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

Jun Wang; Louise B. Thingholm; Jurgita Skiecevičie; 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

doi:10.1038/ng.3695

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

Jun Wang, Louise B. Thingholm, Jurgita Skiecevičie, 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. BergeMatthias 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^*

^*Corresponding author for this work

517 Citations (Scopus)

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 â '/â ' 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 â '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.

Original language	English
Journal	Nature Genetics
Volume	48
Issue number	11
Pages (from-to)	1396-1406
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3695
Publication status	Published - 01.11.2016

Funding

We thank A.D. Paterson and colleagues for support in selection of models for GWAS. We further thank Der Norddeutsche Verbund f?r Hoch- und H?chstleistungsrechnen (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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Wang, J., Thingholm, L. B., Skiecevičie, J., Rausch, P., Kummen, M., Hov, J. R., Degenhardt, F., Heinsen, F. A., Rühlemann, M. C., Szymczak, S., Holm, K., Esko, T., Sun, J., Pricop-Jeckstadt, M., Al-Dury, S., Bohov, P., Bethune, J., Sommer, F., Ellinghaus, D., ... Franke, A. (2016). Genome-wide association analysis identifies variation in Vitamin D receptor and other host factors influencing the gut microbiota. Nature Genetics, 48(11), 1396-1406. https://doi.org/10.1038/ng.3695

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title = "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 {\^a} '/{\^a} ' 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 {\^a} '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.",

author = "Jun Wang and Thingholm, \{Louise B.\} and Jurgita Skiecevi{\v c}ie and Philipp Rausch and Martin Kummen and Hov, \{Johannes R.\} and Frauke Degenhardt and Heinsen, \{Femke Anouska\} and R{\"u}hlemann, \{Malte C.\} and Silke Szymczak and Kristian Holm and T{\"o}nu Esko and Jun Sun and Mihaela Pricop-Jeckstadt and Samer Al-Dury and Pavol Bohov and J{\"o}rn Bethune and Felix Sommer and David Ellinghaus and Berge, \{Rolf K.\} and Matthias H{\"u}benthal and Manja Koch and Karin Schwarz and Gerald Rimbach and Patricia H{\"u}bbe and Pan, \{Wei Hung\} and Raheleh Sheibani-Tezerji and Robert H{\"a}sler and Philipp Rosenstiel and Mauro D'Amato and Katja Cloppenborg-Schmidt and Sven K{\"u}nzel and Matthias Laudes and Marschall, \{Hanns Ulrich\} and Wolfgang Lieb and Ute N{\"o}thlings and Karlsen, \{Tom H.\} and Baines, \{John F.\} and Andre Franke",

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Wang, J, Thingholm, LB, Skiecevičie, J, Rausch, P, Kummen, M, Hov, JR, Degenhardt, F, Heinsen, FA, Rühlemann, MC, Szymczak, S, Holm, K, Esko, T, Sun, J, Pricop-Jeckstadt, M, Al-Dury, S, Bohov, P, Bethune, J, Sommer, F, Ellinghaus, D, Berge, RK, Hübenthal, M, Koch, M, Schwarz, K, Rimbach, G, Hübbe, P, Pan, WH, Sheibani-Tezerji, R, Häsler, R, Rosenstiel, P, D'Amato, M, Cloppenborg-Schmidt, K, Künzel, S, Laudes, M, Marschall, HU, Lieb, W, Nöthlings, U, Karlsen, TH, Baines, JF & Franke, A 2016, 'Genome-wide association analysis identifies variation in Vitamin D receptor and other host factors influencing the gut microbiota', Nature Genetics, vol. 48, no. 11, pp. 1396-1406. https://doi.org/10.1038/ng.3695

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T1 - Genome-wide association analysis identifies variation in Vitamin D receptor and other host factors influencing the gut microbiota

AU - Wang, Jun

AU - Thingholm, Louise B.

AU - Skiecevičie, Jurgita

AU - Rausch, Philipp

AU - Kummen, Martin

AU - Hov, Johannes R.

AU - Degenhardt, Frauke

AU - Heinsen, Femke Anouska

AU - Rühlemann, Malte C.

AU - Szymczak, Silke

AU - Holm, Kristian

AU - Esko, Tönu

AU - Sun, Jun

AU - Pricop-Jeckstadt, Mihaela

AU - Al-Dury, Samer

AU - Bohov, Pavol

AU - Bethune, Jörn

AU - Sommer, Felix

AU - Ellinghaus, David

AU - Berge, Rolf K.

AU - Hübenthal, Matthias

AU - Koch, Manja

AU - Schwarz, Karin

AU - Rimbach, Gerald

AU - Hübbe, Patricia

AU - Pan, Wei Hung

AU - Sheibani-Tezerji, Raheleh

AU - Häsler, Robert

AU - Rosenstiel, Philipp

AU - D'Amato, Mauro

AU - Cloppenborg-Schmidt, Katja

AU - Künzel, Sven

AU - Laudes, Matthias

AU - Marschall, Hanns Ulrich

AU - Lieb, Wolfgang

AU - Nöthlings, Ute

AU - Karlsen, Tom H.

AU - Baines, John F.

AU - Franke, Andre

PY - 2016/11/1

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N2 - 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 â '/â ' 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 â '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.

AB - 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 â '/â ' 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 â '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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DO - 10.1038/ng.3695

M3 - Journal articles

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AN - SCOPUS:84990998440

SN - 1061-4036

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SP - 1396

EP - 1406

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

Abstract

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UN SDGs

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