Age-dependent DNA methylation patterns on the Y chromosome in elderly males

Abstract

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.

Keywords: DNA methylation; Y chromosome; age-dependent patterns; aging; mortality.

Figure 1

Plotted coefficients of the discovery analysis over their chromosome position. Trend lines were fitted by local polynomial regression fitting (LOESS). Colored dots are significant sites (FDR <0.05). Gray dots are nonsignificant sites. Mean cohort age: 66.73, 79.43, 81.69, and 88.51 for MADT (purple), LSADT2 (blue), LSADT1 (green), and LBC1921 (red), respectively

Figure 2

Plots displaying accelerated increase in DNA methylation by significantly hypermethylated CpGs (FDR <0.05) in the four cohorts ordered by increasing mean age. The boxplots in 2a and 2b show the distribution of sample ages and regression coefficients of hypermethylated CpGs in each cohort. Acceleration in DNA hypermethylation with increasing age is clearly illustrated by plotting, for each cohort, the means of ages and means of regression coefficients normalized by MADT (2c)

Figure 3

Scatterplot displaying relationship between age‐related rate of change in DNA methylation and mortality. The empty dots are CpGs significantly methylated with age (FDR <0.05, the larger the dots the higher the statistical significance). The red dots are CpGs associated with mortality with p < 0.05 in the Cox regression model. The figure shows that age‐associated CpGs predominantly contribute to reduced risk of death