Gender-specific pathway differences in the human serum metabolome.
The susceptibility for various diseases as well as the response to treatments differ considerably between men and women. As a basis for a gender-specific personalized healthcare, an extensive characterization of the molecular differences between the two genders is required. In the present study, we conducted a large-scale metabolomics analysis of 507 metabolic markers measured in serum of 1756 participants from the German KORA F4 study (903 females and 853 males). One-third of the metabolites show significant differences between males and females. A pathway analysis revealed strong differences in steroid metabolism, fatty acids and further lipids, a large fraction of amino acids, oxidative phosphorylation, purine metabolism and gamma-glutamyl dipeptides. We then extended this analysis by a network-based clustering approach. Metabolite interactions were estimated using Gaussian graphical models to get an unbiased, fully data-driven metabolic network representation. This approach is not limited to possibly arbitrary pathway boundaries and can even include poorly or uncharacterized metabolites. The network analysis revealed several strongly gender-regulated submodules across different pathways. Finally, a gender-stratified genome-wide association study was performed to determine whether the observed gender differences are caused by dimorphisms in the effects of genetic polymorphisms on the metabolome. With only a single genome-wide significant hit, our results suggest that this scenario is not the case. In summary, we report an extensive characterization and interpretation of gender-specific differences of the human serum metabolome, providing a broad basis for future analyses.
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany ; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Jan
0000-0003-4734-3791
J
Krumsiek
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany ; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Kirstin
K
Mittelstrass
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Kieu Trinh
KT
Do
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Ferdinand
F
Stückler
Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
Janina
J
Ried
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany ; Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany ; Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany.
Jerzy
J
Adamski
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany ; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany ; German Center for Cardiovascular Disease Research (DZHK e.V.), Munich, Germany.
Annette
A
Peters
Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
Thomas
T
Illig
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria.
Florian
F
Kronenberg
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany ; DZHK (German Center for Cardiovascular Research), Greifswald, Greifswald, Germany.
Nele
N
Friedrich
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany ; DZHK (German Center for Cardiovascular Research), Greifswald, Greifswald, Germany.
Matthias
M
Nauck
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany ; DZHK (German Center for Cardiovascular Research), Greifswald, Greifswald, Germany.
Maik
M
Pietzner
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands ; Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands ; Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Qatar Foundation, Doha, Qatar.
Dennis O
DO
Mook-Kanamori
Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Qatar Foundation, Doha, Qatar ; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Karsten
K
Suhre
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany ; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Christian
C
Gieger
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany ; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Harald
H
Grallert
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany ; Department of Mathematics, Technische Universität München, Garching, Germany.
Fabian J
FJ
Theis
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany ; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Gabi
G
Kastenmüller
Epidemiology; Gender differences; Metabolic networks; Metabolomics; Systems biology