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<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 <i>OR51E1–OR51E2</i> locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (<i>P</i> &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 <i>LCT</i>, <i>ABO</i> and <i>FUT2</i>, and provide evidence for new loci <i>MUC12</i>, <i>CORO7–HMOX2</i>, <i>SLC5A11</i>, <i>FOXP1</i> and <i>FUT3–FUT6</i>, 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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月13日

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  • Koen F. Dekkers,
  • Kamalita Pertiwi,
  • Gabriel Baldanzi,
  • Per Lundmark,
  • Ulf Hammar,
  • Marta Riise Moksnes,
  • Eivind Coward,
  • Maria Nethander,
  • Ghassan Ali Salih,
  • Mariam Miari,
  • Diem Nguyen,
  • Sergi Sayols-Baixeras,
  • Aron C. Eklund,
  • Jacob Bak Holm,
  • H. Bjørn Nielsen,
  • Camila Gazolla Volpiano,
  • Guillaume Méric,
  • Manonanthini Thangam,
  • Liisa Hakaste,
  • Tiinamaija Tuomi,
  • Emma Ahlqvist,
  • Christopher A. Smith,
  • Marie Allen,
  • Frank Reimann,
  • Fiona M. Gribble,
  • Claes Ohlsson,
  • Kristian Hveem,
  • Olle Melander,
  • Peter M. Nilsson,
  • Gunnar Engström,
  • J. Gustav Smith,
  • Karl Michaëlsson,
  • Johan Ärnlöv,
  • Marju Orho-Melander,
  • Tove Fall

摘要

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.