title: Genetic and environmental exposures constrain epigenetic drift over the human life course.
abstract: Epigenetic mechanisms such as DNA methylation (DNAm) are essential for regulation of gene expression. DNAm is dynamic, influenced by both environmental and genetic factors. Epigenetic drift is the divergence of the epigenome as a function of age due to stochastic changes in methylation. Here we show that epigenetic drift may be constrained at many CpGs across the human genome by DNA sequence variation and by lifetime environmental exposures. We estimate repeatability of DNAm at 234,811 autosomal CpGs in whole blood using longitudinal data (2-3 repeated measurements) on 478 older people from two Scottish birth cohorts--the Lothian Birth Cohorts of 1921 and 1936. Median age was 79 yr and 70 yr, and the follow-up period was ∼10 yr and ∼6 yr, respectively. We compare this to methylation heritability estimated in the Brisbane Systems Genomics Study, a cross-sectional study of 117 families (offspring median age 13 yr; parent median age 46 yr). CpG repeatability in older people was highly correlated (0.68) with heritability estimated in younger people. Highly heritable sites had strong underlying cis-genetic effects. Thirty-seven and 1687 autosomal CpGs were associated with smoking and sex, respectively. Both sets were strongly enriched for high repeatability. Sex-associated CpGs were also strongly enriched for high heritability. Our results show that a large number of CpGs across the genome, as a result of environmental and/or genetic constraints, have stable DNAm variation over the human lifetime. Moreover, at a number of CpGs, most variation in the population is due to genetic factors, despite some sites being highly modifiable by the environment.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia;
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia;
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom;
authors.forename: Riccardo E
authors.initials: RE
authors.lastname: Marioni
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom;
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Wellcome Trust Clinical Research Facility, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom;
authors.forename: Jude
authors.initials: J
authors.lastname: Gibson
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, 4029, Queensland, Australia;
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom;
authors.forename: Paul
authors.initials: P
authors.lastname: Redmond
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom;
authors.forename: Simon R
authors.initials: SR
authors.lastname: Cox
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom;
authors.forename: Alison
authors.initials: A
authors.lastname: Pattie
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom;
authors.forename: Janie
authors.initials: J
authors.lastname: Corley
authors.affiliation: Wellcome Trust Clinical Research Facility, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom;
authors.forename: Lee
authors.initials: L
authors.lastname: Murphy
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, 4029, Queensland, Australia;
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, 4029, Queensland, Australia;
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom;
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia;
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom;
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia peter.visscher@uq.edu.au.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D002648:Child; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics*; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D005192:Family Health; D005260:Female; D059647:Gene-Environment Interaction; D005828:Genetics, Population / Q000379:methods*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D012907:Smoking; D055815:Young Adult