expression of ESYT3 mRNA was observed to be significantly correlated with N classification and stage classification. GEPIA2, UALCAN databases and KM Plotter showed that low expression levels of ESYT3 was associated with poor survival in LUAD patients. The enrichment analysis indicated that co-expressed genes of ESYT3 were highly enriched in cell division. Then, our study showed ESYT3 was correlated with immune infiltration and immune checkpoints. Additionally, hypomethylation was associated with low ESYT3 expression and poor prognosis in LUAD. In conclusion, this study suggested ESYT3 could be a potential prognostic marker and a promising therapeutic target in LUAD.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc."
-,37628587,NA,NA,"Mitochondrial DNA (mtDNA) is a small fraction of our hereditary material. However, this molecule has had an overwhelming presence in scientific research for decades until the arrival of high-throughput studies. Several appealing properties justify the application of mtDNA to understand how human populations are-from a genetic perspective-and how individuals exhibit phenotypes of biomedical importance. Here, I review the basics of mitochondrial studies with a focus on the dawn of the field, analysis methods and the connection between two sides of mitochondrial genetics: anthropological and biomedical. The particularities of mtDNA, with respect to inheritance pattern, evolutionary rate and dependence on the nuclear genome, explain the challenges of associating mtDNA composition and diseases. Finally, I consider the relevance of this single locus in the context of omics research. The present work may serve as a tribute to a tool that has provided important insights into the past and present of humankind."
-,37556429,"Integrated analysis of human DNA methylation, gene expression, and genomic variation in iMETHYL database using kernel tensor decomposition-based unsupervised feature extraction.",PLoS One,"Integrating gene expression, DNA methylation, and genomic variants simultaneously without location coincidence (i.e., irrespective of distance from each other) or pairwise coincidence (i.e., direct identification of triplets of gene expression, DNA methylation, and genomic variants, and not integration of pairwise coincidences) is difficult. In this study, we integrated gene expression, DNA methylation, and genome variants from the iMETHYL database using the recently proposed kernel tensor decomposition-based unsupervised feature extraction method with limited computational resources (i.e., short CPU time and small memory requirements). Our methods do not require prior knowledge of the subjects because they are fully unsupervised in that unsupervised tensor decomposition is used. The selected genes and genomic variants were significantly targeted by transcription factors that were biologically enriched in KEGG pathway terms as well as in the intra-related regulatory network. The proposed method is promising for integrated analyses of gene expression, methylation, and genomic variants with limited computational resources.Copyright: © 2023 Taguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37629546,Tumor Markers and Their Diagnostic Significance in Ovarian Cancer.,Life (Basel),"Ovarian cancer (OC) is characterized by silent progression and late-stage diagnosis. It is critical to detect and accurately diagnose the disease early to improve survival rates. Tumor markers have emerged as valuable tools in the diagnosis and management of OC, offering non-invasive and cost-effective options for screening, monitoring, and prognosis.This paper explores the diagnostic importance of various tumor markers including CA-125, CA15-3, CA 19-9, HE4,hCG, inhibin, AFP, and LDH, and their impact on disease monitoring and treatment response assessment.Article searches were performed on PubMed, Scopus, and Google Scholar. Keywords used for the searching process were ""Ovarian cancer"", ""Cancer biomarkers"", ""Early detection"", ""Cancer diagnosis"", ""CA-125"",""CA 15-3"",""CA 19-9"", ""HE4"",""hCG"", ""inhibin"", ""AFP"", ""LDH"", and others.HE4, when combined with CA-125, shows improved sensitivity and specificity, particularly in early-stage detection. Additionally, hCG holds promise as a prognostic marker, aiding treatment response prediction and outcome assessment. Novel markers like microRNAs, DNA methylation patterns, and circulating tumor cells offer potential for enhanced diagnostic accuracy and personalized management. Integrating these markers into a comprehensive panel may improve sensitivity and specificity in ovarian cancer diagnosis. However, careful interpretation of tumor marker results is necessary, considering factors such as age, menopausal status, and comorbidities. Further research is needed to validate and refine diagnostic algorithms, optimizing the clinical significance of tumor markers in ovarian cancer management. In conclusion, tumor markers such as CA-125, CA15-3, CA 19-9, HE4, and hCG provide valuable insights into ovarian cancer diagnosis, monitoring, and prognosis, with the potential to enhance early detection."
-,37628794,The Future of Precision Oncology.,Int J Mol Sci,"Our understanding of the molecular mechanisms underlying cancer development and evolution have evolved rapidly over recent years, and the variation from one patient to another is now widely recognized. Consequently, one-size-fits-all approaches to the treatment of cancer have been superseded by precision medicines that target specific disease characteristics, promising maximum clinical efficacy, minimal safety concerns, and reduced economic burden. While precision oncology has been very successful in the treatment of some tumors with specific characteristics, a large number of patients do not yet have access to precision medicines for their disease. The success of next-generation precision oncology depends on the discovery of new actionable disease characteristics, rapid, accurate, and comprehensive diagnosis of complex phenotypes within each patient, novel clinical trial designs with improved response rates, and worldwide access to novel targeted anticancer therapies for all patients. This review outlines some of the current technological trends, and highlights some of the complex multidisciplinary efforts that are underway to ensure that many more patients with cancer will be able to benefit from precision oncology in the near future."
-,37608214,Early detection of lung cancer using artificial intelligence-enhanced optical nanosensing of chromatin alterations in field carcinogenesis.,Sci Rep,"Supranucleosomal chromatin structure, including chromatin domain conformation, is involved in the regulation of gene expression and its dysregulation has been associated with carcinogenesis. Prior studies have shown that cells in the buccal mucosa carry a molecular signature of lung cancer among the cigarette-smoking population, the phenomenon known as field carcinogenesis or field of injury. Thus, we hypothesized that chromatin structural changes in buccal mucosa can be predictive of lung cancer. However, the small size of the chromatin chain (approximately 20 nm) folded into chromatin packing domains, themselves typically below 300 nm in diameter, preclude the detection of alterations in intradomain chromatin conformation using diffraction-limited optical microscopy. In this study, we developed an optical spectroscopic statistical nanosensing technique to detect chromatin packing domain changes in buccal mucosa as a lung cancer biomarker: chromatin-sensitive partial wave spectroscopic microscopy (csPWS). Artificial intelligence (AI) was applied to csPWS measurements of chromatin alterations to enhance diagnostic performance. Our AI-enhanced buccal csPWS nanocytology of 179 patients at two clinical sites distinguished Stage-I lung cancer versus cancer-free controls with an area under the ROC curve (AUC) of 0.92 ± 0.06 for Site 1 (in-state location) and 0.82 ± 0.11 for Site 2 (out-of-state location).© 2023. Springer Nature Limited."
-,37582783,Cross-platform comparisons for targeted bisulfite sequencing of MGISEQ-2000 and NovaSeq6000.,Clin Epigenetics,"An accurate and reproducible next-generation sequencing platform is essential to identify malignancy-related abnormal DNA methylation changes and translate them into clinical applications including cancer detection, prognosis, and surveillance. However, high-quality DNA methylation sequencing has been challenging because poor sequence diversity of the bisulfite-converted libraries severely impairs sequencing quality and yield. In this study, we tested MGISEQ-2000 Sequencer's capability of DNA methylation sequencing with a published non-invasive pancreatic cancer detection assay, using NovaSeq6000 as the benchmark.We sequenced a series of synthetic cell-free DNA (cfDNA) samples with different tumor fractions and found MGISEQ-2000 yielded data with similar quality as NovaSeq6000. The methylation levels measured by MGISEQ-2000 demonstrated high consistency with NovaSeq6000. Moreover, MGISEQ-2000 showed a comparable analytic sensitivity with NovaSeq6000, suggesting its potential for clinical detection. As to evaluate the clinical performance of MGISEQ-2000, we sequenced 24 clinical samples and predicted the pathology of the samples with a clinical diagnosis model, PDACatch classifier. The clinical model performance of MGISEQ-2000's data was highly consistent with that of NovaSeq6000's data, with the area under the curve of 1. We also tested the model's robustness with MGISEQ-2000's data when reducing the sequencing depth. The results showed that MGISEQ-2000's data showed matching robustness of the PDACatch classifier with NovaSeq6000's data.Taken together, MGISEQ-2000 demonstrated similar data quality, consistency of the methylation levels, comparable analytic sensitivity, and matching clinical performance, supporting its application in future non-invasive early cancer detection investigations by detecting distinct methylation patterns of cfDNAs.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37560387,"An overview of DNA methylation markers for early detection of gastric cancer: current status, challenges, and prospects.",Front Genet,"Background:Gastric cancer (GC) is one of the most common malignancies, with a low 5-year survival rate. However, if diagnosed at an early stage, it can be cured by endoscopic treatment and has a good prognosis. While gastrointestinal X-ray and upper endoscopy are used as national GC screening methods in some GC high-risk countries, such as Japan and Korea, their radiation exposure, invasiveness, and high cost suggest that they are not the optimal tools for early detection of GC in many countries. Therefore, a cost-effective, and highly accurate method for GC early detection is urgently needed in clinical settings. DNA methylation plays a key role in cancer progression and metastasis and has been demonstrated as a promising marker for cancer early detection.Aims and methods:This review provides a comprehensive overview of the current status of DNA methylation markers associated with GC, the assays developed for GC early detection, challenges in methylation marker discovery and application, and the future prospects of utilizing methylation markers for early detection of GC. Through our analysis, we found that the currently reported DNA methylation markers related to GC are mainly in the early discovery stage. Most of them have only been evaluated in tissue samples. The majority of non-invasive assays developed based on blood lack standardized sampling protocols, pre-analytical procedures, and multicenter validation, and they exhibit insufficient sensitivity for early-stage GC detection. Meanwhile, the reported GC DNA methylation markers are generally considered pan-cancer markers.Conclusion:Therefore, future endeavors should focus on identifying additional methylation markers specific to GC and establishing non-invasive diagnostic assays that rely on these markers. These assays should undergo multicenter, large-scale prospective validation in diverse populations.Copyright © 2023 Xue, Huang, Pei, Wang and Dai."
-,37561608,Exploring Single-Cell Exposomics by Mass Spectrometry.,Environ Sci Technol,"Single-cell exposomics, a revolutionary approach that investigates cell-environment interactions at cellular and subcellular levels, stands distinct from conventional bulk exposomics. Leveraging advancements in mass spectrometry, it provides a detailed perspective on cellular dynamics, interactions, and responses to environmental stimuli and their impacts on human health. This work delves into this innovative realm, highlighting the nuanced interplay between environmental stressors and biological responses at cellular and subcellular levels. The application of spatial mass spectrometry in single-cell exposomics is discussed, revealing the intricate spatial organization and molecular composition within individual cells. Cell-type-specific exposomics, shedding light on distinct susceptibilities and adaptive strategies of various cell types to environmental exposures, is also examined. The Perspective further emphasizes the integration with molecular and cellular biology approaches to validate hypotheses derived from single-cell exposomics in a comprehensive biological context. Looking toward the future, we anticipate continued technological advancements and convergence with other -omics approaches and discuss implications for environmental health research, disease progression studies, and precision medicine. The final emphasis is on the need for robust computational tools and interdisciplinary collaboration to fully leverage the potential of single-cell exposomics, acknowledging the complexities inherent to this paradigm."
-,37602215,Inferring CTCF-binding patterns and anchored loops across human tissues and cell types.,Patterns (N Y),"CCCTC-binding factor (CTCF) is a transcription regulator with a complex role in gene regulation. The recognition and effects of CTCF on DNA sequences, chromosome barriers, and enhancer blocking are not well understood. Existing computational tools struggle to assess the regulatory potential of CTCF-binding sites and their impact on chromatin loop formation. Here we have developed a deep-learning model, DeepAnchor, to accurately characterize CTCF binding using high-resolution genomic/epigenomic features. This has revealed distinct chromatin and sequence patterns for CTCF-mediated insulation and looping. An optimized implementation of a previous loop model based on DeepAnchor score excels in predicting CTCF-anchored loops. We have established a compendium of CTCF-anchored loops across 52 human tissue/cell types, and this suggests that genomic disruption of these loops could be a general mechanism of disease pathogenesis. These computational models and resources can help investigate how CTCF-mediatedcis-regulatory elements shape context-specific gene regulation in cell development and disease progression.© 2023 The Authors."
-,37589026,Integrative Identification by Hi-C Revealed Distinct Advanced Structural Variations in Lung Adenocarcinoma Tissue.,Phenomics,"Advanced three-dimensional structure variations of chromatin in large genome fragments, such as conversion of A/B compartment, topologically associated domains (TADs) and chromatin loops are related closely to occurrence of malignant tumors. However, the structural characteristics of lung cancer still remain uncovered. In this study, we used high-throughput chromosome (Hi-C) conformation capture technology to detect the advanced structural variations in chromatin of two non-smoking lung adenocarcinoma (LUAD) tumor and paired normal tissues. The results indicate that significant chromatin variations are detected in tumor tissues compared with normal tissues. At compartment scale, the main conversion type of compartment is A → B in tumor tissues, which are concentrated mainly on chromosome 3 (Chr3) (33.6%). A total of 216 tumor-specific TADs are identified in tumor tissues, which are distributed mainly in Chr1 (19), Chr2 (15) and Chr3 (17). Forty-one distinct enhancer-promoter loops are observed in tumor tissue, which are associated closely to tumor-related pathways including mitogen-activated protein kinase (MAPK), Phosphatidylinositol-3-kinase-Protein kinase B (PI3K-AKT), Ras, Wnt and Ras1. The most important observation in this study is that we identify five important genes (SYT16,NCEH1,NXPE3,MB21D2, andDZIP1L), which are detected in both A → B compartment, TADs and chromatin loops in tumor samples, and four of these genes (NCEH1,NXPE3,MB21D2, andDZIP1L) locate on q arm of Chr3. Further gene expression and invasion experiment analysis show thatNCEH1,MB21D2andSYT16are involved in the tumor development. Thus, we provide a comprehensive overview of advanced structures in LUAD for the first time and provide a basis for further research on the genetic variation of this tumor.© International Human Phenome Institutes (Shanghai) 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law."
-,37546906,NA,NA,"The identification of cell-type-specific 3D chromatin interactions between regulatory elements can help to decipher gene regulation and to interpret the function of disease-associated non-coding variants. However, current chromosome conformation capture (3C) technologies are unable to resolve interactions at this resolution when only small numbers of cells are available as input. We therefore present ChromaFold, a deep learning model that predicts 3D contact maps and regulatory interactions from single-cell ATAC sequencing (scATAC-seq) data alone. ChromaFold uses pseudobulk chromatin accessibility, co-accessibility profiles across metacells, and predicted CTCF motif tracks as input features and employs a lightweight architecture to enable training on standard GPUs. Once trained on paired scATAC-seq and Hi-C data in human cell lines and tissues, ChromaFold can accurately predict both the 3D contact map and peak-level interactions across diverse human and mouse test cell types. In benchmarking against a recent deep learning method that uses bulk ATAC-seq, DNA sequence, and CTCF ChIP-seq to make cell-type-specific predictions, ChromaFold yields superior prediction performance when including CTCF ChIP-seq data as an input and comparable performance without. Finally, fine-tuning ChromaFold on paired scATAC-seq and Hi-C in a complex tissue enables deconvolution of chromatin interactions across cell subpopulations. ChromaFold thus achieves state-of-the-art prediction of 3D contact maps and regulatory interactions using scATAC-seq alone as input data, enabling accurate inference of cell-type-specific interactions in settings where 3C-based assays are infeasible."
-,37578609,"Temporal trends of sepsis-related mortality in China, 2006-2020: a population-based study.",Ann Intensive Care,"The scarcity of sepsis epidemiologic data from most low- and middle-income countries (LMICs) hampered estimation of regional and global burden of the disease, and provided limited guidance for policy makers. We aimed to characterize and analyze the temporal trends of sepsis-related mortality in China, by population groups, underlying causes of death, geographic regions, and sociodemographic index (SDI) levels.Sepsis-related deaths were identified from the National Mortality Surveillance System (NMSS) of China from 2006 to 2020. Trends of sepsis-related mortality and years of life lost (YLLs), stratified by age, sex, underlying diseases, and regions were analyzed using the Jointpoint regression analysis. We investigated the association of SDI with trends of sepsis-related mortality.In 2020, sepsis was estimated to be responsible for 986,929 deaths and 17.1 million YLLs in China. Age-standardized sepsis-related mortality significantly declined from 130.2 (95%CI, 129.4-131) per 100,000 population in 2006 to 76.6 (76.3-76.9) in 2020. Age-standardized YLLs decreased from 2172.7 (2169.4-2176) per 100,000 population in 2006 to 1271 (1269.8-1272.2) in 2020. Substantial variations of sepsis-related mortality and YLLs were observed between population groups and regions, with higher burden in males, the elderly, and western China. An inverse relation was noted between SDI and sepsis-related mortality or YLLs.Despite declining trends of age-standardized mortality and YLLs of sepsis in China, significant disparities between population groups and regions highlight a need for targeted policies and measures to close the gaps and improve the outcome of sepsis.© 2023. La Société de Réanimation de Langue Francaise = The French Society of Intensive Care (SRLF)."
-,37568655,Advancements in MRI-Based Radiomics and Artificial Intelligence for Prostate Cancer: A Comprehensive Review and Future Prospects.,Cancers (Basel),"The use of multiparametric magnetic resonance imaging (mpMRI) has become a common technique used in guiding biopsy and developing treatment plans for prostate lesions. While this technique is effective, non-invasive methods such as radiomics have gained popularity for extracting imaging features to develop predictive models for clinical tasks. The aim is to minimize invasive processes for improved management of prostate cancer (PCa). This study reviews recent research progress in MRI-based radiomics for PCa, including the radiomics pipeline and potential factors affecting personalized diagnosis. The integration of artificial intelligence (AI) with medical imaging is also discussed, in line with the development trend of radiogenomics and multi-omics. The survey highlights the need for more data from multiple institutions to avoid bias and generalize the predictive model. The AI-based radiomics model is considered a promising clinical tool with good prospects for application."
-,37627121,A Comprehensive Benchmark of Transcriptomic Biomarkers for Immune Checkpoint Blockades.,Cancers (Basel),"Immune checkpoint blockades (ICBs) have revolutionized cancer therapy by inducing durable clinical responses, but only a small percentage of patients can benefit from ICB treatments. Many studies have established various biomarkers to predict ICB responses. However, different biomarkers were found with diverse performances in practice, and a timely and unbiased assessment has yet to be conducted due to the complexity of ICB-related studies and trials. In this study, we manually curated 29 published datasets with matched transcriptome and clinical data from more than 1400 patients, and uniformly preprocessed these datasets for further analyses. In addition, we collected 39 sets of transcriptomic biomarkers, and based on the nature of the corresponding computational methods, we categorized them into the gene-set-like group (with the self-contained design and the competitive design, respectively) and the deconvolution-like group. Next, we investigated the correlations and patterns of these biomarkers and utilized a standardized workflow to systematically evaluate their performance in predicting ICB responses and survival statuses across different datasets, cancer types, antibodies, biopsy times, and combinatory treatments. In our benchmark, most biomarkers showed poor performance in terms of stability and robustness across different datasets. Two scores (TIDE and CYT) had a competitive performance for ICB response prediction, and two others (PASS-ON and EIGS_ssGSEA) showed the best association with clinical outcome. Finally, we developed ICB-Portal to host the datasets, biomarkers, and benchmark results and to implement the computational methods for researchers to test their custom biomarkers. Our work provided valuable resources and a one-stop solution to facilitate ICB-related research."
-,37583573,Defining cardiac functional recovery in end-stage heart failure at single-cell resolution.,Nat Cardiovasc Res,"Recovery of cardiac function is the holy grail of heart failure therapy yet is infrequently observed and remains poorly understood. In this study, we performed single-nucleus RNA sequencing from patients with heart failure who recovered left ventricular systolic function after left ventricular assist device implantation, patients who did not recover and non-diseased donors. We identified cell-specific transcriptional signatures of recovery, most prominently in macrophages and fibroblasts. Within these cell types, inflammatory signatures were negative predictors of recovery, and downregulation of RUNX1 was associated with recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of recovery. Cardiac recovery mediated by BET inhibition in mice led to decreased macrophage and fibroblast Runx1 expression and diminished chromatin accessibility within a Runx1 intronic peak and acquisition of human recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery."
-,37596694,Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery.,Inflamm Regen,"Crosstalk between the aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is called the ""AhR-Nrf2 gene battery"", which works synergistically in detoxification to support cell survival. Nrf2-dependent phase II gene promoters are controlled by coordinated recruitment of the AhR to adjacent dioxin responsive element (DRE) and Nrf2 recruitment to the antioxidative response element (ARE). The molecular interaction between AhR and Nrf2 members, and the regulation of each target, including phase I and II gene complexes, and their mediators are poorly understood.Knockdown and forced expression of AhR-Nrf2 battery members were used to examine the molecular interactions between the AhR-Nrf2 axis and AhR promoter activation. Sequential immunoprecipitation, chromatin immunoprecipitation, and histology were used to identify each protein complex recruited to their respective cis-elements in the AhR promoter. Actin fiber distribution, cell spreading, and invasion were examined to identify functional differences in the AhR-Jdp2 axis between wild-type and Jdp2 knockout cells. The possible tumorigenic role of Jdp2 in the AhR-Nrf2 axis was examined in mutant Kras-Trp53-driven pancreatic tumors.Crosstalk between AhR and Nrf2 was evident at the transcriptional level. The AhR promoter was activated by phase I ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the AhR-Jdp2-Nrf2 axis in a time- and spatial transcription-dependent manner. Jdp2 was a bifunctional activator of DRE- and ARE-mediated transcription in response to TCDD. After TCDD exposure, Jdp2 activated the AhR promoter at the DRE and then moved to the ARE where it activated the promoter to increase reactive oxygen species (ROS)-mediated functions such as cell spreading and invasion in normal cells, and cancer regression in mutant Kras-Trp53-driven pancreatic tumor cells.Jdp2 plays a critical role in AhR promoter activation through the AhR-Jdp2-Nrf2 axis in a spatiotemporal manner. The AhR functions to maintain ROS balance and cell spreading, invasion, and cancer regression in a mouse model of mutant Kras-Trp53 pancreatic cancer. These findings provide new insights into the roles of Jdp2 in the homeostatic regulation of oxidative stress and in the antioxidation response in detoxification, inflammation, and cancer progression.© 2023. Japanese Society of Inflammation and Regeneration."
-,37582793,Predicting the impact of sequence motifs on gene regulation using single-cell data.,Genome Biol,"The binding of transcription factors at proximal promoters and distal enhancers is central to gene regulation. Identifying regulatory motifs and quantifying their impact on expression remains challenging. Using a convolutional neural network trained on single-cell data, we infer putative regulatory motifs and cell type-specific importance. Our model, scover, explains 29% of the variance in gene expression in multiple mouse tissues. Applying scover to distal enhancers identified using scATAC-seq from the developing human brain, we identify cell type-specific motif activities in distal enhancers. Scover can identify regulatory motifs and their importance from single-cell data where all parameters and outputs are easily interpretable.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37587190,NA,NA,"Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and cellular abnormalities, with FCD type II being the most common and characterized by disrupted organization of the cortex and abnormal neuronal development. In this study, we employed cell-type deconvolution and single-cell signatures to analyze bulk RNA-seq from multiple transcriptomic studies, aiming to characterize the cellular composition of brain lesions in patients with FCD IIa and IIb subtypes. Our deconvolution analyses revealed specific cellular changes in FCD IIb, including neuronal loss and an increase in reactive astrocytes (astrogliosis) when compared to FCD IIa. Astrogliosis in FCD IIb was further supported by a gene signature analysis and histologically confirmed by glial fibrillary acidic protein (GFAP) immunostaining. Overall, our findings demonstrate that FCD II subtypes exhibit differential neuronal and glial compositions, with astrogliosis emerging as a hallmark of FCD IIb. These observations, validated in independent patient cohorts and confirmed using immunohistochemistry, offer novel insights into the involvement of glial cells in FCD type II pathophysiology and may contribute to the development of targeted therapies for this condition.© 2023. Springer Nature Limited."
-,37571224,Research Progress on the Anti-Aging Potential of the Active Components of Ginseng.,Nutrients,"Aging is a cellular state characterized by a permanent cessation of cell division and evasion of apoptosis. DNA damage, metabolic dysfunction, telomere damage, and mitochondrial dysfunction are the main factors associated with senescence. Aging increases β-galactosidase activity, enhances cell spreading, and induces Lamin B1 loss, which further accelerate the aging process. It is associated with a variety of diseases, such as Alzheimer's disease, Parkinson's, type 2 diabetes, and chronic inflammation. Ginseng is a traditional Chinese medicine with anti-aging effects. The active components of ginseng, including saponins, polysaccharides, and active peptides, have antioxidant, anti-apoptotic, neuroprotective, and age-delaying effects. DNA damage is the main factor associated with aging, and the mechanism through which the active ingredients of ginseng reduce DNA damage and delay aging has not been comprehensively described. This review focuses on the anti-aging mechanisms of the active ingredients of ginseng. Furthermore, it broadens the scope of ideas for further research on natural products and aging."
-,37648769,NA,NA,"Previous studies showed that intrauterine growth restrictions, resulting in smaller body size at birth, are associated with altered development and the risk of age-related diseases in adult life. Thus, prenatal development may predict aging trajectories in humans. The study aimed to verify if body size at birth is related to biological age in adult men. The study sample consisted of 159 healthy, non-smoking men with a mean age of 35.24 (SD 3.44) years. Birth weight and length were taken from medical records. The ponderal index at birth was calculated. Biological age was evaluated based on serum levels of s-Klotho, hsCRP, DHEA/S, and oxidative stress markers. Pregnancy age at birth, lifestyle, weight, cortisol, and testosterone levels were controlled. The results showed no relationship between birth size and s-Klotho, DHEA/S level, inflammation, or oxidative stress. Also, men born as small-for-gestational-age (N = 49) and men born as appropriate-for-gestational-age (N = 110) did not differ in terms of biological age markers levels. The results were similar when controlled for pregnancy week at birth, chronological age, BMI, testosterone, or cortisol level. The results suggest that there is no relationship between intrauterine growth and biomarkers of aging in men aged 30-45 years from the affluent population.© 2023. Springer Nature Limited."
-,37560445,Artificial intelligence vs. evolving super-complex tumor intelligence: critical viewpoints.,Front Artif Intell,"Recent developments in various domains have led to a growing interest in the potential of artificial intelligence to enhance our lives and environments. In particular, the application of artificial intelligence in the management of complex human diseases, such as cancer, has garnered significant attention. The evolution of artificial intelligence is thought to be influenced by multiple factors, including human intervention and environmental factors. Similarly, tumors, being heterogeneous and complex diseases, continue to evolve due to changes in the physical, chemical, and biological environment. Additionally, the concept of cellular intelligence within biological systems has been recognized as a potential attribute of biological entities. Therefore, it is plausible that the tumor intelligence present in cancer cells of affected individuals could undergo super-evolution due to changes in the pro-tumor environment. Thus, a comparative analysis of the evolution of artificial intelligence and super-complex tumor intelligence could yield valuable insights to develop better artificial intelligence-based tools for cancer management.Copyright © 2023 Sharma and Sarode."
-,37627102,"Variant Characterization of a Representative Large Pedigree Suggests ""Variant Risk Clusters"" Convey Varying Predisposition of Risk to Lynch Syndrome.",Cancers (Basel),"Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three ""variant risk clusters"" shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different ""variant risk clusters"" can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree."
-,37647071,Evaluation of Neighborhood-Level Disadvantage and Cognition in Mexican American and Non-Hispanic White Adults 50 Years and Older in the US.,JAMA Netw Open,"Understanding how socioeconomic factors are associated with cognitive aging is important for addressing health disparities in Alzheimer disease.To examine the association of neighborhood disadvantage with cognition among a multiethnic cohort of older adults.In this cross-sectional study, data were collected between September 1, 2017, and May 31, 2022. Participants were from the Health and Aging Brain Study-Health Disparities, which is a community-based single-center study in the Dallas/Fort Worth area of Texas. A total of 1614 Mexican American and non-Hispanic White adults 50 years and older were included.Neighborhood disadvantage for participants' current residence was measured by the validated Area Deprivation Index (ADI); ADI Texas state deciles were converted to quintiles, with quintile 1 representing the least disadvantaged area and quintile 5 the most disadvantaged area. Covariates included age, sex, and educational level.Performance on cognitive tests assessing memory, language, attention, processing speed, and executive functioning; measures included the Spanish-English Verbal Learning Test (SEVLT) Learning and Delayed Recall subscales; Wechsler Memory Scale, third edition (WMS-III) Digit Span Forward, Digit Span Backward, and Logical Memory 1 and 2 subscales; Trail Making Test (TMT) parts A and B; Digit Symbol Substitution Test (DSST); Letter Fluency; and Animal Naming. Raw scores were used for analyses. Associations between neighborhood disadvantage and neuropsychological performance were examined via demographically adjusted linear regression models stratified by ethnic group.Among 1614 older adults (mean [SD] age, 66.3 [8.7] years; 980 women [60.7%]), 853 were Mexican American (mean [SD] age, 63.9 [7.9] years; 566 women [66.4%]), and 761 were non-Hispanic White (mean [SD] age, 69.1 [8.7] years; 414 women [54.4%]). Older Mexican American adults were more likely to reside in the most disadvantaged areas (ADI quintiles 3-5), with 280 individuals (32.8%) living in ADI quintile 5, whereas a large proportion of older non-Hispanic White adults resided in ADI quintile 1 (296 individuals [38.9%]). Mexican American individuals living in more disadvantaged areas had worse performance than those living in ADI quintile 1 on 7 of 11 cognitive tests, including SEVLT Learning (ADI quintile 5: β = -2.50; 95% CI, -4.46 to -0.54), SEVLT Delayed Recall (eg, ADI quintile 3: β = -1.11; 95% CI, -1.97 to -0.24), WMS-III Digit Span Forward (eg, ADI quintile 4: β = -1.14; 95% CI, -1.60 to -0.67), TMT part A (ADI quintile 5: β = 7.85; 95% CI, 1.28-14.42), TMT part B (eg, ADI quintile 5: β = 31.5; 95% CI, 12.16-51.35), Letter Fluency (ADI quintile 4: β = -2.91; 95% CI, -5.39 to -0.43), and DSST (eg, ADI quintile 5: β = -4.45; 95% CI, -6.77 to -2.14). In contrast, only non-Hispanic White individuals living in ADI quintile 4 had worse performance than those living in ADI quintile 1 on 4 of 11 cognitive tests, including SEVLT Learning (β = -2.35; 95% CI, -4.40 to -0.30), SEVLT Delayed Recall (β = -0.95; 95% CI, -1.73 to -0.17), TMT part B (β = 15.95; 95% CI, 2.47-29.44), and DSST (β = -3.96; 95% CI, -6.49 to -1.43).In this cross-sectional study, aging in a disadvantaged area was associated with worse cognitive functioning, particularly for older Mexican American adults. Future studies examining the implications of exposure to neighborhood disadvantage across the life span will be important for improving cognitive outcomes in diverse populations."
