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

Jesper B Lund,Shuxia Li,Ian J Deary,Qihua Tan,Riccardo E Marioni,John Starr,Jonas Mengel‐From,Jan Baumbach,Mette Soerensen,Kaare Christensen,Alison Pattie

doi:10.1111/acel.12907

Jesper B Lund, Shuxia Li + Show 9 more

Open Access

https://doi.org/10.1111/acel.12907

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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.

Highlights

The Y chromosome, the sex‐determining chromosome found only in the male phenotype of the population, contains circa 57 million DNA base pairs
In comparison with the recent upsurge in omics studies focusing on autosomal chromosomes, the sex chromosomes are often not included in analyses, especially within genome‐wide association studies (GWAS), epigenome‐wide association studies (EWAS), and transcriptome‐wide association studies (TWAS) on complex diseases and traits (Wise, Gyi, & Manolio, 2013)
We identified significant CpG sites that change their methylation levels across ages

Summary

| INTRODUCTION

The Y chromosome, the sex‐determining chromosome found only in the male phenotype of the population, contains circa 57 million DNA base pairs In comparison with the recent upsurge in omics studies focusing on autosomal chromosomes, the sex chromosomes are often not included in analyses, especially within genome‐wide association studies (GWAS), epigenome‐wide association studies (EWAS), and transcriptome‐wide association studies (TWAS) on complex diseases and traits (Wise, Gyi, & Manolio, 2013). This is unfortunate because the sex chromosomes could be influential (directly or indirectly) on certain diseases with sex differences (Khramtsova et al 2019). We replicate findings across datasets and correlate age‐related methylation changes with all‐cause mortality and discuss potential implications in the epigenetics of aging

| RESULTS

| DISCUSSION

| MATERIALS AND METHODS

Findings

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