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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Main Authors: 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
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2012-01-01
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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