1 Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.
2 Department of Medicine and Surgery, LUM University, Casamassima, Italy.
3 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
4 Nuffield Department of Population Health, University of Oxford, Oxford, UK.
5 Institute for Genetics and Biomedical Research, National Research Council, Cagliari, Italy.
6 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.
7 Center for Structural and Functional Genomics, Biology Department, Concordia University, Montreal, Québec, Canada.
8 Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
9 Department of Molecular Medicine Medical Biotechnology, University of Naples Federico II, Naples, Italy.
10 CEINGE Biotecnologie Avanzate Franco Salvatore s. c. a r. l, Naples, Italy.
11 Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain damato@lum.it.
12 Ikerbasque, Basque Foundation for Science, Bilbao, Spain.

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 (r_g=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.