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Krumsiek, J. ; Mittelstraß, K. ; Do, K.T. ; Stückler, F. ; Ried, J.S. ; Adamski, J. ; Peters, A. ; Illig, T.* ; Kronenberg, F.* ; Friedrich, N.* ; Nauck, M.* ; Pietzner, M.* ; Mook-Kanamori, D.O.* ; Suhre, K. ; Gieger, C. ; Grallert, H. ; Theis, F.J. ; Kastenmüller, G.

Gender-specific pathway differences in the human serum metabolome.

Metabolomics 11, 1815-1833 (2015)

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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.

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