Genetic and environmental exposures constrain epigenetic drift over the human life course

Genome Research - Tập 24 Số 11 - Trang 1725-1733 - 2014
Sonia Shah1, Allan F. McRae1, Riccardo E. Marioni1,2,3, Sarah E. Harris2,3, Jude Gibson4, Anjali K. Henders5, Paul Redmond6, Simon R. Cox3,6, Ville Karhunen6, Janie Corley6, Lee Murphy4, Nicholas G. Martin5, Grant W. Montgomery5, Robert Plomin3,7, Naomi R. Wray1, Ian J. Deary3,6, Peter M. Visscher1,3,8
11Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia
22Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom
33Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom
44Wellcome Trust Clinical Research Facility, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom
55QIMR Berghofer Medical Research Institute, Brisbane, 4029, Queensland, Australia
66Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom
77Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom
88University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia

Tóm tắt

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.

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Genome Research

Tập 24 Số 11

1725-1733

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