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

Bell, Jordana T and Tsai, Pei-Chien and Yang, Tsun-Po and Pidsley, Ruth and Nisbet, James and Glass, Daniel and Mangino, Massimo and Zhai, Guangju and Zhang, Feng and Valdes, Ana and Shin, So-Youn and Dempster, Emma L and Murray, Robin M and Grundberg, Elin and Hedman, Asa K and Nica, Alexandra and Small, Kerrin S and Dermitzakis, Emmanouil T and McCarthy, Mark I and Mill, Jonathan and Spector, Tim D and Deloukas, Panos and Tsaprouni, Loukia (2012) Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS genetics, 8 (4). e1002629. ISSN 1553-7404

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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.

Item Type: Article
Subjects: C400 Genetics
C700 Molecular Biology, Biophysics and Biochemistry
C900 Others in Biological Sciences
Divisions: Faculty of Health, Education and Life Sciences > School of Health Sciences
Depositing User: Loukia Tsaprouni
Date Deposited: 17 Jul 2017 08:45
Last Modified: 17 Jul 2017 08:45
URI: http://www.open-access.bcu.ac.uk/id/eprint/4790

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