An epigenome-wide association study of sex-specific chronological ageing

Daniel L. McCartney, Futao Zhang, Robert Hillary, Qian Zhang, Anna J. Stevenson, Rosie M. Walker, Mairead L. Bermingham, Thibaud Boutin, Stewart W. Morris, Archie Campbell, Alison D. Murray, Heather C. Whalley, David J. Porteous, Caroline Hayward, Kathryn L. Evans, Tamir Chandra, Ian J. Deary, Andrew M. McIntosh, Jian Yang, Peter M. VisscherAllan F. McRae, Riccardo E. Marioni

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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

Keywords / Materials (for Non-textual outputs)

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


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