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, Emmanouil T Dermitzakis, Mark I McCarthy, Jonathan MillTim D Spector, Panos Deloukas, MuTHER Consortium

Research output: Contribution to journalArticle (Academic Journal)peer-review

438 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)e1002629
JournalPLoS Genetics
Volume8
Issue number4
DOIs
Publication statusPublished - 2012

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging
  • Cell Aging
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Gene-Environment Interaction
  • Genetic Association Studies
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Longevity
  • Middle Aged
  • Quantitative Trait Loci
  • Twins, Monozygotic

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