Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population

作者：Jordana T. Bell, Pei-Chien Tsai, Tsun-Po Yang, Ruth Pidsley, James P. Nisbet, Daniel Glass, Massimo Mangino, Guangju Zhai, Feng Zhang, Ana Maria Valdes, So–Youn Shin, Emma Dempster, Robin M. Murray, Elin Grundberg, Åsa K. Hedman, Alexandra Nica, Kerrin S. Small, Emmanouil T. Dermitzakis, Mark I. McCarthy, Jonathan S. Mill, Tim D. Spector, Panos Deloukas · 发表于：PLoS Genetics · 年份：2012 · DOI：10.1371/journal.pgen.1002629 · 被引用次数：725 · 研究领域：Epigenetics and DNA Methylation、Genetic Syndromes and Imprinting、RNA modifications and cancer

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 g...