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

By Jordana T. Bell, P. Tsai, Tsun-Po Yang, Ruth Pidsley, James P. Nisbet, D. Glass, M. Mangino, G. Zhai, Feng Zhang, A. Valdes and 12 more. PLoS Genetics, 2012

711 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c7ecae1cffc111f357f79fa9c72960938b71c70f

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Citations in the corpus

DNA methylation age of human tissues and cell types (2013, background): “A vast literature characterizes genes or genomic regions that either get hypermethylated or hypomethylated with age [6-14].”
DNA methylation and healthy human aging (2015, background): “A number of studies have published lists of epigenetic clock sites in blood (Bocklandt et al., 2011; Rakyan et al., 2011; Bell et al., 2012; Numata et al., 2012; Hannum et al., 2013; Horvath, 2013; Florath et al., 2014; Weidner et al., 2014).”
A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue (2013, neutral): “%) with three studies reporting aging-differentially methylated regions (a-DMRs) in a total of 597 unique positions [28–30].”
Accounting for cellular heterogeneity is critical in epigenome-wide association studies (2014, methodology): “papers reporting age-related changes of DNAm profiles have been published [6-14].”