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 2,586 individuals between the ages of 18 and 87 years, with replication in a further 4,450 individuals between the ages of 18 and 93 years. 
Linear regression models were applied, with stringent genome-wide significance thresholds (P<3.6x10-8) 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.
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.

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.
Original languageEnglish
Article number1
JournalGenome Biology
Publication statusPublished - 31 Dec 2019


  • DNA methylation
  • ageing
  • sexual dimorphism
  • X-chromosome
  • Generation Scotland


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