{ "abstract": "Background\n\nFunctional dyspepsia (FD) affects over 7% of the global population, impairing quality of life and driving significant healthcare burden. Although genetic contributions to FD pathophysiology have been suspected, large, well-powered genetic studies remain limited. We aimed to identify FD genetic risk factors and implicated biological pathways.Methods\n\nWe performed a FD genome-wide association study in 1,168,899 European individuals, including 29,584 FD cases from five large biobanks. We dissected the genetic architecture of FD and its overlap with gastrointestinal and psychiatric disorders and conducted comprehensive gene-prioritization, regulatory, and cell-type enrichment analyzes to identify pathophysiological mechanisms and actionable targets.Key results\n\nWe show FD is a complex, highly polygenic trait with a significant genetic component (3.63% heritability) but lower than similar gastrointestinal disorders like irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD). Mendelian randomization revealed causal effects of depression and anxiety on FD risk. We observed substantial local genetic correlations with IBS and GERD, including shared genome-wide significant signals at the human leukocyte antigen region, supporting immune-mediated mechanisms. Gene-prioritization analyzes converged on DEAH-Box Helicase 36 (DHX36), involved in immune responses to microbial infections. Integrative expression-quantitative trait loci and colocalization analyzes indicated that higher genetic risk of FD is causally associated with a reduced DHX36 expression in gastrointestinal tissues, potentially triggering increased proinflammatory cytokine production.Conclusions & inferences\n\nThis study implicates immune-driven pathways in FD susceptibility, adds insights into the pathophysiological mechanisms of the disease, and reveals DHX36 as a candidate target for future investigation.", "abstract_shown": true, "affiliations": [ "Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.", "Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.", "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.", "Department of Gastroenterology, AZ Sint-Lucas Brugge, Brugge, Belgium.", "Gastroenterology Clinic, University Hospital in Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic.", "Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd -Networked Biomedical Research Centre in Hepatic and Digestive Diseases, San Sebastian, Spain.", "Department of Gastroenterology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania.", "2nd Department of Internal Medicine, \"Iuliu Hatieganu\" University of Medicine and Pharmacy, Cluj-Napoca, Romania.", "Department of Physiology, CHU Rouen, UMR INSERM 1073 - CIC-CRB1404, Univ Rouen Normandie, Rouen, France.", "Department of Gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.", "Clinic of Internal Medicine-Gastroenterology, Jessenius Faculty of Medicine in Martin, University Hospital in Martin, Comenius University, Martin, Slovakia.", "Department of Gastroenterology, CHU Rouen, ADEN INSERM UMR 1073 - CIC-CRB1404, Univ Rouen Normandie, Rouen, France.", "Digestive System Research Unit, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.", "Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.", "Department of Gastroenterology, Athens Naval Hospital, Athens, Greece.", "Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.", "Department of Medicine and Surgery, LUM University, Casamassima, Italy.", "Ikerbasque, Basque Foundation for Science, Bilbao, Spain." ], "article_type": "research article", "arxiv": null, "author_total": 20, "authors": [ { "affs": [ 0 ], "name": "Cristian Díaz-Muñoz", "orcid": "0000-0002-1593-2885" }, { "affs": [ 1 ], "name": "Bert Broeders", "orcid": "0000-0001-6050-8461" }, { "affs": [ 2, 3 ], "name": "Ferdinando Bonfiglio", "orcid": "0000-0003-2488-3867" }, { "affs": [ 0 ], "name": "Andreea Zamfir-Taranu", "orcid": "0000-0001-7087-6735" }, { "affs": [ 4 ], "name": "Joris Arts", "orcid": "0009-0002-4372-6701" }, { "affs": [ 5 ], "name": "Peter Banovcin", "orcid": "0000-0001-6694-9364" }, { "affs": [ 6 ], "name": "Luis Bujanda", "orcid": "0000-0002-4353-9968" }, { "affs": [ 7 ], "name": "Vasile Drug", "orcid": "0000-0002-7596-2656" }, { "affs": [ 8 ], "name": "Dan Dumitrascu", "orcid": "0000-0001-5404-7662" }, { "affs": [ 9 ], "name": "Guillaume Gourcerol", "orcid": "0000-0001-8220-9155" }, { "affs": [ 10 ], "name": "Sébastien Kindt", "orcid": "0000-0002-4282-4230" }, { "affs": [ 11 ], "name": "Peter Lipták", "orcid": "0000-0001-8257-8567" }, { "affs": [ 12 ], "name": "Chloé Melchior", "orcid": "0000-0002-8146-1540" }, { "affs": [ 13 ], "name": "Carolina Malagelada", "orcid": "0000-0001-7097-1492" }, { "affs": [ 14 ], "name": "Edoardo Vincenzo Savarino", "orcid": "0000-0002-3187-2894" }, { "affs": [ 15 ], "name": "Artemis Trikola", "orcid": "0009-0005-9550-8417" }, { "affs": [ 1 ], "name": "Jara Lehoucq", "orcid": "0009-0009-1556-8129" }, { "affs": [ 1, 16 ], "name": "Florencia Carbone", "orcid": "0000-0003-1790-7904" }, { "affs": [ 1, 16 ], "name": "Jan Tack", "orcid": "0000-0002-3206-6704" }, { "affs": [ 0, 17, 18 ], "name": "Mauro D'Amato", "orcid": "0000-0003-2743-5197" } ], "bibtex": "https://research.draconitic.com/paper/bdx5ymha0kyh2.bib", "cited_by": 0, "doi": "10.1111/nmo.70469", "fulltext_url": "https://europepmc.org/articles/PMC13680535", "id": "bdx5ymha0kyh2", "issns": [ "1350-1925", "1365-2982" ], "landing_url": "https://europepmc.org/article/MED/42897685", "language": "eng", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2715|Gastrointestinal motility and disorders" ] ], "openalex": "W7222920756", "pdf_url": "https://europepmc.org/articles/PMC13680535?pdf=render", "pmcid": "PMC13680535", "pmid": "42897685", "published": "2026-10-01", "publisher": null, "ris": "https://research.draconitic.com/paper/bdx5ymha0kyh2.ris", "sources": [ { "first_seen": "2026-10-30T12:19:37Z", "native_id": "MED:42897685", "source": "europepmc", "url": "https://europepmc.org/article/MED/42897685" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2715|Gastrointestinal motility and disorders", "subfield": "general" } ], "title": "A Genome-Wide Meta-Analysis of Functional Dyspepsia in 1,168,899 Individuals Implicates Immune Pathways in Disease Susceptibility.", "title_text": "A Genome-Wide Meta-Analysis of Functional Dyspepsia in 1,168,899 Individuals Implicates Immune Pathways in Disease Susceptibility.", "type": "peer-reviewed", "updated_at": "2026-10-30T12:19:37Z", "url": "https://research.draconitic.com/paper/bdx5ymha0kyh2", "venue": "Neurogastroenterology and motility", "versions": [] }