Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population
Jordana T. Bell,Pei-Chien Tsai,Tsun-Po Yang,Ruth Pidsley,James Nisbet,Daniel Glass,Massimo Mangino,Guangju Zhai,Guangju Zhai,Feng Zhang,Ana M. Valdes,So-Youn Shin,Emma Dempster,Robin M. Murray,Elin Grundberg,Elin Grundberg,Åsa K. Hedman,Alexandra C. Nica,Kerrin S. Small,Emmanouil T. Dermitzakis,Mark I. McCarthy,Mark I. McCarthy,Mark I. McCarthy,Jonathan Mill,Tim D. Spector,Panos Deloukas +25 more
TLDR
The 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, and that a-DMRs may initiate at an earlier age.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.read more
Citations
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DNA methylation age of human tissues and cell types
TL;DR: It is proposed that DNA methylation age measures the cumulative effect of an epigenetic maintenance system, and can be used to address a host of questions in developmental biology, cancer and aging research.
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Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates
Gregory Hannum,Justin Guinney,Ling Zhao,Ling Zhao,Li Zhang,Guy Hughes,Srinivas R. Sadda,Brandy Klotzle,Marina Bibikova,Jian-Bing Fan,Yuan Gao,Rob Deconde,Menzies Chen,Indika Rajapakse,Stephen H. Friend,Trey Ideker,Kang Zhang,Kang Zhang +17 more
TL;DR: A quantitative model of aging is built using measurements at more than 450,000 CpG markers from the whole blood of 656 human individuals, aged 19 to 101, to measure the rate at which an individual's methylome ages, which is impacted by gender and genetic variants.
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DNA methylation-based biomarkers and the epigenetic clock theory of ageing
Steve Horvath,Ken Raj +1 more
TL;DR: Biomarkers of ageing based on DNA methylation data enable accurate age estimates for any tissue across the entire life course and link developmental and maintenance processes to biological ageing, giving rise to a unified theory of life course.
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Accounting for cellular heterogeneity is critical in epigenome-wide association studies
TL;DR: This work examines data from five previously published studies, and finds strong evidence of cell composition change across age in blood, and demonstrates that, in these studies, cellular composition explains much of the observed variability in DNA methylation.
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DNA methylation age of blood predicts all-cause mortality in later life.
Riccardo E. Marioni,Riccardo E. Marioni,Sonia Shah,Allan F. McRae,Brian H. Chen,Elena Colicino,Sarah E. Harris,Jude Gibson,Anjali K. Henders,Paul Redmond,Simon R. Cox,Alison Pattie,Janie Corley,Lee Murphy,Nicholas G. Martin,Grant W. Montgomery,Andrew P. Feinberg,M. Daniele Fallin,M. Daniele Fallin,Michael L. Multhaup,Andrew E. Jaffe,Roby Joehanes,Roby Joehanes,Joel Schwartz,Allan C. Just,Kathryn L. Lunetta,Kathryn L. Lunetta,Joanne M. Murabito,Joanne M. Murabito,John M. Starr,Steve Horvath,Andrea A. Baccarelli,Daniel Levy,Peter M. Visscher,Peter M. Visscher,Naomi R. Wray,Ian J. Deary +36 more
TL;DR: DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.
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