-,37652986,Multiplexed transcriptomic profiling of the fate of human CAR T cells in vivo via genetic barcoding with shielded small nucleotides.,Nat Biomed Eng,"The design of chimeric antigen receptor (CAR) T cells would benefit from knowledge of the fate of the cells in vivo. This requires the permanent labelling of CAR T cell products and their pooling in the same microenvironment. Here, we report a cell-barcoding method for the multiplexed longitudinal profiling of cells in vivo using single-cell RNA sequencing (scRNA-seq). The method, which we named shielded-small-nucleotide-based scRNA-seq (SSN-seq), is compatible with both 3' and 5' single-cell profiling, and enables the recording of cell identity, from cell infusion to isolation, by leveraging the ubiquitous Pol III U6 promoters to robustly express small-RNA barcodes modified with direct-capture sequences. By using SSN-seq to track the dynamics of the states of CAR T cells in a tumour-rechallenge mouse model of leukaemia, we found that a combination of cytokines and small-molecule inhibitors that are used in the ex vivo manufacturing of CAR T cells promotes the in vivo expansion of persistent populations of CD4+memory T cells. By facilitating the probing of cell-state dynamics in vivo, SSN-seq may aid the development of adoptive cell therapies.© 2023. The Author(s), under exclusive licence to Springer Nature Limited."
-,37590228,The specious art of single-cell genomics.,PLoS Comput Biol,"Dimensionality reduction is standard practice for filtering noise and identifying relevant features in large-scale data analyses. In biology, single-cell genomics studies typically begin with reduction to 2 or 3 dimensions to produce ""all-in-one"" visuals of the data that are amenable to the human eye, and these are subsequently used for qualitative and quantitative exploratory analysis. However, there is little theoretical support for this practice, and we show that extreme dimension reduction, from hundreds or thousands of dimensions to 2, inevitably induces significant distortion of high-dimensional datasets. We therefore examine the practical implications of low-dimensional embedding of single-cell data and find that extensive distortions and inconsistent practices make such embeddings counter-productive for exploratory, biological analyses. In lieu of this, we discuss alternative approaches for conducting targeted embedding and feature exploration to enable hypothesis-driven biological discovery.Copyright: © 2023 Chari, Pachter. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37563440,Droplet-based single-cell joint profiling of histone modifications and transcriptomes.,Nat Struct Mol Biol,"We previously reported Paired-Tag, a combinatorial indexing-based method that can simultaneously map histone modifications and gene expression at single-cell resolution at scale. However, the lengthy procedure of Paired-Tag has hindered its general adoption in the community. To address this bottleneck, we developed a droplet-based Paired-Tag protocol that is faster and more accessible than the previous method. Using cultured mammalian cells and primary brain tissues, we demonstrate its superior performance at identifying candidate cis-regulatory elements and associating their dynamic chromatin state to target gene expression in each constituent cell type in a complex tissue.© 2023. The Author(s)."
-,37523521,Quantifying common and distinct information in single-cell multimodal data with Tilted Canonical Correlation Analysis.,Proc Natl Acad Sci U S A,"Multimodal single-cell technologies profile multiple modalities for each cell simultaneously, enabling a more thorough characterization of cell populations. Existing dimension-reduction methods for multimodal data capture the ""union of information,"" producing a lower-dimensional embedding that combines the information across modalities. While these tools are useful, we focus on a fundamentally different task of separating and quantifying the information among cells that is shared between the two modalities as well as unique to only one modality. Hence, we develop Tilted Canonical Correlation Analysis (Tilted-CCA), a method that decomposes a paired multimodal dataset into three lower-dimensional embeddings-one embedding captures the ""intersection of information,"" representing the geometric relations among the cells that is common to both modalities, while the remaining two embeddings capture the ""distinct information for a modality,"" representing the modality-specific geometric relations. We analyze single-cell multimodal datasets sequencing RNA along surface antibodies (i.e., CITE-seq) as well as RNA alongside chromatin accessibility (i.e., 10x) for blood cells and developing neurons via Tilted-CCA. These analyses show that Tilted-CCA enables meaningful visualization and quantification of the cross-modal information. Finally, Tilted-CCA's framework allows us to perform two specific downstream analyses. First, for single-cell datasets that simultaneously profile transcriptome and surface antibody markers, we show that Tilted-CCA helps design the target antibody panel to complement the transcriptome best. Second, for developmental single-cell datasets that simultaneously profile transcriptome and chromatin accessibility, we show that Tilted-CCA helps identify development-informative genes and distinguish between transient versus terminal cell types."
-,37600846,Cobind: quantitative analysis of the genomic overlaps.,Bioinform Adv,"Analyzing the overlap between two sets of genomic intervals is a frequent task in the field of bioinformatics. Typically, this is accomplished by counting the number (or proportion) of overlapped regions, which applies an arbitrary threshold to determine if two genomic intervals are overlapped. By making binary calls but disregarding the magnitude of the overlap, such an approach often leads to biased, non-reproducible, and incomparable results.We developed the cobind package, which incorporates six statistical measures: the Jaccard coefficient, Sørensen-Dice coefficient, Szymkiewicz-Simpson coefficient, collocation coefficient, pointwise mutual information (PMI), and normalized PMI. These measures allow for a quantitative assessment of the collocation strength between two sets of genomic intervals. To demonstrate the effectiveness of these methods, we applied them to analyze CTCF's binding sites identified from ChIP-seq, cancer-specific open-chromatin regions (OCRs) identified from ATAC-seq of 17 cancer types, and oligodendrocytes-specific OCRs identified from scATAC-seq. Our results indicated that these new approaches effectively re-discover CTCF's cofactors, as well as cancer-specific and oligodendrocytes-specific master regulators implicated in disease and cell type development.The cobind package is implemented in Python and freely available at https://cobind.readthedocs.io/en/latest/.© The Author(s) 2023. Published by Oxford University Press."
-,37587197,Whole genome deconvolution unveils Alzheimer's resilient epigenetic signature.,Nat Commun,"Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) accurately depicts the chromatin regulatory state and altered mechanisms guiding gene expression in disease. However, bulk sequencing entangles information from different cell types and obscures cellular heterogeneity. To address this, we developed Cellformer, a deep learning method that deconvolutes bulk ATAC-seq into cell type-specific expression across the whole genome. Cellformer enables cost-effective cell type-specific open chromatin profiling in large cohorts. Applied to 191 bulk samples from 3 brain regions, Cellformer identifies cell type-specific gene regulatory mechanisms involved in resilience to Alzheimer's disease, an uncommon group of cognitively healthy individuals that harbor a high pathological load of Alzheimer's disease. Cell type-resolved chromatin profiling unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience that may illuminate therapeutic opportunities to limit the cognitive impact of the disease. Cellformer is freely available to facilitate future investigations using high-throughput bulk ATAC-seq data.© 2023. Springer Nature Limited."
-,37580817,Dissection of transcriptomic and epigenetic heterogeneity of grade 4 gliomas: implications for prognosis.,Acta Neuropathol Commun,"Grade 4 glioma is the most aggressive and currently incurable brain tumor with a median survival of one year in adult patients. Elucidating novel transcriptomic and epigenetic contributors to the molecular heterogeneity underlying its aggressiveness may lead to improved clinical outcomes.To identify grade 4 glioma -associated 5-hydroxymethylcytosine (5hmC) and transcriptomic features as well as their cross-talks, genome-wide 5hmC and transcriptomic profiles of tissue samples from 61 patients with grade 4 gliomas and 9 normal controls were obtained for differential and co-regulation/co-modification analyses. Prognostic models on overall survival based on transcriptomic features and the 5hmC modifications summarized over genic regions (promoters, gene bodies) and brain-derived histone marks were developed using machine learning algorithms.Despite global reduction, the majority of differential 5hmC features showed higher modification levels in grade 4 gliomas as compared to normal controls. In addition, the bi-directional correlations between 5hmC modifications over promoter regions or gene bodies and gene expression were greatly disturbed in grade 4 gliomas regardless of IDH1 mutation status. Phenotype-associated co-regulated 5hmC-5hmC modules and 5hmC-mRNA modules not only are enriched with different molecular pathways that are indicative of the pathogenesis of grade 4 gliomas, but also are of prognostic significance comparable to IDH1 mutation status. Lastly, the best-performing 5hmC model can predict patient survival at a much higher accuracy (c-index = 74%) when compared to conventional prognostic factor IDH1 (c-index = 57%), capturing the molecular characteristics of tumors that are independent of IDH1 mutation status and gene expression-based molecular subtypes.The 5hmC-based prognostic model could offer a robust tool to predict survival in patients with grade 4 gliomas, potentially outperforming existing prognostic factors such as IDH1 mutations. The crosstalk between 5hmC and gene expression revealed another layer of complexity underlying the molecular heterogeneity in grade 4 gliomas, offering opportunities for identifying novel therapeutic targets.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37629335,NA,NA,"The need to improve health outcomes, as well as disease prognosis, has led clinicians and researchers to propose new ways of identifying COPD in its earliest forms. This initiative is based on the hypothesis that an earlier intervention would have a greater prognostic impact. However, the operational definition of a patient in the initial stages of the disease is complex, and there is still no unanimously accepted definition. GOLD has recently proposed different concepts to identify COPD in its early stages, such as COPD in young people or COPD with mild functional impairment. In addition, GOLD proposes two other concepts, called pre-COPD (symptomatic non-obstructive patients) and PRISm (preserved ratio with impaired spirometry), which aim to identify the patient at risk of developing this chronic airflow obstruction. However, despite the attractiveness of these concepts, none have been taken up universally by the medical community. A universally accepted identification of how to define COPD in its early stages is necessary as a preliminary step in order to design clinical trials to find out the best way to treat these patients. This review deals with these concepts of COPD at the onset of the disease, highlighting their importance and the problems involved in identifying them as therapeutic targets in real clinical practice."
-,37653545,NA,NA,"Variant transthyretin amyloidosis (A-ATTRv) is an autosomal dominant disease caused by a range of TTR gene variants which entail great phenotypical heterogeneity and penetrance. In Majorca, the A-ATTRv caused by the V30M gene variant (A-ATTRV30M) is the most common. Since asymptomatic carriers are at risk of developing the disease, estimating age of onset is vital for proper management and follow-up. Thus, the aim of this study was to estimate age-related penetrance in ATTRV30M variant carriers from Majorca.The disease risk among carriers from ATTRV30M families from Majorca was estimated by Non-parametric survival estimation. Factors potentially involved in the disease expression, namely gender and parent of origin were also analysed.A total of 48 heterozygous ATTRV30M families (147 affected patients and 123 were asymptomatic carriers) were included in the analysis. Penetrance progressively increased from 6% at 30 years to 75% at 90 years of age. In contrast to other European populations, we observe a similar risk for both males and females, and no difference of risk according to the parent of origin.In this first study assessing the age-related penetrance of ATTRV30M variant in Majorcan families, no effect of gender or parent of origin was observed. These findings will be helpful for improving management and follow-up of TTR variant carrier individuals.© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM)."
-,37612512,The complete sequence of a human Y chromosome.,Nature,"The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure that includes long palindromes, tandem repeats and segmental duplications1-3. As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished4,5. Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference, showing the complete ampliconic structures of gene families TSPY, DAZ and RBMY; 41 additional protein-coding genes, mostly from the TSPY family; and an alternating pattern of human satellite 1 and 3 blocks in the heterochromatic Yq12 region. We have combined T2T-Y with a previous assembly of the CHM13 genome4and mapped available population variation, clinical variants and functional genomics data to produce a complete and comprehensive reference sequence for all 24 human chromosomes.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply."
-,37599304,"Single-molecule targeted accessibility and methylation sequencing of centromeres, telomeres and rDNAs in Arabidopsis.",Nat Plants,"The short read-length of next-generation sequencing makes it challenging to characterize highly repetitive regions (HRRs) such as centromeres, telomeres and ribosomal DNAs. Based on recent strategies that combined long-read sequencing and exogenous enzymatic labelling of open chromatin, we developed single-molecule targeted accessibility and methylation sequencing (STAM-seq) in plants by further integrating nanopore adaptive sampling to investigate the HRRs in wild-type Arabidopsis and DNA methylation mutants that are defective in CG- or non-CG methylation. We found that CEN180 repeats show higher chromatin accessibility and lower DNA methylation on their forward strand, individual rDNA units show a negative correlation between their DNA methylation and accessibility, and both accessibility and CHH methylation levels are lower at telomere compared to adjacent subtelomeric region. Moreover, DNA methylation-deficient mutants showed increased chromatin accessibility at HRRs, consistent with the role of DNA methylation in maintaining heterochromatic status in plants. STAM-seq can be applied to study accessibility and methylation of repetitive sequences across diverse plant species.© 2023. The Author(s), under exclusive licence to Springer Nature Limited."
-,37640747,Knockdown of Porf-2 restores visual function after optic nerve crush injury.,Cell Death Dis,"Retinal ganglion cells (RGCs), the sole output neurons in the eyes, are vulnerable to diverse insults in many pathological conditions, which can lead to permanent vision dysfunction. However, the molecular and cellular mechanisms that contribute to protecting RGCs and their axons from injuries are not completely known. Here, we identify that Porf-2, a member of the Rho GTPase activating protein gene group, is upregulated in RGCs after optic nerve crush. Knockdown of Porf-2 protects RGCs from apoptosis and promotes long-distance optic nerve regeneration after crush injury in both young and aged mice in vivo. In vitro, we find that inhibition of Porf-2 induces axon growth and growth cone formation in retinal explants. Inhibition of Porf-2 provides long-term and post-injury protection to RGCs and eventually promotes the recovery of visual function after crush injury in mice. These findings reveal a neuroprotective impact of the inhibition of Porf-2 on RGC survival and axon regeneration after optic nerve injury, providing a potential therapeutic strategy for vision restoration in patients with traumatic optic neuropathy.© 2023. The Author(s)."
-,37634152,Chaotic aging: intrinsically disordered proteins in aging-related processes.,Cell Mol Life Sci,"The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1702 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is however less than the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the used here aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels, revealing the importance of ""structure-function continuum"" in aging. Protein-protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment has simultaneously high liquid-liquid phase separation (LLPS) probability, ""nuclear"" localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, and stem cells exhaustion. Intrinsic disorder, LLPS, and aggregation propensity should be considered as features that could be markers of pathogenic proteins. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss of function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG."
-,37649721,Inflammatory biomarkers and delirium: a Mendelian randomization study.,Front Aging Neurosci,"The association between inflammatory biomarkers and individual delirium symptoms remains controversial in observational studies. We investigated the relationship between inflammatory biomarkers and the risk of developing delirium.A bidirectional two-sample Mendelian randomization (MR) was performed. Genetic instruments associated with peripheral tumor necrosis factor-a (TNF-a) C-reactive protein (CRP), interleukin (IL)-1α, IL-1β, IL-2, IL-8, IL-6, soluble IL-6 receptor alpha (sIL-6Rα), and soluble gp130 were identified in three different large summary genome-wide association studies (GWAS) conducted in the European population. Summary-level statistics for delirium not induced by alcohol and other psychoactive substances were obtained from the FinnGen consortium (2,612 cases and 325,306 controls). The estimated causal effects were performed using instruments' variants at the genome-wide significant level (P< 5e-8 andP< 5e-6), applying a linkage disequilibrium clumping approach with a threshold ofr2< 0.001 for each of the exposures. Reverse causation was also performed. The inverse-variance weighted method (IVW), MR-Egger method, weighted median method, MR-Egger regression, and MR Pleiotropy RESidual Sum were used for MR analyses.At the genome-wide significant level (P< 5e-8,r2< 0.001), genetically predicted sIL-6Rα was significantly associated with a decreased risk of delirium with less than three single-nucleotide polymorphisms (SNPs) in all three GWAS data sources (ORWaldratio= 0.89, 95% CI: 0.79-0.96,PWaldratio= 0.0016; ORIVW= 0.88, 95% CI: 0.79-0.97,PIVW= 0.008; ORIVW= 0.88, 95% CI: 0.80-0.96,PIVW= 0.004). The causal relationship between sIL-6Rα and delirium became non-significant when a more liberal threshold ofPof < 5e-6 was applied (allPIVW> 0.05). At the two genome-wide significance levels (P< 5e-8 andP< 5e-6), we found no evidence for the causal effects of peripheral TNF-α, CRP, IL-1α, IL-1β, IL-2, IL-6, IL-8, and soluble gp130 on delirium (allP> 0.05). The MR-Egger intercept and MR-PRESSO results indicated that no SNP had possible pleiotropy (allP> 0.05). Regarding the reverse, no evidence for an effect of delirium on these inflammatory biomarkers could be found (allP> 0.05).The results of this MR analysis did not support that peripheral TNF-α, CRP, IL-1α, IL-1β, IL-2, IL-6, sIL-6Rα, soluble gp130, and IL-8 were causally associated with delirium. More research is needed to explore the role of inflammatory factors in the pathogenesis of delirium.Copyright © 2023 Yu, Li, Li and Ge."
-,37575092,Association between air pollution and primary liver cancer in European and east Asian populations: a Mendelian randomization study.,Front Public Health,"The incidence of primary liver cancer is increasing year by year, with environmental factors playing a non-negligible role. At present, many studies are still disputing whether air pollution is associated with primary liver cancer incidence, and it is difficult to draw causal inferences. Therefore, in this study, we used two-sample Mendelian randomization (MR) to assess the causal relationship between air pollution (including PM2.5, PM2.5-10, PM10, nitrogen dioxide and nitrogen oxides) and primary liver cancer risk and its related biomarkers (Alpha-fetoprotein, Osteopontin, Glypican-3 and Arginase-1).We used large-scale publicly available genome-wide association studies (GWAS) summary data to conduct MR analyses of European and East Asian populations. Inverse variance weighted (IVW) method was used as the main analysis method, and weighted median model, MR-Egger, simple model and weighted model methods were selected for quality control. Heterogeneity was checked by the Cochran's Q test. The MR-Egger regression and the MR-PRESSO global test detect pleiotropy. The sensitivity analysis was performed using the leave-one-out method.Between air pollution and primary liver cancer in either European (PM2.5:p = 0.993; PM2.5-10:p = 0.833; PM10:p = 0.257; nitrogen dioxide:p = 0.215; nitrogen oxides:p = 0.614) or East Asian (PM2.5:p = 0.718; PM2.5-10:p = 0.362; PM10:p = 0.720; nitrogen dioxide:p = 0.101; nitrogen oxides:p = 0.760) populations were found no statistical association. Notably, there was a causal relationship between nitrogen oxides and Arginase-1, a biomarker associated with hepatocellular differentiation, statistically significant associations remained after deletion for single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency, Body mass index (BMI) and cancers (Beta: 4.46; 95%CI: 0.83-8.08;p = 0.015). There was no heterogeneity or pleiotropy in the results.This MR study found no evidence to support a causality between air pollution and primary liver cancer in European and East Asian populations, but nitrogen oxides may affect hepatocellular differentiation.Copyright © 2023 Sun, Gao, Luo, Wang, Zhong and Qin."
-,37645979,NA,NA,"Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation analysis indicated candidate genes,HAND2,TBX3, andRAP2C/FRMD7,at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors (PGR). Furthermore, there were strong genetic correlations with birth weight, gestational duration, and uterine fibroids. Early bleeding during pregnancy (28,898 cases and 302,894 controls) yielded no genome-wide association signals, but showed strong genetic correlation with a variety of human traits, indicative of polygenic and pleiotropic effects. Our results suggest that postpartum bleeding is related to myometrium dysregulation, whereas early bleeding is a complex trait related to underlying health and possibly socioeconomic status."
-,37670378,RUN(X) out of blood: emerging RUNX1 functions beyond hematopoiesis and links to Down syndrome.,Hum Genomics,"RUNX1 is a transcription factor and a master regulator for the specification of the hematopoietic lineage during embryogenesis and postnatal megakaryopoiesis. Mutations and rearrangements on RUNX1 are key drivers of hematological malignancies. In humans, this gene is localized to the 'Down syndrome critical region' of chromosome 21, triplication of which is necessary and sufficient for most phenotypes that characterize Trisomy 21.Individuals with Down syndrome show a higher predisposition to leukemias. Hence, RUNX1 overexpression was initially proposed as a critical player on Down syndrome-associated leukemogenesis. Less is known about the functions of RUNX1 in other tissues and organs, although growing reports show important implications in development or homeostasis of neural tissues, muscle, heart, bone, ovary, or the endothelium, among others. Even less is understood about the consequences on these tissues of RUNX1 gene dosage alterations in the context of Down syndrome. In this review, we summarize the current knowledge on RUNX1 activities outside blood/leukemia, while suggesting for the first time their potential relation to specific Trisomy 21 co-occurring conditions.Our concise review on the emerging RUNX1 roles in different tissues outside the hematopoietic context provides a number of well-funded hypotheses that will open new research avenues toward a better understanding of RUNX1-mediated transcription in health and disease, contributing to novel potential diagnostic and therapeutic strategies for Down syndrome-associated conditions.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37601646,Mechanism and clinical evidence of immunotherapy in allergic rhinitis.,Front Allergy,"Allergic rhinitis is a common upper airway disease caused by hypersensitivity to various aeroallergens. It causes increased inflammation throughout the body and may be complicated by other otolaryngological pathologies such as chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media. Allergic rhinitis is an IgE-mediated disease and immunotherapy can be a possible approach for patients to limit the use of antihistamines and corticosteroids. There is evidence that allergen immunotherapy can prevent the development of new sensitizations and reduce the risk of later development of asthma in patients with allergic rhinitis. However, some patients do not benefit from this approach and the efficacy of immunotherapy in reducing the severity and relapse of symptoms is still a matter of debate. This review highlights new aspects of allergic rhinitis with a particular focus on the impact of sexual dimorphism on the disease manifestation and efficacy to the allergen specific immunotherapy.© 2023 De Carli, Capezzali, Tonon and Frossi."
-,37601647,"Immunologic, genetic, and ecological interplay of factors involved in allergic diseases.",Front Allergy,"An allergic or type I hypersensitivity reaction involves a misdirected immune overreaction to innocuous environmental and dietary antigens called allergens. The genetic predisposition to allergic disease, referred to as atopy, can be expressed as a variety of manifestations-e.g., allergic rhinitis, allergic conjunctivitis, atopic dermatitis, allergic asthma, anaphylaxis. Globally, allergic diseases are one the most common types of chronic conditions. Several factors have been identified to contribute to the pathogenesis and progression of the disease, leading to distinctively variable clinical symptoms. The factors which can attenuate or exacerbate allergic reactions can range from genetic heterozygosity, the prominence of various comorbid infections, and other factors such as pollution, climate, and interactions with other organisms and organism-derived products, and the surrounding environment. As a result, the effective prevention and control of allergies remains to be one of the most prominent public health problems. Therefore, to contextualize the current knowledge about allergic reactions, this review paper attempts to synthesize different aspects of an allergic response to describe its significance in the global health scheme. Specifically, the review shall characterize the biomolecular mechanisms of the pathophysiology of the disease based on underlying disease theories and current findings on ecologic interactions and describe prevention and control strategies being utilized. An integrated perspective that considers the underlying genetic, immunologic, and ecologic aspects of the disease would enable the development of more effective and targeted diagnostic tools and therapeutic strategies for the management and control of allergic diseases.© 2023 Falcon and Caoili."
-,37627214,NA,NA,"Acute lymphoblastic leukemia (ALL) is a hematological disease characterized by the dysfunction of the hematopoietic system that leads to arrest at a specific stage of stem cells development, suppressing the average production of cellular hematologic components. BCP-ALL is a neoplasm of the B-cell lineage progenitor. BCP-ALL is caused and perpetuated by several mechanisms that provide the disease with its tumor potential and genetic and cytological characteristics. These pathological features are used for diagnosis and the prognostication of BCP-ALL. However, most of these paraclinical tools can only be obtained by bone marrow aspiration, which, as it is an invasive study, can delay the diagnosis and follow-up of the disease, in addition to the anesthetic risk it entails for pediatric patients. For this reason, it is crucial to find noninvasive and accessible ways to supply information concerning diagnosis, prognosis, and the monitoring of the disease, such as circulating biomarkers. In oncology, a biomarker is any measurable indicator that demonstrates the presence of malignancy, tumoral behavior, prognosis, or responses to treatments. This review summarizes circulating molecules associated with BCP-ALL with potential diagnostic value, classificatory capacity during monitoring specific clinic features of the disease, and/or capacity to identify each BCP-ALL stage regarding its evolution and outcome of the patients with BCP-ALL. In the same way, we provide and classify biomarkers that may be used in further studies focused on clinical approaches or therapeutic target identification for BCP-ALL."
-,37627481,The Evolution and Ecology of Oxidative and Antioxidant Status: A Comparative Approach in African Mole-Rats.,Antioxidants (Basel),"The naked mole-rat of the family Bathyergidae has been the showpiece for ageing research as they contradict the traditional understanding of the oxidative stress theory of ageing. Some other bathyergids also possess increased lifespans, but there has been a remarkable lack of comparison between species within the family Bathyergidae. This study set out to investigate how plasma oxidative markers (total oxidant status (TOS), total antioxidant capacity (TAC), and the oxidative stress index (OSI)) differ between five species and three subspecies of bathyergids, differing in their maximum lifespan potential (MLSP), resting metabolic rate, aridity index (AI), and sociality. We also investigated how oxidative markers may differ between captive and wild-caught mole-rats. Our results reveal that increased TOS, TAC, and OSI are associated with increased MLSP. This pattern is more prevalent in the social-living species than the solitary-living species. We also found that oxidative variables decreased with an increasing AI and that wild-caught individuals typically have higher antioxidants. We speculate that the correlation between higher oxidative markers and MLSP is due to the hypoxia-tolerance of the mole-rats investigated. Hormesis (the biphasic response to oxidative stress promoting protection) is a likely mechanism behind the increased oxidative markers observed and promotes longevity in some members of the Bathyergidae family."
-,37628641,NA,NA,"Environmental heat stress triggers a series of compensatory mechanisms in sheep that are dependent on their genetic regulation of thermotolerance. Our objective was to identify genes and regulatory pathways associated with thermotolerance in ewes exposed to heat stress. We performed next-generation RNA sequencing on blood collected from 16 pregnant ewes, which were grouped as tolerant and non-tolerant to heat stress according to a physiological indicator. Additional samples were collected to measure complete blood count. A total of 358 differentially expressed genes were identified after applying selection criteria. Gene expression analysis detected 46 GO terms and 52 KEGG functional pathways. The top-three signaling pathways were p53, RIG-I-like receptor and FoxO, which suggested gene participation in biological processes such as apoptosis, cell signaling and immune response to external stressors. Network analysis revealedATM,ISG15,IRF7,MDM4,DHX58andTGFβR1as over-expressed genes with high regulatory potential. A co-expression network involving the immune-related genesISG15,IRF7andDXH58was detected in lymphocytes and monocytes, which was consistent with hematological findings. In conclusion, transcriptomic analysis revealed a non-viral immune mechanism involving apoptosis, which is induced by external stressors and appears to play an important role in the molecular regulation of heat stress tolerance in ewes."
-,37644045,Next generation synthetic memory via intercepting recombinase function.,Nat Commun,"Here we present a technology to facilitate synthetic memory in a living system via repurposing Transcriptional Programming (i.e., our decision-making technology) parts, to regulate (intercept) recombinase function post-translation. We show that interception synthetic memory can facilitate programmable loss-of-function via site-specific deletion, programmable gain-of-function by way of site-specific inversion, and synthetic memory operations with nested Boolean logical operations. We can expand interception synthetic memory capacity more than 5-fold for a single recombinase, with reconfiguration specificity for multiple sites in parallel. Interception synthetic memory is ~10-times faster than previous generations of recombinase-based memory. We posit that the faster recombination speed of our next-generation memory technology is due to the post-translational regulation of recombinase function. This iteration of synthetic memory is complementary to decision-making via Transcriptional Programming - thus can be used to develop intelligent synthetic biological systems for myriad applications.© 2023. Springer Nature Limited."
-,37575184,CRISPR interference provides increased cell type-specificity compared to the Cre-loxP system.,iScience,"Cre-mediated recombination is frequently used for cell type-specific loss of function (LOF) studies. A major limitation of this system is recombination in unwanted cell types. CRISPR interference (CRISPRi) has been used effectively for global LOF in mice. However, cell type-specific CRISPRi, independent of recombination-based systems, has not been reported. To test the feasibility of cell type-specific CRISPRi, we produced two novel knock-in mouse models that achieve gene suppression when used together: one expressing dCas9::KRAB under the control of a cell type-specific promoter and the other expressing a single guide RNA from a safe harbor locus. We then compared the phenotypes of mice in which the same gene was targeted by either CRISPRi or the Cre-loxP system, with cell specificity conferred byDmp1regulatory elements in both cases. We demonstrate that CRISPRi is effective for cell type-specific LOF and that it provides improved cell type-specificity compared to the Cre-loxP system.© 2023 The Author(s)."
-,37573356,The APC/C E3 ligase subunit ANAPC11 mediates FOXO3 protein degradation to promote cell proliferation and lymph node metastasis in urothelial bladder cancer.,Cell Death Dis,"Urothelial bladder cancer (UBC) is one of the most prevalent malignancies worldwide, with striking tumor heterogeneity. Elucidating the molecular mechanisms that can be exploited for the treatment of aggressive UBC is a particularly relevant goal. Protein ubiquitination is a critical post-translational modification (PTM) that mediates the degradation of target protein via the proteasome. However, the roles of aberrant protein ubiquitination in UBC development and the underlying mechanisms by which it drives tumor progression remain unclear. In this study, taking advantage of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) 9 technology, we identified the ubiquitin E3 ligase ANAPC11, a critical subunit of the anaphase-promoting complex/cyclosome (APC/C), as a potential oncogenic molecule in UBC cells. Our clinical analysis showed that elevated expression of ANAPC11 was significantly correlated with high T stage, positive lymph node (LN) metastasis, and poor outcomes in UBC patients. By employing a series of in vitro experiments, we demonstrated that ANAPC11 enhanced the proliferation and invasiveness of UBC cells, while knockout of ANAPC11 inhibited the growth and LN metastasis of UBC cells in vivo. By conducting immunoprecipitation coupled with mass spectrometry, we confirmed that ANAPC11 increased the ubiquitination level of the Forkhead transcription factor FOXO3. The resulting decrease in FOXO3 protein stability led to the downregulation of the cell cycle regulator p21 and decreased expression of GULP1, a downstream effector of androgen receptor signaling. Taken together, these findings indicated that ANAPC11 plays an oncogenic role in UBC by modulating FOXO3 protein degradation. The ANAPC11-FOXO3 regulatory axis might serve as a novel therapeutic target for UBC.© 2023. The Author(s)."
-,37612510,NA,NA,"The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date1and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes2. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established1boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.© 2023. The Author(s), under exclusive licence to Springer Nature Limited."
