Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota
Open accessAbstract
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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Twin studies and GWAS show that host genetics can influence the microbiome composition, and microbes can exert effects on the host genome, although the environment has an important role.
“Twin studies and GWAS show that host genetics can influence the microbiome composition, and microbes can exert effects on the host genome, although the environment has an important role [121,122].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [122]
The Abstract describes twin-study evidence and this paper’s GWAS evidence that host genetics influence gut microbiome composition. The Discussion says non-genetic factors, including diet, have a similar cumulative influence. Neither passage supports the separate claim that microbes exert effects on the host genome. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVariants in the gene encoding the vitamin D receptor affect the composition of the microbiome.
“For example, variants in the gene encoding the vitamin D receptor affect the composition of the microbiome,76”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [76]
Many of the highlighted genetic loci were involved in the host immune response.
“Interestingly, many of the highlighted genetic loci were involved in the host immune response. 78”
From Key determinants of success in fecal microbiota transplantation: From microbiome to clinic (2023) · cites this paper as [78]
Specific associations between gene polymorphisms and taxa have been identified by multiple genome-wide association studies from different countries and cohorts.
“Specific associations between gene polymorphisms and taxa have been identified by multiple genomewide association studies from different countries and cohorts. 77,78”
From Key determinants of success in fecal microbiota transplantation: From microbiome to clinic (2023) · cites this paper as [78]
Studies have found evidence for heritability of relative bacterial abundances or specific taxa.
“with studies finding evidence for heritability of relative bacterial abundances or specific taxa [15, 63–68]”
From Population structure of human gut bacteria in a diverse cohort from rural Tanzania and Botswana (2019) · cites this paper as [15]
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- Authors
- Wang, J., Thingholm, L. B., Skiecevičienė, 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., Berge, R. K., Hübenthal, M., Koch, M., Schwarz, K., Rimbach, G., Hübbe, P., Pan, W.-H., Sheibani-Tezerji, R., Häsler, R., Rosenstiel, P., D'Amato, M., Cloppenborg-Schmidt, K., Künzel, S., Laudes, M., Marschall, H.-U., Lieb, W., Nöthlings, U., Karlsen, T. H., Baines, J. F., & Franke, A.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- Oslo University Hospital (NO)
- University of Illinois Chicago (US)
- University of Gothenburg (SE)
- University of Bergen (NO)
- Haukeland University Hospital (NO)
- Max Planck Institute for Evolutionary Biology (DE)
- University Hospital Schleswig-Holstein (DE)
- University of Bonn (DE)
- ORCID
- Thingholm, Louise B
- Skiecevičienė, Jurgita
- Rausch, Philipp
- Kummen, Martin
- Hov, Johannes R
- Degenhardt, Frauke
- Heinsen, Femke-Anouska
- Rühlemann, Malte C
- Szymczak, Silke
- Holm, Kristian
- Esko, Tönu
- Sun, Jun
- Al-Dury, Samer
- Bohov, Pavol
- Bethune, Jörn
- Sommer, Felix
- Ellinghaus, David
- Hübenthal, Matthias
- Koch, Manja
- Schwarz, Karin
- Rimbach, Gerald
- Häsler, Robert
- Künzel, Sven
- Laudes, Matthias
- Marschall, Hanns-Ulrich
- Lieb, Wolfgang
- Nöthlings, Ute
- Karlsen, Tom H
- Baines, John F
- Venue
- Nature Genetics
- Published
- 2016-10-10
- Volume
- 48
- Issue
- 11
- Pages
- 1396-1406
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5626933
- OpenAlex
- W2531570974
- Cited by
- 625
- References
- 67
- Citations by year
- 2026: 22 · 2025: 42 · 2024: 42 · 2023: 59 · 2022: 90 · 2021: 86 · 2020: 87 · 2019: 73 · 2018: 65 · 2017: 50 · 2016: 7 · 2012: 1
- FWCI
- 33.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Max Planck Digital Library (submittedVersion)
- Lithuanian University of Health Sciences (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Engineering and Physical Sciences Research Council (EP/K032208/1)
- National Institute of Diabetes and Digestive and Kidney Diseases (R03DK089010, R01DK105118)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- gut microbiota, host genetics, vitamin D receptor, vitamin D receptor gene, bile acids, fatty acids, sterol metabolism, susceptibility genes, host-microbe interactions, microbial diversity, VDR knockout mice, serum metabolites
- MeSH terms
- Gastrointestinal Microbiome, Adult, Aged, Aged, 80 and over, Animals, Bacteria, Diet, Female, Humans, Male, Middle Aged, Cohort Studies, Receptors, Calcitriol, Mice, Knockout, Polymorphism, Single Nucleotide, Mice, Genome-Wide Association Study
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