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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.
SUBMITTER: McCartney DL
PROVIDER: S-EPMC6938636 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
McCartney Daniel L DL Zhang Futao F Hillary Robert F RF Zhang Qian Q Stevenson Anna J AJ Walker Rosie M RM Bermingham Mairead L ML Boutin Thibaud T Morris Stewart W SW Campbell Archie A Murray Alison D AD Whalley Heather C HC Porteous David J DJ Hayward Caroline C Evans Kathryn L KL Chandra Tamir T Deary Ian J IJ McIntosh Andrew M AM Yang Jian J Visscher Peter M PM McRae Allan F AF Marioni Riccardo E RE
Genome medicine 20191231 1
<h4>Background</h4>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 t ...[more]