-,37580559,UniAligner: a parameter-free framework for fast sequence alignment.,Nat Methods,"Even though the recent advances in 'complete genomics' revealed the previously inaccessible genomic regions, analysis of variations in centromeres and other extra-long tandem repeats (ETRs) faces an algorithmic challenge since there are currently no tools for accurate sequence comparison of ETRs. Counterintuitively, the classical alignment approaches, such as the Smith-Waterman algorithm, fail to construct biologically adequate alignments of ETRs. We present UniAligner-the parameter-free sequence alignment algorithm with sequence-dependent alignment scoring that automatically changes for any pair of compared sequences. UniAligner prioritizes matches of rare substrings that are more likely to be relevant to the evolutionary relationship between two sequences. We apply UniAligner to estimate the mutation rates in human centromeres, and quantify the extremely high rate of large duplications and deletions in centromeres. This high rate suggests that centromeres may represent some of the most rapidly evolving regions of the human genome with respect to their structural organization.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
-,37574471,Mechanisms and regulation of defensins in host defense.,Signal Transduct Target Ther,"As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms. Next, we cover the role of defensins in immune homeostasis, chemotaxis, mucosal barrier function, gut microbiota regulation, intestinal development and regulation of cell death. Further, we discuss their clinical relevance and therapeutic potential in various diseases, including infectious disease, inflammatory bowel disease, diabetes and obesity, chronic inflammatory lung disease, periodontitis and cancer. Finally, we summarize the current knowledge regarding the nutrient-dependent regulation of defensins, including fatty acids, amino acids, microelements, plant extracts, and probiotics, while considering the clinical application of such regulation. Together, the review summarizes the various biological functions, mechanism of actions and potential clinical significance of defensins, along with the challenges in developing defensins-based therapy, thus providing crucial insights into their biology and potential clinical utility.© 2023. West China Hospital, Sichuan University."
-,37546784,Efficient Formation of Single-copy Human Artificial Chromosomes.,bioRxiv,"Large DNA assembly methodologies underlie milestone achievements in synthetic prokaryotic and budding yeast chromosomes. While budding yeast control chromosome inheritance through �125 bp DNA sequence-defined centromeres, mammals and many other eukaryotes use large, epigenetic centromeres. Harnessing centromere epigenetics permits human artificial chromosome (HAC) formation but is not sufficient to avoid rampant multimerization of the initial DNA molecule upon introduction to cells. Here, we describe an approach that efficiently forms single-copy HACs. It employs a �750 kb construct that is sufficiently large to house the distinct chromatin types present at the inner and outer centromere, obviating the need to multimerize. Delivery to mammalian cells is streamlined by employing yeast spheroplast fusion. These developments permit faithful chromosome engineering in the context of metazoan cells.A quarter century after the first human artificial chromosomes, a solution to their uncontrolled multimerization is achieved."
-,37541261,Centromere Plasticity With Evolutionary Conservation and Divergence Uncovered by Wheat 10+ Genomes.,Mol Biol Evol,"Centromeres (CEN) are the chromosomal regions that play a crucial role in maintaining genomic stability. The underlying highly repetitive DNA sequences can evolve quickly in most eukaryotes, and promote karyotype evolution. Despite their variability, it is not fully understood how these widely variable sequences ensure the homeostasis of centromere function. In this study, we investigated the genetics and epigenetics of CEN in a population of wheat lines from global breeding programs. We captured a high degree of sequences, positioning, and epigenetic variations in the large and complex wheat CEN. We found that most CENH3-associated repeats are Cereba element of retrotransposons and exhibit phylogenetic homogenization across different wheat lines, but the less-associated repeat sequences diverge on their own way in each wheat line, implying specific mechanisms for selecting certain repeat types as functional core CEN. Furthermore, we observed that CENH3 nucleosome structures display looser wrapping of DNA termini on complex centromeric repeats, including the repositioned CEN. We also found that strict CENH3 nucleosome positioning and intrinsic DNA features play a role in determining centromere identity among different lines. Specific non-B form DNAs were substantially associated with CENH3 nucleosomes for the repositioned centromeres. These findings suggest that multiple mechanisms were involved in the adaptation of CENH3 nucleosomes that can stabilize CEN. Ultimately, we proposed a remarkable epigenetic plasticity of centromere chromatin within the diverse genomic context, and the high robustness is crucial for maintaining centromere function and genome stability in wheat 10+ lines as a result of past breeding selections.© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution."
-,37660182,NA,NA,"Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that N7-guanosine methylation (m7G) of tRNAs, mediated by METTL1, regulates survival to stress conditions in cancer cells. Mechanistically, we find that m7G in tRNAs protects them from stress-induced cleavage and processing into 5' tRNA fragments. Our analyses reveal that the loss of tRNA m7G methylation activates stress response pathways, sensitising cancer cells to stress. Furthermore, we find that the loss of METTL1 reduces tumour growth and increases cytotoxic stress in vivo. Our study uncovers the role of m7G methylation of tRNAs in stress responses and highlights the potential of targeting METTL1 to sensitise cancer cells to chemotherapy.© 2023. The Author(s)."
-,37644165,Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment.,Cell Mol Immunol,"Although DNA mutation drives stem cell aging, how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood. Here, using a mouse model of irradiation-induced premature aging and middle-aged mice, we show that DNA mutation accumulation in hematopoietic stem cells (HSCs) during aging upregulates their surface expression of major histocompatibility complex class II (MHCII). MHCII upregulation increases the chance for recognition by bone marrow (BM)-resident regulatory T cells (Tregs), resulting in their clonal expansion and accumulation in the HSC niche. On the basis of the establishment of connexin 43 (Cx43)-mediated gap junctions, BM Tregs transfer cyclic adenosine monophosphate (cAMP) to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A (PKA) signaling. Importantly, targeting the HSC-Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs. These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.© 2023. The Author(s), under exclusive licence to CSI and USTC."
-,37626896,NA,NA,"Since Joseph Altman published his pioneering work demonstrating neurogenesis in the hippocampus of adult rats, the number of publications in this field increased exponentially. Today, we know that the adult hippocampus harbors a pool of adult neural stem cells (NSCs) that are the source of life-long neurogenesis and plasticity. The functions of these NSCs are regulated by extrinsic cues arising from neighboring cells and the systemic environment. However, this tight regulation is subject to imbalance with age, resulting in a decline in adult NSCs and neurogenesis, which contributes to the progressive deterioration of hippocampus-related cognitive functions. Despite extensive investigation, the mechanisms underlying this age-related decline in neurogenesis are only incompletely understood, but appear to include an increase in NSC quiescence, changes in differentiation patterns, and NSC exhaustion. In this review, we summarize recent work that has improved our knowledge of hippocampal NSC aging, focusing on NSC-intrinsic mechanisms as well as cellular and molecular changes in the niche and systemic environment that might be involved in the age-related decline in NSC functions. Additionally, we identify future directions that may advance our understanding of NSC aging and the concomitant loss of hippocampal neurogenesis and plasticity."
-,37621775,Lessons in aging from Myc knockout mouse models.,Front Cell Dev Biol,"DespiteMYCbeing among the most intensively studied oncogenes, its role in normal development has not been determined asMyc-/-mice do not survival beyond mid-gestation.Myc± mice live longer than their wild-type counterparts and are slower to accumulate many age-related phenotypes. However,Mychaplo-insufficiency likely conceals other important phenotypes as many high-affinity Myc targets genes continue to be regulated normally. By delayingMycinactivation until after birth it has recently been possible to study the consequences of its near-complete total body loss and thus to infer its normal function. Against expectation, these""MycKO"" mice lived significantly longer than control wild-type mice but manifested a marked premature aging phenotype. This seemingly paradoxical behavior was potentially explained by a >3-fold lower lifetime incidence of cancer, normally the most common cause of death in mice and often Myc-driven.Mycloss accelerated the accumulation of numerous ""Aging Hallmarks"", including the loss of mitochondrial and ribosomal structural and functional integrity, the generation of reactive oxygen species, the acquisition of genotoxic damage, the detrimental rewiring of metabolism and the onset of senescence. In both mice and humans, normal aging in many tissues was accompaniued by the downregulation of Myc and the loss of Myc target gene regulation. Unlike most mouse models of premature aging, which are based on monogenic disorders of DNA damage recognition and repair, theMycKO mouse model directly impacts most Aging Hallmarks and may therefore more faithfully replicate the normal aging process of both mice and humans. It further establishes that the strong association between aging and cancer can be genetically separated and is maintained by a single gene.Copyright © 2023 Prochownik and Wang."
-,37664617,Transcriptomic and proteomic assessment of tocilizumab response in a randomized controlled trial of patients hospitalized with COVID-19.,iScience,"High interleukin (IL)-6 levels are associated with greater COVID-19 severity. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways modified by tocilizumab in peripheral blood samples from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial of the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. We identified markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury that predict disease severity and clinical outcomes. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab and identified novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to placebo and potentially leading to faster recovery in patients hospitalized with COVID-19.© 2023 The Authors."
-,37561710,Leveraging type 1 diabetes human genetic and genomic data in the T1D knowledge portal.,PLoS Biol,"To address the challenge of translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight, we have developed the T1D Knowledge Portal (T1DKP), an open-access resource for hypothesis development and target discovery in T1D.Copyright: © 2023 Kudtarkar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37559109,The specific DNA methylation landscape in focal cortical dysplasia ILAE type 3D.,Acta Neuropathol Commun,"Focal Cortical Dysplasia (FCD) is a frequent cause of drug-resistant focal epilepsy in children and young adults. The international FCD classifications of 2011 and 2022 have identified several clinico-pathological subtypes, either occurring isolated, i.e., FCD ILAE Type 1 or 2, or in association with a principal cortical lesion, i.e., FCD Type 3. Here, we addressed the DNA methylation signature of a previously described new subtype of FCD 3D occurring in the occipital lobe of very young children and microscopically defined by neuronal cell loss in cortical layer 4. We studied the DNA methylation profile using 850 K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1 A, 2 A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or Germany. DNA was extracted from formalin-fixed paraffin-embedded tissue blocks with microscopically confirmed lesions, and DNA methylation profiles were bioinformatically analyzed with a recently developed deep learning algorithm. Our results revealed a distinct position of FCD 3D in the DNA methylation map of common FCD subtypes, also different from non-FCD epilepsy surgery controls or non-epileptic postmortem controls. Within the FCD 3D cohort, the DNA methylation signature separated three histopathology subtypes, i.e., glial scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 mapped explicitly to biological pathways related to neurodegeneration, biogenesis of the extracellular matrix (ECM) components, axon guidance, and regulation of the actin cytoskeleton. Our data suggest that DNA methylation signatures in cortical malformations are not only of diagnostic value but also phenotypically relevant, providing the molecular underpinnings of structural and histopathological features associated with epilepsy. Further studies will be necessary to confirm these results and clarify their functional relevance and epileptogenic potential in these difficult-to-treat children.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37626760,Understanding Fibroblast Heterogeneity in Form and Function.,Biomedicines,"Historically believed to be a homogeneous cell type that is often overlooked, fibroblasts are more and more understood to be heterogeneous in nature. Though the mechanisms behind how fibroblasts participate in homeostasis and pathology are just beginning to be understood, these cells are believed to be highly dynamic and play key roles in fibrosis and remodeling. Focusing primarily on fibroblasts within the skin and during wound healing, we describe the field's current understanding of fibroblast heterogeneity in form and function. From differences due to embryonic origins to anatomical variations, we explore the diverse contributions that fibroblasts have in fibrosis and plasticity. Following this, we describe molecular techniques used in the field to provide deeper insights into subpopulations of fibroblasts and their varied roles in complex processes such as wound healing. Limitations to current work are also discussed, with a focus on future directions that investigators are recommended to take in order to gain a deeper understanding of fibroblast biology and to develop potential targets for translational applications in a clinical setting."
-,37594959,Diabetes in Pregnancy for Mothers and Offspring: Reflection on 30 Years of Clinical and Translational Research: The 2022 Norbert Freinkel Award Lecture.,Diabetes Care,"Hyperglycemia during pregnancy is a double-edged sword, affecting both mothers and their offspring and creating a vicious cycle that can affect multiple generations. Research in this field over the past 30 years has greatly improved our understanding of this disease and formed the basis of improved strategies to improve the health of mothers and their babies. Despite this progress, gestational and preexisting diabetes continue to have significant effects on both short- and long-term health of mothers and their offspring. In this article, I provide an overview of the work that my colleagues and I have done to advance the knowledge base around diabetes and pregnancy in four areas: 1) diabetes risk after gestational diabetes mellitus (GDM), including racial and ethnic disparities; 2) the pathophysiology of GDM and subsequent diabetes in Hispanic women; 3) diabetes prevention and β-cell preservation following GDM; and 4) evidence for multiple potential developmental effects in offspring that vary according to the timing of exposure and severity of maternal diabetes during pregnancy. This research continues the legacy of Norbert Freinkel and the concepts that he contributed to the field of diabetes and pregnancy. With the epidemic of obesity, increasing rates of type 1 and type 2 diabetes in youth, and rising prevalence of GDM across all racial and ethnic groups, we have a lot more work to do to combat this disease to break the vicious cycle.© 2023 by the American Diabetes Association."
-,37612705,"Emergence and influence of sequence bias in evolutionarily malleable, mammalian tandem arrays.",BMC Biol,"The radiation of mammals at the extinction of the dinosaurs produced a plethora of new forms-as diverse as bats, dolphins, and elephants-in only 10-20 million years. Behind the scenes, adaptation to new niches is accompanied by extensive innovation in large families of genes that allow animals to contact the environment, including chemosensors, xenobiotic enzymes, and immune and barrier proteins. Genes in these ""outward-looking"" families are allelically diverse among humans and exhibit tissue-specific and sometimes stochastic expression.Here, we show that these tandem arrays of outward-looking genes occupy AT-biased isochores and comprise the ""tissue-specific"" gene class that lack CpG islands in their promoters. Models of mammalian genome evolution have not incorporated the sharply different functions and transcriptional patterns of genes in AT- versus GC-biased regions. To examine the relationship between gene family expansion, sequence content, and allelic diversity, we use population genetic data and comparative analysis. First, we find that AT bias can emerge during evolutionary expansion of gene families in cis. Second, human genes in AT-biased isochores or with GC-poor promoters experience relatively low rates of de novo point mutation today but are enriched for non-synonymous variants. Finally, we find that isochores containing gene clusters exhibit low rates of recombination.Our analyses suggest that tolerance of non-synonymous variation and low recombination are two forces that have produced the depletion of GC bases in outward-facing gene arrays. In turn, high AT content exerts a profound effect on their chromatin organization and transcriptional regulation.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37488355,NA,NA,"In mammals, only the zygote and blastomeres of the early embryo are totipotent. This totipotency is mirrored in vitro by mouse '2-cell-like cells' (2CLCs), which appear at low frequency in cultures of embryonic stem cells (ESCs). Because totipotency is not completely understood, we carried out a genome-wide CRISPR knockout screen in mouse ESCs, searching for mutants that reactivate the expression of Dazl, a gene expressed in 2CLCs. Here we report the identification of four mutants that reactivate Dazl and a broader 2-cell-like signature: the E3 ubiquitin ligase adaptor SPOP, the Zinc-Finger transcription factor ZBTB14, MCM3AP, a component of the RNA processing complex TREX-2, and the lysine demethylase KDM5C. All four factors function upstream of DPPA2 and DUX, but not via p53. In addition, SPOP binds DPPA2, and KDM5C interacts with ncPRC1.6 and inhibits 2CLC gene expression in a catalytic-independent manner. These results extend our knowledge of totipotency, a key phase of organismal life.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
-,37466164,NA,NA,"In recent years, quantitative mass spectrometry-based interaction proteomics technology has proven very useful in identifying specific DNA-protein interactions using single pull-downs from crude lysates. Here, we applied a SILAC/TMT-based higher-order multiplexing approach to develop an interaction proteomics workflow called Protein-nucleic acid Affinity and Specificity quantification by MAss spectrometry in Nuclear extracts or PASMAN. In PASMAN, DNA pull-downs using a concentration range of specific and control DNA baits are performed in SILAC-labeled nuclear extracts. MS1-based quantification to determine specific DNA-protein interactions is then combined with sequential TMT-based quantification of fragmented SILAC peptides, allowing the generation of Hill-like curves and determination of apparent binding affinities. We benchmarked PASMAN using the SP/KLF motif and further applied it to gain insights into two CGCG-containing consensus DNA motifs. These motifs are recognized by two BEN domain-containing proteins, BANP and BEND3, which we find to interact with these motifs with distinct affinities. Finally, we profiled the BEND3 proximal proteome, revealing the NuRD complex as the major BEND3 proximal protein complex in vivo. In summary, PASMAN represents, to our knowledge, the first higher-order multiplexing-based interaction proteomics method that can be used to decipher specific DNA-protein interactions and their apparent affinities in various biological and pathological contexts."
-,37660146,Probing the communication patterns of different chondrocyte subtypes in osteoarthritis at the single cell level using pattern recognition and manifold learning.,Sci Rep,"The patterns of communication among different chondrocyte subtypes in human cartilage degeneration and regeneration help us understand the microenvironment of osteoarthritis and optimize cell-targeted therapies. Here, a single-cell transcriptome dataset of chondrocytes is used to explore the synergistic and communicative patterns of different chondrocyte subtypes. We collected 1600 chondrocytes from 10 patients with osteoarthritis and analyzed the active communication patterns for the first time based on network analysis and pattern recognition at the single-cell level. Manifold learning and quantitative contrasts were performed to analyze conserved and specific communication pathways. We found that ProCs (Proliferative chondrocytes), ECs (Effector chondrocytes), preHTCs (Prehypertrophic chondrocytes), HTCs (Hypertrophic chondrocytes), and FCs (Fibrocartilage chondrocytes) are more active in incoming and outgoing signaling patterns, which is consistent with studies on their close functional cooperation. Among them, preHTCs play multiple roles in chondrocyte communication, and ProCs and preHTCs have many overlapping pathways. These two subtypes are the most active among all chondrocyte subtypes. Interestingly, ECs and FCs are a pair of ""mutually exclusive"" subtypes, of which ECs are predominant in incoming patterns and FCs in outgoing patterns. The active signaling pathways of ECs and FCs largely do not overlap. COLLAGEN and LAMININ are the main pivotal pathways, which means they are very important in the repair and expansion of joint homeostasis. Notably, only preHTCs assume multiple roles (including sender, receiver, mediator, and influencer) and are involved in multiple communication pathways. We have examined their communication patterns from the perspective of cellular interactions, revealed the relationships among different chondrocyte subtypes, and, in particular, identified a number of active subtypes and pathways that are important for targeted therapy in the osteoarthritic microenvironment. Our findings provide a new research paradigm and new insights into understanding chondrocyte activity patterns in the osteoarthritic microenvironment.© 2023. Springer Nature Limited."
-,37592342,Spatial transcriptomics: recent developments and insights in respiratory research.,Mil Med Res,"The respiratory system's complex cellular heterogeneity presents unique challenges to researchers in this field. Although bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) have provided insights into cell types and heterogeneity in the respiratory system, the relevant specific spatial localization and cellular interactions have not been clearly elucidated. Spatial transcriptomics (ST) has filled this gap and has been widely used in respiratory studies. This review focuses on the latest iterative technology of ST in recent years, summarizing how ST can be applied to the physiological and pathological processes of the respiratory system, with emphasis on the lungs. Finally, the current challenges and potential development directions are proposed, including high-throughput full-length transcriptome, integration of multi-omics, temporal and spatial omics, bioinformatics analysis, etc. These viewpoints are expected to advance the study of systematic mechanisms, including respiratory studies.© 2023. People´s Military Medical Press."
-,37577623,Model-based compound hypothesis testing for snATAC-seq data with PACS.,bioRxiv,"Single nucleus ATAC-seq (snATAC-seq) experimental designs have become increasingly complex with multiple factors that might affect chromatin accessibility, including cell type, tissue of origin, sample location, batch, etc., whose compound effects are difficult to test by existing methods. In addition, current snATAC-seq data present statistical difficulties due to their sparsity and variations in individual sequence capture. To address these problems, we present a zero-adjusted statistical model, PACS, that can allow complex hypothesis testing of factors that affect accessibility while accounting for sparse and incomplete data. For differential accessibility analysis, PACS controls the false positive rate and achieves on average a 17% to 122% higher power than existing tools. We demonstrate the effectiveness of PACS through several analysis tasks including supervised cell type annotation, compound hypothesis testing, batch effect correction, and spatiotemporal modeling. We apply PACS to several datasets from a variety of tissues and show its ability to reveal previously undiscovered insights in snATAC-seq data."
-,37640936,scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells.,Nat Methods,"The high-order three-dimensional (3D) organization of regulatory genomic elements provides a topological basis for gene regulation, but it remains unclear how multiple regulatory elements across the mammalian genome interact within an individual cell. To address this, herein, we developed scNanoHi-C, which applies Nanopore long-read sequencing to explore genome-wide proximal high-order chromatin contacts within individual cells. We show that scNanoHi-C can reliably and effectively profile 3D chromatin structures and distinguish structure subtypes among individual cells. This method could also be used to detect genomic variations, including copy-number variations and structural variations, as well as to scaffold the de novo assembly of single-cell genomes. Notably, our results suggest that extensive high-order chromatin structures exist in active chromatin regions across the genome, and multiway interactions between enhancers and their target promoters were systematically identified within individual cells. Altogether, scNanoHi-C offers new opportunities to investigate high-order 3D genome structures at the single-cell level.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
-,37574486,Analysis of Copy Number Variation of DNA Repair/Damage Response Genes in Tumor Tissues.,Methods Mol Biol,"Cells experience increased genome instability through the course of disease development including cancer initiation and progression. Point mutations, insertion/deletions, translocations, and amplifications of both coding and noncoding regions all contribute to cancer phenotypes. Copy number variation (CNV), i.e., changes of the number of copies of nuclear DNA, occurs in the genome of even normal somatic cells. Studies to understand the effects of CNV on tumor development, especially aspects concerning tumor aggressiveness and the influence on outcomes of therapeutic modalities, have been reignited by the breakthrough technologies of the molecular genomics. This section discusses the significance of analyzing CNVs that cause simultaneous increase/decrease of clusters of genes, using the expression profile of XRCC1 with its neighbor genes LIG1, PNKP, and POLD1 as an example. Methods for CNV assay at the individual gene level on formalin-fixed, paraffin-embedded (FFPE) tissues using the NanoString nCounter technology will then be described.© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature."
-,37601966,Genotyping and population characteristics of the China Kadoorie Biobank.,Cell Genom,"The China Kadoorie Biobank (CKB) is a population-based prospective cohort of >512,000 adults recruited from 2004 to 2008 from 10 geographically diverse regions across China. Detailed data from questionnaires and physical measurements were collected at baseline, with additional measurements at three resurveys involving �5% of surviving participants. Analyses of genome-wide genotyping, for >100,000 participants using custom-designed Axiom arrays, reveal extensive relatedness, recent consanguinity, and signatures reflecting large-scale population movements from recent Chinese history. Systematic genome-wide association studies of incident disease, captured through electronic linkage to death and disease registries and to the national health insurance system, replicate established disease loci and identify 14 novel disease associations. Together with studies of candidate drug targets and disease risk factors and contributions to international genetics consortia, these demonstrate the breadth, depth, and quality of the CKB data. Ongoing high-throughput omics assays of collected biosamples and planned whole-genome sequencing will further enhance the scientific value of this biobank.© 2023 The Authors."
-,37475546,Abnormal phase separation of biomacromolecules in human diseases.,Acta Biochim Biophys Sin (Shanghai),"Membrane-less organelles (MLOs) formed through liquid-liquid phase separation (LLPS) are associated with numerous important biological functions, but the abnormal phase separation will also dysregulate the physiological processes. Emerging evidence points to the importance of LLPS in human health and diseases. Nevertheless, despite recent advancements, our knowledge of the molecular relationship between LLPS and diseases is frequently incomplete. In this review, we outline our current understanding about how aberrant LLPS affects developmental disorders, tandem repeat disorders, cancers and viral infection. We also examine disease mechanisms driven by aberrant condensates, and highlight potential treatment approaches. This study seeks to expand our understanding of LLPS by providing a valuable new paradigm for understanding phase separation and human disorders, as well as to further translate our current knowledge regarding LLPS into therapeutic discoveries."
-,37464880,Sequence variations of phase-separating proteins and resources for studying biomolecular condensates.,Acta Biochim Biophys Sin (Shanghai),"Phase separation (PS) is an important mechanism underlying the formation of biomolecular condensates. Physiological condensates are associated with numerous biological processes, such as transcription, immunity, signaling, and synaptic transmission. Changes in particular amino acids or segments can disturb the protein's phase behavior and interactions with other biomolecules in condensates. It is thus presumed that variations in the phase-separating-prone domains can significantly impact the properties and functions of condensates. The dysfunction of condensates contributes to a number of pathological processes. Pharmacological perturbation of these condensates is proposed as a promising way to restore physiological states. In this review, we characterize the variations observed in PS proteins that lead to aberrant biomolecular compartmentalization. We also showcase recent advancements in bioinformatics of membraneless organelles (MLOs), focusing on available databases useful for screening PS proteins and describing endogenous condensates, guiding researchers to seek the underlying pathogenic mechanisms of biomolecular condensates."
-,37428142,Accelerating bioinformatics implementation in public health.,Microb Genom,"We have adopted an open bioinformatics ecosystem to address the challenges of bioinformatics implementation in public health laboratories (PHLs). Bioinformatics implementation for public health requires practitioners to undertake standardized bioinformatic analyses and generate reproducible, validated and auditable results. It is essential that data storage and analysis are scalable, portable and secure, and that implementation of bioinformatics fits within the operational constraints of the laboratory. We address these requirements using Terra, a web-based data analysis platform with a graphical user interface connecting users to bioinformatics analyses without the use of code. We have developed bioinformatics workflows for use with Terra that specifically meet the needs of public health practitioners. These Theiagen workflows perform genome assembly, quality control, and characterization, as well as construction of phylogeny for insights into genomic epidemiology. Additonally, these workflows use open-source containerized software and the WDL workflow language to ensure standardization and interoperability with other bioinformatics solutions, whilst being adaptable by the user. They are all open source and publicly available in Dockstore with the version-controlled code available in public GitHub repositories. They have been written to generate outputs in standardized file formats to allow for further downstream analysis and visualization with separate genomic epidemiology software. Testament to this solution meeting the requirements for bioinformatic implementation in public health, Theiagen workflows have collectively been used for over 5 million sample analyses in the last 2 years by over 90 public health laboratories in at least 40 different countries. Continued adoption of technological innovations and development of further workflows will ensure that this ecosystem continues to benefit PHLs."
-,37639434,Prediction of DNA Methylation based on Multi-dimensional feature encoding and double convolutional fully connected convolutional neural network.,PLoS Comput Biol,"DNA methylation takes on critical significance to the regulation of gene expression by affecting the stability of DNA and changing the structure of chromosomes. DNA methylation modification sites should be identified, which lays a solid basis for gaining more insights into their biological functions. Existing machine learning-based methods of predicting DNA methylation have not fully exploited the hidden multidimensional information in DNA gene sequences, such that the prediction accuracy of models is significantly limited. Besides, most models have been built in terms of a single methylation type. To address the above-mentioned issues, a deep learning-based method was proposed in this study for DNA methylation site prediction, termed the MEDCNN model. The MEDCNN model is capable of extracting feature information from gene sequences in three dimensions (i.e., positional information, biological information, and chemical information). Moreover, the proposed method employs a convolutional neural network model with double convolutional layers and double fully connected layers while iteratively updating the gradient descent algorithm using the cross-entropy loss function to increase the prediction accuracy of the model. Besides, the MEDCNN model can predict different types of DNA methylation sites. As indicated by the experimental results,the deep learning method based on coding from multiple dimensions outperformed single coding methods, and the MEDCNN model was highly applicable and outperformed existing models in predicting DNA methylation between different species. As revealed by the above-described findings, the MEDCNN model can be effective in predicting DNA methylation sites.Copyright: © 2023 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37664640,Machine learning reveals genetic modifiers of the immune microenvironment of cancer.,iScience,"Heritability in the immune tumor microenvironment (iTME) has been widely observed yet remains largely uncharacterized. Here, we developed a machine learning approach to map iTME modifiers within loci from genome-wide association studies (GWASs) for breast cancer (BrCa) incidence. A random forest model was trained on a positive set of immune-oncology (I-O) targets, and then used to assign I-O target probability scores to 1,362 candidate genes in linkage disequilibrium with 155 BrCa GWAS loci. Cluster analysis of the most probable candidates revealed two subfamilies of genes related to effector functions and adaptive immune responses, suggesting that iTME modifiers impact multiple aspects of anticancer immunity. Two of the top ranking BrCa candidates,LSP1andTLR1, were orthogonally validated as iTME modifiers using BrCa patient biopsies and comparative mapping studies, respectively. Collectively, these data demonstrate a robust and flexible framework for functionally fine-mapping GWAS risk loci to identify translatable therapeutic targets.© 2023 The Author(s)."
-,37655340,Mendelian randomization supports causality between gut microbiota and chronic hepatitis B.,Front Microbiol,"Observational studies have provided evidence of a close association between gut microbiota and the progression of chronic hepatitis B (CHB). However, establishing a causal relationship between gut microbiota and CHB remains a subject of investigation.Genome-wide association study (GWAS) summary data of gut microbiota came from the MiBioGen consortium, while the GWAS summary data of CHB came from the Medical Research Council Integrative Epidemiology Unit (IEU) Open GWAS project. Based on the maximum likelihood (ML), Mendelian randomization (MR)-Egger regression, inverse variance weighted (IVW), MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and weighted-mode and weighted-median methods, we conducted a bidirectional, two-sample, MR analysis to explore the causal relationship between the gut microbiota and CHB. Additionally, we evaluated the genetic associations between individual gut microbes and CHB using the Linkage disequilibrium score regression (LDSC) program.According to the IVW method estimates, genetically predicted class Alphaproteobacteria (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.34-0.96; false discovery rate [FDR] = 0.046), genusFamily XIII AD3011group (OR = 0.60; 95% CI, 0.39-0.91; FDR = 0.026), genusPrevotella 7(OR = 0.73; 95% CI, 0.56-0.94; FDR = 0.022) exhibited a protective effect against CHB. On the other hand, family Family XIII (OR = 1.79; 95% CI, 1.03-3.12; FDR = 0.061), genusEggerthellagroup (OR = 1.34; 95% CI, 1.04-1.74; FDR = 0.043), genusEubacterium ventriosumgroup (OR = 1.59; 95% CI, 1.01-2.51; FDR = 0.056), genusHoldemania(OR = 1.35; 95% CI, 1.00-1.82; FDR = 0.049), and genusRuminococcus gauvreauiigroup (OR = 1.69; 95% CI, 1.10-2.61; FDR = 0.076) were associated with an increased risk of CHB. The results from LDSC also indicated a significant genetic correlation between most of the aforementioned gut microbiota and CHB. Our reverse MR analysis demonstrated no causal relationship between genetically predicted CHB and gut microbiota, and we observed no significant horizontal pleiotropy or heterogeneity of instrumental variables (IVs).In this study, we identified three types of gut microbiota with a protective effect on CHB and five types with an adverse impact on CHB. We postulate that this information will facilitate the clinical prevention and treatment of CHB through fecal microbiota transplantation.Copyright © 2023 Zhang, Zhou, Zhang, Mao and Zhang."
-,37612393,NA,NA,"The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.© 2023. Springer Nature Limited."
-,37601974,NA,NA,"Stroke is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, possibly due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetics of ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI) and further combined the results with previously published MegaStroke. Five novel loci for ischemic stroke (LAMC1,CALCRL,PLSCR1,CDKN1A, andSWAP70) were identified after replication in four additional datasets. One previously reported locus showed significant ancestry heterogeneity (ABO), and one showed significant sex heterogeneity (ALDH2). TheALDH2association was male specific (males p = 1.67e-24, females p = 0.126) and was additionally observed only in the East Asian ancestry (male) samples. These findings emphasize the need for more diverse datasets with large sample sizes to further understand the genetic predisposition of stroke in different ancestry and sex groups.© 2023 The Authors."
