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

Abstract

BackgroundAdvanced 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.MethodsLinear 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.ResultsUsing 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.ConclusionThe 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.

Age-related DNA methylation changes are sex-specific: a comprehensive assessment

“…Finally, we searched for those probes displaying different DNA methylation trajectories in males and females during aging. We identified 8 probes having age-by-sex interaction, 2 of which were recently reported by McCartney et al in an independent dataset [32]. In particular we found that FIGN gene, which encodes for an ATP-dependent microtubule severing enzyme which catalyzes internal breaks in microtubules, included both probes from the saDMPs list and displaying age-by-sex interactions.…”

“…Meta-analysis resulted in 8 CpG probes whose methylation showed different aging trajectories according to sex (Supplementary File 4). Two of these CpG sites were previously identified as having age-by-sex interaction in whole blood [32], and the most significant CpG site (cg18834375) mapped within FIGN gene, that was the top ranker also in the list of saDMPs and included multiple CpG sites showing sex-and age-dependent methylation (cg01620164, cg19156483, cg10864319, cg18834375, cg15259986 and cg03878133).…”

“…Furthermore, although some ancestries are included, many are missing, and the study of additional populations will be necessary to distinguish the effects of sex and gender in shaping age-related methylation changes. Finally, similarly to [22], our study includes only autosomal probes (after the removal of crossreactive probes), while recently McCartney et al found that many of the probes with a sex by age interaction are on the X chromosome [32].…”

“…Our results are compared with the only study that, to the best of our knowledge, recently investigated normative age-by-sex DNA methylation differences in whole blood of a single population, i.e. a large Scottish cohort [32].…”

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

“…The IEAA-associated locus on chromosome 3 (lead SNP rs1047210) colocalized with an eQTL for TRIM59. DNA methylation levels at TRIM59 have been robustly associated with chronological age and its expression has been noted in multiple cancers [53,54,55,56,57].…”