{
  "abstract": "Background Genetic studies of stool frequency (SF), an indirect proxy for gastrointestinal transit, may reveal therapeutically tractable pathways relevant to IBS and other dysmotility disorders.Objective To identify genes and mechanisms involved in gut motility, providing a foundation for clinical translation.Design We performed a multiancestry genome-wide association study (GWAS) meta-analysis of SF in 268 606 European and East Asian individuals. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS signals were fine-mapped and functionally annotated to prioritise candidate genes and pathways. Findings implicating thiamine metabolism were followed-up with dietary interaction analyses in UK Biobank (UKB).Results SF heritability was comparable in Europeans (7.0%) and East Asians (5.6%). We observed strong genetic correlations with gastrointestinal and psychiatric disorders (r g=0.18–0.47), and causal effects on IBS. Novel correlations with cardiovascular traits (rg=0.12–0.14) were supported by drug signature enrichment analyses. We identified 21 independent loci, including 10 novel signals implicating bile acid synthesis (KLB) and cholinergic signalling (COLQ). Fine-mapping converged on vitamin B1 metabolism, highlighting single-variant causal effects at SLC35F3 (a thiamine transporter) and XPR1 (phosphate exporter essential for thiamine activation). In 98 449 UKB participants, thiamine intake was positively associated with SF (p<0.0001), and a combined SLC35F3/XPR1 genotype score significantly modulated this effect (p<0.0001).Conclusions We identify therapeutically tractable mechanisms involved in the control of gut motility, including a previously unrecognised role for vitamin B1. These findings warrant mechanistic and clinical studies to evaluate their translational potential in IBS and other dysmotility syndromes.",
  "authors": [
    {
      "affiliations": [
        "Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain"
      ],
      "name": "Cristian Díaz-Muñoz"
    },
    {
      "affiliations": [
        "Department of Medicine and Surgery, LUM University, Casamassima, Italy"
      ],
      "name": "Isotta Bozzarelli"
    },
    {
      "affiliations": [
        "Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands"
      ],
      "name": "Esteban Alexander Lopera-Maya"
    },
    {
      "affiliations": [
        "Nuffield Department of Population Health, University of Oxford, Oxford, UK"
      ],
      "name": "Lazaros Belbasis"
    },
    {
      "affiliations": [
        "Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands",
        "Institute for Genetics and Biomedical Research, National Research Council, Cagliari, Italy"
      ],
      "name": "Valeria Lo Faro"
    },
    {
      "affiliations": [
        "Hypertension Research Laboratory, Victorian Heart Institute and Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia"
      ],
      "name": "Leticia Camargo Tavares"
    },
    {
      "affiliations": [
        "Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain"
      ],
      "name": "Francisco Heredia-Fernández"
    },
    {
      "affiliations": [
        "Department of Medicine and Surgery, LUM University, Casamassima, Italy"
      ],
      "name": "Biagio Di Lorenzo"
    },
    {
      "affiliations": [
        "Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands"
      ],
      "name": "Trishla Sinha"
    },
    {
      "affiliations": [
        "Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain"
      ],
      "name": "Cristina Esteban Blanco"
    },
    {
      "affiliations": [
        "Center for Structural and Functional Genomics, Biology Department, Concordia University, Montreal, Québec, Canada",
        "Ontario Institute for Cancer Research, Toronto, Ontario, Canada"
      ],
      "name": "Marie-Julie Favé"
    },
    {
      "affiliations": [
        "Center for Structural and Functional Genomics, Biology Department, Concordia University, Montreal, Québec, Canada",
        "Ontario Institute for Cancer Research, Toronto, Ontario, Canada"
      ],
      "name": "Philip Awadalla"
    },
    {
      "affiliations": [
        "Nuffield Department of Population Health, University of Oxford, Oxford, UK"
      ],
      "name": "Robin G Walters"
    },
    {
      "affiliations": [
        "Department of Molecular Medicine Medical Biotechnology, University of Naples Federico II, Naples, Italy",
        "CEINGE Biotecnologie Avanzate Franco Salvatore s. c. a r. l, Naples, Italy"
      ],
      "name": "Ferdinando Bonfiglio"
    },
    {
      "affiliations": [
        "Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands"
      ],
      "name": "Alexandra Zhernakova"
    },
    {
      "affiliations": [
        "Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands",
        "Institute for Genetics and Biomedical Research, National Research Council, Cagliari, Italy"
      ],
      "name": "Serena Sanna"
    },
    {
      "affiliations": [
        "Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain",
        "Department of Medicine and Surgery, LUM University, Casamassima, Italy",
        "Ikerbasque, Basque Foundation for Science, Bilbao, Spain"
      ],
      "name": "Mauro D’Amato"
    }
  ],
  "title": "Genetic dissection of stool frequency implicates vitamin B1 metabolism and other actionable pathways in the modulation of gut motility",
  "uid": "7bd71ef9-79b9-5ca2-ab14-424f5e5a111c"
}