Gender-specific pathway differences in the human serum metabolome

Jan Krumsiek, Kirstin Mittelstrass, Kieu Trinh Do, Ferdinand Stückler, Janina Ried, Jerzy Adamski, Annette Peters, Thomas Illig, Florian Kronenberg, Nele Friedrich, Matthias Nauck, Maik Pietzner, Dennis O. Mook-Kanamori, Karsten Suhre, Christian Gieger, Harald Grallert, Fabian J. Theis, Gabi Kastenmüller

Research output: Contribution to journalArticle

55 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1815-1833
Number of pages19
Issue number6
Publication statusPublished - 1 Dec 2015
Externally publishedYes



  • Epidemiology
  • Gender differences
  • Metabolic networks
  • Metabolomics
  • Systems biology

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry

Cite this

Krumsiek, J., Mittelstrass, K., Do, K. T., Stückler, F., Ried, J., 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. (2015). Gender-specific pathway differences in the human serum metabolome. Metabolomics, 11(6), 1815-1833.