Abstract

Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr−/− mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10−8) associations at multiple additional loci identify other important points of host–microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.

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Acknowledgements

We thank A.D. Paterson and colleagues for support in selection of models for GWAS. We further thank Der Norddeutsche Verbund für Hoch- und Höchstleistungsrechnen (HLRN) and S. Knief and H. Marten for computational resources and support. This work was supported by German Research Foundation (DFG) Collaborative Research Center 1182, 'Origin and Function of Metaorganisms' (J.F.B. and A.F.) and Excellence Cluster 306, 'Inflammation at Interfaces' (J.F.B. and A.F.) and by German Federal Ministry of Education and Research (BMBF) project 'SysINFLAME' (J.F.B. and A.F.). Project support was also provided by the Norwegian PSC Research Center and the Western Norway Regional Health Authority (grant 911802) (T.H.K.). M.K. is the recipient of a Postdoctoral Research Fellowship from the German Research Foundation (DFG). J.R.H. was funded by the Norwegian Research Council (240787/F20).

Author information

Author notes

    • Jun Wang
    •  & Silke Szymczak

    Present addresses: Department of Microbiology and Immunology, KU Leuven and Center for the Biology of Disease, VIB, Leuven, Belgium (J.W.) and Institute of Medical Informatics and Statistics, Christian Albrechts University of Kiel, Kiel, Germany (S.S.).

    • Jun Wang
    • , Louise B Thingholm
    •  & Jurgita Skiecevičienė

    These authors contributed equally to this work.

    • Tom H Karlsen
    • , John F Baines
    •  & Andre Franke

    These authors jointly directed this work.

Affiliations

  1. Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Plön, Germany.

    • Jun Wang
    • , Philipp Rausch
    • , Sven Künzel
    •  & John F Baines
  2. Institute for Experimental Medicine, Christian Albrechts University of Kiel, Kiel, Germany.

    • Jun Wang
    • , Philipp Rausch
    • , Katja Cloppenborg-Schmidt
    •  & John F Baines
  3. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • Louise B Thingholm
    • , Jurgita Skiecevičienė
    • , Frauke Degenhardt
    • , Femke-Anouska Heinsen
    • , Malte C Rühlemann
    • , Silke Szymczak
    • , Jörn Bethune
    • , Felix Sommer
    • , David Ellinghaus
    • , Matthias Hübenthal
    • , Wei-Hung Pan
    • , Raheleh Sheibani-Tezerji
    • , Robert Häsler
    • , Philipp Rosenstiel
    •  & Andre Franke
  4. Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo, Norway.

    • Martin Kummen
    • , Johannes R Hov
    • , Kristian Holm
    •  & Tom H Karlsen
  5. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

    • Martin Kummen
    • , Johannes R Hov
    • , Kristian Holm
    •  & Tom H Karlsen
  6. K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Martin Kummen
    • , Johannes R Hov
    • , Kristian Holm
    •  & Tom H Karlsen
  7. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.

    • Martin Kummen
    • , Johannes R Hov
    • , Kristian Holm
    •  & Tom H Karlsen
  8. Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.

    • Johannes R Hov
    •  & Tom H Karlsen
  9. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tönu Esko
  10. Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

    • Jun Sun
  11. Department of Nutrition and Food Sciences, Nutritional Epidemiology, University of Bonn, Bonn, Germany.

    • Mihaela Pricop-Jeckstadt
    •  & Ute Nöthlings
  12. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Samer Al-Dury
    •  & Hanns-Ulrich Marschall
  13. Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Pavol Bohov
    •  & Rolf K Berge
  14. Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.

    • Rolf K Berge
  15. Institute of Epidemiology, Christian Albrechts University of Kiel, Kiel, Germany.

    • Manja Koch
    •  & Wolfgang Lieb
  16. Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany.

    • Karin Schwarz
    • , Gerald Rimbach
    •  & Patricia Hübbe
  17. BioDonostia Health Research Institute, San Sebastian and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.

    • Mauro D'Amato
  18. Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

    • Mauro D'Amato
  19. Department of Internal Medicine I, University Hospital S.-H. (UKSH, Campus Kiel), Kiel, Germany.

    • Matthias Laudes
  20. Department of Clinical Medicine, University of Bergen, Bergen, Norway.

    • Tom H Karlsen

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Contributions

A.F., J.F.B. and T.H.K. conceived the project. U.N., W.L., M.L. and K.S. organized recruitment and sample collection for the PopGen and FoCus cohorts. Genotyping data were collected and processed by L.B.T., J. Skiecevicˇienė, J.R.H., F.D. and K.H.; nutritional data were generated and processed by S.S., M.P.-J., M. Koch and U.N.; microbiome data were generated and processed by J.W., P. Rausch, F.-A.H., M.C.R., P. Rosenstiel, K.C.-S., S.K. and J.F.B.; and bile acid and fatty acid data were generated and processed by S.A.-D., P.B., R.K.B., M.D'A. and H.-U.M. T.E., J. Sun, J.B., F.S., D.E., M.H., G.R., P.H., W.-H.P., R.S.-T., R.H. and P. Rosenstiel contributed to additional experiments and data for this study. Statistical analyses were performed by J.W., L.B.T., J. Skiecevicˇienė, P. Rausch and M. Kummen, and J.W., L.B.T., J. Skiecevicˇienė, P. Rausch, M. Kummen, J.R.H., M.D'A., H.-U.M., T.H.K., J.F.B. and A.F. interpreted the results. J.W., L.B.T., J. Skiecevicˇienė, P. Rausch, M. Kummen, J.R.H., T.H.K., J.F.B. and A.F. wrote the manuscript, with input from all other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andre Franke.

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DOI

https://doi.org/10.1038/ng.3695

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