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Genome-wide association analyses highlight the role of the intestinal molecular environment in human gut microbiota variation

Dekkers, Koen F. ; Pertiwi, Kamalita ; Baldanzi, Gabriel ; Lundmark, Per ; Hammar, Ulf ; Moksnes, Marta Riise ; Coward, Eivind ; Nethander, Maria ; Salih, Ghassan Ali and Miari, Mariam LU , et al. (2026) In Nature Genetics
Abstract

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 × 10−11) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported... (More)

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 × 10−11) 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.

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publication status
epub
subject
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Nature Genetics
publisher
Nature Publishing Group
external identifiers
  • scopus:105030155459
  • pmid:41688638
ISSN
1061-4036
DOI
10.1038/s41588-026-02512-2
language
English
LU publication?
yes
id
ebec0b7c-22e0-4d66-b8fb-21c52d966497
date added to LUP
2026-03-02 13:05:36
date last changed
2026-03-02 14:59:22
@article{ebec0b7c-22e0-4d66-b8fb-21c52d966497,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{Dekkers, Koen F. and Pertiwi, Kamalita and Baldanzi, Gabriel and Lundmark, Per and Hammar, Ulf and Moksnes, Marta Riise and Coward, Eivind and Nethander, Maria and Salih, Ghassan Ali and Miari, Mariam and Nguyen, Diem and Sayols-Baixeras, Sergi and Eklund, Aron C. and Holm, Jacob Bak and Nielsen, H. Bjørn and Volpiano, Camila Gazolla and Méric, Guillaume and Thangam, Manonanthini and Hakaste, Liisa and Tuomi, Tiinamaija and Ahlqvist, Emma and Smith, Christopher A. and Allen, Marie and Reimann, Frank and Gribble, Fiona M. and Ohlsson, Claes and Hveem, Kristian and Melander, Olle and Nilsson, Peter M. and Engström, Gunnar and Smith, J. Gustav and Michaëlsson, Karl and Ärnlöv, Johan and Orho-Melander, Marju and Fall, Tove}},
  issn         = {{1061-4036}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Genome-wide association analyses highlight the role of the intestinal molecular environment in human gut microbiota variation}},
  url          = {{http://dx.doi.org/10.1038/s41588-026-02512-2}},
  doi          = {{10.1038/s41588-026-02512-2}},
  year         = {{2026}},
}