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

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

*Corresponding author for this work

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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 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. Methods 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. 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.
Original languageEnglish
Article number1
Number of pages11
JournalGenome Medicine
Publication statusPublished - 31 Dec 2019

Bibliographical note

Availability of Data and Material

According to the terms of consent for GS participants, access to individual-level data (omics and phenotypes) must be reviewed by the GS Access Committee. Applications should be made to Full summary statistics for the analyses presented are publicly available online at


GS received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping and DNA methylation profiling of the GS samples was carried out by the Genetics Core Laboratory at the Clinical Research Facility, University of Edinburgh, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” ([STRADL; Reference 104036/Z/14/Z]). DLM and REM are supported by Alzheimer’s Research UK major project grant ARUK-PG2017B-10. PMV and AFM are supported by the NHMRC Fellowship Scheme (1078037, 1078901, and 1083656). JY is supported by an ARC Future Fellowship (FT180100186). RFH and AJS are supported by funding from the Wellcome Trust 4-year PhD in Translational Neuroscience – training the next generation of basic neuroscientists to embrace clinical research [108890/Z/15/Z]. CH and TB are supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease).


We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole GS team that includes

interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants, and nurses.


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


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