Genetic and environmental exposures constrain epigenetic drift over the human life course
- Sonia Shah1,
- Allan F McRae1,
- Riccardo E Marioni2,
- Sarah E Harris2,
- Jude Gibson2,
- Anjali K Henders3,
- Paul Redmond2,
- Simon R Cox2,
- Alison Pattie2,
- Janie Corley2,
- Lee Murphy2,
- Nicholas G Martin3,
- Grant W Montgomery3,
- John M Starr2,
- Naomi R Wray1,
- Ian J Deary2 and
- Peter M Visscher1,4
- ↵* Corresponding author; email: peter.visscher{at}uq.edu.au
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 79yrs and 70yrs, and the follow-up period was ~10yrs and ~6yrs, respectively. We compare this to methylation heritability estimated in the Brisbane Systems Genomics Study, a cross-sectional study of 117 families (offspring median age 13yrs; parent median age 46yrs). 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. 37 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 life-time. 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.
- Received April 9, 2014.
- Accepted September 8, 2014.
- Published by Cold Spring Harbor Laboratory Press
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