-,37596272,LINC02015 modulates the cell proliferation and apoptosis of aortic vascular smooth muscle cells by transcriptional regulation and protein interaction network.,Cell Death Discov,"Long intergenic nonprotein coding RNA 2015 (LINC02015) is a long non-coding RNA that has been found elevated in various cell proliferation-related diseases. However, the functions and interactive mechanism of LINC02015 remain unknown. This study aimed to explore the role of LINC02015 in the cell proliferation and apoptosis of vascular smooth muscle cells (VSMCs) to explain the pathogenesis of aortic diseases. Ascending aorta samples and angiotensin-II (AT-II) treated primary human aortic VSMCs (HAVSMCs) were used to evaluate the LINC02015 expression. RNA sequencing, chromatin isolation by RNA purification sequencing, RNA pull-down, and mass spectrometry (MS) were applied to explore the potential interacting mechanisms. LINC02015 expression was found elevated in aortic dissection and AT-II-treated HAVSMCs. Cell proliferation and cell cycle were activated in HAVSMCs with LINC02015 knockdown. The cyclins family and caspase family were found to participate in regulating the cell cycle and apoptosis via the NF-κB signaling pathway. RXRA was discovered as a possible hub gene for LINC02015 transcriptional regulating networks. Besides, the protein interaction network of LINC02015 was revealed with candidate regulating molecules. It was concluded that the knockdown of LINC02015 could promote cell proliferation and inhibit the apoptosis of HAVSMCs through an RXRA-related transcriptional regulation network, which could provide a potential therapeutic target for aortic diseases.© 2023. Cell Death Differentiation Association (ADMC)."
-,37546732,Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.,medRxiv,"Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of theHLA-DQB1gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk.We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association thresholdp<4.5Ă—10-4and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reportedHLA-DQB1association in the subset of studies independent of the original report.The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. TheHLA-DQB1association was not replicated in the independent IPF studies.Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF."
-,37661968,NA,NA,"New tools for health information technology have been developed in recent times, such as Clinical Decision Support (CDS) systems, which are any digital solutions designed to help healthcare professionals when making clinical decisions. The study aimed to show how we have adopted a CDS system in the San Juan de Alicante Clinical Laboratory and facilitate the implementation of our protocol in other clinical laboratories. We have user experience and the motivation to improve healthcare tools. The improvement, measurement, and monitoring of interventions and laboratory tests has been our motto for years.A descriptive research was conducted. All stages in the design of the project are as follows: 1. Set up a multidisciplinary workgroup. 2. Review patients' data. 3. Identify relevant data from main sources. 4. Design the likely outcomes. 5. Define a complete integration scenario. 6. Monitor and track the impact. To set up this protocol, two new software systems were implemented in our laboratory: AlinIQ CDS v8.2 as Rule Engine, and AlinIQ AIP Integrated Platform v1.6 as Business Intelligence (BI) tool.Our protocol shows the workflow and actions that can be done with a CDS system and also how it could be integrated with other monitoring systems, as well as some examples of KPIs and their outcomes.CDS could be a great strategic asset for clinical laboratories to improve the integration of care, optimize the use of laboratory tests, and add more clinical value to physicians in the interpretation of results.© 2023 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology."
-,37627783,Recent Advancements in Deep Learning Using Whole Slide Imaging for Cancer Prognosis.,Bioengineering (Basel),"This review furnishes an exhaustive analysis of the latest advancements in deep learning techniques applied to whole slide images (WSIs) in the context of cancer prognosis, focusing specifically on publications from 2019 through 2023. The swiftly maturing field of deep learning, in combination with the burgeoning availability of WSIs, manifests significant potential in revolutionizing the predictive modeling of cancer prognosis. In light of the swift evolution and profound complexity of the field, it is essential to systematically review contemporary methodologies and critically appraise their ramifications. This review elucidates the prevailing landscape of this intersection, cataloging major developments, evaluating their strengths and weaknesses, and providing discerning insights into prospective directions. In this paper, a comprehensive overview of the field aims to be presented, which can serve as a critical resource for researchers and clinicians, ultimately enhancing the quality of cancer care outcomes. This review's findings accentuate the need for ongoing scrutiny of recent studies in this rapidly progressing field to discern patterns, understand breakthroughs, and navigate future research trajectories."
-,37609238,Benchmark Pathology Report Text Corpus with Cancer Type Classification.,medRxiv,"In cancer research, pathology report text is a largely un-tapped data source. Pathology reports are routinely generated, more nuanced than structured data, and contain added insight from pathologists. However, there are no publicly-available datasets for benchmarking report-based models. Two recent advances suggest the urgent need for a benchmark dataset. First, improved optical character recognition (OCR) techniques will make it possible to access older pathology reports in an automated way, increasing data available for analysis. Second, recent improvements in natural language processing (NLP) techniques using AI allow more accurate prediction of clinical targets from text. We apply state-of-the-art OCR and customized post- processing to publicly available report PDFs from The Cancer Genome Atlas, generating a machine-readable corpus of 9,523 reports. We perform a proof-of-principle cancer-type classification across 32 tissues, achieving 0.992 average AU-ROC. This dataset will be useful to researchers across specialties, including research clinicians, clinical trial investigators, and clinical NLP researchers."
-,37603131,Magnetic resonance-based imaging biopsy with signatures including topological Betti number features for prediction of primary brain metastatic sites.,Phys Eng Sci Med,"This study incorporated topology Betti number (BN) features into the prediction of primary sites of brain metastases and the construction of magnetic resonance-based imaging biopsy (MRB) models. The significant features of the MRB model were selected from those obtained from gray-scale and three-dimensional wavelet-filtered images, BN and inverted BN (iBN) maps, and clinical variables (age and gender). The primary sites were predicted as either lung cancer or other cancers using MRB models, which were built using seven machine learning methods with significant features chosen by three feature selection methods followed by a combination strategy. Our study dealt with a dataset with relatively smaller brain metastases, which included effective diameters greater than 2 mm, with metastases ranging from 2 to 9 mm accounting for 17% of the dataset. The MRB models were trained by T1-weighted contrast-enhanced images of 494 metastases chosen from 247 patients and applied to 115 metastases from 62 test patients. The most feasible model attained an area under the receiver operating characteristic curve (AUC) of 0.763 for the test patients when using a signature including features of BN and iBN maps, gray-scale and wavelet-filtered images, and clinical variables. The AUCs of the model were 0.744 for non-small cell lung cancer and 0.861 for small cell lung cancer. The results suggest that the BN signature boosted the performance of MRB for the identification of primary sites of brain metastases including small tumors.© 2023. Australasian College of Physical Scientists and Engineers in Medicine."
-,37588985,Identification of fibroblast-related genes based on single-cell and machine learning to predict the prognosis and endocrine metabolism of pancreatic cancer.,Front Endocrinol (Lausanne),"Single-cell sequencing technology has become an indispensable tool in tumor mechanism and heterogeneity studies. Pancreatic adenocarcinoma (PAAD) lacks early specific symptoms, and comprehensive bioinformatics analysis for PAAD contributes to the developmental mechanisms.We performed dimensionality reduction analysis on the single-cell sequencing data GSE165399 of PAAD to obtain the specific cell clusters. We then obtained cell cluster-associated gene modules by weighted co-expression network analysis and identified tumorigenesis-associated cell clusters and gene modules in PAAD by trajectory analysis. Tumor-associated genes of PAAD were intersected with cell cluster marker genes and within the signature module to obtain genes associated with PAAD occurrence to construct a prognostic risk assessment tool by the COX model. The performance of the model was assessed by the Kaplan-Meier (K-M) curve and the receiver operating characteristic (ROC) curve. The score of endocrine pathways was assessed by ssGSEA analysis.The PAAD single-cell dataset GSE165399 was filtered and downscaled, and finally, 17 cell subgroups were filtered and 17 cell clusters were labeled. WGCNA analysis revealed that the brown module was most associated with tumorigenesis. Among them, the brown module was significantly associated with C11 and C14 cell clusters. C11 and C14 cell clusters belonged to fibroblast and circulating fetal cells, respectively, and trajectory analysis showed low heterogeneity for fibroblast and extremely high heterogeneity for circulating fetal cells. Next, through differential analysis, we found that genes within the C11 cluster were highly associated with tumorigenesis. Finally, we constructed the RiskScore system, and K-M curves and ROC curves revealed that RiskScore possessed objective clinical prognostic potential and demonstrated consistent robustness in multiple datasets. The low-risk group presented a higher endocrine metabolism and lower immune infiltrate state.We identified prognostic models consisting of APOL1, BHLHE40, CLMP, GNG12, LOX, LY6E, MYL12B, RND3, SOX4, and RiskScore showed promising clinical value. RiskScore possibly carries a credible clinical prognostic potential for PAAD.Copyright © 2023 Xu, Chen, Liu, Chu and Wang."
-,37581167,Using Machine Learning to Predict Surgical Site Infection After Lumbar Spine Surgery.,Infect Drug Resist,"The objective of this study was to utilize machine learning techniques to analyze perioperative factors and identify blood glucose levels that can predict the occurrence of surgical site infection following posterior lumbar spinal surgery.A total of 4019 patients receiving lumbar internal fixation surgery from an institute were enrolled between June 2012 and February 2021. First, the filtered data were randomized into the test and verification groups. Second, in the test group, specific variables were screened using logistic regression analysis, Lasso regression analysis, support vector machine, and random forest. Specific variables obtained using the four methods were intersected, and a dynamic model was constructed. ROC and calibration curves were constructed to assess model performance. Finally, internal model performance was verified in the verification group using ROC and calibration curves.The data from 4019 patients were collected. In total, 1327 eligible cases were selected. By combining logistic regression analysis with three machine learning algorithms, this study identified four predictors associated with SSI, namely Modic changes, sebum thickness, hemoglobin, and glucose. Using this information, a prediction model was developed and visually represented. Then, we constructed ROC and calibration curves using the test group; the area under the ROC curve was 0.988. Further, calibration curve analysis revealed favorable consistency of nomogram-predicted values compared with real measurements. The C-index of our model was 0.986 (95% CI 0.981-0.994). Finally, we used the validation group to validate the model internally; the AUC was 0.987. Calibration curve analysis revealed favorable consistency of nomogram-predicted values compared with real measurements. The C-index was 0.982 (95% CI 0.974-0.999).Logistic regression analysis and machine learning were employed to select four risk factors: Modic changes, sebum thickness, hemoglobin, and glucose. Then, a dynamic prediction model was constructed to help clinicians simplify the monitoring and prevention of SSI.© 2023 Chen et al."
-,37568624,Reliability and Efficiency of the CAPRI-3 Metastatic Prostate Cancer Registry Driven by Artificial Intelligence.,Cancers (Basel),"Manual data collection is still the gold standard for disease-specific patient registries. However, CAPRI-3 uses text mining (an artificial intelligence (AI) technology) for patient identification and data collection. The aim of this study is to demonstrate the reliability and efficiency of this AI-driven approach.CAPRI-3 is an observational retrospective multicenter cohort registry on metastatic prostate cancer. We tested the patient-identification algorithm and automated data extraction through manual validation of the same patients in two pilots in 2019 and 2022.Pilot one identified 2030 patients and pilot two 9464 patients. The negative predictive value of the algorithm was maximized to prevent false exclusions and reached 94.8%. The completeness and accuracy of the automated data extraction were 92.3% or higher, except for date fields and inaccessible data (images/pdf) (10-88.9%). Additional manual quality control took over 3 h less time per patient than the original fully manual CAPRI registry (105 vs. 300 min).The CAPRI-3 patient-identification algorithm is a sound replacement for excluding ineligible candidates. The AI-driven data extraction is largely accurate and complete, but manual quality control is needed for less reliable and inaccessible data. Overall, the AI-driven approach of the CAPRI-3 registry is reliable and timesaving."
-,37568612,"Modelling the Tumour Microenvironment, but What Exactly Do We Mean by ""Model""?",Cancers (Basel),"The Oxford English Dictionary includes 17 definitions for the word ""model"" as a noun and another 11 as a verb. Therefore, context is necessary to understand the meaning of the word model. For instance, ""model railways"" refer to replicas of railways and trains at a smaller scale and a ""model student"" refers to an exemplary individual. In some cases, a specific context, like cancer research, may not be sufficient to provide one specific meaning for model. Even if the context is narrowed, specifically, to research related to the tumour microenvironment, ""model"" can be understood in a wide variety of ways, from an animal model to a mathematical expression. This paper presents a review of different ""models"" of the tumour microenvironment, as grouped by different definitions of the word into four categories: model organisms, in vitro models, mathematical models and computational models. Then, the frequencies of different meanings of the word ""model"" related to the tumour microenvironment are measured from numbers of entries in the MEDLINE database of the United States National Library of Medicine at the National Institutes of Health. The frequencies of the main components of the microenvironment and the organ-related cancers modelled are also assessed quantitatively with specific keywords. Whilst animal models, particularly xenografts and mouse models, are the most commonly used ""models"", the number of these entries has been slowly decreasing. Mathematical models, as well as prognostic and risk models, follow in frequency, and these have been growing in use."
-,37643174,An integrated multi-omics analysis of identifies distinct molecular characteristics in pulmonary infections of Pseudomonas aeruginosa.,PLoS Pathog,"Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we performed assays for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To identify the pivotal factors that are involved in host immune defense, we integrated chromatin accessibility and gene expression to investigate molecular changes in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics. Our multi-omics investigation discovered a significant concordance for innate immunological and inflammatory responses following P. aeruginosa infection between hosts and alveolar macrophages. Furthermore, we discovered that multi-omics changes in pioneer factors Stat1 and Stat3 play a crucial role in the immunological regulation of P. aeruginosa infection and that their downstream molecules (e.g., Fas) may be implicated in both immunosuppressive and inflammation-promoting processes. Taken together, these findings indicate that transcription factors and their downstream signaling molecules play a critical role in the mobilization and rebalancing of the host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, providing insights and resources for omics analyses.Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37580546,Associations of Urban Built Environment with Cardiovascular Risks and Mortality: a Systematic Review.,J Urban Health,"With rapid urbanization, built environment has emerged as a set of modifiable factors of cardiovascular disease (CVD) risks. We conducted a systematic review to synthesize evidence on the associations of attributes of urban built environment (e.g. residential density, land use mix, greenness and walkability) with cardiovascular risk factors (e.g. hypertension and arterial stiffness) and major CVD events including mortality. A total of 63 studies, including 31 of cross-sectional design and 32 of longitudinal design conducted across 21 geographical locations and published between 2012 and 2023 were extracted for review. Overall, we report moderately consistent evidence of protective associations of greenness with cardiovascular risks and major CVD events (cross-sectional studies: 12 of 15 on hypertension/blood pressure (BP) and 2 of 3 on arterial stiffness; and longitudinal studies: 6 of 8 on hypertension/BP, 7 of 8 on CVD mortality, 3 of 3 on ischemic heart disease mortality and 5 of 8 studies on stroke hospitalization or mortality reporting significant inverse associations). Consistently, walkability was associated with lower risks of hypertension, arterial stiffness and major CVD events (cross-sectional studies: 11 of 12 on hypertension/BP and 1 of 1 on arterial stiffness; and longitudinal studies: 3 of 6 on hypertension/BP and 1 of 2 studies on CVD events being protective). Sixty-seven percent of the studies were rated as ""probably high"" risk of confounding bias because of inability to adjust for underlying comorbidities/family history of diseases in their statistical models. Forty-six percent and 14% of the studies were rated as ""probably high"" risk of bias for exposure and outcome measurements, respectively. Future studies with robust design will further help elucidate the linkages between urban built environment and cardiovascular health, thereby informing planning policies for creating healthy cities.© 2023. The New York Academy of Medicine."
-,37631988,Host DNA Demethylation Induced by DNMT1 Inhibition Up-Regulates Antiviral OASL Protein during Influenza a Virus Infection.,Viruses,"Influenza A virus (IAV) is a leading cause of human respiratory infections and poses a major public health concern. IAV replication can affect the expression of DNA methyltransferases (DNMTs), and the subsequent changes in DNA methylation regulate gene expression and may lead to abnormal gene transcription and translation, yet the underlying mechanisms of virus-induced epigenetic changes from DNA methylation and its role in virus-host interactions remain elusive. Here in this paper, we showed that DNMT1 expression could be suppressed following the inhibition of miR-142-5p or the PI3K/AKT signaling pathway during IAV infection, resulting in demethylation of the promotor region of the 2'-5'-oligoadenylate synthetase-like (OASL) protein and promotion of its expression in A549 cells. OASL expression enhanced RIG-I-mediated interferon induction and then suppressed replication of IAV. Our study elucidated an innate immunity mechanism by which up-regulation of OASL contributes to host antiviral responses via epigenetic modifications in IAV infection, which could provide important insights into the understanding of viral pathogenesis and host antiviral defense."
-,37591855,"A tool for rapid, automated characterization of population epigenomics in plants.",Sci Rep,"Epigenetic variation in plant populations is an important factor in determining phenotype and adaptation to the environment. However, while advances have been made in the molecular and computational methods to analyze the methylation status of a given sample of DNA, tools to profile and compare the methylomes of multiple individual plants or groups of plants at high resolution and low cost are lacking. Here, we describe a computational approach and R package (sounDMR) that leverages the benefits of long read nanopore sequencing to enable robust identification of differential methylation from complex experimental designs, as well as assess the variability within treatment groups and identify individual plants of interest. We demonstrate the utility of this approach by profiling a population of Arabidopsis thaliana exposed to a demethylating agent and identify genomic regions of high epigenetic variability between individuals. Given the low cost of nanopore sequencing devices and the ease of sample preparation, these results show that high resolution epigenetic profiling of plant populations can be made more broadly accessible in plant breeding and biotechnology.© 2023. Springer Nature Limited."
-,37432452,Long-read sequencing reveals the complex structure of extra dic(21;21) chromosome and its biological effects.,Hum Genet,"Complex congenital chromosome abnormalities are rare but often cause severe symptoms. However, the structures and biological impacts of such abnormalities have seldomly been analyzed at the molecular level. Previously, we reported a Japanese female patient with severe developmental defects. The patient had an extra dicentric chromosome 21 (chr21) consisting of two partial chr21 copies fused together within their long arms along with two centromeres and many copy number changes. In this study, we performed whole-genome, transcriptional, and DNA methylation analyses, coupled with novel bioinformatic approaches, to reveal the complex structure of the extra chromosome and its transcriptional and epigenetic changes. Long-read sequencing accurately identified the structures of junctions related to the copy number changes in extra chr21 and suggested the mechanism of the structural changes. Our transcriptome analysis showed the overexpression of genes in extra chr21. Additionally, an allele-specific DNA methylation analysis of the long-read sequencing data suggested that the centromeric region of extra chr21 was hypermethylated, a property associated with the inactivation of one centromere in the extra chromosome. Our comprehensive analysis provides insights into the molecular mechanism underlying the generation of the extra chromosome and its pathogenic roles.© 2023. The Author(s)."
-,37591874,Cell-specific and shared regulatory elements control a multigene locus active in mammary and salivary glands.,Nat Commun,"Regulation of high-density loci harboring genes with different cell-specificities remains a puzzle. Here we investigate a locus that evolved through gene duplication and contains eight genes and 20 candidate regulatory elements, including one super-enhancer. Casein genes (Csn1s1, Csn2, Csn1s2a, Csn1s2b, Csn3) are expressed in mammary glands, induced 10,000-fold during pregnancy and account for 50% of mRNAs during lactation, Prr27 and Fdcsp are salivary-specific and Odam has dual specificity. We probed the function of 12 candidate regulatory elements, individually and in combination, in the mouse genome. The super-enhancer is essential for the expression of Csn3, Csn1s2b, Odam and Fdcsp but largely dispensable for Csn1s1, Csn2 and Csn1s2a. Csn3 activation also requires its own local enhancer. Synergism between local enhancers and cytokine-responsive promoter elements facilitates activation of Csn2 during pregnancy. Our work identifies the regulatory complexity of a multigene locus with an ancestral super-enhancer active in mammary and salivary tissue and local enhancers and promoter elements unique to mammary tissue.© 2023. Springer Nature Limited."
-,37564646,RSV replication modifies the XBP1s binding complex on the IRF1 upstream enhancer to potentiate the mucosal anti-viral response.,Front Immunol,"The unfolded protein response (UPR) has emerged as an important signaling pathway mediating anti-viral defenses to Respiratory Syncytial Virus (RSV) infection. Earlier we found that RSV replication predominantly activates the evolutionarily conserved Inositol Requiring Enzyme 1α (IRE1α)-X-Box Binding Protein 1 spliced (XBP1s) arm of the Unfolded Protein Response (UPR) producing inflammation, metabolic adaptation and cellular plasticity, yet the mechanisms how the UPR potentiates inflammation are not well understood.To understand this process better, we examined the genomic response integrating RNA-seq and Cleavage Under Targets and Release Using Nuclease (CUT&RUN) analyses. These data were integrated with an RNA-seq analysis conducted on RSV-infected small airway cells ± an IRE1α RNAse inhibitor.We identified RSV induced expression changes in ~3.2K genes; of these, 279 required IRE1α and were enriched in IL-10/cytokine signaling pathways. From this data set, we identify those genes directly under XBP1s control by CUT&RUN. Although XBP1s binds to ~4.2 K high-confidence genomic binding sites, surprisingly only a small subset of IL10/cytokine signaling genes are directly bound. We further apply CUT&RUN to find that RSV infection enhances XBP1s loading on 786 genomic sites enriched in AP1/Fra-1, RELA and SP1 binding sites. These control a subset of cytokine regulatory factor genes including IFN response factor 1 (IRF1), CSF2, NFKB1A and DUSP10. Focusing on the downstream role of IRF1, selective knockdown (KD) and overexpression experiments demonstrate IRF1 induction controls type I and -III interferon (IFN) and IFN-stimulated gene (ISG) expression, demonstrating that ISG are indirectly regulated by XBP1 through IRF1 transactivation. Examining the mechanism of IRF1 activation, we observe that XBP1s directly binds a 5' enhancer sequence whose XBP1s loading is increased by RSV. The functional requirement for the enhancer is demonstrated by targeting a dCas9-KRAB silencer, reducing IRF1 activation. Chromatin immunoprecipitation shows that XBP1 is required, but not sufficient, for RSV-induced recruitment of activated phospho-Ser2 Pol II to the enhancer.We conclude that XBP1s is a direct activator of a core subset of IFN and cytokine regulatory genes in response to RSV. Of these IRF1 is upstream of the type III IFN and ISG response. We find that RSV modulates the XBP1s binding complex on the IRF1 5' enhancer whose activation is required for IRF1 expression. These findings provide novel insight into how the IRE1α-XBP1s pathway potentiates airway mucosal anti-viral responses.Copyright © 2023 Qiao, Xu, Zhang, Yang and Brasier."
-,37591842,A deep learning method for replicate-based analysis of chromosome conformation contacts using Siamese neural networks.,Nat Commun,"The organisation of the genome in nuclear space is an important frontier of biology. Chromosome conformation capture methods such as Hi-C and Micro-C produce genome-wide chromatin contact maps that provide rich data containing quantitative and qualitative information about genome architecture. Most conventional approaches to genome-wide chromosome conformation capture data are limited to the analysis of pre-defined features, and may therefore miss important biological information. One constraint is that biologically important features can be masked by high levels of technical noise in the data. Here we introduce a replicate-based method for deep learning from chromatin conformation contact maps. Using a Siamese network configuration our approach learns to distinguish technical noise from biological variation and outperforms image similarity metrics across a range of biological systems. The features extracted from Hi-C maps after perturbation of cohesin and CTCF reflect the distinct biological functions of cohesin and CTCF in the formation of domains and boundaries, respectively. The learnt distance metrics are biologically meaningful, as they mirror the density of cohesin and CTCF binding. These properties make our method a powerful tool for the exploration of chromosome conformation capture data, such as Hi-C capture Hi-C, and Micro-C.© 2023. Springer Nature Limited."
-,37573342,SnapFISH: a computational pipeline to identify chromatin loops from multiplexed DNA FISH data.,Nat Commun,"Multiplexed DNA fluorescence in situ hybridization (FISH) imaging technologies have been developed to map the folding of chromatin fibers at tens of nanometers and up to several kilobases in resolution in single cells. However, computational methods to reliably identify chromatin loops from such imaging datasets are still lacking. Here we present a Single-Nucleus Analysis Pipeline for multiplexed DNA FISH (SnapFISH), to process the multiplexed DNA FISH data and identify chromatin loops. SnapFISH can identify known chromatin loops from mouse embryonic stem cells with high sensitivity and accuracy. In addition, SnapFISH obtains comparable results of chromatin loops across datasets generated from diverse imaging technologies. SnapFISH is freely available at https://github.com/HuMingLab/SnapFISH .© 2023. Springer Nature Limited."
-,37642765,Caveolin-1 promotes glioma progression and maintains its mitochondrial inhibition resistance.,Discov Oncol,"Glioma is a lethal brain cancer and lacking effective therapies. Challenges include no effective therapeutic target, intra- and intertumoral heterogeneity, inadequate effective drugs, and an immunosuppressive microenvironment, etc. Deciphering the pathogenesis of gliomas and finding out the working mechanisms are urgent and necessary for glioma treatment. Identification of prognostic biomarkers and targeting the biomarker genes will be a promising therapy.From our RNA-sequencing data of the oxidative phosphorylation (OXPHOS)-inhibition sensitive and OXPHOS-resistant cell lines, we found that the scaffolding protein caveolin 1 (CAV1) is highly expressed in the resistant group but not in the sensitive group. By comprehensive analysis of our RNA sequencing data, Whole Genome Bisulfite Sequencing (WGBS) data and public databases, we found that CAV1 is highly expressed in gliomas and its expression is positively related with pathological processes, higher CAV1 predicts shorter overall survival.Further analysis indicated that (1) the differentiated genes in CAV1-high groups are enriched in immune infiltration and immune response; (2) CAV1 is positively correlated with tumor metastasis markers; (3) the methylation level of CAV1 promoters in glioma group is lower in higher stage than that in lower stage; (4) CAV1 is positively correlated with glioma stemness; (5) higher expression of CAV1 renders the glioma cells' resistant to oxidative phosphorylation inhibitors.Therefore, we identified a key gene CAV1 and deciphered its function in glioma progression and prognosis, proposing that CAV1 may be a therapeutic target for gliomas.© 2023. Springer Science+Business Media, LLC."
-,37667001,Comparative single-cell transcriptomic analysis of primate brains highlights human-specific regulatory evolution.,Nat Ecol Evol,"Enhanced cognitive function in humans is hypothesized to result from cortical expansion and increased cellular diversity. However, the mechanisms that drive these phenotypic innovations remain poorly understood, in part because of the lack of high-quality cellular resolution data in human and non-human primates. Here, we take advantage of single-cell expression data from the middle temporal gyrus of five primates (human, chimp, gorilla, macaque and marmoset) to identify 57 homologous cell types and generate cell type-specific gene co-expression networks for comparative analysis. Although orthologue expression patterns are generally well conserved, we find 24% of genes with extensive differences between human and non-human primates (3,383 out of 14,131), which are also associated with multiple brain disorders. To assess the functional significance of gene expression differences in an evolutionary context, we evaluate changes in network connectivity across meta-analytic co-expression networks from 19 animals. We find that a subset of these genes has deeply conserved co-expression across all non-human animals, and strongly divergent co-expression relationships in humans (139 out of 3,383, <1% of primate orthologues). Genes with human-specific cellular expression and co-expression profiles (such as NHEJ1, GTF2H2, C2 and BBS5) typically evolve under relaxed selective constraints and may drive rapid evolutionary change in brain function.© 2023. The Author(s)."
-,37576401,Diagnostic value of aberrant decreased 5-Methylcytosine RNA modification in leukocytes for non-small cell lung cancer.,J Cancer,"Background:Non-small cell lung cancer (NSCLC) was a disease with poor outcomes, partly because there were no high-efficiency non-invasive diagnostic biomarkers. The RNA modification status of 5-Methylcytosine (m5C) has been shown to be a biomarker for various diseases, but its potentiality to be a diagnostic biomarker for NSCLC remained inconclusive.Methods:In this research, we collected peripheral leukocyte samples from 141 patients with NSCLC and 90 normal people as controls to evaluate the extent of m5C RNA modification.Results:We found that the m5C modification levels in leukocytes of NSCLC patients were decreased dramatically, which were compared to the normal controls, and levels of m5C modification decreased progressively with tumor stage. Importantly, m5C modification exhibited superior diagnostic value compared to carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), cytokeratin 19 fragment (Cyfra21-1), and carbohydrate antigen 125 (CA125), which demonstrated area under the curves (AUCs) of 0.912, 0.773, 0.669, 0.754, and 0.732, respectively. The combination of m5C modification with these serum tumor biomarkers further improved the AUC to 0.960. A nomogram model incorporating m5C modification also provided an effectively diagnostic tool for NSCLC.Conclusion:Collectively, our findings suggested that m5C modification in leukocytes held promise as a prospective biomarker for NSCLC diagnosis.© The author(s)."
-,37550793,Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis.,Clin Epigenetics,"Long-term environmental exposure to metals leads to epigenetic changes and may increase risks to human health. The relationship between the type and level of metal exposure and epigenetic changes in subjects exposed to high concentrations of metals in the environment is not yet clear. The aim of our study is to find the possible association of environmental long-term exposure to metals with DNA methylation changes of genes related to immune response and carcinogenesis. We investigated the association of plasma levels of 21 essential and non-essential metals detected by ICP-MS and the methylation level of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5, IGF2 and H19 genes assessed by targeted bisulfite sequencing in a cohort of 40 subjects living near metal mining area and 40 unexposed subjects. Linear regression was conducted to find differentially methylated positions with adjustment for gender, age, BMI class, smoking and metal concentration.In the metal-exposed group, five CpGs in the NFKB1 promoter region were hypomethylated compared to unexposed group. Four differentially methylated positions (DMPs) were associated with multiple metals, two of them are located on NFKB1 gene, and one each on CDKN2A gene and ESR1 gene. Two DMPs located on NFKB1 (chr4:102500951, associated with Be) and IGF2 (chr11:2134198, associated with U) are associated with specific metal levels. The methylation status of the seven CpGs located on NFKB1 (3), ESR1 (2) and CDKN2A (2) positively correlated with plasma levels of seven metals (As, Sb, Zn, Ni, U, I and Mn).Our study revealed methylation changes in NFKB1, CDKN2A, IGF2 and ESR1 genes in individuals with long-term human exposure to metals. Further studies are needed to clarify the effect of environmental metal exposure on epigenetic mechanisms and pathways involved.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37645044,Unraveling the Link between Periodontitis and Inflammatory Bowel Disease: Challenges and Outlook.,ArXiv,"Periodontitis and Inflammatory Bowel Disease (IBD) are chronic inflammatory conditions, characterized by microbial dysbiosis and hyper-immunoinflammatory responses. Growing evidence suggest an interconnection between periodontitis and IBD, implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an Oral-Gut axis, marked by a higher prevalence of periodontitis in IBD patients and vice versa. The specific mechanisms linking periodontitis and IBD remain to be fully elucidated, but emerging evidence points to the ectopic colonization of the gut by oral bacteria, which promote intestinal inflammation by activating host immune responses. This review presents an in-depth examination of the interconnection between periodontitis and IBD, highlighting the shared microbiological and immunological pathways, and proposing a multi-hit hypothesis in the pathogenesis of periodontitis-mediated intestinal inflammation. Furthermore, the review underscores the critical need for a collaborative approach between dentists and gastroenterologists to provide holistic oral-systemic healthcare."
