PLoS Genetics (Jan 2012)

Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.

  • Jordana T Bell,
  • Pei-Chien Tsai,
  • Tsun-Po Yang,
  • Ruth Pidsley,
  • James Nisbet,
  • Daniel Glass,
  • Massimo Mangino,
  • Guangju Zhai,
  • Feng Zhang,
  • Ana Valdes,
  • So-Youn Shin,
  • Emma L Dempster,
  • Robin M Murray,
  • Elin Grundberg,
  • Asa K Hedman,
  • Alexandra Nica,
  • Kerrin S Small,
  • MuTHER Consortium,
  • Emmanouil T Dermitzakis,
  • Mark I McCarthy,
  • Jonathan Mill,
  • Tim D Spector,
  • Panos Deloukas

DOI
https://doi.org/10.1371/journal.pgen.1002629
Journal volume & issue
Vol. 8, no. 4
p. e1002629

Abstract

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Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.