Genetic and environmental influences interact with age and sex in shaping the human methylome

The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.

[1]  David I. K. Martin,et al.  Epigenetic inheritance at the agouti locus in the mouse , 1999, Nature Genetics.

[2]  R. Jaenisch,et al.  Nuclear Cloning and Epigenetic Reprogramming of the Genome , 2001, Science.

[3]  Shaun Purcell,et al.  Variance components models for gene-environment interaction in twin analysis. , 2002, Twin research : the official journal of the International Society for Twin Studies.

[4]  Andrew P Feinberg,et al.  An integrated epigenetic and genetic approach to common human disease. , 2004, Trends in genetics : TIG.

[5]  M. Hanson,et al.  Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. , 2005, The Journal of nutrition.

[6]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Arturas Petronis,et al.  Complex disease, gender and epigenetics , 2006, Annals of medicine.

[8]  G. Willemsen,et al.  Gene-Environment Interaction in Adults’ IQ Scores: Measures of Past and Present Environment , 2008, Behavior genetics.

[9]  T. Mikkelsen,et al.  Genome-scale DNA methylation maps of pluripotent and differentiated cells , 2008, Nature.

[10]  Jim Stalker,et al.  A Novel CpG Island Set Identifies Tissue-Specific Methylation at Developmental Gene Loci , 2008, PLoS biology.

[11]  H. Putter,et al.  DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. , 2009, Human molecular genetics.

[12]  René S. Kahn,et al.  The Relationship of DNA Methylation with Age, Gender and Genotype in Twins and Healthy Controls , 2009, PloS one.

[13]  Martin J Aryee,et al.  Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts , 2009, Nature Genetics.

[14]  A. Feinberg,et al.  Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores , 2008, Nature Genetics.

[15]  Wolfgang Wagner,et al.  Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. , 2010, Genome research.

[16]  V. Calhoun,et al.  A Study of the Influence of Sex on Genome Wide Methylation , 2010, PloS one.

[17]  T. Lehner,et al.  The Netherlands Twin Register Biobank: A Resource for Genetic Epidemiological Studies , 2010, Twin Research and Human Genetics.

[18]  T. Mikkelsen,et al.  The NIH Roadmap Epigenomics Mapping Consortium , 2010, Nature Biotechnology.

[19]  W. G. Hill,et al.  Genome partitioning of genetic variation for complex traits using common SNPs , 2011, Nature Genetics.

[20]  Andrew E. Teschendorff,et al.  Independent surrogate variable analysis to deconvolve confounding factors in large-scale microarray profiling studies , 2011, Bioinform..

[21]  D. Pinto,et al.  A novel approach identifies new differentially methylated regions (DMRs) associated with imprinted genes. , 2011, Genome research.

[22]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[23]  Steve Horvath,et al.  Epigenetic Predictor of Age , 2011, PloS one.

[24]  K. Gunderson,et al.  High density DNA methylation array with single CpG site resolution. , 2011, Genomics.

[25]  Ritsert C. Jansen,et al.  MixupMapper: correcting sample mix-ups in genome-wide datasets increases power to detect small genetic effects , 2011, Bioinform..

[26]  S. Horvath,et al.  Aging effects on DNA methylation modules in human brain and blood tissue , 2012, Genome Biology.

[27]  L. Gordon,et al.  Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance , 2013, Genome Biology.

[28]  Robin M. Murray,et al.  Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population , 2012, PLoS genetics.

[29]  Julia A. Taylor,et al.  DNA methylation changes in whole blood is associated with exposure to the environmental contaminants, mercury, lead, cadmium and bisphenol A, in women undergoing ovarian stimulation for IVF. , 2012, Human reproduction.

[30]  P. Visscher,et al.  Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence , 2012, Genome research.

[31]  H. Putter,et al.  Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs , 2012, Aging cell.

[32]  Dorret I. Boomsma,et al.  The continuing value of twin studies in the omics era , 2012, Nature Reviews Genetics.

[33]  T. Byers,et al.  Sex-specific association of sequence variants in CBS and MTRR with risk for promoter hypermethylation in the lung epithelium of smokers. , 2012, Carcinogenesis.

[34]  E. Gamazon,et al.  Enrichment of Cis-Regulatory Gene Expression SNPs and Methylation Quantitative Trait Loci Among Bipolar Disorder Susceptibility Variants , 2012, Molecular Psychiatry.

