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Epigenome-wide scan...
Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
- Article/chapterEnglish2012
Publisher, publication year, extent ...
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2012-04-19
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Public Library of Science (PLoS),2012
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LIBRIS-ID:oai:DiVA.org:uu-275694
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-275694URI
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https://doi.org/10.1371/journal.pgen.1002629DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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.
Added entries (persons, corporate bodies, meetings, titles ...)
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Tsai, Pei-Chien
(author)
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Yang, Tsun-Po
(author)
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Pidsley, Ruth
(author)
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Nisbet, James
(author)
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Glass, Daniel
(author)
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Mangino, Massimo
(author)
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Zhai, Guangju
(author)
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Zhang, Feng
(author)
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Valdes, Ana
(author)
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Shin, So-Youn
(author)
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Dempster, Emma L
(author)
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Murray, Robin M
(author)
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Grundberg, Elin
(author)
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Hedman, Asa K
(author)
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Nica, Alexandra
(author)
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Small, Kerrin S
(author)
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Dermitzakis, Emmanouil T
(author)
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McCarthy, Mark I
(author)
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Mill, Jonathan
(author)
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Spector, Tim D
(author)
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Deloukas, Panos
(author)
Related titles
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In:PLOS Genetics: Public Library of Science (PLoS)8:41553-73901553-7404
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- By the author/editor
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Bell, Jordana T
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Tsai, Pei-Chien
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Yang, Tsun-Po
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Pidsley, Ruth
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Nisbet, James
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Glass, Daniel
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show more...
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Mangino, Massimo
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Zhai, Guangju
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Zhang, Feng
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Valdes, Ana
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Shin, So-Youn
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Dempster, Emma L
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Murray, Robin M
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Grundberg, Elin
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Hedman, Asa K
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Nica, Alexandra
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Small, Kerrin S
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Dermitzakis, Emm ...
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McCarthy, Mark I
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Mill, Jonathan
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Spector, Tim D
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Deloukas, Panos
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- Articles in the publication
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PLOS Genetics
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Uppsala University