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


RESULTS
In 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.


CONCLUSIONS
Our 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.
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
Paula
P
Singmann
Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.
Doron
D
Shem-Tov
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Simone
S
Wahl
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Harald
H
Grallert
Human Genetics Foundation-Torino, Turin, Italy ; Department of Medical Sciences, University of Torino, Turin, Italy.
Giovanni
G
Fiorito
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK ; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
So-Youn
SY
Shin
Institute of Human Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Human Genetics, Technical University Munich, Munich, Germany.
Katharina
K
Schramm
Institute of Human Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Human Genetics, Technical University Munich, Munich, Germany.
Petra
P
Wolf
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
Sonja
S
Kunze
Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.
Yael
Y
Baran
Human Genetics Foundation-Torino, Turin, Italy ; Department of Medical Sciences, University of Torino, Turin, Italy.
Simonetta
S
Guarrera
Human Genetics Foundation-Torino, Turin, Italy ; Epidemiology and Public Health, Imperial College London, London, UK.
Paolo
P
Vineis
Epidemiology and Prevention Unit, Fondazione IRCSS Istituto Nazionale Tumori, Milan, Italy.
Vittorio
V
Krogh
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
Salvatore
S
Panico
Cancer Registry and Histopathology Unit, "Civile-M.P. Arezzo" Hospital, ASP 7, Ragusa, Italy.
Rosario
R
Tumino
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
Anja
A
Kretschmer
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
Christian
C
Gieger
Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Annette
A
Peters
Institute of Human Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Human Genetics, Technical University Munich, Munich, Germany.
Holger
H
Prokisch
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK ; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Caroline L
CL
Relton
Human Genetics Foundation-Torino, Turin, Italy ; Department of Medical Sciences, University of Torino, Turin, Italy.
Giuseppe
G
Matullo
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Hannover Unified Biobank, Hannover Medical School, Hannover, Germany ; Institute for Human Genetics, Hannover Medical School, Hannover, Germany.
Thomas
T
Illig
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany ; Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
Melanie
M
Waldenberger
Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel ; Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv, Israel ; International Computer Science Institute, Berkeley, CA USA.
Eran
E
Halperin
ALSPAC; CpG; DNA methylation; EPICOR; EWAS; Enrichment analysis; Imprinting; KORA; Sex