-,37607912,Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides.,Nat Commun,"Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease.© 2023. Springer Nature Limited."
-,37580713,Global serum profiling: an opportunity for earlier cancer detection.,J Exp Clin Cancer Res,"The advances in cancer research achieved in the last 50 years have been remarkable and have provided a deeper knowledge of this disease in many of its conceptual and biochemical aspects. From viewing a tumor as a 'simple' aggregate of mutant cells and focusing on detecting key cell changes leading to the tumorigenesis, the understanding of cancer has broadened to consider it as a complex organ interacting with its close and far surroundings through tumor and non-tumor cells, metabolic mechanisms, and immune processes. Metabolism and the immune system have been linked to tumorigenesis and malignancy progression along with cancer-specific genetic mutations. However, most technologies developed to overcome the barriers to earlier detection are focused solely on genetic information. The concept of cancer as a complex organ has led to research on other analytical techniques, with the quest of finding a more sensitive and cost-effective comprehensive approach. Furthermore, artificial intelligence has gained broader consensus in the oncology community as a powerful tool with the potential to revolutionize cancer diagnosis for physicians. We herein explore the relevance of the concept of cancer as a complex organ interacting with the bodily surroundings, and focus on promising emerging technologies seeking to diagnose cancer earlier, such as liquid biopsies. We highlight the importance of a comprehensive approach to encompass all the tumor and non-tumor derived information salient to earlier cancer detection.© 2023. Italian National Cancer Institute �Regina Elena’."
-,37632244,NA,NA,"There are limited data from non-industrialized settings on the effects of early life viral respiratory disease on childhood respiratory illness. We followed a birth cohort in tropical Ecuador to understand how early viral respiratory disease, in the context of exposures affecting airway inflammation including ascariasis, affect wheezing illness, asthma, and rhinoconjunctivitis in later childhood.A surveillance cohort nested within a birth cohort was monitored for respiratory infections during the first 2 years in rural Ecuador and followed for 8 years for the development of wheeze and rhinoconjunctivitis. Nasal swabs were examined for viruses by polymerase chain reaction and respiratory symptom data on recent wheeze and rhinoconjunctivitis were collected by periodic questionnaires at 3, 5, and 8 years. Stools from pregnant mothers and periodically from children aged 2 years were examined microscopically for soil-transmitted helminths. Atopy was measured by allergen skin prick testing at 2 years. Spirometry, fractional exhaled nitric oxide measurement, and nasal washes were performed at 8 years. Associations between clinically significant respiratory disease (CSRD) and wheezing or rhinoconjunctivitis at 3, 5, and 8 years were estimated using multivariable logistic regression.Four hundred and twenty six children were followed of which 67.7% had at least one CSRD episode; 12% had respiratory syncytial virus (RSV)+CSRD and 36% had rhinovirus (RHV)+CSRD. All-cause CSRD was associated with increased wheeze at 3 (OR 2.33 [95% confidence intervals (CI) 1.23-4.40]) and 5 (OR: 2.12 [95% CI 1.12-4.01]) years. RHV+CSRD was more strongly associated with wheeze at 3 years in STH-infected (STH-infected [OR 13.41, 95% CI 1.56-115.64] vs. uninfected [OR 1.68, 95% CI 0.73-3.84]) and SPT+ (SPT+ [OR 9.42, 95% CI 1.88-47.15] versus SPT- [OR 1.92, 95% CI 0.84-4.38]) children. No associations were observed between CSRD and rhinoconjunctivitis.CSRD was significantly associated with childhood wheeze with stronger associations observed for RHV+CSRD in SPT+ and STH-infected children.© 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology."
-,37663254,Diosgenin normalization of disrupted behavioral and central neurochemical activity after single prolonged stress.,Front Pharmacol,"Introduction:Post-traumatic stress disorder (PTSD) is a chronic mental illness triggered by traumatic experiences such as wars, natural disasters, or catastrophes, and it is characterized by anxiety, depression and cognitive impairment. Diosgenin is a steroidal sapogenin with known neuroprotective and antioxidant properties. This study aimed to assess the pharmacological potential of diosgenin in a single prolonged stress (SPS) model of PTSD, plus other behavioral models along with any consequent alterations in brain neurochemistry in male mice.Methodology:SPS was induced by restraining animals for 2 h, followed by 20 min of forced swim, recuperation for 15 min, and finally, exposure to ether to induce anesthesia. The SPS-exposed animals were treated with diosgenin (20, 40, and 60 mg/kg) and compared with the positive controls, fluoxetine or donepezil, then they were observed for any changes in anxiety/depression-like behaviors, and cognitive impairment. After behavioral screening, postmortem serotonin, noradrenaline, dopamine, vitamin C, adenosine and its metabolites inosine and hypoxanthine were quantified in the frontal cortex, hippocampus, and striatum by high-performance liquid chromatography. Additionally, animal serum was screened for changes in corticosterone levels.Results:The results showed that diosgenin reversed anxiety- and depression-like behaviors, and ameliorated cognitive impairment in a dose-dependent manner. Additionally, diosgenin restored monoamine and vitamin C levels dose-dependently and modulated adenosine and its metabolites in the brain regions. Diosgenin also reinstated otherwise increased serum corticosterone levels in SPS mice.Conclusion:The findings suggest that diosgenin may be a potential candidate for improving symptoms of PTSD.Copyright © 2023 Malik, Usman, Arif, Ahmed, Ali, Rauf and Sewell."
-,37664139,The Ripple Effect: Unveiling the Bidirectional Relationship Between Negative Life Events and Depressive Symptoms in Medical Cadets.,Psychol Res Behav Manag,"Previous studies have explored the relationship between negative life events and depression, but little is known about the bidirectional relationship between negative life events and depression, particularly in specific groups of medical cadets.This study aimed to explore the relationship between negative life events and depressive symptoms among medical cadets during their four years of college.An analysis of 4-wave longitudinal data collected from 2015-2018 was conducted using a cross-lagged panel network (CLPN) model to explore the complex causal relationship between negative life events and depressive symptoms in medical cadets (N=433).We found differences in negative life events and depressive symptoms among medical cadets across four network models over four years of university. Nodes A-21, A-20, A-23 and A-24, and depressive symptoms D-6 showed greater lagged effect values.Our findings suggest that there is a lagged and mutually causal interaction between negative life events and depressive symptoms in medical cadets over 4 years of college, but that the predictability of negative life events is more important. However, more attention needs to be paid to the predictive role of depressive symptoms, especially those in early life which are often overlooked. Our study provides new insights into the relationship between negative life events and depressive symptoms in university students and helps to refine strategies for prevention and intervention of depression.© 2023 Li et al."
-,37601971,Accurate microRNA annotation of animal genomes using trained covariance models of curated microRNA complements in MirMachine.,Cell Genom,"The annotation of microRNAs depends on the availability of transcriptomics data and expert knowledge. This has led to a gap between the availability of novel genomes and high-quality microRNA complements. Using >16,000 microRNAs from the manually curated microRNA gene database MirGeneDB, we generated trained covariance models for all conserved microRNA families. These models are available in our tool MirMachine, which annotates conserved microRNAs within genomes. We successfully applied MirMachine to a range of animal species, including those with large genomes and genome duplications and extinct species, where small RNA sequencing is hard to achieve. We further describe a microRNA score of expected microRNAs that can be used to assess the completeness of genome assemblies. MirMachine closes a long-persisting gap in the microRNA field by facilitating automated genome annotation pipelines and deeper studies into the evolution of genome regulation, even in extinct organisms.© 2023 The Author(s)."
-,37596405,NA,NA,"The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival.Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH).Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis.Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.© 2023. The Author(s)."
-,37592016,Genomic map of inflammatory blood proteins.,Nat Immunol,NA
-,37670150,MIL-CELL: a tool for multi-scale simulation of yeast replication and prion transmission.,Eur Biophys J,"The single-celled baker's yeast, Saccharomyces cerevisiae, can sustain a number of amyloid-based prions, the three most prominent examples being [URE3], [PSI+], and [PIN+]. In the laboratory, haploid S. cerevisiae cells of a single mating type can acquire an amyloid prion in one of two ways (i) spontaneous nucleation of the prion within the yeast cell, and (ii) receipt via mother-to-daughter transmission during the cell division cycle. Similarly, prions can be lost due to (i) dissolution of the prion amyloid by its breakage into non-amyloid monomeric units, or (ii) preferential donation/retention of prions between the mother and daughter during cell division. Here we present a computational tool (Monitoring Induction and Loss of prions in Cells; MIL-CELL) for modelling these four general processes using a multiscale approach describing both spatial and kinetic aspects of the yeast life cycle and the amyloid-prion behavior. We describe the workings of the model, assumptions upon which it is based and some interesting simulation results pertaining to the wave-like spread of the epigenetic prion elements through the yeast population. MIL-CELL is provided as a stand-alone GUI executable program for free download with the paper. MIL-CELL is equipped with a relational database allowing all simulated properties to be searched, collated and graphed. Its ability to incorporate variation in heritable properties means MIL-CELL is also capable of simulating loss of the isogenic nature of a cell population over time. The capability to monitor both chronological and reproductive age also makes MIL-CELL potentially useful in studies of cell aging.© 2023. The Author(s)."
-,37628735,The Role of Hydrogen Sulfide (H(2)S) in Epigenetic Regulation of Neurodegenerative Diseases: A Systematic Review.,Int J Mol Sci,"This review explores the emerging role of hydrogen sulfide (H2S) in modulating epigenetic mechanisms involved in neurodegenerative diseases. Accumulating evidence has begun to elucidate the multifaceted ways in which H2S influences the epigenetic landscape and, subsequently, the progression of various neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. H2S can modulate key components of the epigenetic machinery, such as DNA methylation, histone modifications, and non-coding RNAs, impacting gene expression and cellular functions relevant to neuronal survival, inflammation, and synaptic plasticity. We synthesize recent research that positions H2S as an essential player within this intricate network, with the potential to open new therapeutic avenues for these currently incurable conditions. Despite significant progress, there remains a considerable gap in our understanding of the precise molecular mechanisms and the potential therapeutic implications of modulating H2S levels or its downstream targets. We conclude by identifying future directions for research aimed at exploiting the therapeutic potential of H2S in neurodegenerative diseases."
-,37566041,The Promise of Epigenetics Research in the Treatment of Appendiceal Neoplasms.,Cells,"Appendiceal cancers (AC) are a rare and heterogeneous group of malignancies. Historically, appendiceal neoplasms have been grouped with colorectal cancers (CRC), and treatment strategies have been modeled after CRC management guidelines due to their structural similarities and anatomical proximity. However, the two have marked differences in biological behavior and treatment response, and evidence suggests significant discrepancies in their respective genetic profiles. In addition, while the WHO classification for appendiceal cancers is currently based on traditional histopathological criteria, studies have demonstrated that histomorphology does not correlate with survival or treatment response in AC. Due to their rarity, appendiceal cancers have not been studied as extensively as other gastrointestinal cancers. However, their incidence has been increasing steadily over the past decade, making it crucial to identify new and more effective strategies for detection and treatment. Recent efforts to map and understand the molecular landscape of appendiceal cancers have unearthed a wealth of information that has made it evident that appendiceal cancers possess a unique molecular profile, distinct from other gastrointestinal cancers. This review focuses on the epigenetic landscape of epithelial appendiceal cancers and aims to provide a comprehensive overview of the current state of knowledge of epigenetic changes across different appendiceal cancer subtypes, highlighting the challenges as well as the promise of employing epigenetics in the quest for the detection of biomarkers, therapeutic targets, surveillance markers, and predictors of treatment response and survival in epithelial appendiceal neoplasms."
-,37577516,Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice.,bioRxiv,"Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically exhibits phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption - the root of the pathogenesis - is similar in the different disease-relevant cell types. This is possible in principle, since all these cell-types are subject to effects from the same causative gene, that has the same kind of function (e.g. methylates histones) and is disrupted by the same germline variant. We focus on mouse models for Kabuki syndrome types 1 and 2, and find that the chromatin accessibility abnormalities in neurons are mostly distinct from those in B or T cells. This is not because the neuronal abnormalities occur at regulatory elements that are only active in neurons. Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging. A sensitive analysis reveals that the regions disrupted in B/T cells do exhibit chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we are able to identify a small set of regulatory elements disrupted in all three cell types. Our findings reveal the cellular-context-specific effect of variants in epigenetic regulators, and suggest that blood-derived ""episignatures"" may not be well-suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery."
-,37559624,Analysis of the role of glucose metabolism-related genes in dilated cardiomyopathy based on bioinformatics.,J Thorac Dis,"Dilated cardiomyopathy (DCM) is a prevalent condition with diverse etiologies, including viral infection, autoimmune response, and genetic factors. Despite the crucial role of energy metabolism in cardiac function, therapeutic targets for key genes in DCM's energy metabolism remain scarce.Our study employed the GSE79962 and GSE42955 datasets from the Gene Expression Omnibus (GEO) database for myocardial tissue sample collection and target gene identification via differential gene expression screening. Using various R packages, GSEA software, and the STRING database, we conducted data analysis, gene set enrichment, and protein-protein interaction predictions. The least absolute shrinkage and selection operator (LASSO) and Support Vector Machine (SVM) algorithms aided in feature gene selection, while the predictive model's efficiency was evaluated via the receiver operating characteristic (ROC) curve analysis. We used the non-negative matrix factorization (NMF) method for molecular typing and the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm for predicting immune cell infiltration.TheDLATandLDHAgenes may regulate the immune microenvironment of DCM by influencing activated dendritic cells, activated mast cells, and M0 macrophages, respectively. TheBPGM, DLAT, PGM2, ADH1A, ADH1C, LDHA, andPFKMgenes may regulate m6A methylation in DCM by affecting theZC3H13, ALKBH5, RBMX, HNRNPC, METTL3, andYTHDC1genes. Further regulatory mechanism analysis suggested thatPFKM, DLAT, PKLR, PGM2, LDHA, BPGM, ADH1A, andADH1Ccould be involved in the development of cardiomyopathy by regulating the Toll-like receptor signaling pathway.PFKM, DLAT, PKLR, PGM2, LDHA, BPGM, ADH1A, andADH1Cmay serve as potential targets for guiding the diagnosis, treatment, and follow-up of DCM.2023 Journal of Thoracic Disease. All rights reserved."
-,37665382,Predicting neurologic recovery after severe acute brain injury using resting-state networks.,J Neurol,"There is a lack of reliable tools used to predict functional recovery in unresponsive patients following a severe brain injury. The objective of the study is to evaluate the prognostic utility of resting-state functional magnetic resonance imaging for predicting good neurologic recovery in unresponsive patients with severe brain injury in the intensive-care unit.Each patient underwent a 5.5-min resting-state scan and ten resting-state networks were extracted via independent component analysis. The Glasgow Outcome Scale was used to classify patients into good and poor outcome groups. The Nearest Centroid classifier used each patient's ten resting-state network values to predict best neurologic outcome within 6 months post-injury.Of the 25 patients enrolled (mean age = 43.68, range = [19-69]; GCS ≤ 9; 6 females), 10 had good and 15 had poor outcome. The classifier correctly and confidently predicted 8/10 patients with good and 12/15 patients with poor outcome (mean = 0.793, CI = [0.700, 0.886], Z = 2.843, p = 0.002). The prediction performance was largely determined by three visual (medial: Z = 3.11, p = 0.002; occipital pole: Z = 2.44, p = 0.015; lateral: Z = 2.85, p = 0.004) and the left frontoparietal network (Z = 2.179, p = 0.029).Our approach correctly identified good functional outcome with higher sensitivity (80%) than traditional prognostic measures. By revealing preserved networks in the absence of discernible behavioral signs, functional connectivity may aid in the prognostic process and affect the outcome of discussions surrounding withdrawal of life-sustaining measures.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany."
-,37640858,Cell-free DNA methylome analysis for early preeclampsia prediction.,Nat Med,"Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis in the prevention of PE, pregnancies at risk of PE must be identified early-in the first trimester. To identify at-risk pregnancies we profiled methylomes of plasma-derived, cell-free DNA from 498 pregnant women, of whom about one-third developed early-onset PE. We detected DNA methylation differences between control and PE pregnancies that enabled risk stratification at PE diagnosis but also presymptomatically, at around 12 weeks of gestation (range 9-14 weeks). The first-trimester risk prediction model was validated in an external cohort collected from two centers (area under the curve (AUC) = 0.75) and integrated with routinely available maternal risk factors (AUC = 0.85). The combined risk score correctly predicted 72% of patients with early-onset PE at 80% specificity. These preliminary results suggest that cell-free DNA methylation profiling is a promising tool for presymptomatic PE risk assessment, and has the potential to improve treatment and follow-up in the obstetric clinic.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
-,37654976,Elevated Maternal Testosterone Levels Alter PFOA Elimination and Tissue Distribution in Pregnant Rats.,J Environ Sci Public Health,"Perfluorooctanoic acid (PFOA) is an enduring synthetic chemical that harms human health. Recent studies indicate heightened bioaccumulation of PFOA, particularly in pregnant women experiencing preeclampsia. Since plasma testosterone levels are elevated in pregnant women with preeclampsia, we hypothesized that hyperandrogenic conditions during pregnancy may hinder PFOA elimination and contribute to their higher body burden. Pregnant Sprague-Dawley rats were s/c injected with vehicle or testosterone propionate from gestational day (GD) 15 to 20 to increase plasma testosterone levels by 2-fold, similar to levels in preeclampsia. On GD 16, [14C]-PFOA (9.4 pmol/kg) was given intravenously, and subsequently,14C radioactivity was measured in maternal blood, urine, feces, and tissues. PFOA was primarily eliminated through urine; however, less PFOA was excreted in urine of pregnant rats with elevated testosterone levels than controls. Fecal excretion of PFOA was minimal and did not significantly differ between groups. The total elimination of PFOA (urine plus feces) was significantly reduced by 12% in pregnant rats with elevated testosterone levels. In controls, PFOA distribution was highest in placenta, followed by the kidneys, liver, brain, heart, lungs, and spleen. Pregnant rats with elevated testosterone levels displayed 12% higher concentrations of PFOA in these tissues than controls. Furthermore, the renal expression ofOat2andOat3was significantly decreased, whileOatp1andOat-kexpression was significantly increased in pregnant rats with elevated testosterone levels than controls. In conclusion, elevated maternal testosterone levels decrease urinary elimination of PFOA, possibly through altered expression of renal transporters leading to increased tissue concentrations of PFOA in pregnant rats."
-,37620817,Association of mitochondrial DNA copy number with chronic kidney disease in older adults.,BMC Geriatr,"Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of chronic kidney disease (CKD). Estimation of mitochondrial DNA copy number (mtDNA-CN) is considered a convenient method for representing mitochondrial function in large samples. However, no study has investigated the association between mtDNA-CN and CKD in older adults with the highest prevalence. The objective is to examine cross-sectional and prospective associations between mtDNA-CN values and CKD risk in older adults to determine whether mtDNA-CN represents a novel potential biomarker for the recognition of CKD risk.In a Chinese community-based cohort of over 65-year-olds, we included 14,467 participants (52.6% females). CKD was defined by eGFR < 60 mL/min/1.73 m2or ICD-10 codes (patients = 3831 (26.5%)). Participants had peripheral blood levels of mtDNA-CN calculated from probe intensities of the Axiom CAS Array.The risk of CKD prevalence decreased with mtDNA-CN per 1-SD increment, independent of established risk factors for older CKD (odds ratio [OR] per SD 0.90, 95% confidence interval [CI] 0.86, 0.93, P < 0.001), and has comparable strength of association with these established risk factors. Furthermore, the progression of kidney function was stratified according to the worsening of eGFR categories. The risk of kidney function progression to a more severe stage gradually decreased as the mtDNA-CN increased (P trend < 0.001). Non-CKD participants in the highest quartile of mtDNA-CN had a lower risk of developing CKD compared to the lowest quartile within 2 years of follow-up, reducing the risk of CKD by 36% (95% CI 0.42, 0.97; P = 0.037).Based on the analysis of the largest sample to date investigating the association between mtDNA-CN and CKD in older adults, higher levels of mtDNA-CN were found to be associated with a lower risk of CKD, suggesting that a reduced level of mtDNA-CN is a potential risk factor for CKD.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37584774,Technical skill assessment in minimally invasive surgery using artificial intelligence: a systematic review.,Surg Endosc,"Technical skill assessment in surgery relies on expert opinion. Therefore, it is time-consuming, costly, and often lacks objectivity. Analysis of intraoperative data by artificial intelligence (AI) has the potential for automated technical skill assessment. The aim of this systematic review was to analyze the performance, external validity, and generalizability of AI models for technical skill assessment in minimally invasive surgery.A systematic search of Medline, Embase, Web of Science, and IEEE Xplore was performed to identify original articles reporting the use of AI in the assessment of technical skill in minimally invasive surgery. Risk of bias (RoB) and quality of the included studies were analyzed according to Quality Assessment of Diagnostic Accuracy Studies criteria and the modified Joanna Briggs Institute checklists, respectively. Findings were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.In total, 1958 articles were identified, 50 articles met eligibility criteria and were analyzed. Motion data extracted from surgical videos (n = 25) or kinematic data from robotic systems or sensors (n = 22) were the most frequent input data for AI. Most studies used deep learning (n = 34) and predicted technical skills using an ordinal assessment scale (n = 36) with good accuracies in simulated settings. However, all proposed models were in development stage, only 4 studies were externally validated and 8 showed a low RoB.AI showed good performance in technical skill assessment in minimally invasive surgery. However, models often lacked external validity and generalizability. Therefore, models should be benchmarked using predefined performance metrics and tested in clinical implementation studies.© 2023. The Author(s)."
-,37608017,NA,NA,"Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.© 2023. Springer Nature Limited."
-,37588090,Association study between C10orf90 gene polymorphisms and colorectal cancer.,Front Oncol,"Colorectal cancer (CRC) is the third most common malignant tumor in the world. The morbidity and mortality rates in Western countries have decreased, but they are still on the rise in China.C10orf90is associated with a variety of cancers, but the correlation betweenC10orf90and CRC is not yet known.A total of 1,339 subjects were randomly enrolled in our study. After extracting their DNA, three single-nucleotide polymorphisms (SNPs) ofC10orf90were genotyped to analyze the potential relationship between these variants and CRC risk. PLINK software packages (version 1.07) were used to evaluate multiple genetic models by calculating the odds ratio (OR) and 95% confidence interval (95% CI). The best SNP-SNP interaction model was defined by the multifactor dimensionality reduction (MDR) analysis.C10orf90rs12412320 was significantly associated with CRC risk (p= 0.006) and might be associated with the lower CRC risk (OR: 0.78; 95% CI: 0.65-0.93). The relationship of rs12412320 with lower CRC risk was found in people aged >60 years and ≤60 years, women, non-smokers, or non-drinkers. Rs11245008 in people aged ≤60 years and rs11245007 among men had a higher CRC susceptibility. Rs12412320 was related to the lower risk of advanced stages (III/IV stage), while rs11245007 might be associated with the higher risk of advanced stages (III/IV stage). Moreover, rs12412320 had the most significant relationship with the susceptibility to rectal cancer.This study is the first to report betweenC10orf90gene polymorphisms and CRC risk in Chinese people, which suggests thatC10orf90rs12412320 might play a crucial role in preventing CRC occurrence.Copyright © 2023 Song, Wang, Chen, Zhong, Li, Guo and Yu."
-,37592018,Pan-mammalian methylation clocks reveal evolutionarily conserved aging effects.,Nat Aging,NA
-,37564648,Microglial crosstalk with astrocytes and immune cells in amyotrophic lateral sclerosis.,Front Immunol,"In recent years, biomedical research efforts aimed to unravel the mechanisms involved in motor neuron death that occurs in amyotrophic lateral sclerosis (ALS). While the main causes of disease progression were first sought in the motor neurons, more recent studies highlight the gliocentric theory demonstrating the pivotal role of microglia and astrocyte, but also of infiltrating immune cells, in the pathological processes that take place in the central nervous system microenvironment. From this point of view, microglia-astrocytes-lymphocytes crosstalk is fundamental to shape the microenvironment toward a pro-inflammatory one, enhancing neuronal damage. In this review, we dissect the current state-of-the-art knowledge of the microglial dialogue with other cell populations as one of the principal hallmarks of ALS progression. Particularly, we deeply investigate the microglia crosstalk with astrocytes and immune cells reportingin vitroandin vivostudies related to ALS mouse models and human patients. At last, we highlight the current experimental therapeutic approaches that aim to modulate microglial phenotype to revert the microenvironment, thus counteracting ALS progression.Copyright © 2023 Calafatti, Cocozza, Limatola and Garofalo."
-,37592121,NA,NA,"Circulatory shock is defined syndromically as hypotension associated with tissue hypoperfusion and often subcategorized according to hemodynamic profile (e.g., distributive, cardiogenic, hypovolemic) and etiology (e.g., infection, myocardial infarction, trauma, among others). These shock subgroups are generally considered homogeneous entities in research and clinical practice. This current definition fails to consider the complex pathophysiology of shock and the influence of patient heterogeneity. Recent translational evidence highlights previously under-appreciated heterogeneity regarding the underlying pathways with distinct host-response patterns in circulatory shock syndromes. This heterogeneity may confound the interpretation of trial results as a given treatment may preferentially impact distinct subgroups. Re-analyzing results of major 'neutral' treatment trials from the perspective of biological mechanisms (i.e., host-response signatures) may reveal treatment effects in subgroups of patients that share treatable traits (i.e., specific biological signatures that portend a predictable response to a given treatment). In this review, we discuss the emerging literature suggesting the existence of distinct biomarker-based host-response patterns of circulatory shock syndrome independent of etiology or hemodynamic profile. We further review responses to newly prescribed treatments in the intensive care unit designed to personalize treatments (biomarker-driven or endotype-driven patient selection in support of future clinical trials).© 2023. The Author(s)."
-,37649712,Computational approaches in rheumatic diseases - Deciphering complex spatio-temporal cell interactions.,Comput Struct Biotechnol J,"Inflammatory arthritis, including rheumatoid (RA), and psoriatic (PsA) arthritis, are clinically and immunologically heterogeneous diseases with no identified cure. Chronic inflammation of the synovial tissue ushers loss of function of the joint that severely impacts the patient's quality of life, eventually leading to disability and life-threatening comorbidities. The pathogenesis of synovial inflammation is the consequence of compounded immune and stromal cell interactions influenced by genetic and environmental factors. Deciphering the complexity of the synovial cellular landscape has accelerated primarily due to the utilisation of bulk and single cell RNA sequencing. Particularly the capacity to generate cell-cell interaction networks could reveal evidence of previously unappreciated processes leading to disease. However, there is currently a lack of universal nomenclature as a result of varied experimental and technological approaches that discombobulates the study of synovial inflammation. While spatial transcriptomic analysis that combines anatomical information with transcriptomic data of synovial tissue biopsies promises to provide more insights into disease pathogenesis, in vitro functional assays with single-cell resolution will be required to validate current bioinformatic applications. In order to provide a comprehensive approach and translate experimental data to clinical practice, a combination of clinical and molecular data with machine learning has the potential to enhance patient stratification and identify individuals at risk of arthritis that would benefit from early therapeutic intervention. This review aims to provide a comprehensive understanding of the effect of computational approaches in deciphering synovial inflammation pathogenesis and discuss the impact that further experimental and novel computational tools may have on therapeutic target identification and drug development.© 2023 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology."
-,37480402,Single-cell multi-omics profiling reveals key regulatory mechanisms that poise germinal vesicle oocytes for maturation in pigs.,Cell Mol Life Sci,"The molecular mechanisms controlling the transition from meiotic arrest to meiotic resumption in mammalian oocytes have not been fully elucidated. Single-cell omics technology provides a new opportunity to decipher the early molecular events of oocyte growth in mammals. Here we focused on analyzing oocytes that were collected from antral follicles in different diameters of porcine pubertal ovaries, and used single-cell M&T-seq technology to analyze the nuclear DNA methylome and cytoplasmic transcriptome in parallel for 62 oocytes. 10× Genomics single-cell transcriptomic analyses were also performed to explore the bi-directional cell-cell communications within antral follicles. A new pipeline, methyConcerto, was developed to specifically and comprehensively characterize the methylation profile and allele-specific methylation events for a single-cell methylome. We characterized the gene expressions and DNA methylations of individual oocyte in porcine antral follicle, and both active and inactive gene's bodies displayed high methylation levels, thereby enabled defining two distinct types of oocytes. Although the methylation levels of Type II were higher than that of Type I, Type II contained nearly two times more of cytoplasmic transcripts than Type I. Moreover, the imprinting methylation patterns of Type II were more dramatically divergent than Type I, and the gene expressions and DNA methylations of Type II were more similar with that of MII oocytes. The crosstalk between granulosa cells and Type II oocytes was active, and these observations revealed that Type II was more poised for maturation. We further confirmed Insulin Receptor Substrate-1 in insulin signaling pathway is a key regulator on maturation by in vitro maturation experiments. Our study provides new insights into the regulatory mechanisms between meiotic arrest and meiotic resumption in mammalian oocytes. We also provide a new analytical package for future single-cell methylomics study.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG."
-,37442235,Spontaneous histone exchange between nucleosomes.,J Biol Chem,"The nucleosome is the fundamental gene-packing unit in eukaryotes. Nucleosomes comprise �147 bp DNA wrapped around an octameric histone protein core composed of two H2A-H2B dimers and one (H3-H4)2tetramer. The strong yet flexible DNA-histone interactions are the physical basis of the dynamic regulation of genes packaged in chromatin. The dynamic nature of DNA-histone interactions also implies that nucleosomes dissociate DNA-histone contacts both transiently and repeatedly. This kinetic instability may lead to spontaneous nucleosome disassembly or histone exchange between nucleosomes. At high nucleosome concentrations, nucleosome-nucleosome collisions and subsequent histone exchange would be a more likely event, where nucleosomes could act as their own histone chaperone. This spontaneous histone exchange could serve as a mechanism for maintaining overall chromatin stability, although it has never been reported. Here we employed three-color single-molecule FRET (smFRET) to demonstrate that histone H2A-H2B dimers are exchanged spontaneously between nucleosomes on a time scale of a few tens of seconds at a physiological nucleosome concentration. We show that the rate of histone exchange increases at a higher monovalent salt concentration, with histone-acetylated nucleosomes, and in the presence of histone chaperone Nap1, while it remains unchanged at a higher temperature, and decreases upon DNA methylation. These results support the notion of histone exchange via transient and repetitive partial disassembly of the nucleosome and corroborate spontaneous histone diffusion in a compact chromatin context, modulating the local concentrations of histone modifications and variants.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved."