[35]  Andrew E. Teschendorff,et al.  Age-associated epigenetic drift: implications, and a case of epigenetic thrift? , 2013, Human molecular genetics.

[36]  R. Weksberg,et al.  Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray , 2013, Epigenetics.

[37]  A. Gnirke,et al.  Charting a dynamic DNA methylation landscape of the human genome , 2013, Nature.

[38]  N. Patterson,et al.  Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits , 2013, PLoS genetics.

[39]  Martin J. Aryee,et al.  Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in Rheumatoid Arthritis , 2013, Nature Biotechnology.

[40]  Nicholas G Martin,et al.  Contribution of genetic variation to transgenerational inheritance of DNA methylation , 2014, Genome Biology.

[41]  Mark I. McCarthy,et al.  Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements. , 2013, American journal of human genetics.

[42]  J. Mathers,et al.  Nutritional factors and gender influence age-related DNA methylation in the human rectal mucosa , 2012, Aging cell.

[43]  Shane J. Neph,et al.  Developmental Fate and Cellular Maturity Encoded in Human Regulatory DNA Landscapes , 2013, Cell.

[44]  C. Hertzman,et al.  Epigenetic vestiges of early developmental adversity: childhood stress exposure and DNA methylation in adolescence. , 2013, Child development.

[45]  S. Horvath.  DNA methylation age of human tissues and cell types , 2013, Genome Biology.

[46]  F. Perera,et al.  Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure , 2013, Proceedings of the National Academy of Sciences.

[47]  Eric-Wubbo Lameijer,et al.  Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array , 2013, Epigenetics & Chromatin.

[48]  Bastiaan T. Heijmans,et al.  From promises to practical strategies in epigenetic epidemiology , 2013, Nature Reviews Genetics.

[49]  A. Hofman,et al.  DNA methylation profiles at birth and child ADHD symptoms. , 2014, Journal of psychiatric research.

[50]  William Wheeler,et al.  Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue , 2014, Nature Communications.

[51]  K. Hansen,et al.  Functional normalization of 450k methylation array data improves replication in large cancer studies , 2014, Genome Biology.

[52]  C. Gieger,et al.  DNA methylation and body-mass index: a genome-wide analysis , 2014, The Lancet.

[53]  P. Gluckman,et al.  The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes , 2014, Genome research.

[54]  Pieter B. T. Neerincx,et al.  Supplementary Information Whole-genome sequence variation , population structure and demographic history of the Dutch population , 2022 .

[55]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[56]  Wei Zhang,et al.  Linking the genetic architecture of cytosine modifications with human complex traits. , 2014, Human molecular genetics.

[57]  R. Marioni,et al.  Genetic and environmental exposures constrain epigenetic drift over the human life course , 2014, Genome research.

[58]  Hein Putter,et al.  DNA methylation signatures link prenatal famine exposure to growth and metabolism , 2014, Nature Communications.

[59]  Hemant K. Tiwari,et al.  Epigenome-Wide Association Study of Fasting Measures of Glucose, Insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network Study , 2014, Diabetes.

[60]  R. Jansen,et al.  Mapping the Epigenetic Basis of Complex Traits , 2014, Science.

[61]  P. Eline Slagboom,et al.  MethylAid: visual and interactive quality control of large Illumina 450k datasets , 2014, Bioinform..

[62]  Rafael A. Irizarry,et al.  Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays , 2014, Bioinform..

[63]  D. Boomsma,et al.  Epigenetic Variation in Monozygotic Twins: A Genome-Wide Analysis of DNA Methylation in Buccal Cells , 2014, Genes.

[64]  Christian Gieger,et al.  Epigenetics meets metabolomics: an epigenome-wide association study with blood serum metabolic traits , 2013, Human molecular genetics.

[65]  Paolo Vineis,et al.  Dynamics of smoking-induced genome-wide methylation changes with time since smoking cessation. , 2015, Human molecular genetics.

[66]  S. Horvath,et al.  DNA methylation age of blood predicts all-cause mortality in later life , 2015, Genome Biology.

[67]  Steve Horvath,et al.  The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936 , 2015, International journal of epidemiology.

[68]  Xin Li,et al.  Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin , 2015, Genome Biology.

[69]  D. Hernandez,et al.  DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels , 2015, Circulation. Cardiovascular genetics.

[70]  Donna K Arnett,et al.  Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study , 2014, Aging cell.

[71]  D. Boomsma,et al.  Detection of gene–environment interaction in pedigree data using genome-wide genotypes , 2016, European Journal of Human Genetics.