Abstract
BackgroundEpigenetic 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.MethodsWe 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.ResultsOverall, 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 < 1E−07) were enriched for immune and inflammation pathways while 2020 low stability sites showed enrichment in stress‐related pathways.ConclusionsAcross 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.
Highlights
The functional profiles of genes are not static and vary across time, and across the lifespan, in part as a result of different environmental exposures and contexts
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)
We examine whether surrounding “shores” and “shelves” are differentially heritable compared to islands and whether sites identified as associated with rate of aging in epigenome-wide association study (EWAS) or individual CpG clock sites are differentially heritable
Summary
The functional profiles of genes are not static and vary across time, and across the lifespan, in part as a result of different environmental exposures and contexts (van Dongen et al, 2016; Jones, Goodman, & Kobor, 2015; Lappe & Landecker, 2015; McClearn, 2006). We evaluate individual differences in DNA methylation at individual CpG sites across the methylome across 10 years in two Scandinavian samples of same-sex aging twins, estimating the genetic and environmental contributions to stability as well as to novel influences that emerge. In a combined sample of aging twins, assessed a decade apart in late-life, we test two competing hypotheses about the longitudinal stability and change in DNA methylation that stem from prior cross-sectional work (van Dongen et al, 2016): (a) the contribution of genetic influences changes with age, reflecting diminishing influence across time, and (b) non-shared factors accumulate in importance, signaling an increasing diversity of response to environmental exposures
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