-,37649077,A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature.,Genome Biol,"The Fe (II)- and α-ketoglutarate-dependent AlkB family dioxygenases are implicated in nucleotide demethylation. AlkB homolog1 (ALKBH1) is shown to demethylate DNA adenine methylation (6mA) preferentially from single-stranded or unpaired DNA, while its demethylase activity and function in the chromatin context are unclear.Here, we find that loss-of-function of the rice ALKBH1 gene leads to increased 6mA in the R-loop regions of the genome but has a limited effect on the overall 6mA level. However, in the context of mixed tissues, rather than on individual loci, the ALKBH1 mutation or overexpression mainly affects the expression of genes with a specific combination of chromatin modifications in the body region marked with H3K4me3 and H3K27me3 but depleted of DNA CG methylation. In the similar context of mixed tissues, further analysis reveals that the ALKBH1 protein preferentially binds to genes marked by the chromatin signature and has a function to maintain a high H3K4me3/H3K27me3 ratio by impairing the binding of Polycomb repressive complex 2 (PRC2) to the targets, which is required for both the basal and stress-induced expression of the genes.Our findings unravel a function of ALKBH1 to control the balance between the antagonistic histone methylations for gene activity and provide insight into the regulatory mechanism of PRC2-mediated H3K27me3 deposition within the gene body region.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37644049,NA,NA,"Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells lacking the effects of the pathway, TEs become increasingly mobile during the adult lifespan, and their activity is associated with genomic instability. Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology. Here we show that in the nematode Caenorhabditis elegans, the downregulation of active TE families extends lifespan. Ectopic activation of Piwi proteins in the soma also promotes longevity. Furthermore, DNA N6-adenine methylation at TE stretches gradually rises with age, and this epigenetic modification elevates their transcription as the animal ages. These results indicate that TEs represent a novel genetic determinant of ageing, and that N6-adenine methylation plays a pivotal role in ageing control.© 2023. Springer Nature Limited."
-,37554202,Functions and mechanisms of protein lysine butyrylation (Kbu): Therapeutic implications in human diseases.,Genes Dis,"Post-translational modifications (PTM) are covalent modifications of proteins or peptides caused by proteolytic cleavage or the attachment of moieties to one or more amino acids. PTMs play essential roles in biological function and regulation and have been linked with several diseases. Modifications of protein acylation (Kac), a type of PTM, are known to induce epigenetic regulatory processes that promote various diseases. Thus, an increasing number of studies focusing on acylation modifications are being undertaken. Butyrylation (Kbu) is a new acylation process found in animals and plants. Kbu has been recently linked to the onset and progression of several diseases, such as cancer, cardiovascular diseases, diabetes, and vascular dementia. Moreover, the mode of action of certain drugs used in the treatment of lymphoma and colon cancer is based on the regulation of butyrylation levels, suggesting that butyrylation may play a therapeutic role in these diseases. In addition, butyrylation is also commonly involved in rice gene expression and thus plays an important role in the growth, development, and metabolism of rice. The tools and analytical methods that could be utilized for the prediction and detection of lysine butyrylation have also been investigated. This study reviews the potential role of histone Kbu, as well as the mechanisms underlying this process. It also summarizes various enzymes and analytical methods associated with Kbu, with the goal of providing new insights into the role of Kbu in gene regulation and diseases.© 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd."
-,37670250,Impact of media compositions and culture systems on the immunophenotypes of patient-derived breast cancer cells.,BMC Cancer,"Heterogeneous tumor cells are thought to be a significant factor in the failure of endocrine therapy in estrogen receptor-positive (ER+) cancers. Culturing patient-derived breast cancer cells (PDBCCs) provides an invaluable tool in pre-clinical and translational research for the heterogeneity of cancer cells. This study aimed to investigate the effects of different media components and culture methods on the BCSC-associated immunophenotypes and gene expression in ER + PDBCCs.Ten patients with ER + breast cancer were employed in this study, six of whom had neoadjuvant chemotherapy and four of whom did not. PDBCCs were isolated by enzymatic methods using collagen I and hyaluronidase. PDBCCs were grown as monolayers in mediums with different compositions and as multicellular spheroid in a suspended condition. Collagen I-coated plate and ultralow attachment plate coated with polymer-X were used for monolayer and spheroid culture. Flow cytometry, immunofluorescent staining, RT-PCR, and RNA-sequencing were employed to examine the immunophenotype and genetic profile of PDBCCs.More than 95% of PDBCCs sustain EpCAM high/+/fibroblast marker- phenotypes in monolayer conditions by subculturing 3-4 times. A83-01 removal induced senescent cells with high β-galactosidase activity. PDBCCs grown as monolayers were characterized by the majority of cells having an EpCAM+/CD49f + phenotype. Compared to full media in monolayer culture, EGF removal increased EpCAM+/CD49f - phenotype (13.8-fold, p = 0.028), whereas R-spondin removal reduced it (0.8-fold, p = 0.02). A83-01 removal increased EpCAM+/CD24 + phenotype (1.82-fold, p = 0.023) and decreased EpCAM low/-/CD44+/CD24- phenotype (0.45-fold, p = 0.026). Compared to monolayer, spheroid resulted in a significant increase in the population with EpCAM-/CD49+ (14.6-fold, p = 0.006) and EpCAM low/-/CD44+/CD24- phenotypes (4.16-fold, p = 0.022) and ALDH high activity (9.66-fold, p = 0.037). ALDH1A and EMT-related genes were upregulated. In RNA-sequencing analysis between spheroids and monolayers, a total of 561 differentially expressed genes (2-fold change, p < 0.05) were enriched in 27 KEGG pathways including signaling pathways regulating pluripotency of stem cells. In a recurrence-free survival analysis based on the Kaplan-Meier Plotter database of the up-and down-regulated genes identified in spheroids, 15 up-, and 14 down-regulated genes were associated with poor prognosis of breast cancer patients.The media composition and spheroid culture method change in the BCSCs and EMT markers of PDBCCs, implying the importance of defining the media composition and culture method for studying PDBCCs in vitro.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37551117,An Externally Validated Nomogram for Predicting the Overall Survival of Patients With Diffuse Large B-Cell Lymphoma Based on Clinical Characteristics and Systemic Inflammatory Markers.,Technol Cancer Res Treat,"Background:Systemic inflammatory indicators are clinically significant in guiding diffuse large B-cell lymphoma (DLBCL) prognosis. However, which inflammatory markers are the best predictors of DLBCL prognosis is still unclear. In this study, we aimed to create a nomogram based on the best inflammatory markers and clinical indicators to predict the overall survival of patients with DLBCL.Patients and methods:We analyzed data from 423 DLBCL patients from two institutions and divided them into a training set, an internal validation set, and an external validation set (n = 228, 97, and 98, respectively). The least absolute shrinkage and selection operator and Cox regression analysis were used to develop nomograms. We assessed model fit using the Akaike information criterion and Bayesian information criterion. The concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to assess the nomogram's predictive performance and clinical net benefit and compared with the International Prognostic Index (IPI) and National Comprehensive Cancer Network (NCCN)-IPI.Results:The inclusion variables for the nomogram model were age, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase level, the systemic immune-inflammation index (SII), the prognostic nutritional index (PNI), and β-2 microglobulin (β-2 MG) level. In the training cohort, the nomogram showed better goodness of fit than the IPI and NCCN-IPI. The C-index of the nomogram (0.804, 95% CI: 0.751-0.857) outperformed the IPI (0.690, 95% CI: 0.629-0.751) and NCCN-IPI (0.691, 95% CI: 0.632-0.750). The calibration curve, ROC curve, and DCA curve analysis showed that the nomogram has satisfactory predictive power and clinical utility. Similar results were found in the validation cohort.Conclusion:The nomogram integrated with the clinical characteristics and inflammatory markers is beneficial to predict the prognosis of patients with DLBCL."
-,37587380,Epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose.,Neuropsychopharmacology,NA
-,37559446,NA,NA,"Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.© 2023 The Author(s)."
-,37490719,Identifying the oncogenic roles of FAP in human cancers based on systematic analysis.,Aging (Albany NY),"Fibroblast activation protein-α (FAP) is a specific marker of cancer-associated fibroblasts (CAFs) and plays a crucial role in tumor development. However, the biological processes underlying FAP expression in tumor progression and tumor immunity have not been fully elucidated.We utilized RNA-seq data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to perform differential analysis of FAP expression in tumor tissues and matched-normal tissues. The relationship between FAP expression and clinical prognosis, DNA methylation, and tumor-infiltrating immune cells in pan-cancer was assessed using R Studio (version 4.2.1). Additionally, we employed gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) to investigate the biological functions and pathways associated with FAP expression.FAP exhibits high expression in most malignancies, albeit to a lesser extent in CESC, KICH, UCEC, SKCM, THCA, and UCS. Furthermore, FAP is either positively or negatively associated with the prognosis of several malignancies. In seven types of cancer, FAP expression is positively correlated with DNA methylation. CIBERSORT analysis revealed an inverse correlation between FAP expression and T cells, B cells, monocytes, and NK cells, while it exhibited a positive correlation with M0, M1, and M2 macrophages. Enrichment analysis further demonstrated that FAP modulates the cell cycle, epithelial-mesenchymal transition (EMT) process, angiogenesis, and immune-related functions and pathways.Our findings indicate a close relationship between FAP expression and tumorigenesis as well as tumor immunity. FAP has the potential to serve as a diagnostic, prognostic, and immunotherapy marker."
-,37564640,NA,NA,"C-reactive protein (CRP) is well-recognized as a sensitive biomarker of inflammation. Association of elevations in plasma/serum CRP level with disease state has received considerable attention, even though CRP is not a specific indicator of a single disease state. Circulating CRP levels have been monitored with a varying degree of success to gauge disease severity or to predict disease progression and outcome. Elevations in CRP level have been implicated as a useful marker to identify patients at risk for cardiovascular disease and certain cancers, and to guide therapy in a context-dependent manner. Since even strong associations do not establish causality, the pathogenic role of CRP has often been over-interpreted. CRP functions as an important modulator of host defense against bacterial infection, tissue injury and autoimmunity. CRP exists in conformationally distinct forms, which exhibit distinct functional properties and help explaining the diverse, often contradictory effects attributed to CRP. In particular, dissociation of native pentameric CRP into its subunits, monomeric CRP, unmasks ""hidden"" pro-inflammatory activities in pentameric CRP. Here, we review recent advances in CRP targeting strategies, therapeutic lowering of circulating CRP level and development of CRP antagonists, and a conformation change inhibitor in particular. We will also discuss their therapeutic potential in mitigating the deleterious actions attributed to CRP under various pathologies, including cardiovascular, pulmonary and autoimmune diseases and cancer.Copyright © 2023 Rizo-Téllez, Sekheri and Filep."
-,37589983,Nonhuman Primate Eyes Display Variable Growth and Aging Rates in Alignment With Human Eyes.,Invest Ophthalmol Vis Sci,"To assess age-related biometric changes of the eye in nonhuman primates (NHPs), to and decipher the growth and aging rates and their comparability with humans.Ocular anatomic measurements were performed on 341 macaca fascicularis aged 0.5 to 23 years via multimodal approaches including IOLMaster 700. Linear or polynomial regression models were simulated to determine the best fitted age-related function. The metrics were compared with human equivalents in published reports.Macaques exhibited a postnatal eye growth pattern similar to humans, characterized by continuous eye extension coordinated with dramatic reshaping of the lens but not the cornea. The age-related growth of lens thickness (LT), anterior chamber depth (ACD), and axis length (AL) exhibited nonlinear and bipolar patterns. The inflection points were 10 to 12 years old for LT and ACD and 13 to 15 years old for AL in macaques, which were comparable in chronological age at a ratio of �1: ratio with that in humans. In contrast, the speed of aging, including the increase in lens density and the decrease in retinal nerve fiber layer thickness, was comparable in relative age at a ratio of �1:3 according to the differences in lifespan between macaques and humans. Lens density was a robust indicator for the aging process.Macaque eyes recapitulated the age-related process of human eyes to varying extents with different growth and aging rates. Chronological age or relative age should be considered in different scenarios when macaques are included in preclinical studies."
-,37575883,Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma.,JHEP Rep,"Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells. In addition, we highlight the role of enzymes in dysregulated metabolic activity and consequent dysfunctional signalling. Finally, we discuss the potential uses and challenges of novel therapeutic strategies to prevent and treat NAFLD/T2D-associated HCC.© 2023 The Author(s)."
-,37609320,Single-cell somatic copy number variants in brain using different amplification methods and reference genomes.,bioRxiv,"The presence of somatic mutations, including copy number variants (CNVs), in the brain is well recognized. Comprehensive study requires single-cell whole genome amplification, with several methods available, prior to sequencing. We compared PicoPLEX with two recent adaptations of multiple displacement amplification (MDA): primary template-directed amplification (PTA) and droplet MDA, across 93 human brain cortical nuclei. We demonstrated different properties for each, with PTA providing the broadest amplification, PicoPLEX the most even, and distinct chimeric profiles. Furthermore, we performed CNV calling on two brains with multiple system atrophy and one control brain using different reference genomes. We found that 38% of brain cells have at least one Mb-scale CNV, with some supported by bulk sequencing or single-cells from other brain regions. Our study highlights the importance of selecting whole genome amplification method and reference genome for CNV calling, while supporting the existence of somatic CNVs in healthy and diseased human brain."
-,37584660,scNCL: transferring labels from scRNA-seq to scATAC-seq data with neighborhood contrastive regularization.,Bioinformatics,"scATAC-seq has enabled chromatin accessibility landscape profiling at the single-cell level, providing opportunities for determining cell-type-specific regulation codes. However, high dimension, extreme sparsity, and large scale of scATAC-seq data have posed great challenges to cell-type identification. Thus, there has been a growing interest in leveraging the well-annotated scRNA-seq data to help annotate scATAC-seq data. However, substantial computational obstacles remain to transfer information from scRNA-seq to scATAC-seq, especially for their heterogeneous features.We propose a new transfer learning method, scNCL, which utilizes prior knowledge and contrastive learning to tackle the problem of heterogeneous features. Briefly, scNCL transforms scATAC-seq features into gene activity matrix based on prior knowledge. Since feature transformation can cause information loss, scNCL introduces neighborhood contrastive learning to preserve the neighborhood structure of scATAC-seq cells in raw feature space. To learn transferable latent features, scNCL uses a feature projection loss and an alignment loss to harmonize embeddings between scRNA-seq and scATAC-seq. Experiments on various datasets demonstrated that scNCL not only realizes accurate and robust label transfer for common types, but also achieves reliable detection of novel types. scNCL is also computationally efficient and scalable to million-scale datasets. Moreover, we prove scNCL can help refine cell-type annotations in existing scATAC-seq atlases.The source code and data used in this paper can be found in https://github.com/CSUBioGroup/scNCL-release.© The Author(s) 2023. Published by Oxford University Press."
-,37598284,Redefining precision radiotherapy through liquid biopsy.,Br J Cancer,"Precision radiotherapy refers to the ability to deliver radiation doses with sub-millimetre accuracy. It does not however consider individual variation in tumour or normal tissue response, failing to maximise tumour control and minimise toxicity. Combining precise delivery with personalised dosing, through analysis of cell-free DNA, would redefine precision in radiotherapy.© 2023. The Author(s)."
-,37662552,Linking brain activity across scales with simultaneous opto- and electrophysiology.,Neurophotonics,"The brain enables adaptive behavior via the dynamic coordination of diverse neuronal signals across spatial and temporal scales: from fast action potential patterns in microcircuits to slower patterns of distributed activity in brain-wide networks. Understanding principles of multiscale dynamics requires simultaneous monitoring of signals in multiple, distributed network nodes. Combining optical and electrical recordings of brain activity is promising for collecting data across multiple scales and can reveal aspects of coordinated dynamics invisible to standard, single-modality approaches. We review recent progress in combining opto- and electrophysiology, focusing on mouse studies that shed new light on the function of single neurons by embedding their activity in the context of brain-wide activity patterns. Optical and electrical readouts can be tailored to desired scales to tackle specific questions. For example, fast dynamics in single cells or local populations recorded with multi-electrode arrays can be related to simultaneously acquired optical signals that report activity in specified subpopulations of neurons, in non-neuronal cells, or in neuromodulatory pathways. Conversely, two-photon imaging can be used to densely monitor activity in local circuits while sampling electrical activity in distant brain areas at the same time. The refinement of combined approaches will continue to reveal previously inaccessible and under-appreciated aspects of coordinated brain activity.© 2023 The Authors."
-,37645732,Voyager: exploratory single-cell genomics data analysis with geospatial statistics.,bioRxiv,"Exploratory spatial data analysis (ESDA) can be a powerful approach to understanding single-cell genomics datasets, but it is not yet part of standard data analysis workflows. In particular, geospatial analyses, which have been developed and refined for decades, have yet to be fully adapted and applied to spatial single-cell analysis. We introduce the Voyager platform, which systematically brings the geospatial ESDA tradition to (spatial) -omics, with local, bivariate, and multivariate spatial methods not yet commonly applied to spatial -omics, united by a uniform user interface. Using Voyager, we showcase biological insights that can be derived with its methods, such as biologically relevant negative spatial autocorrelation. Underlying Voyager is the SpatialFeatureExperiment data structure, which combines Simple Feature with SingleCellExperiment and AnnData to represent and operate on geometries bundled with gene expression data. Voyager has comprehensive tutorials demonstrating ESDA built on GitHub Actions to ensure reproducibility and scalability, using data from popular commercial technologies. Voyager is implemented in both R/Bioconductor and Python/PyPI, and features compatibility tests to ensure that both implementations return consistent results."
-,37640721,"Deep self-learning enables fast, high-fidelity isotropic resolution restoration for volumetric fluorescence microscopy.",Light Sci Appl,"One intrinsic yet critical issue that troubles the field of fluorescence microscopy ever since its introduction is the unmatched resolution in the lateral and axial directions (i.e., resolution anisotropy), which severely deteriorates the quality, reconstruction, and analysis of 3D volume images. By leveraging the natural anisotropy, we present a deep self-learning method termed Self-Net that significantly improves the resolution of axial images by using the lateral images from the same raw dataset as rational targets. By incorporating unsupervised learning for realistic anisotropic degradation and supervised learning for high-fidelity isotropic recovery, our method can effectively suppress the hallucination with substantially enhanced image quality compared to previously reported methods. In the experiments, we show that Self-Net can reconstruct high-fidelity isotropic 3D images from organelle to tissue levels via raw images from various microscopy platforms, e.g., wide-field, laser-scanning, or super-resolution microscopy. For the first time, Self-Net enables isotropic whole-brain imaging at a voxel resolution of 0.2 × 0.2 × 0.2 μm3, which addresses the last-mile problem of data quality in single-neuron morphology visualization and reconstruction with minimal effort and cost. Overall, Self-Net is a promising approach to overcoming the inherent resolution anisotropy for all classes of 3D fluorescence microscopy.© 2023. Changchun Institute of Optics, Fine Mechanics and Physics (CIOMP), CAS."
-,37612141,NA,NA,"The brain is a complex system comprising a myriad of interacting neurons, posing significant challenges in understanding its structure, function, and dynamics. Network science has emerged as a powerful tool for studying such interconnected systems, offering a framework for integrating multiscale data and complexity. To date, network methods have significantly advanced functional imaging studies of the human brain and have facilitated the development of control theory-based applications for directing brain activity. Here, we discuss emerging frontiers for network neuroscience in the brain atlas era, addressing the challenges and opportunities in integrating multiple data streams for understanding the neural transitions from development to healthy function to disease. We underscore the importance of fostering interdisciplinary opportunities through workshops, conferences, and funding initiatives, such as supporting students and postdoctoral fellows with interests in both disciplines. By bringing together the network science and neuroscience communities, we can develop novel network-based methods tailored to neural circuits, paving the way toward a deeper understanding of the brain and its functions, as well as offering new challenges for network science.Copyright © 2023 the authors."
-,37631874,"Next-Generation TB Vaccines: Progress, Challenges, and Prospects.",Vaccines (Basel),"Tuberculosis (TB), caused byMycobacterium tuberculosis(MTB), is a prevalent global infectious disease and a leading cause of mortality worldwide. Currently, the only available vaccine for TB prevention is Bacillus Calmette-Guérin (BCG). However, BCG demonstrates limited efficacy, particularly in adults. Efforts to develop effective TB vaccines have been ongoing for nearly a century. In this review, we have examined the current obstacles in TB vaccine research and emphasized the significance of understanding the interaction mechanism between MTB and hosts in order to provide new avenues for research and establish a solid foundation for the development of novel vaccines. We have also assessed various TB vaccine candidates, including inactivated vaccines, attenuated live vaccines, subunit vaccines, viral vector vaccines, DNA vaccines, and the emerging mRNA vaccines as well as virus-like particle (VLP)-based vaccines, which are currently in preclinical stages or clinical trials. Furthermore, we have discussed the challenges and opportunities associated with developing different types of TB vaccines and outlined future directions for TB vaccine research, aiming to expedite the development of effective vaccines. This comprehensive review offers a summary of the progress made in the field of novel TB vaccines."
-,37664036,New insights into molecular signaling pathways and current advancements in prostate cancer diagnostics & therapeutics.,Front Oncol,"Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer.Copyright © 2023 Thakur, Quazi, Naik, Jha and Singh."
-,37601269,Prognostic and clinicopathological role of RACK1 for cancer patients: a systematic review and meta-analysis.,PeerJ,"The receptor for activated C kinase 1 (RACK1) expression is associated with clinicopathological characteristics and the prognosis of various cancers; however, the conclusions are controversial. As a result, this study aimed to explore the clinicopathological and prognostic values of RACK1 expression in patients with cancer.PubMed, Embase, Web of Science, Cochrane Library, and Scopus were comprehensively explored from their inception to April 20, 2023, for selecting studies on the clinicopathological and prognostic role of RACK1 in patients with cancer that met the criteria for inclusion in this review. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to assess the prognosis-predictive value of RACK1 expression, while pooled odds ratios (ORs) and 95% CIs were used to evaluate the correlation between RACK1 expression and the clinicopathological characteristics of patients with cancer. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale.Twenty-two studies (13 on prognosis and 20 on clinicopathological characteristics) were included in this systematic review and meta-analysis. The findings indicated that high RACK1 expression was significantly associated with poor overall survival (HR = 1.62; 95% CI, 1.13-2.33;P = 0.009; I2= 89%) and reversely correlated with disease-free survival/recurrence-free survival (HR = 1.87; 95% CI, 1.22-2.88;P = 0.004; I2= 0%). Furthermore, increased RACK1 expression was significantly associated with lymphatic invasion/N+ stage (OR = 1.74; 95% CI, 1.04-2.90;P = 0.04; I2= 79%) of tumors.RACK1 may be a global predictive marker of poor prognosis in patients with cancer and unfavorable clinicopathological characteristics. However, further clinical studies are required to validate these findings.©2023 Wang et al."
-,37641116,Recent advances in targeted strategies for triple-negative breast cancer.,J Hematol Oncol,"Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, negatively expresses estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2 (HER2). Although chemotherapy is the main form of treatment for patients with TNBC, the effectiveness of chemotherapy for TNBC is still limited. The search for more effective therapies is urgent. Multiple targeted therapeutic strategies have emerged according to the specific molecules and signaling pathways expressed in TNBC. These include PI3K/AKT/mTOR inhibitors, epidermal growth factor receptor inhibitors, Notch inhibitors, poly ADP-ribose polymerase inhibitors, and antibody-drug conjugates. Moreover, immune checkpoint inhibitors, for example, pembrolizumab, atezolizumab, and durvalumab, are widely explored in the clinic. We summarize recent advances in targeted therapy and immunotherapy in TNBC, with the aim of serving as a reference for the development of individualized treatment of patients with TNBC in the future.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37628978,"Prostate Cancer: Genetics, Epigenetics and the Need for Immunological Biomarkers.",Int J Mol Sci,"Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocyte-derived and TAM-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer."
-,37568652,Cancer Bioenergetics and Tumor Microenvironments-Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems.,Cancers (Basel),"Cancer is an impending bottleneck in the advanced scientific workflow to achieve diagnostic, prognostic, and therapeutic success. Most cancers are refractory to conventional diagnostic and chemotherapeutics due to their limited targetability, specificity, solubility, and side effects. The inherent ability of each cancer to evolve through various genetic and epigenetic transformations and metabolic reprogramming underlies therapeutic limitations. Though tumor microenvironments (TMEs) are quite well understood in some cancers, each microenvironment differs from the other in internal perturbations and metabolic skew thereby impeding the development of appropriate diagnostics, drugs, vaccines, and therapies. Cancer associated bioenergetics modulations regulate TME, angiogenesis, immune evasion, generation of resistant niches and tumor progression, and a thorough understanding is crucial to the development of metabolic therapies. However, this remains a missing element in cancer theranostics, necessitating the development of modalities that can be adapted for targetability, diagnostics and therapeutics. In this challenging scenario, nanomaterials are modular platforms for understanding TME and achieving successful theranostics. Several nanoscale particles have been successfully researched in animal models, quite a few have reached clinical trials, and some have achieved clinical success. Nanoparticles exhibit an intrinsic capability to interact with diverse biomolecules and modulate their functions. Furthermore, nanoparticles can be functionalized with receptors, modulators, and drugs to facilitate specific targeting with reduced toxicity. This review discusses the current understanding of different theranostic nanosystems, their synthesis, functionalization, and targetability for therapeutic modulation of bioenergetics, and metabolic reprogramming of the cancer microenvironment. We highlight the potential of nanosystems for enhanced chemotherapeutic success emphasizing the questions that remain unanswered."
-,37568620,The Current Landscape of Glioblastoma Biomarkers in Body Fluids.,Cancers (Basel),"Glioblastoma (GBM) is a highly aggressive and lethal primary brain cancer that necessitates early detection and accurate diagnosis for effective treatment and improved patient outcomes. Traditional diagnostic methods, such as imaging techniques and tissue biopsies, have limitations in providing real-time information and distinguishing treatment-related changes from tumor progression. Liquid biopsies, used to analyze biomarkers in body fluids, offer a non-invasive and dynamic approach to detecting and monitoring GBM. This article provides an overview of GBM biomarkers in body fluids, including circulating tumor cells (CTCs), cell-free DNA (cfDNA), cell-free RNA (cfRNA), microRNA (miRNA), and extracellular vesicles. It explores the clinical utility of these biomarkers for GBM detection, monitoring, and prognosis. Challenges and limitations in implementing liquid biopsy strategies in clinical practice are also discussed. The article highlights the potential of liquid biopsies as valuable tools for personalized GBM management but underscores the need for standardized protocols and further research to optimize their clinical utility."
-,37670254,Causal associations between thyroid cancer and IgA nephropathy: a Mendelian randomization study.,BMC Genomics,"The incidence of kidney disease caused by thyroid cancer is rising worldwide. Observational studies cannot recognize whether thyroid cancer is independently associated with kidney disease. We performed the Mendelian randomization (MR) approach to genetically investigate the causality of thyroid cancer on immunoglobulin A nephropathy (IgAN).We explored the causal effect of thyroid cancer on IgAN by MR analysis. Fifty-two genetic loci and single nucleotide polymorphisms were related to thyroid cancer. The primary approach in this MR analysis was the inverse variance weighted (IVW) method, and MR‒Egger was the secondary method. Weighted mode and penalized weighted median were used to analyze the sensitivity. In this study, the random-effect IVW models showed the causal impact of genetically predicted thyroid cancer across the IgAN risk (OR, 1.191; 95% CI, 1.131-1.253, P < 0.001). Similar results were also obtained in the weighted mode method (OR, 1.048; 95% CI, 0.980-1.120, P = 0.179) and penalized weighted median (OR, 1.185; 95% CI, 1.110-1.264, P < 0.001). However, the MR‒Egger method revealed that thyroid cancer decreased the risk of IgAN, but this difference was not significant (OR, 0.948; 95% CI, 0.855-1.051, P = 0.316). The leave-one-out sensitivity analysis did not reveal the driving influence of any individual SNP on the association between thyroid cancer and IgAN.The IVW model indicated a significant causality of thyroid cancer with IgAN. However, MR‒Egger had a point estimation in the opposite direction. According to the MR principle, the evidence of this study did not support a stable significant causal association between thyroid cancer and IgAN. The results still need to be confirmed by future studies.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37662924,Systematic Mendelian randomization study of the effect of gut microbiome and plasma metabolome on severe COVID-19.,Front Immunol,"COVID-19 could develop severe respiratory symptoms in certain infected patients, especially in the patients with immune disorders. Gut microbiome and plasma metabolome act important immunological modulators in the human body and could contribute to the immune responses impacting the progression of COVID-19. However, the causal relationship between specific intestinal bacteria, metabolites and severe COVID-19 remains not clear.Based on two-sample Mendelian randomization (MR) framework, the causal effects of 131 intestinal taxa and 452 plasma metabolites on severe COVID-19 were evaluated. Single nucleotide polymorphisms (SNPs) strongly associated with the abundance of intestinal taxa and the concentration of plasma metabolites had been utilized as the instrument variables to infer whether they were causal factors of severe COVID-19. In addition, mediation analysis was conducted to find the potential association between the taxon and metabolite, and further colocalization analysis had been performed to validate the causal relationships.MR analysis identified 13 taxa and 53 metabolites, which were significantly associated with severe COVID-19 as causal factors. Mediation analysis revealed 11 mediated relationships. Myo-inositol, 2-stearoylglycerophosphocholine, and alpha-glutamyltyrosine, potentially contributed to the association ofHowardellaandRuminiclostridium 6with severe COVID-19, respectively.ButyrivibrioandRuminococcus gnavuscould mediate the association of myo-inositol and N-acetylalanine, respectively. In addition,Ruminococcus torquesabundance was colocalized with severe COVID-19 (PP.H4 = 0.77) and the colon expression of permeability related protein RASIP1 (PP.H4 = 0.95).Our study highlights the potential causal relationships between gut microbiome, plasma metabolome and severe COVID-19, which potentially serve as clinical biomarkers for risk stratification and prognostication and benefit the mechanism mechanistic investigation of severe COVID-19.Copyright © 2023 Yan, Zhao, Huang, Xie, Cai, Qu, Zhang, Luo, Zhang and Li."
-,37666988,NA,NA,"Modified parental histones are segregated symmetrically to daughter DNA strands during replication and can be inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here we show that transmission of histone-based information during DNA replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused derepression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Furthermore, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian cell differentiation.© 2023. The Author(s)."
-,37621747,NA,NA,"Bone resorption occurs after bone grafting, however, contemporaneous reconstruction of the innervation of the bone graft is a potential treatment to maintain the bone mass of the graft. The innervation of bone is an emerging research topic. To understand the potential molecular mechanisms of bone innervation after bone grafting, we collected normal iliac bone tissue as well as bone grafts with or without innervation from nine patients 1 year after surgery and performed RNA sequencing. We identified differentially expressed genes) from these samples and used the gene ontology and Kyoto Encyclopedia of Genes and Genomes databases for functional enrichment and signaling pathway analysis. In parallel, we established protein-protein interaction networks to screen functional modules. Based on bioinformatic results, we validatedin vitrothe osteogenic differentiation potential of rat bone marrow mesenchymal stem cells (BMMSCs) after calcitonin gene-related peptide (CGRP) stimulation and the expression of p38 MAPK and Wnt6/β-catenin pathways during osteogenesis. Our transcriptome analysis of bone grafts reveals functional modules and signaling pathways of innervation which play a vital role in the structural and functional integration of the bone graft. Simultaneously, we demonstrate that CGRP regulates the differentiation of BMMSCs through p38 MAPK and Wnt6/β-catenin.Copyright © 2023 Ziqian Wu et al."
