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.
journal_name
Genome Medjournal_title
Genome medicineauthors
McCartney DL,Zhang F,Hillary RF,Zhang Q,Stevenson AJ,Walker RM,Bermingham ML,Boutin T,Morris SW,Campbell A,Murray AD,Whalley HC,Porteous DJ,Hayward C,Evans KL,Chandra T,Deary IJ,McIntosh AM,Yang J,Visscher PM,McRadoi
10.1186/s13073-019-0693-zsubject
Has Abstractpub_date
2019-12-31 00:00:00pages
1issue
1issn
1756-994Xpii
10.1186/s13073-019-0693-zjournal_volume
12pub_type
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