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

Jun Wang, Louise B Thingholm, Jurgita Skiecevičienė, Philipp Rausch, Martin Kummen, Johannes R Hov, Frauke Degenhardt, Femke-Anouska Heinsen, Malte C Rühlemann, Silke Szymczak, Kristian Holm, Tönu Esko, Jun Sun, Mihaela Pricop-Jeckstadt, Samer Al-Dury, Pavol Bohov, Jörn Bethune, Felix Sommer, David Ellinghaus, Rolf K Berge, Matthias Hübenthal, Manja Koch, Karin Schwarz, Gerald Rimbach, Patricia Hübbe, Wei-Hung Pan, Raheleh Sheibani-Tezerji, Robert Häsler, Philipp Rosenstiel, Mauro D'Amato, Katja Cloppenborg-Schmidt, Sven Künzel, Matthias Laudes, Hanns-Ulrich Marschall, Wolfgang Lieb, Ute Nöthlings, Tom H Karlsen, John F Baines, Andre Franke

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.