Characterization of whole-genome autosomal differences of DNA methylation between men and women.

Paula Singmann,Petra Wolf,Yael Baran,Eran Halperin,Simone Wahl,Giuseppe Matullo,Doron Shem-Tov,Rosario Tumino,Annette Peters,Simonetta Guarrera,Holger Prokisch,Thomas Illig,Vittorio Krogh,Giovanni Fiorito,Anja Kretschmer,Salvatore Panico,Christian Gieger,Sonja Kunze,Katharina Schramm,Harald Grallert,Caroline L Relton ,So Youn Shin ,Mélanie Waldenberger ,Paolo Víneis

doi:10.1186/s13072-015-0035-3

Abstract

BackgroundDisease risk and incidence between males and females reveal differences, and sex is an important component of any investigation of the determinants of phenotypes or disease etiology. Further striking differences between men and women are known, for instance, at the metabolic level. The extent to which men and women vary at the level of the epigenome, however, is not well documented. DNA methylation is the best known epigenetic mechanism to date.ResultsIn order to shed light on epigenetic differences, we compared autosomal DNA methylation levels between men and women in blood in a large prospective European cohort of 1799 subjects, and replicated our findings in three independent European cohorts. We identified and validated 1184 CpG sites to be differentially methylated between men and women and observed that these CpG sites were distributed across all autosomes. We showed that some of the differentially methylated loci also exhibit differential gene expression between men and women. Finally, we found that the differentially methylated loci are enriched among imprinted genes, and that their genomic location in the genome is concentrated in CpG island shores.ConclusionOur epigenome-wide association study indicates that differences between men and women are so substantial that they should be considered in design and analyses of future studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0035-3) contains supplementary material, which is available to authorized users.

Highlights

Disease risk and incidence between males and females reveal differences, and sex is an important component of any investigation of the determinants of phenotypes or disease etiology
Differences exist in risk and incidence of diseases between males and females, and sex is an important component of any investigation of the determinants of phenotype or disease etiology [1, 2]
Enrichment of sex‐methylation associations (SMAs) in imprinted genes In order to investigate the distribution of sex methylation association (SMA) across the genome further, we explored the possibility that DNA methylation (DNAm) varies in imprinted genes between sexes

Summary

Introduction

Disease risk and incidence between males and females reveal differences, and sex is an important component of any investigation of the determinants of phenotypes or disease etiology. Further striking differences between men and women are known, for instance, at the metabolic level. Differences exist in risk and incidence of diseases between males and females, and sex is an important component of any investigation of the determinants of phenotype or disease etiology [1, 2]. The relation between DNAm and sex in humans has been studied previously [5,6,7,8]. These studies, were limited in their scope and in their statistical power. Others have focused on specific pathways or loci (e.g., cancer sites [13], specific genes [11, 14], low numbers of CpGs across the genome [15]), or restricted their analysis to certain chromosomes [16, 17]

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