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Age-dependent DNA methylation patterns on the Y chromosome in elderly males.
Lund JB, Li S, Christensen K, Mengel-From J, Soerensen M, Marioni RE, Starr J, Pattie A, Deary IJ, Baumbach J, Tan Q
The Y chromosome, a sex chromosome that only exists in males, has been ignored in traditional epigenetic association studies for multiple reasons. However, sex differences in aging-related phenotypes and mortality could suggest a critical role of the sex chromosomes in the aging process. We obtained blood-based DNA methylation data on the Y chromosome for 624 men from four cohorts and performed a chromosome-wide epigenetic association analysis to detect Y-linked CpGs differentially methylated over age and cross-validated the significant CpGs in the four cohorts. We identified 40-219 significant CpG sites (false discovery rate <0.05) with >82% of them hypermethylated with increasing age, which is in strong contrast to the patterns reported on the autosomal chromosomes. Comparing the rate of change in the Y-linked DNA methylation across cohorts that represent different age intervals revealed a trend of acceleration in DNA methylation with increasing age. The age-dependent DNA methylation patterns on the Y chromosome were further examined for their association with all-cause mortality with results suggesting that the predominant pattern of age-related hypermethylation on the Y chromosome is associated with reduced risk of death.