The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population
Open accessAbstract
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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Cites
Howie, B. N., Donnelly, P., & Marchini, J. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000529 · Cited by 3,928
Epigenetic differences arise during the lifetime of monozygotic twins
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Self-citationGOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists
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Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain
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Epigenetics and aging: the targets and the marks
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“On the other hand, environment-dependent changes in DNA methylation in MZ twins have been reported to occur preferentially in gene-poor regions (see [34]).”
BackgroundTobacco-smoking-related differential DNA methylation: 27K discovery and replication
Breitling, L. P., Yang, R., Korn, B., Burwinkel, B., & Brenner, H. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.03.003 · Cited by 640
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Cited by
DNA methylation age of human tissues and cell types
Horvath, S. (2013) · Genome Biology · doi:10.1186/gb-2013-14-10-r115 · Cited by 7,075
Genome-wide methylation profiles reveal quantitative views of human aging rates
Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S., Klotzle, B., Bibikova, M., Fan, J.-B., Gao, Y., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.10.016 · Cited by 4,270
DNA methylation-based biomarkers and the epigenetic clock theory of ageing
Horvath, S., & Raj, K. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0004-3 · Cited by 3,095
Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines
Rea, I. M., Gibson, D. S., McGilligan, V., McNerlan, S. E., Alexander, H. D., & Ross, O. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00586 · Cited by 1,267
DNA methylation age of blood predicts all-cause mortality in later life
Marioni, R. E., Shah, S., McRae, A. F., Chen, B. H., Colicino, E., Harris, S. E., Gibson, J., Henders, A. K., Redmond, P., Cox, S. R., et al. (2015) · Genome Biology · doi:10.1186/s13059-015-0584-6 · Cited by 1,261
Metadata
- Authors
- Bell, J. T., Tsai, P.-C., Yang, T.-P., Pidsley, R., Nisbet, J., Glass, D., Mangino, M., Zhai, G., Zhang, F., Valdes, A., Shin, S.-Y., Dempster, E. L., Murray, R. M., Grundberg, E., Hedman, A. K., Nica, A., Small, K. S., The MuTHER Consortium, Dermitzakis, E. T., McCarthy, M. I., Mill, J., Spector, T. D., & Deloukas, P.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-04-19
- Volume
- 8
- Issue
- 4
- Pages
- e1002629
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- OpenAlex
- W2136691282
- Cited by
- 685
- References
- 13
- FWCI
- 26.72
- Type
- journal article
- Language
- en
- Open access
- gold
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- Bell, J. T., Tsai, P.-C., Yang, T.-P., Pidsley, R., Nisbet, J., Glass, D., Mangino, M., Zhai, G., Zhang, F., Valdes, A., Shin, S.-Y., Dempster, E. L., Murray, R. M., Grundberg, E., Hedman, A. K., Nica, A., Small, K. S., The MuTHER Consortium, Dermitzakis, E. T., . . . Deloukas, P. (2012). Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1002629
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