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An epigenome-wide association study of sex-specific chronological ageing
Open accessPublished version of a preprint
Abstract
Background: Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 individuals between the ages of 18 and 87 years, with replication in a further 4450 individuals between the ages of 18 and 93 years. Methods: Linear regression models were applied, with stringent genome-wide significance thresholds ( p < 3.6 × 10 −8 ) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds. Results: Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10 , an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = − 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction. Conclusion: The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.
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“As advanced aging is the strongest factor for AD, we also compared our results with those from Yusipov et al. [94] and McCartney et al. [35], which identified 8 and 52 autosomal CpGs differentially affected by aging, but we did not find any overlap with these previous studies.”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [35]
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Metadata
- Authors
- McCartney, D. L., Zhang, F., Hillary, R. F., Zhang, Q., Stevenson, A. J., Walker, R. M., Bermingham, M. L., Boutin, T., Morris, S. W., Campbell, A., Murray, A. D., Whalley, H. C., Porteous, D. J., Hayward, C., Evans, K. L., Chandra, T., Deary, I. J., McIntosh, A. M., Yang, J., Visscher, P. M., McRae, A. F., & Marioni, R. E.
- Affiliations
- Institute of Genetics and Cancer (GB)
- The University of Queensland (AU)
- University of Aberdeen (GB)
- Royal Edinburgh Hospital (GB)
- University of Edinburgh (GB)
- Corresponding author
- Marioni, Riccardo E.
- ORCID
- McCartney, Daniel L.
- Zhang, Futao
- Hillary, Robert F.
- Zhang, Qian
- Stevenson, Anna J.
- Walker, Rosie M.
- Bermingham, Mairead L.
- Boutin, Thibaud
- Campbell, Archie
- Murray, Alison D.
- Whalley, Heather C.
- Porteous, David J.
- Hayward, Caroline
- Evans, Kathryn L.
- Chandra, Tamir
- Deary, Ian J.
- McIntosh, Andrew M.
- Yang, Jian
- Visscher, Peter M.
- McRae, Allan F.
- Marioni, Riccardo E.
- Venue
- Genome Medicine
- Published
- 2019-12-31
- Volume
- 12
- Issue
- 1
- Pages
- 1-1
- ISSN
- 1756-994X (ISSN-L)
- PMC
- PMC6938636
- OpenAlex
- W2992920781
- Cited by
- 152
- References
- 63
- Citations by year
- 2026: 7 · 2025: 32 · 2024: 26 · 2023: 17 · 2022: 26 · 2021: 40 · 2020: 4
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Wellcome Trust (104036/Z/14/Z, 108890/Z/15/Z)
- Alzheimer’s Research UK (ARUK-PG2017B-10)
- National Health and Medical Research Council (1078037, 1083656)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA methylation, chronological aging, sex differences, X chromosome, epigenome-wide association study, sexually dimorphic traits, blood DNA methylation, linear mixed models
- MeSH terms
- Adult, Aged, Aging, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Sex Characteristics, Linear Models, CpG Islands, DNA Methylation, Quantitative Trait Loci, Chromosomes, Human, X, Genome-Wide Association Study
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