Abstract
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.
Funder
Wellcome Trust
Alzheimer’s Research UK
National Health and Medical Research Council
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
Reference54 articles.
1. Alberts SC, Archie EA, Gesquiere LR, et al. The male-female health-survival paradox: A comparative perspective on sex differences in aging and mortality. In: Sociality, Hierarchy, Health: Comparative Biodemography: A Collection of Papers. 2014.
2. Regitz-Zagrosek V. Sex and gender differences in health. EMBO Rep. 2012. https://doi.org/10.1038/embor.2012.87.
3. National Records of Scotland. Life Tables for Scotland 2015–2017. https://www.nrscotland.gov.uk/statistics-and-data/statistics/statistics-by-theme/life-expectancy/life-expectancy-at-scotland-level/scottish-national-life-tables/2015-2017
.
4. Vijg J, Suh Y. Genome instability and aging. Annu Rev Physiol. 2013. https://doi.org/10.1146/annurev-physiol-030212-183715.
5. Harley CB. Telomere loss: mitotic clock or genetic time bomb? Mutat Res DNAging. 1991. https://doi.org/10.1016/0921-8734(91)90018-7.
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