-,37627009,Profound Non-Randomness in Dinucleotide Arrangements within Ultra-Conserved Non-Coding Elements and the Human Genome.,Biology (Basel),"Long human ultra-conserved non-coding elements (UCNEs) do not have any sequence similarity to each other or other characteristics that make them unalterable during vertebrate evolution. We hypothesized that UCNEs have unique dinucleotide (DN) composition and arrangements compared to the rest of the genome. A total of 4272 human UCNE sequences were analyzed computationally and compared with the whole genomes of human, chicken, zebrafish, and fly. Statistical analysis was performed to assess the non-randomness in DN spacing arrangements within the entire human genome and within UCNEs. Significant non-randomness in DN spacing arrangements was observed in the entire human genome. Additionally, UCNEs exhibited distinct patterns in DN arrangements compared to the rest of the genome. Approximately 83% of all DN pairs within UCNEs showed significant (>10%) non-random genomic arrangements at short distances (2-6 nucleotides) relative to each other. At the extremes, non-randomness in DN spacing distances deviated up to 40% from expected values and were frequently associated with GpC, CpG, ApT, and GpG/CpC dinucleotides. The described peculiarities in DN arrangements have persisted for hundreds of millions of years in vertebrates. These distinctive patterns may suggest that UCNEs have specific DNA conformations."
-,37654626,Whole-genome CpG-resolution DNA Methylation Profiling of HNSCC Reveals Distinct Mechanisms of Carcinogenesis for Fine-scale HPV+ Cancer Subtypes.,Cancer Res Commun,"DNA methylation is a vital early step in carcinogenesis. Most findings of aberrant DNA methylation in head and neck squamous cell carcinomas (HNSCC) are array based with limited coverage and resolution, and mainly explored by human papillomavirus (HPV) status, ignoring the high heterogeneity of this disease. In this study, we performed whole-genome bisulfite sequencing on a well-studied HNSCC cohort (n= 36) and investigated the methylation changes between fine-scaled HNSCC subtypes in relation to genomic instability, repetitive elements, gene expression, and key carcinogenic pathways. The previously observed hypermethylation phenotype in HPV-positive (HPV+) tumors compared with HPV-negative tumors was robustly present in the immune-strong (IMU) HPV+ subtype but absent in the highly keratinized (KRT) HPV+ subtype. Methylation levels of IMU tumors were significantly higher in repetitive elements, and methylation showed a significant correlation with genomic stability, consistent with the IMU subtype having more genomic stability and better prognosis. Expression quantitative trait methylation (cis-eQTM) analysis revealed extensive functionally-relevant differences, and differential methylation pathway analysis recapitulated gene expression pathway differences between subtypes. Consistent with their characteristics, KRT and HPV-negative tumors had high regulatory potential for multiple regulators of keratinocyte differentiation, which positively correlated with an expression-based keratinization score. Together, our findings revealed distinct mechanisms of carcinogenesis between subtypes in HPV+ HNSCC and uncovered previously ignored epigenomic differences and clinical implications, illustrating the importance of fine-scale subtype analysis in cancer.This study revealed that the previously observed hypermethylation of HPV(+) HNSCC is due solely to the IMU subtype, illustrating the importance of fine-scale subtype analysis in such a heterogeneous disease. Particularly, IMU has significantly higher methylation of transposable elements, which can be tested as a prognosis biomarker in future translational studies.© 2023 The Authors; Published by the American Association for Cancer Research."
-,37568867,NA,NA,"Methylation sequencing is a promising approach to infer the tissue of origin of cell-free DNA (cfDNA). In this study, a single- and a double-stranded library preparation approach were evaluated with respect to their technical biases when applied on cfDNA from plasma and urine. Additionally, tissue of origin (TOO) proportions were evaluated using two deconvolution methods. Sequencing cfDNA from urine using the double-stranded method resulted in a substantial within-read methylation bias and a lower global methylation (56.0% vs. 75.8%,p≤ 0.0001) compared to plasma cfDNA, both of which were not observed with the single-stranded approach. Individual CpG site-based TOO deconvolution resulted in a significantly increased proportion of undetermined TOO with the double-stranded method (urine: 32.3% vs. 1.9%; plasma: 5.9% vs. 0.04%;p≤ 0.0001), but no major differences in proportions of individual cell types. In contrast, fragment-level deconvolution led to multiple cell types, with significantly different TOO proportions between the two methods. This study thus outlines potential limitations of double-stranded library preparation for methylation analysis of cfDNA especially for urinary cfDNA. While the double-stranded method allows jagged end analysis in addition to TOO analysis, it leads to significant methylation bias in urinary cfDNA, which single-stranded methods can overcome."
-,37569861,Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.,Int J Mol Sci,"The progressive deterioration of function and structure of brain cells in neurodegenerative diseases is accompanied by mitochondrial dysfunction, affecting cellular metabolism, intracellular signaling, cell differentiation, morphogenesis, and the activation of programmed cell death. However, most of the efforts to develop therapies for Alzheimer's and Parkinson's disease have focused on restoring or maintaining the neurotransmitters in affected neurons, removing abnormal protein aggregates through immunotherapies, or simply treating symptomatology. However, none of these approaches to treating neurodegeneration can stop or reverse the disease other than by helping to maintain mental function and manage behavioral symptoms. Here, we discuss alternative molecular targets for neurodegeneration treatments that focus on mitochondrial functions, including regulation of calcium ion (Ca2+) transport, protein modification, regulation of glucose metabolism, antioxidants, metal chelators, vitamin supplementation, and mitochondrial transference to compromised neurons. After pre-clinical evaluation and studies in animal models, some of these therapeutic compounds have advanced to clinical trials and are expected to have positive outcomes in subjects with neurodegeneration. These mitochondria-targeted therapeutic agents are an alternative to established or conventional molecular targets that have shown limited effectiveness in treating neurodegenerative diseases."
-,37624788,Univariable and multivariable mendelian randomization study revealed the modifiable risk factors of urolithiasis.,PLoS One,"Urolithiasis is a common urological disease with increasing incidence worldwide, and preventing its risk poses significant challenges. Here, we used Mendelian randomization (MR) framework to genetically assess the causal nature of multifaceted risk factors on urolithiasis.17 potential risk factors associated with urolithiasis were collected from recently published observational studies, which can be categorized basically into lifestyle factors and circulating biomarkers. The instrumental variables of risk factors were selected from large-scale genome-wide association studies (N ≤ 607,291). Summary-level data on urolithiasis were obtained from UK Biobank (UKB) (3,625 cases and 459,308 noncases) and the FinnGen consortium (5,347 cases and 213,445 noncases). The univariable and multivariable MR analyses were applied to evaluate the causal, independent effect of these potential risk factors upon urolithiasis. Effects from the two consortia were combined by the meta-analysis methods.Higher genetically predicted sex hormone-binding globulin (SHBG, OR, 0.708; 95% CI, 0.555 to 0.903), estradiol (OR, 0.179; 95% CI, 0.042 to 0.751), tea intake (OR, 0.550; 95% CI, 0.345 to 0.878), alcoholic drinks per week (OR, 0.992; 95% CI, 0.987 to 0.997), and some physical activity (e.g., swimming, cycling, keeping fit, and bowling, OR, 0.054; 95% CI, 0.008 to 0.363) were significantly associated with a lower risk of urolithiasis. In the Multivariate Mendelian Randomization (MVMR) analyses, the significant causal associations between estradiol, SHBG, tea intake, and alcoholic drinks per week with urolithiasis were robust even after adjusting for potential confounding variables. However, the previously observed causal association between other exercises and urolithiasis was no longer significant after adjusting for these factors.The univariable and multivariable MR findings highlight the independent and significant roles of estradiol, SHBG, tea intake, and alcoholic drinks per week in the development of urolithiasis, which might provide a deeper insight into urolithiasis risk factors and supply potential preventative strategies.Copyright: © 2023 Fang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37419091,Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes.,Am J Hum Genet,"The existing framework of Mendelian randomization (MR) infers the causal effect of one or multiple exposures on one single outcome. It is not designed to jointly model multiple outcomes, as would be necessary to detect causes of more than one outcome and would be relevant to model multimorbidity or other related disease outcomes. Here, we introduce multi-response Mendelian randomization (MR2), an MR method specifically designed for multiple outcomes to identify exposures that cause more than one outcome or, conversely, exposures that exert their effect on distinct responses. MR2uses a sparse Bayesian Gaussian copula regression framework to detect causal effects while estimating the residual correlation between summary-level outcomes, i.e., the correlation that cannot be explained by the exposures, and vice versa. We show both theoretically and in a comprehensive simulation study how unmeasured shared pleiotropy induces residual correlation between outcomes irrespective of sample overlap. We also reveal how non-genetic factors that affect more than one outcome contribute to their correlation. We demonstrate that by accounting for residual correlation, MR2has higher power to detect shared exposures causing more than one outcome. It also provides more accurate causal effect estimates than existing methods that ignore the dependence between related responses. Finally, we illustrate how MR2detects shared and distinct causal exposures for five cardiovascular diseases in two applications considering cardiometabolic and lipidomic exposures and uncovers residual correlation between summary-level outcomes reflecting known relationships between cardiovascular diseases.Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved."
-,37627332,High-Throughput Antibody Profiling Identifies Targets of Protective Immunity against P. falciparum Malaria in Thailand.,Biomolecules,"Malaria poses a significant global health challenge, resulting in approximately 600,000 deaths each year. Individuals living in regions with endemic malaria have the potential to develop partial immunity, thanks in part to the presence of anti-plasmodium antibodies. As efforts are made to optimize and implement strategies to reduce malaria transmission and ultimately eliminate the disease, it is crucial to understand how these interventions impact naturally acquired protective immunity. To shed light on this, our study focused on assessing antibody responses to a carefully curated library ofP. falciparumrecombinant proteins (n = 691) using samples collected from individuals residing in a low-malaria-transmission region of Thailand. We conducted the antibody assays using the AlphaScreen system, a high-throughput homogeneous proximity-based bead assay that detects protein interactions. We observed that out of the 691 variable surface and merozoite stage proteins included in the library, antibodies to 268 antigens significantly correlated with the absence of symptomatic malaria in an univariate analysis. Notably, the most prominent antigens identified wereP. falciparumerythrocyte membrane protein 1 (PfEMP1) domains. These results align with our previous research conducted in Uganda, suggesting that similar antigens like PfEMP1s might play a pivotal role in determining infection outcomes in diverse populations. To further our understanding, it remains critical to conduct functional characterization of these identified proteins, exploring their potential as correlates of protection or as targets for vaccine development."
-,37451260,NA,NA,"Human gliogenesis remains poorly understood, and derivation of astrocytes from human pluripotent stem cells (hPSCs) is inefficient and cumbersome. Here, we report controlled glial differentiation from hPSCs that bypasses neurogenesis, which otherwise precedes astrogliogenesis during brain development and in vitro differentiation. hPSCs were first differentiated into radial glial cells (RGCs) resembling resident RGCs of the fetal telencephalon, and modulation of specific cell signaling pathways resulted in direct and stepwise induction of key astroglial markers (NFIA, NFIB, SOX9, CD44, S100B, glial fibrillary acidic protein [GFAP]). Transcriptomic and genome-wide epigenetic mapping and single-cell analysis confirmed RGC-to-astrocyte differentiation, obviating neurogenesis and the gliogenic switch. Detailed molecular and cellular characterization experiments uncovered new mechanisms and markers for human RGCs and astrocytes. In summary, establishment of a glia-exclusive neural lineage progression model serves as a unique serum-free platform of manufacturing large numbers of RGCs and astrocytes for neuroscience, disease modeling (e.g., Alexander disease), and regenerative medicine.Published by Elsevier Inc."
-,37644058,Barcoded multiple displacement amplification for high coverage sequencing in spatial genomics.,Nat Commun,"Determining mutational landscapes in a spatial context is essential for understanding genetically heterogeneous cell microniches. Current approaches, such as Multiple Displacement Amplification (MDA), offer high genome coverage but limited multiplexing, which hinders large-scale spatial genomic studies. Here, we introduce barcoded MDA (bMDA), a technique that achieves high-coverage genomic analysis of low-input DNA while enhancing the multiplexing capabilities. By incorporating cell barcodes during MDA, bMDA streamlines library preparation in one pot, thereby overcoming a key bottleneck in spatial genomics. We apply bMDA to the integrative spatial analysis of triple-negative breast cancer tissues by examining copy number alterations, single nucleotide variations, structural variations, and kataegis signatures for each spatial microniche. This enables the assessment of subclonal evolutionary relationships within a spatial context. Therefore, bMDA has emerged as a scalable technology with the potential to advance the field of spatial genomics significantly.© 2023. Springer Nature Limited."
-,37626852,Spatial Transcriptomic Technologies.,Cells,"Spatial transcriptomic technologies enable measurement of expression levels of genes systematically throughout tissue space, deepening our understanding of cellular organizations and interactions within tissues as well as illuminating biological insights in neuroscience, developmental biology and a range of diseases, including cancer. A variety of spatial technologies have been developed and/or commercialized, differing in spatial resolution, sensitivity, multiplexing capability, throughput and coverage. In this paper, we review key enabling spatial transcriptomic technologies and their applications as well as the perspective of the techniques and new emerging technologies that are developed to address current limitations of spatial methodologies. In addition, we describe how spatial transcriptomics data can be integrated with other omics modalities, complementing other methods in deciphering cellar interactions and phenotypes within tissues as well as providing novel insight into tissue organization."
-,37577665,SpaRx: Elucidate single-cell spatial heterogeneity of drug responses for personalized treatment.,bioRxiv,"Spatial cellular heterogeneity contributes to differential drug responses in a tumor lesion and potential therapeutic resistance. Recent emerging spatial technologies such as CosMx SMI, MERSCOPE, and Xenium delineate the spatial gene expression patterns at the single cell resolution. This provides unprecedented opportunities to identify spatially localized cellular resistance and to optimize the treatment for individual patients. In this work, we present a graph-based domain adaptation model, SpaRx, to reveal the heterogeneity of spatial cellular response to drugs. SpaRx transfers the knowledge from pharmacogenomics profiles to single-cell spatial transcriptomics data, through hybrid learning with dynamic adversarial adaption. Comprehensive benchmarking demonstrates the superior and robust performance of SpaRx at different dropout rates, noise levels, and transcriptomics coverage. Further application of SpaRx to the state-of-art single-cell spatial transcriptomics data reveals that tumor cells in different locations of a tumor lesion present heterogenous sensitivity or resistance to drugs. Moreover, resistant tumor cells interact with themselves or the surrounding constituents to form an ecosystem for drug resistance. Collectively, SpaRx characterizes the spatial therapeutic variability, unveils the molecular mechanisms underpinning drug resistance, and identifies personalized drug targets and effective drug combinations.We have developed a novel graph-based domain adaption model named SpaRx, to reveal the heterogeneity of spatial cellular response to different types of drugs, which bridges the gap between pharmacogenomics knowledgebase and single-cell spatial transcriptomics data.SpaRx is developed tailored for single-cell spatial transcriptomics data and is provided available as a ready-to-use open-source software, which demonstrates high accuracy and robust performance.SpaRx uncovers that tumor cells located in different areas within tumor lesion exhibit varying levels of sensitivity or resistance to drugs. Moreover, SpaRx reveals that tumor cells interact with themselves and the surrounding microenvironment to form an ecosystem capable of drug resistance."
-,37630804,Potential Epigenetic Effects of Human Milk on Infants' Neurodevelopment.,Nutrients,"The advantages of human milk feeding, especially in preterm babies, are well recognized. Infants' feeding with breast milk lowers the likelihood of developing a diverse range of non-communicable diseases later in life and it is also associated with improved neurodevelopmental outcomes. Although the precise mechanisms through which human milk feeding is linked with infants' neurodevelopment are still unknown, potential epigenetic effects of breast milk through its bioactive components, including non-coding RNAs, stem cells and microbiome, could at least partly explain this association. Micro- and long-non-coding RNAs, enclosed in milk exosomes, as well as breast milk stem cells, survive digestion, reach the circulation and can cross the blood-brain barrier. Certain non-coding RNAs potentially regulate genes implicated in brain development and function, whereas nestin-positive stem cells can possibly differentiate into neural cells or/and act as epigenetic regulators in the brain. Furthermore, breast milk microbiota contributes to the establishment of infant's gut microbiome, which is implicated in brain development via epigenetic modifications and key molecules' regulation. This narrative review provides an updated analysis of the relationship between breast milk feeding and infants' neurodevelopment via epigenetics, pointing out how breast milk's bioactive components could have an impact on the neurodevelopment of both full-term and preterm babies."
-,37503007,ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes.,bioRxiv,"Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. An activator of BAT is 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with body mass index (BMI) and which directly improves metabolism in other tissues. Here we profile plasma lipidomics from a cohort of 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME both replicably inversely associate with BMI and mechanistically activate calcium fluxes in mouse brown and white adipocytes in vitro. ScreenDMT can be applied to test directional replication, directional mediation, and qualitative interactions, and our results identify 9,10-diHOME and the pathway stimulated by linoleic acid diols as candidate therapeutic targets to improve systemic metabolism."
-,37559907,MOCSS: Multi-omics data clustering and cancer subtyping via shared and specific representation learning.,iScience,"Cancer is an extremely complex disease and each type of cancer usually has several different subtypes. Multi-omics data can provide more comprehensive biological information for identifying and discovering cancer subtypes. However, existing unsupervised cancer subtyping methods cannot effectively learn comprehensive shared and specific information of multi-omics data. Therefore, a novel method is proposed based on shared and specific representation learning. For each omics data, two autoencoders are applied to extract shared and specific information, respectively. To reduce redundancy and mutual interference, orthogonality constraint is introduced to separate shared and specific information. In addition, contrastive learning is applied to align the shared information and strengthen their consistency. Finally, the obtained shared and specific information for all samples are used for clustering tasks to achieve cancer subtyping. Experimental results demonstrate that the proposed method can effectively capture shared and specific information of multi-omics data and outperform other state-of-the-art methods on cancer subtyping.© 2023 The Author(s)."
-,37660099,Themes and variations on piRNA-guided transposon control.,Mob DNA,"PIWI-interacting RNAs (piRNAs) are responsible for preventing the movement of transposable elements in germ cells and protect the integrity of germline genomes. In this review, we examine the common elements of piRNA-guided silencing as well as the differences observed between species. We have categorized the mechanisms of piRNA biogenesis and function into modules. Individual PIWI proteins combine these modules in various ways to produce unique PIWI-piRNA pathways, which nevertheless possess the ability to perform conserved functions. This modular model incorporates conserved core mechanisms and accommodates variable co-factors. Adaptability is a hallmark of this RNA-based immune system. We believe that considering the differences in germ cell biology and resident transposons in different organisms is essential for placing the variations observed in piRNA biology into context, while still highlighting the conserved themes that underpin this process.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37610667,From parasites to partners: exploring the intricacies of host-transposon dynamics and coevolution.,Funct Integr Genomics,"Transposable elements, often referred to as ""jumping genes,"" have long been recognized as genomic parasites due to their ability to integrate and disrupt normal gene function and induce extensive genomic alterations, thereby compromising the host's fitness. To counteract this, the host has evolved a plethora of mechanisms to suppress the activity of the transposons. Recent research has unveiled the host-transposon relationships to be nuanced and complex phenomena, resulting in the coevolution of both entities. Transposition increases the mutational rate in the host genome, often triggering physiological pathways such as immune and stress responses. Current gene transfer technologies utilizing transposable elements have potential drawbacks, including off-target integration, induction of mutations, and modifications of cellular machinery, which makes an in-depth understanding of the host-transposon relationship imperative. This review highlights the dynamic interplay between the host and transposable elements, encompassing various factors and components of the cellular machinery. We provide a comprehensive discussion of the strategies employed by transposable elements for their propagation, as well as the mechanisms utilized by the host to mitigate their parasitic effects. Additionally, we present an overview of recent research identifying host proteins that act as facilitators or inhibitors of transposition. We further discuss the evolutionary outcomes resulting from the genetic interactions between the host and the transposable elements. Finally, we pose open questions in this field and suggest potential avenues for future research.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature."
-,37651425,Backup transcription factor binding sites protect human genes from mutations in the promoter.,PLoS One,"This study was designed to test the idea that the regulatory regions of human genes have evolved to be resistant to the effects of mutations in their primary function, the control of gene expression. It is proposed that the transcription factor/transcription factor binding site (TF/TFBS) pair having the greatest effect on control of a gene is the one with the highest abundance among the regulatory elements. Other pairs would have the same effect on gene expression and would predominate in the event of a mutation in the most abundant pair. It is expected that the overall regulatory design proposed here will be highly resistant to mutagenic change that would otherwise affect expression of the gene. The idea was tested beginning with a database of 42 human genes highly specific for expression in brain. For each gene, the five most abundant TF/TFBS pairs were identified and compared in their TFBS occupancy as measured by their ChIP-seq signal. A similar signal was observed and interpreted as evidence that the TF/TFBS pairs can substitute for one another. TF/TFBS pairs were also compared in their ability to substitute for one another in their effect on the level of gene expression. The study of brain specific genes was complemented with the same analysis performed with 31 human liver specific genes. Like the study of brain genes, the liver results supported the view that TF/TFBS pairs in liver specific genes can substitute for one another in the event of mutagenic damage. Finally, the TFBSs in the brain specific and liver specific gene populations were compared with each other with the goal of identifying any brain selective or liver selective TFBSs. Of the 89 TFBSs in the pooled population, 58 were found only in brain specific but not liver specific genes, 8 only in liver specific but not brain specific genes and 23 were found in both brain and liver specific genes. The results were interpreted to emphasize the large number of TFBS in brain specific genes.Copyright: © 2023 Jay C. Brown. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
-,37640939,scNanoHi-C uncovers single-cell high-order chromatin structures and gene regulation.,Nat Methods,NA
-,37664631,REFINED-CNN framework for survival prediction with high-dimensional features.,iScience,"Robust and accurate survival prediction of clinical trials using high-throughput genomics data is a fundamental challenge in pharmacogenomics. Current machine learning tools often provide limited predictive performance and model interpretation in these settings. In the present study, we extend the application of REFINED-CNN from regression tasks to making survival predictions, by mapping high-dimensional RNA sequencing data into REFINED images which are conducive to CNN modeling. We show that the REFINED-CNN survival model can be easily adapted to new tasks of a similar nature (e.g., predicting on new cancer types) using transfer learning with a low number of patients. Furthermore, the model can also be interpreted both locally and globally through risk score back propagation that quantifies each feature (e.g., gene) importance in survival prediction task for the patient or cancer type of interest.© 2023 The Author(s)."
-,37627927,NA,NA,"Radiomics refers to the acquisition of traces of quantitative features that are usually non-perceptible to human vision and are obtained from different imaging techniques and subsequently transformed into high-dimensional data. Diffuse midline gliomas (DMG) represent approximately 20% of pediatric CNS tumors, with a median survival of less than one year after diagnosis. We aimed to identify which radiomics can discriminate DMG tumor regions (viable tumor and peritumoral edema) from equivalent midline normal tissue (EMNT) in patients with the positive H3.F3K27M mutation, which is associated with a worse prognosis.This was a retrospective study. From a database of 126 DMG patients (children, adolescents, and young adults), only 12 had H3.3K27M mutation and available brain magnetic resonance DICOM file. The MRI T1 post-gadolinium and T2 sequences were uploaded to LIFEx software to post-process and extract radiomic features. Statistical analysis included normal distribution tests and the Mann-Whitney U test performed using IBM SPSS®(Version 27.0.0.1, International Business Machines Corp., Armonk, NY, USA), considering a significant statisticalp-value ≤ 0.05.EMNT vs. Tumor: From the T1 sequence 10 radiomics were identified, and 14 radiomics from the T2 sequence, but only one radiomic identified viable tumors in both sequences (p< 0.05) (DISCRETIZED_Q1). Peritumoral edema vs. EMNT: From the T1 sequence, five radiomics were identified, and four radiomics from the T2 sequence. However, four radiomics could discriminate peritumoral edema in both sequences (p< 0.05) (CONVENTIONAL_Kurtosis, CONVENTIONAL_ExcessKurtosis, DISCRETIZED_Kurtosis, and DISCRETIZED_ExcessKurtosis). There were no radiomics useful for distinguishing tumor tissue from peritumoral edema in both sequences.Less than 5% of the radiomic characteristics identified tumor regions of medical-clinical interest in T1 and T2 sequences of conventional magnetic resonance imaging. The first-order and second-order radiomic features suggest support to investigators and clinicians for careful evaluation for diagnosis, patient classification, and multimodality cancer treatment planning."
-,37559123,LAST-seq: single-cell RNA sequencing by direct amplification of single-stranded RNA without prior reverse transcription and second-strand synthesis.,Genome Biol,"Existing single-cell RNA sequencing (scRNA-seq) methods rely on reverse transcription (RT) and second-strand synthesis (SSS) to convert single-stranded RNA into double-stranded DNA prior to amplification, with the limited RT/SSS efficiency compromising RNA detectability. Here, we develop a new scRNA-seq method, Linearly Amplified Single-stranded-RNA-derived Transcriptome sequencing (LAST-seq), which directly amplifies the original single-stranded RNA molecules without prior RT/SSS. LAST-seq offers a high single-molecule capture efficiency and a low level of technical noise for single-cell transcriptome analyses. Using LAST-seq, we characterize transcriptional bursting kinetics in human cells, revealing a role of topologically associating domains in transcription regulation.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37546924,Multiscale modelling of chromatin 4D organization in SARS-CoV-2 infected cells.,bioRxiv,"SARS-CoV-2 is able to re-structure chromatin organization and alters the epigenomic landscape of the host genome, though the mechanisms that produce such changes are still poorly understood. Here, we investigate with polymer physics chromatin re-organization of the host genome, in space and time upon SARS-CoV-2 viral infection. We show that re-structuring of A/B compartments is well explained by a re-modulation of intra-compartment homotypic affinities, which leads to the weakening of A-A interactions and enhances A-B mixing. At TAD level, re-arrangements are physically described by a general reduction of the loop extrusion activity coupled with an alteration of chromatin phase-separation properties, resulting in more intermingling between different TADs and spread in space of TADs themselves. In addition, the architecture of loci relevant to the antiviral interferon (IFN) response, such as DDX58 or IFIT, results more variable within the 3D single-molecule population of the infected model, suggesting that viral infection leads to a loss of chromatin structural specificity. Analysis of time trajectories of pairwise gene-enhancer and higher-order contacts reveals that such variability derives from a more fluctuating dynamics in infected case, suggesting that SARS-CoV-2 alters gene regulation by impacting the stability of the contact network in time. Overall, our study provides the first polymer-physics based 4D reconstruction of SARS-CoV-2 infected genome with mechanistic insights on the consequent gene mis-regulation."
-,37577525,Continuous lifelong learning for modeling of gene regulation from single cell multiome data by leveraging atlas-scale external data.,bioRxiv,"Accurate context-specific Gene Regulatory Networks (GRNs) inference from genomics data is a crucial task in computational biology. However, existing methods face limitations, such as reliance on gene expression data alone, lower resolution from bulk data, and data scarcity for specific cellular systems. Despite recent technological advancements, including single-cell sequencing and the integration of ATAC-seq and RNA-seq data, learning such complex mechanisms from limited independent data points still presents a daunting challenge, impeding GRN inference accuracy. To overcome this challenge, we present LINGER (LIfelong neural Network for GEne Regulation), a novel deep learning-based method to infer GRNs from single-cell multiome data with paired gene expression and chromatin accessibility data from the same cell. LINGER incorporates both 1) atlas-scale external bulk data across diverse cellular contexts and 2) the knowledge of transcription factor (TF) motif matching tocis-regulatory elements as a manifold regularization to address the challenge of limited data and extensive parameter space in GRN inference. Our results demonstrate that LINGER achieves 2-3 fold higher accuracy over existing methods. LINGER reveals a complex regulatory landscape of genome-wide association studies, enabling enhanced interpretation of disease-associated variants and genes. Additionally, following the GRN inference from a reference sc-multiome data, LINGER allows for the estimation of TF activity solely from bulk or single-cell gene expression data, leveraging the abundance of available gene expression data to identify driver regulators from case-control studies. Overall, LINGER provides a comprehensive tool for robust gene regulation inference from genomics data, empowering deeper insights into cellular mechanisms."
-,37614671,Day-night fluctuations in choroid plexus transcriptomics and cerebrospinal fluid metabolomics.,PNAS Nexus,"The cerebrospinal fluid (CSF) provides mechanical protection for the brain and serves as a brain dispersion route for nutrients, hormones, and metabolic waste. The CSF secretion rate is elevated in the dark phase in both humans and rats, which could support the CSF flow along the paravascular spaces that may be implicated in waste clearance. The similar diurnal CSF dynamics pattern observed in the day-active human and the nocturnal rat suggests a circadian regulation of this physiological variable, rather than sleep itself. To obtain a catalog of potential molecular drivers that could provide the day-night-associated modulation of the CSF secretion rate, we determined the diurnal fluctuation in the rat choroid plexus transcriptomic profile with RNA-seq and in the CSF metabolomics with ultraperformance liquid chromatography combined with mass spectrometry. We detected significant fluctuation of 19 CSF metabolites and differential expression of 2,778 choroid plexus genes between the light and the dark phase, the latter of which encompassed circadian rhythm-related genes and several choroid plexus transport mechanisms. The fluctuating components were organized with joint pathway analysis, of which several pathways demonstrated diurnal regulation. Our results illustrate substantial transcriptional and metabolic light-dark phase-mediated changes taking place in the rat choroid plexus and its encircling CSF. The combined data provide directions toward future identification of the molecular pathways governing the fluctuation of this physiological process and could potentially be harnessed to modulate the CSF dynamics in pathology.© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences."
-,37551357,Central resources of variant discovery and annotation and its role in precision medicine.,Asian Biomed (Res Rev News),"Rapid technological advancement in high-throughput genomics, microarray, and deep sequencing technologies has accelerated the possibility of more complex precision medicine research using large amounts of heterogeneous health-related data from patients, including genomic variants. Genomic variants can be identified and annotated based on the reference human genome either within the sequence as a whole or in a putative functional genomic element. The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) mutually created standards and guidelines for the appraisal of proof to expand consistency and straightforwardness in clinical variation interpretations. Various efforts toward precision medicine have been facilitated by many national and international public databases that classify and annotate genomic variation. In the present study, several resources are highlighted with recognition and data spreading of clinically important genetic variations.© 2023 Hashim Halim-Fikri et al., published by Sciendo."
