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...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Journal article |
| Lenguaje: | English |
| Publicado: |
2012
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| _version_ | 1826302929288560640 |
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| author | Bell, J Tsai, P Yang, T Pidsley, R Nisbet, J Glass, D Mangino, M Zhai, G Zhang, F Valdes, A Shin, S Dempster, E Murray, R Grundberg, E Hedman, A Nica, A Small, K Dermitzakis, E McCarthy, M Mill, J Spector, T Deloukas, P |
| author_facet | Bell, J Tsai, P Yang, T Pidsley, R Nisbet, J Glass, D Mangino, M Zhai, G Zhang, F Valdes, A Shin, S Dempster, E Murray, R Grundberg, E Hedman, A Nica, A Small, K Dermitzakis, E McCarthy, M Mill, J Spector, T Deloukas, P |
| author_sort | Bell, J |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-07T05:54:54Z |
| format | Journal article |
| id | oxford-uuid:ea32e390-c842-4e0e-bf94-7c5a13c66799 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:54:54Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:ea32e390-c842-4e0e-bf94-7c5a13c667992022-03-27T11:00:07ZEpigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ea32e390-c842-4e0e-bf94-7c5a13c66799EnglishSymplectic Elements at Oxford2012Bell, JTsai, PYang, TPidsley, RNisbet, JGlass, DMangino, MZhai, GZhang, FValdes, AShin, SDempster, EMurray, RGrundberg, EHedman, ANica, ASmall, KDermitzakis, EMcCarthy, MMill, JSpector, TDeloukas, PAge-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. |
| spellingShingle | Bell, J Tsai, P Yang, T Pidsley, R Nisbet, J Glass, D Mangino, M Zhai, G Zhang, F Valdes, A Shin, S Dempster, E Murray, R Grundberg, E Hedman, A Nica, A Small, K Dermitzakis, E McCarthy, M Mill, J Spector, T Deloukas, P Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. |
| 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 |
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