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

TY - JOUR

T1 - Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population

AU - Bell, Jordana T.

AU - Tsai, Pei-Chien

AU - Yang, Tsun-Po

AU - Pidsley, Ruth

AU - Nisbet, James

AU - Glass, Daniel

AU - Mangino, Massimo

AU - Zhai, Guangju

AU - Zhang, Feng

AU - Valdes, Ana

AU - Shin, So-Youn

AU - Dempster, Emma L.

AU - Murray, Robin M.

AU - Grundberg, Elin

AU - Hedman, Asa K.

AU - Nica, Alexandra

AU - Small, Kerrin S.

AU - Dermitzakis, Emmanouil T.

AU - McCarthy, Mark I.

AU - Mill, Jonathan

AU - Spector, Tim D.

AU - Deloukas, Panos

AU - MuTHER Consortium

PY - 2012/4

Y1 - 2012/4

N2 - 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.

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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Aging

KW - Cell Aging

KW - CpG Islands

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Female

KW - Gene-Environment Interaction

KW - Genetic Association Studies

KW - Genome, Human

KW - Genome-Wide Association Study

KW - Humans

KW - Longevity

KW - Middle Aged

KW - Quantitative Trait Loci

KW - Twins, Monozygotic

U2 - 10.1371/journal.pgen.1002629

DO - 10.1371/journal.pgen.1002629

M3 - Article

C2 - 22532803

SN - 1553-7390

VL - 8

SP - 189

EP - 200

JO - PL o S Genetics

JF - PL o S Genetics

IS - 4

M1 - e1002629

ER -