-,37648906,"The relationship between klotho, testosterone, and sexual health parameters among US adult men.",J Endocrinol Invest,"Klotho is a pleotropic hormone involved in a multitude of biological processes necessary for healthy aging, and affords protection from adverse events such as cardiovascular disease, inflammation, and various cancers. Emerging evidence suggests that klotho is also an important component of biochemical pathways that regulate hormone balance, which may include those pathways governing testosterone production and men's sexual health, though data are limited and results are mixed.Using a cohort of 767 men from the NHANES 2015-2016 survey cycle, we set out to quantify the association between serum klotho levels and serum testosterone levels, as well as clinical markers of men's sexual health (e.g., testosterone:estrogen ratio, bioavailable testosterone, and free testosterone).Multivariable linear and logistic regression models while controlling for potential confounders were constructed to quantify the relationship between serum klotho and testosterone, as well as between serum klotho and odds of low testosterone (serum testosterone < 300 ng/dL).A positive association was observed between serum klotho and testosterone (β = 0.18, p = 0.04). Serum klotho levels were also stratified into quartiles, and we observed statistically significant increases in testosterone for increasing quartile level of klotho using the first quartile as the reference group (β = 90.51, p = 0.001, β = 106.93, p = 0.002, β = 95.33, p = 0.03 for quartiles 2, 3, and 4, respectively). The average testosterone values by quartiles of klotho were 306.9 ng/dL, 390 ng/dL, 409.3 ng/dL, and 436.6 ng/dL, respectively. We modeled important proxies for sexual health including bioavailable and free testosterone, the testosterone:estradiol ratio, and C-reactive protein. Men in the second quartile of klotho had a significantly lower odds of an abnormal testosterone:estradiol ratio compared to the first quartile [OR = 0.18, 95% CI = (0.03, 0.98)].We observed null associations between continuous serum klotho and odds of low testosterone [OR = 1.0, 95% CI = (1.0, 1.0)], and when stratified by quartile, we observed a significant decrease in the odds of low testosterone for individuals in the second quartile of klotho compared to the first quartile [OR = 0.21, 95% CI = (0.05, 0.91)]. In addition, C-reactive protein was inversely associated with testosterone in men (β = - 4.65, p = 0.001), and inversely associated with quartiles of klotho (β = - 2.28, p = 0.04, β = - 2.22, p = 0.04, β = - 2.28, p = 0.03, for quartiles 2, 3, and 4, respectively).Our findings support previous studies suggesting a role for klotho in testosterone levels and sexual function among men. Future studies are warranted to corroborate these findings, determine clinical significance, and elucidate potential mechanisms underlying these associations.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply."
-,37603743,NA,NA,"Metabolite levels shape cellular physiology and disease susceptibility, yet the general principles governing metabolome evolution are largely unknown. Here, we introduce a measure of conservation of individual metabolite levels among related species. By analyzing multispecies tissue metabolome datasets in phylogenetically diverse mammals and fruit flies, we show that conservation varies extensively across metabolites. Three major functional properties, metabolite abundance, essentiality, and association with human diseases predict conservation, highlighting a striking parallel between the evolutionary forces driving metabolome and protein sequence conservation. Metabolic network simulations recapitulated these general patterns and revealed that abundant metabolites are highly conserved due to their strong coupling to key metabolic fluxes in the network. Finally, we show that biomarkers of metabolic diseases can be distinguished from other metabolites simply based on evolutionary conservation, without requiring any prior clinical knowledge. Overall, this study uncovers simple rules that govern metabolic evolution in animals and implies that most tissue metabolome differences between species are permitted, rather than favored by natural selection. More broadly, our work paves the way toward using evolutionary information to identify biomarkers, as well as to detect pathogenic metabolome alterations in individual patients."
-,37632661,Personalized Cancer Monitoring Assay for the Detection of ctDNA in Patients with Solid Tumors.,Mol Diagn Ther,"Highly sensitive molecular assays have been developed to detect plasma-based circulating tumor DNA (ctDNA), and emerging evidence suggests their clinical utility for monitoring minimal residual disease and recurrent disease, providing prognostic information, and monitoring therapy responses in patients with solid tumors. The Invitae Personalized Cancer Monitoring™assay uses a patient-specific, tumor-informed variant signature identified through whole exome sequencing to detect ctDNA in peripheral blood of patients with solid tumors.The assay's tumor whole exome sequencing and ctDNA detection components were analytically validated using 250 unique human specimens and nine commercial reference samples that generated 1349 whole exome sequencing and cell-free DNA (cfDNA)-derived libraries. A comparison of tumor and germline whole exome sequencing was used to identify patient-specific tumor variant signatures and generate patient-specific panels, followed by targeted next-generation sequencing of plasma-derived cfDNA using the patient-specific panels with anchored multiplex polymerase chain reaction chemistry leveraging unique molecular identifiers.Whole exome sequencing resulted in overall sensitivity of 99.8% and specificity of > 99.9%. Patient-specific panels were successfully designed for all 63 samples (100%) with ≥ 20% tumor content and 24 (80%) of 30 samples with ≥ 10% tumor content. Limit of blank studies using 30 histologically normal, formalin-fixed paraffin-embedded specimens resulted in 100% expected panel design failure. The ctDNA detection component demonstrated specificity of > 99.9% and sensitivity of 96.3% for a combination of 10 ng of cfDNA input, 0.008% allele frequency, 50 variants on the patient-specific panels, and a baseline threshold. Limit of detection ranged from 0.008% allele frequency when utilizing 60 ng of cfDNA input with 18-50 variants in the patient-specific panels (> 99.9% sensitivity) with a baseline threshold, to 0.05% allele frequency when using 10 ng of cfDNA input with an 18-variant panel with a monitoring threshold (> 99.9% sensitivity).The Invitae Personalized Cancer Monitoring assay, featuring a flexible patient-specific panel design with 18-50 variants, demonstrated high sensitivity and specificity for detecting ctDNA at variant allele frequencies as low as 0.008%. This assay may support patient prognostic stratification, provide real-time data on therapy responses, and enable early detection of residual/recurrent disease.© 2023. The Author(s)."
-,37645045,Genome assembly in the telomere-to-telomere era.,ArXiv,"De novo assembly is the process of reconstructing the genome sequence of an organism from sequencing reads. Genome sequences are essential to biology, and assembly has been a central problem in bioinformatics for four decades. Until recently, genomes were typically assembled into fragments of a few megabases at best but technological advances in long-read sequencing now enable near complete chromosome-level assembly, also known as telomere-to-telomere assembly, for many organisms. Here we review recent progress on assembly algorithms and protocols. We focus on how to derive near telomere-to-telomere assemblies and discuss potential future developments."
-,37527006,Short-read aligner performance in germline variant identification.,Bioinformatics,"Read alignment is an essential first step in the characterization of DNA sequence variation. The accuracy of variant-calling results depends not only on the quality of read alignment and variant-calling software but also on the interaction between these complex software tools.In this review, we evaluate short-read aligner performance with the goal of optimizing germline variant-calling accuracy. We examine the performance of three general-purpose short-read aligners-BWA-MEM, Bowtie 2, and Arioc-in conjunction with three germline variant callers: DeepVariant, FreeBayes, and GATK HaplotypeCaller. We discuss the behavior of the read aligners with regard to the data elements on which the variant callers rely, and illustrate how the runtime configurations of these software tools combine to affect variant-calling performance.The quick brown fox jumps over the lazy dog.© The Author(s) 2023. Published by Oxford University Press."
-,37442649,Diversity in hematology research.,Hematol Transfus Cell Ther,NA
-,37563539,Application of Nanopore Sequencing in the Diagnosis and Treatment of Pulmonary Infections.,Mol Diagn Ther,"This review provides an in-depth discussion of the development, principles and utility of nanopore sequencing technology and its diverse applications in the identification of various pulmonary pathogens. We examined the emergence and advancements of nanopore sequencing as a significant player in this field. We illustrate the challenges faced in diagnosing mixed infections and further scrutinize the use of nanopore sequencing in the identification of single pathogens, including viruses (with a focus on its use in epidemiology, outbreak investigation, and viral resistance), bacteria (emphasizing 16S targeted sequencing, rare bacterial lung infections, and antimicrobial resistance studies), fungi (employing internal transcribed spacer sequencing), tuberculosis, and atypical pathogens. Furthermore, we discuss the role of nanopore sequencing in metagenomics and its potential for unbiased detection of all pathogens in a clinical setting, emphasizing its advantages in sequencing genome repeat areas and structural variant regions. We discuss the limitations in dealing with host DNA removal, the inherent high error rate of nanopore sequencing technology, along with the complexity of operation and processing, while acknowledging the possibilities provided by recent technological improvements. We compared nanopore sequencing with the BioFire system, a rapid molecular diagnostic system based on polymerase chain reaction. Although the BioFire system serves well for the rapid screening of known and common pathogens, it falls short in the identification of unknown or rare pathogens and in providing comprehensive genome analysis. As technological advancements continue, it is anticipated that the role of nanopore sequencing technology in diagnosing and treating lung infections will become increasingly significant.© 2023. The Author(s)."
-,37612597,"Acute cigarette smoke exposure leads to higher viral infection in human bronchial epithelial cultures by altering interferon, glycolysis and GDF15-related pathways.",Respir Res,"Acute exacerbations of chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), are frequently associated with rhinovirus (RV) infections. Despite these associations, the pathogenesis of virus-induced exacerbations is incompletely understood. We aimed to investigate effects of cigarette smoke (CS), a primary risk factor for COPD, on RV infection in airway epithelium and identify novel mechanisms related to these effects.Primary bronchial epithelial cells (PBEC) from COPD patients and controls were differentiated by culture at the air-liquid interface (ALI) and exposed to CS and RV-A16. Bulk RNA sequencing was performed using samples collected at 6 and 24 h post infection (hpi), and viral load, mediator and L-lactate levels were measured at 6, 24 and 48hpi. To further delineate the effect of CS on RV-A16 infection, we performed growth differentiation factor 15 (GDF15) knockdown, L-lactate and interferon pre-treatment in ALI-PBEC. We performed deconvolution analysis to predict changes in the cell composition of ALI-PBEC after the various exposures. Finally, we compared transcriptional responses of ALI-PBEC to those in nasal epithelium after human RV-A16 challenge.CS exposure impaired antiviral responses at 6hpi and increased viral replication at 24 and 48hpi in ALI-PBEC. At 24hpi, CS exposure enhanced expression of RV-A16-induced epithelial interferons, inflammation-related genes and CXCL8. CS exposure increased expression of oxidative stress-related genes, of GDF15, and decreased mitochondrial membrane potential. GDF15 knockdown experiments suggested involvement of this pathway in the CS-induced increase in viral replication. Expression of glycolysis-related genes and L-lactate production were increased by CS exposure, and was demonstrated to contribute to higher viral replication. No major differences were demonstrated between COPD and non-COPD-derived cultures. However, cellular deconvolution analysis predicted higher secretory cells in COPD-derived cultures at baseline.Altogether, our findings demonstrate that CS exposure leads to higher viral infection in human bronchial epithelium by altering not only interferon responses, but likely also through a switch to glycolysis, and via GDF15-related pathways.© 2023. BioMed Central Ltd., part of Springer Nature."
-,37546860,NA,NA,"Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia1-4. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans5. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-É‘ and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-196, was associated with lower levels of CXCL10, CCL8, and CCL2-molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells7. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19."
-,37535681,Block Aligner: an adaptive SIMD-accelerated aligner for sequences and position-specific scoring matrices.,Bioinformatics,"Efficiently aligning sequences is a fundamental problem in bioinformatics. Many recent algorithms for computing alignments through Smith-Waterman-Gotoh dynamic programming (DP) exploit Single Instruction Multiple Data (SIMD) operations on modern CPUs for speed. However, these advances have largely ignored difficulties associated with efficiently handling complex scoring matrices or large gaps (insertions or deletions).We propose a new SIMD-accelerated algorithm called Block Aligner for aligning nucleotide and protein sequences against other sequences or position-specific scoring matrices. We introduce a new paradigm that uses blocks in the DP matrix that greedily shift, grow, and shrink. This approach allows regions of the DP matrix to be adaptively computed. Our algorithm reaches over 5-10 times faster than some previous methods while incurring an error rate of less than 3% on protein and long read datasets, despite large gaps and low sequence identities.Our algorithm is implemented for global, local, and X-drop alignments. It is available as a Rust library (with C bindings) at https://github.com/Daniel-Liu-c0deb0t/block-aligner.© The Author(s) 2023. Published by Oxford University Press."
-,37580899,NA,NA,"A number types of extracellular DNA (eg, cell-free, cfDNA) circulate in human blood, including mitochondrial, transcriptome, and regulatory DNA, usually at low concentrations. Larger amounts of cfDNA appear in any inflammatory condition, including organ damage due to a variety of reasons. The role of cfDNA in solid organ transplantation is discussed in this review as a valuable additional tool in the standard of care of transplant patients. Post-transplant monitoring requires the use of high-quality biomarkers for early detection of graft damage or rejection to be able to apply early therapeutic intervention. CfDNA complements the traditional monitoring strategies, being a risk stratification tool and an important prognostic marker. However, improving the sensitivity and specificity of cfDNA detection is necessary to facilitate personalized patient management, warranting further research in terms of measurement, test standardization, and storage, processing, and shipping. A diagnostic test (Allosure, CareDx, Inc., Brisbane, CA) for kidney, heart and lung transplant patients is now commercially available, and validation for other organs (eg, liver) is pending. To date, donor-derived cfDNA in combination with other biomarkers appears to be a promising tool in graft rejection as it is minimally invasive, time-sensitive, and cost-effective. However, improvement of sensitivity and specificity is required to facilitate personalized patient management. Whether it could be an alternate to graft biopsy remains unclear."
-,37666948,Harnessing deep learning for population genetic inference.,Nat Rev Genet,"In population genetics, the emergence of large-scale genomic data for various species and populations has provided new opportunities to understand the evolutionary forces that drive genetic diversity using statistical inference. However, the era of population genomics presents new challenges in analysing the massive amounts of genomes and variants. Deep learning has demonstrated state-of-the-art performance for numerous applications involving large-scale data. Recently, deep learning approaches have gained popularity in population genetics; facilitated by the advent of massive genomic data sets, powerful computational hardware and complex deep learning architectures, they have been used to identify population structure, infer demographic history and investigate natural selection. Here, we introduce common deep learning architectures and provide comprehensive guidelines for implementing deep learning models for population genetic inference. We also discuss current challenges and future directions for applying deep learning in population genetics, focusing on efficiency, robustness and interpretability.© 2023. Springer Nature Limited."
-,37668698,Pilot study of relationship between prenatal stress during the COVID-19 pandemic and social-emotional development of 12-month-old children: the mediation effects of home environment.,Eur Child Adolesc Psychiatry,"There is increasing evidence that prenatal stress elevates the risk of children's social-emotional development, but the mechanisms underlying this association are unclear. Home environment provides learning opportunities and stimulation required for children's early development and can be influenced by prenatal maternal stress. This study aimed to examine whether home environment can mediate the association between prenatal stress during the pandemic of coronavirus disease 2019 (COVID-19) and their offspring's social-emotional problems thereafter. A pilot sample was derived from 2020 to 2021 Maternal and Child Health Cohort study (N = 82) with the pregnant women recruited during the COVID-19 lockdown period in 2020. Prenatal stress was assessed using the Perceived Stress Scale. Home environment was measured using the Child Home Nurture Environment Scales. Mother-reported toddler social-emotional problems were assessed at 12 months of age. The mediation model was used for data analysis. The mean scores of social-emotional problems, which include externalizing, internalizing, dysregulation, and competence, were 10.98 (5.08), 14.72 (6.49), 15.15 (6.31), and 36.73 (10.26), respectively. Prenatal stress, home environment, and social-emotional problems were significantly related (P < 0.05). Home environment significantly mediated the association between prenatal stress and social-emotional problems with the indirect effect [95% CI] of 0.06 [0.01, 0.14] for externalizing behaviors, 0.10 [0.00, 0.24] for internalizing behaviors, - 0.15 [- 0.31, - 0.01] for competence, 0.08 [0.01, 0.17] and 0.08 [0.01, 0.21] for dysregulation. These findings suggest that prenatal stress may affect offspring's social-emotional problems through the home environment. Screening for prenatal stress and promoting supportive home environment may be potential strategies for social-emotional problems interventions in children.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany."
-,37580517,Explaining the male bias in cancers.,Nat Rev Genet,NA
-,37569686,The Bladder Tumor Microenvironment Components That Modulate the Tumor and Impact Therapy.,Int J Mol Sci,"The tumor microenvironment (TME) is complex and involves many different cell types that seemingly work together in helping cancer cells evade immune monitoring and survive therapy. The advent of single-cell sequencing has greatly increased our knowledge of the cell types present in the tumor microenvironment and their role in the developing cancer. This, coupled with clinical data showing that cancer development and the response to therapy may be influenced by drugs that indirectly influence the tumor environment, highlights the need to better understand how the cells present in the TME work together. This review looks at the different cell types (cancer cells, cancer stem cells, endothelial cells, pericytes, adipose cells, cancer-associated fibroblasts, and neuronal cells) in the bladder tumor microenvironment. Their impact on immune activation and on shaping the microenvironment are discussed as well as the effects of hypertensive drugs and anesthetics on bladder cancer."
+x,37640946,Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects,Nat Biotechnol,"Oxidative modification of 5-methylcytosine (5mC) by ten-eleven translocation (TET) DNA dioxygenases generates 5-hydroxymethylcytosine (5hmC), the most abundant form of oxidized 5mC. Existing single-cell bisulfite sequencing methods cannot resolve 5mC and 5hmC, leaving the cell-type-specific regulatory mechanisms of TET and 5hmC largely unknown. Here, we present joint single-nucleus (hydroxy)methylcytosine sequencing (Joint-snhmC-seq), a scalable and quantitative approach that simultaneously profiles 5hmC and true 5mC in single cells by harnessing differential deaminase activity of APOBEC3A toward 5mC and chemically protected 5hmC. Joint-snhmC-seq profiling of single nuclei from mouse brains reveals an unprecedented level of epigenetic heterogeneity of both 5hmC and true 5mC at single-cell resolution. We show that cell-type-specific profiles of 5hmC or true 5mC improve multimodal single-cell data integration, enable accurate identification of neuronal subtypes and uncover context-specific regulatory effects on cell-type-specific genes by TET enzymes.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
+x,37622096,Calibrating epigenetic clocks with training data error.,Evol Appl,"Animal age data are valuable for management of wildlife populations. Yet, for most species, there is no practical method for determining the age of unknown individuals. However, epigenetic clocks, a molecular-based method, are capable of age prediction by sampling specific tissue types and measuring DNA methylation levels at specific loci. Developing an epigenetic clock requires a large number of samples from animals of known ages. For most species, there are no individuals whose exact ages are known, making epigenetic clock calibration inaccurate or impossible. For many epigenetic clocks, calibration samples with inaccurate age estimates introduce a degree of error to epigenetic clock calibration. In this study, we investigated how much error in the training data set of an epigenetic clock can be tolerated before it resulted in an unacceptable increase in error for age prediction. Using four publicly available data sets, we artificially increased the training data age error by iterations of 1% and then tested the model against an independent set of known ages. A small effect size increase (Cohen's d >0.2) was detected when the error in age was higher than 22%. The effect size increased linearly with age error. This threshold was independent of sample size. Downstream applications for age data may have a more important role in deciding how much error can be tolerated for age prediction. If highly precise age estimates are required, then it may be futile to embark on the development of an epigenetic clock when there is no accurately aged calibration population to work with. However, for other problems, such as determining the relative age order of pairs of individuals, a lower-quality calibration data set may be adequate.© 2023 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd."
+x,37620601,Multiparameter prediction of myeloid neoplasia risk.,Nat Genet,"The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis. By analyzing differences between 'pre-MN' and controls, we develop and validate Cox regression models quantifying the risk of progression to each myeloid neoplasm subtype. We construct 'MN-predict', a web application that generates time-dependent predictions with the input of basic blood tests and genetic data. Our study demonstrates that many individuals that develop myeloid neoplasms can be identified years in advance and provides a framework for disease-specific prognostication that will be of substantial use to researchers and physicians.© 2023. The Author(s)."
+x,37606673,Evaluation of Large-Scale Proteomics for Prediction of Cardiovascular Events.,JAMA,"Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk factors and polygenic risk scores, is uncertain.To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations.The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals.Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling.Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death.In the primary event population test set (4018 individuals [59.0% women]; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 [95% CI, 0.007 to 0.038]). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 [95% CI, 0.002 to 0.028]). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 [95% CI, 0.011 to 0.042]). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population.A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination."
+x,37580596,In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis,Nat Genet,"Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis.© 2023. The Author(s)."
+x,37608214,Early detection of lung cancer using artificial intelligence-enhanced optical nanosensing of chromatin alterations in field carcinogenesis.,Sci Rep,"Supranucleosomal chromatin structure, including chromatin domain conformation, is involved in the regulation of gene expression and its dysregulation has been associated with carcinogenesis. Prior studies have shown that cells in the buccal mucosa carry a molecular signature of lung cancer among the cigarette-smoking population, the phenomenon known as field carcinogenesis or field of injury. Thus, we hypothesized that chromatin structural changes in buccal mucosa can be predictive of lung cancer. However, the small size of the chromatin chain (approximately 20 nm) folded into chromatin packing domains, themselves typically below 300 nm in diameter, preclude the detection of alterations in intradomain chromatin conformation using diffraction-limited optical microscopy. In this study, we developed an optical spectroscopic statistical nanosensing technique to detect chromatin packing domain changes in buccal mucosa as a lung cancer biomarker: chromatin-sensitive partial wave spectroscopic microscopy (csPWS). Artificial intelligence (AI) was applied to csPWS measurements of chromatin alterations to enhance diagnostic performance. Our AI-enhanced buccal csPWS nanocytology of 179 patients at two clinical sites distinguished Stage-I lung cancer versus cancer-free controls with an area under the ROC curve (AUC) of 0.92 ± 0.06 for Site 1 (in-state location) and 0.82 ± 0.11 for Site 2 (out-of-state location).© 2023. Springer Nature Limited."
+x,37582783,Cross-platform comparisons for targeted bisulfite sequencing of MGISEQ-2000 and NovaSeq6000.,Clin Epigenetics,"An accurate and reproducible next-generation sequencing platform is essential to identify malignancy-related abnormal DNA methylation changes and translate them into clinical applications including cancer detection, prognosis, and surveillance. However, high-quality DNA methylation sequencing has been challenging because poor sequence diversity of the bisulfite-converted libraries severely impairs sequencing quality and yield. In this study, we tested MGISEQ-2000 Sequencer's capability of DNA methylation sequencing with a published non-invasive pancreatic cancer detection assay, using NovaSeq6000 as the benchmark.We sequenced a series of synthetic cell-free DNA (cfDNA) samples with different tumor fractions and found MGISEQ-2000 yielded data with similar quality as NovaSeq6000. The methylation levels measured by MGISEQ-2000 demonstrated high consistency with NovaSeq6000. Moreover, MGISEQ-2000 showed a comparable analytic sensitivity with NovaSeq6000, suggesting its potential for clinical detection. As to evaluate the clinical performance of MGISEQ-2000, we sequenced 24 clinical samples and predicted the pathology of the samples with a clinical diagnosis model, PDACatch classifier. The clinical model performance of MGISEQ-2000's data was highly consistent with that of NovaSeq6000's data, with the area under the curve of 1. We also tested the model's robustness with MGISEQ-2000's data when reducing the sequencing depth. The results showed that MGISEQ-2000's data showed matching robustness of the PDACatch classifier with NovaSeq6000's data.Taken together, MGISEQ-2000 demonstrated similar data quality, consistency of the methylation levels, comparable analytic sensitivity, and matching clinical performance, supporting its application in future non-invasive early cancer detection investigations by detecting distinct methylation patterns of cfDNAs.© 2023. BioMed Central Ltd., part of Springer Nature."
+x,37590228,The specious art of single-cell genomics.,PLoS Comput Biol,"Dimensionality reduction is standard practice for filtering noise and identifying relevant features in large-scale data analyses. In biology, single-cell genomics studies typically begin with reduction to 2 or 3 dimensions to produce ""all-in-one"" visuals of the data that are amenable to the human eye, and these are subsequently used for qualitative and quantitative exploratory analysis. However, there is little theoretical support for this practice, and we show that extreme dimension reduction, from hundreds or thousands of dimensions to 2, inevitably induces significant distortion of high-dimensional datasets. We therefore examine the practical implications of low-dimensional embedding of single-cell data and find that extensive distortions and inconsistent practices make such embeddings counter-productive for exploratory, biological analyses. In lieu of this, we discuss alternative approaches for conducting targeted embedding and feature exploration to enable hypothesis-driven biological discovery.Copyright: © 2023 Chari, Pachter. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
+x,37612512,The complete sequence of a human Y chromosome.,Nature,"The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure that includes long palindromes, tandem repeats and segmental duplications1-3. As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished4,5. Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference, showing the complete ampliconic structures of gene families TSPY, DAZ and RBMY; 41 additional protein-coding genes, mostly from the TSPY family; and an alternating pattern of human satellite 1 and 3 blocks in the heterochromatic Yq12 region. We have combined T2T-Y with a previous assembly of the CHM13 genome4and mapped available population variation, clinical variants and functional genomics data to produce a complete and comprehensive reference sequence for all 24 human chromosomes.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply."
+x,37612510,Assembly of 43 human Y chromosomes reveals extensive complexity and variation,Nature,"The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date1and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes2. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established1boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.© 2023. The Author(s), under exclusive licence to Springer Nature Limited."
+x,37639434,Prediction of DNA Methylation based on Multi-dimensional feature encoding and double convolutional fully connected convolutional neural network.,PLoS Comput Biol,"DNA methylation takes on critical significance to the regulation of gene expression by affecting the stability of DNA and changing the structure of chromosomes. DNA methylation modification sites should be identified, which lays a solid basis for gaining more insights into their biological functions. Existing machine learning-based methods of predicting DNA methylation have not fully exploited the hidden multidimensional information in DNA gene sequences, such that the prediction accuracy of models is significantly limited. Besides, most models have been built in terms of a single methylation type. To address the above-mentioned issues, a deep learning-based method was proposed in this study for DNA methylation site prediction, termed the MEDCNN model. The MEDCNN model is capable of extracting feature information from gene sequences in three dimensions (i.e., positional information, biological information, and chemical information). Moreover, the proposed method employs a convolutional neural network model with double convolutional layers and double fully connected layers while iteratively updating the gradient descent algorithm using the cross-entropy loss function to increase the prediction accuracy of the model. Besides, the MEDCNN model can predict different types of DNA methylation sites. As indicated by the experimental results,the deep learning method based on coding from multiple dimensions outperformed single coding methods, and the MEDCNN model was highly applicable and outperformed existing models in predicting DNA methylation between different species. As revealed by the above-described findings, the MEDCNN model can be effective in predicting DNA methylation sites.Copyright: © 2023 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
+x,37612393,From target discovery to clinical drug development with human genetics,Nature,"The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.© 2023. Springer Nature Limited."
+x,37563310,Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets,Nat Immunol,"Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-? in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization."
+x,37640858,Cell-free DNA methylome analysis for early preeclampsia prediction.,Nat Med,"Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis in the prevention of PE, pregnancies at risk of PE must be identified early-in the first trimester. To identify at-risk pregnancies we profiled methylomes of plasma-derived, cell-free DNA from 498 pregnant women, of whom about one-third developed early-onset PE. We detected DNA methylation differences between control and PE pregnancies that enabled risk stratification at PE diagnosis but also presymptomatically, at around 12 weeks of gestation (range 9-14 weeks). The first-trimester risk prediction model was validated in an external cohort collected from two centers (area under the curve (AUC) = 0.75) and integrated with routinely available maternal risk factors (AUC = 0.85). The combined risk score correctly predicted 72% of patients with early-onset PE at 80% specificity. These preliminary results suggest that cell-free DNA methylation profiling is a promising tool for presymptomatic PE risk assessment, and has the potential to improve treatment and follow-up in the obstetric clinic.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc."
+x,37620817,Association of mitochondrial DNA copy number with chronic kidney disease in older adults.,BMC Geriatr,"Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of chronic kidney disease (CKD). Estimation of mitochondrial DNA copy number (mtDNA-CN) is considered a convenient method for representing mitochondrial function in large samples. However, no study has investigated the association between mtDNA-CN and CKD in older adults with the highest prevalence. The objective is to examine cross-sectional and prospective associations between mtDNA-CN values and CKD risk in older adults to determine whether mtDNA-CN represents a novel potential biomarker for the recognition of CKD risk.In a Chinese community-based cohort of over 65-year-olds, we included 14,467 participants (52.6% females). CKD was defined by eGFR < 60 mL/min/1.73 m2or ICD-10 codes (patients = 3831 (26.5%)). Participants had peripheral blood levels of mtDNA-CN calculated from probe intensities of the Axiom CAS Array.The risk of CKD prevalence decreased with mtDNA-CN per 1-SD increment, independent of established risk factors for older CKD (odds ratio [OR] per SD 0.90, 95% confidence interval [CI] 0.86, 0.93, P < 0.001), and has comparable strength of association with these established risk factors. Furthermore, the progression of kidney function was stratified according to the worsening of eGFR categories. The risk of kidney function progression to a more severe stage gradually decreased as the mtDNA-CN increased (P trend < 0.001). Non-CKD participants in the highest quartile of mtDNA-CN had a lower risk of developing CKD compared to the lowest quartile within 2 years of follow-up, reducing the risk of CKD by 36% (95% CI 0.42, 0.97; P = 0.037).Based on the analysis of the largest sample to date investigating the association between mtDNA-CN and CKD in older adults, higher levels of mtDNA-CN were found to be associated with a lower risk of CKD, suggesting that a reduced level of mtDNA-CN is a potential risk factor for CKD.© 2023. BioMed Central Ltd., part of Springer Nature."
+x,37592018,Pan-mammalian methylation clocks reveal evolutionarily conserved aging effects.,Nat Aging,NA
+x,35301427,Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose,Mol Psychiatry,"Opioid use disorder is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. Opioid overdose, the most severe outcome of opioid use disorder, remains the leading cause of accidental death in the United States. We interrogated the effects of opioid overdose on the brain using ChIP-seq to quantify patterns of H3K27 acetylation in dorsolateral prefrontal cortical neurons isolated from 51 opioid-overdose cases and 51 accidental death controls. Among opioid cases, we observed global hypoacetylation and identified 388 putative enhancers consistently depleted for H3K27ac. Machine learning on H3K27ac patterns predicted case-control status with high accuracy. We focused on case-specific regulatory alterations, revealing 81,399 hypoacetylation events, uncovering vast inter-patient heterogeneity. We developed a strategy to decode this heterogeneity based on convergence analysis, which leveraged promoter-capture Hi-C to identify five genes over-burdened by alterations in their regulatory network or ""plexus"": ASTN2, KCNMA1, DUSP4, GABBR2, ENOX1. These convergent loci are enriched for opioid use disorder risk genes and heritability for generalized anxiety, number of sexual partners, and years of education. Overall, our multi-pronged approach uncovers neurobiological aspects of opioid use disorder and captures genetic and environmental factors perpetuating the opioid epidemic."
+x,37628978,"Prostate Cancer: Genetics, Epigenetics and the Need for Immunological Biomarkers.",Int J Mol Sci,"Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocyte-derived and TAM-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer."
+x,37664631,REFINED-CNN framework for survival prediction with high-dimensional features.,iScience,"Robust and accurate survival prediction of clinical trials using high-throughput genomics data is a fundamental challenge in pharmacogenomics. Current machine learning tools often provide limited predictive performance and model interpretation in these settings. In the present study, we extend the application of REFINED-CNN from regression tasks to making survival predictions, by mapping high-dimensional RNA sequencing data into REFINED images which are conducive to CNN modeling. We show that the REFINED-CNN survival model can be easily adapted to new tasks of a similar nature (e.g., predicting on new cancer types) using transfer learning with a low number of patients. Furthermore, the model can also be interpreted both locally and globally through risk score back propagation that quantifies each feature (e.g., gene) importance in survival prediction task for the patient or cancer type of interest.© 2023 The Author(s)."