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Title

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

Authors
Bell, Jordana T
Tsai, Pei-Chien
Yang, Tsun-Po
Pidsley, Ruth
Nisbet, James
Glass, Daniel
Mangino, Massimo
Zhai, Guangju
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Published in PLOS Genetics. 2012, vol. 8, no. 4, p. e1002629
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.
Keywords AdultAgedAged, 80 and overAging/geneticsCell Aging/geneticsCpG Islands/geneticsDNA Methylation/geneticsEpigenesis, Genetic/geneticsFemaleGene-Environment InteractionGenetic Association StudiesGenome, HumanGenome-Wide Association StudyHumansLongevity/geneticsMiddle AgedQuantitative Trait Loci/geneticsTwins, Monozygotic/genetics
Identifiers
PMID: 22532803
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Article (Published version) (571 Kb) - public document Free access
Structures
Research group Population Genomics and Genetics of Complex Traits (892)
Project Jeantet
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BELL, Jordana T et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. In: PLOS Genetics, 2012, vol. 8, n° 4, p. e1002629. https://archive-ouverte.unige.ch/unige:32175

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Deposited on : 2013-12-16

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