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Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota

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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Figure 1: Overview of variation in the gut microbiota and significantly associated non-genetic parameters.
Figure 2: Individual and combined effects of significant loci and overview of all significant loci identified in this study.
Figure 3: VDR and POMC as examples of genes associated with β diversity.

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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).

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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.

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Correspondence to Andre Franke.

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Wang, J., Thingholm, L., Skiecevičienė, J. et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet 48, 1396–1406 (2016). https://doi.org/10.1038/ng.3695

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