Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
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...
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Public Library of Science (PLoS)
2012-01-01
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Series: | PLoS Genetics |
Online Access: | http://europepmc.org/articles/PMC3330116?pdf=render |
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author | Jordana T Bell Pei-Chien Tsai Tsun-Po Yang Ruth Pidsley James Nisbet Daniel Glass Massimo Mangino Guangju Zhai Feng Zhang Ana Valdes So-Youn Shin Emma L Dempster Robin M Murray Elin Grundberg Asa K Hedman Alexandra Nica Kerrin S Small MuTHER Consortium Emmanouil T Dermitzakis Mark I McCarthy Jonathan Mill Tim D Spector Panos Deloukas |
author_facet | Jordana T Bell Pei-Chien Tsai Tsun-Po Yang Ruth Pidsley James Nisbet Daniel Glass Massimo Mangino Guangju Zhai Feng Zhang Ana Valdes So-Youn Shin Emma L Dempster Robin M Murray Elin Grundberg Asa K Hedman Alexandra Nica Kerrin S Small MuTHER Consortium Emmanouil T Dermitzakis Mark I McCarthy Jonathan Mill Tim D Spector Panos Deloukas |
author_sort | Jordana T Bell |
collection | DOAJ |
description | 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. |
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spelling | doaj.art-c1216b10080a4acab90a7bd69e0211442022-12-21T18:14:27ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-0184e100262910.1371/journal.pgen.1002629Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.Jordana T BellPei-Chien TsaiTsun-Po YangRuth PidsleyJames NisbetDaniel GlassMassimo ManginoGuangju ZhaiFeng ZhangAna ValdesSo-Youn ShinEmma L DempsterRobin M MurrayElin GrundbergAsa K HedmanAlexandra NicaKerrin S SmallMuTHER ConsortiumEmmanouil T DermitzakisMark I McCarthyJonathan MillTim D SpectorPanos DeloukasAge-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.http://europepmc.org/articles/PMC3330116?pdf=render |
spellingShingle | Jordana T Bell Pei-Chien Tsai Tsun-Po Yang Ruth Pidsley James Nisbet Daniel Glass Massimo Mangino Guangju Zhai Feng Zhang Ana Valdes So-Youn Shin Emma L Dempster Robin M Murray Elin Grundberg Asa K Hedman Alexandra Nica Kerrin S Small MuTHER Consortium Emmanouil T Dermitzakis Mark I McCarthy Jonathan Mill Tim D Spector Panos Deloukas Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genetics |
title | Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. |
title_full | Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. |
title_fullStr | Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. |
title_full_unstemmed | Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. |
title_short | Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. |
title_sort | epigenome wide scans identify differentially methylated regions for age and age related phenotypes in a healthy ageing population |
url | http://europepmc.org/articles/PMC3330116?pdf=render |
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