Genome-wide association analyses highlight the role of the intestinal molecular environment in human gut microbiota variation
Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic data from 16,017 adults in four Swedish population-based studies, with replication in 12,652 people from the Norwegian HUNT study. We identified variants in the OR51E1-OR51E2 locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (P < 5.4 × 10<sup>-11</sup>) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported associations at LCT, ABO and FUT2, and provide evidence for new loci MUC12, CORO7-HMOX2, SLC5A11, FOXP1 and FUT3-FUT6, with supporting data from metabolomics and gene expression analyses. Our findings link gut microbial variation genetically to gastrointestinal functions, including enteroendocrine fatty acid sensing, bile composition and mucosal layer composition.
Authors
- Sergi Sayols-Baixeras (ORCID: https://orcid.org/0000-0002-1181-6262)
- Gabriel Baldanzi (ORCID: https://orcid.org/0000-0003-3962-3953)
- Fiona M. Gribble (ORCID: https://orcid.org/0000-0002-4232-2898)
- Aron C. Eklund (ORCID: https://orcid.org/0000-0003-0861-1001)
- T Fall
- Manonanthini Thangam (ORCID: https://orcid.org/0000-0002-7164-6525)
- Camila Gazolla Volpiano (ORCID: https://orcid.org/0000-0002-8251-1685)
- Per Lundmark
- Emma Ahlqvist
- Ghassan Ali Salih
- Jacob Bak Holm (ORCID: https://orcid.org/0000-0003-1756-0875)
- Mariam Miari
- Guillaume Méric (ORCID: https://orcid.org/0000-0001-6288-9958)
- Koen F. Dekkers (ORCID: https://orcid.org/0000-0002-4074-7235)
- Marta R. Moksnes (ORCID: https://orcid.org/0000-0002-2690-5153)
- Marie Allen
- Eivind Coward
- Ulf Hammar
- Marju Orho-Melander
- Liisa Hakaste
- Johan Ärnlöv
- Tiinamaija Tuomi
- Karl Michaëlsson
- Frank Reimann
- Maria Nethander
- Christopher A. Smith
- Peter M. Nilsson
- Diem Nguyen
- Kamalita Pertiwi
- H. Bjørn Nielsen
- J. Gustav Smith
Institutions
- Dalarna University (SE)
- Uppsala University (SE)
- Statistics Denmark (DK)
- University of Baghdad (IQ)
- Baker Heart and Diabetes Institute (AU)
- The University of Melbourne (AU)
- Lund University (SE)
- La Trobe University (AU)
- Norwegian University of Science and Technology (NO)
- University of Cambridge (GB)
- Science for Life Laboratory (SE)
- Levanger Hospital (NO)
- Helsinki University Hospital (FI)
- Sahlgrenska University Hospital (SE)
- Instituto de Salud Carlos III (ES)
- Karolinska Institutet (SE)
- Centro de Investigación en Red en Enfermedades Cardiovasculares (ES)
- Region Västra Götaland (SE)
- Wellcome/MRC Institute of Metabolic Science (GB)
- Wallenberg Wood Science Center (SE)
- Center for Clinical Research Dalarna (SE)
- Institute for Molecular Medicine Finland (FI)
- Skåne University Hospital (SE)
- Folkhälsans Forskningscentrum (FI)
- University of Bath (GB)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-02-13
- DOI
- https://doi.org/10.1038/s41588-026-02512-2
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.00