TY  - JOUR
AU  - Bell, JT
AU  - Tsai, P-C
AU  - Yang, T-P
AU  - Pidsley, R
AU  - Nisbet, J
AU  - Glass, D
AU  - Mangino, M
AU  - Zhai, G
AU  - Zhang, F
AU  - Valdes, A
AU  - Shin, S-Y
AU  - Dempster, EL
AU  - Murray, RM
AU  - Grundberg, E
AU  - Hedman, AK
AU  - Nica, A
AU  - Small, KS
AU  - MuTHER Consortium,
AU  - Dermitzakis, ET
AU  - McCarthy, MI
AU  - Mill, J
AU  - Spector, TD
AU  - Deloukas, P
Y2  - 2020/12/17
Y1  - 2012
SN  - 1553-7390
UR  - http://hdl.handle.net/11343/255325
AB  - 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.
LA  - eng
PB  - Public Library of Science (PLoS)
T1  - Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
DO  - 10.1371/journal.pgen.1002629
IS  - PLoS Genetics
VL  - 8
IS  - 4
SP  - e1002629-
L1  - /bitstream/handle/11343/255325/PMC3330116.pdf?sequence=1&isAllowed=y
ER  -