{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:41:46Z","timestamp":1792467706999,"version":"4.5.0"},"reference-count":57,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:00:00Z","timestamp":1792368000000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004040","name":"KU Leuven","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004040","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neurogastroenterology Motil"],"published-print":{"date-parts":[[2026,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Functional 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\u2010powered genetic studies remain limited. We aimed to identify FD genetic risk factors and implicated biological pathways.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We performed a\n FD<\/jats:styled-content>\n genome\u2010wide association study in 1,168,899 European individuals, including 29,584\n FD<\/jats:styled-content>\n cases from five large biobanks. We dissected the genetic architecture of\n FD<\/jats:styled-content>\n and its overlap with gastrointestinal and psychiatric disorders and conducted comprehensive gene\u2010prioritization, regulatory, and cell\u2010type enrichment analyzes to identify pathophysiological mechanisms and actionable targets.\n <\/jats:p>\n <\/jats:sec>\n \n Key Results<\/jats:title>\n \n We 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\u2010wide significant signals at the human leukocyte antigen region, supporting immune\u2010mediated mechanisms. Gene\u2010prioritization analyzes converged on DEAH\u2010Box Helicase 36 (\n DHX36<\/jats:italic>\n ), involved in immune responses to microbial infections. Integrative expression\u2010quantitative trait loci and colocalization analyzes indicated that higher genetic risk of FD is causally associated with a reduced\n DHX36<\/jats:italic>\n expression in gastrointestinal tissues, potentially triggering increased proinflammatory cytokine production.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions & Inferences<\/jats:title>\n \n This study implicates immune\u2010driven pathways in FD susceptibility, adds insights into the pathophysiological mechanisms of the disease, and reveals\n DHX36<\/jats:italic>\n as a candidate target for future investigation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/nmo.70469","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:33:24Z","timestamp":1792467204000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Genome\u2010Wide Meta\u2010Analysis of Functional Dyspepsia in 1,168,899 Individuals Implicates Immune Pathways in Disease Susceptibility"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1593-2885","authenticated-orcid":false,"given":"Cristian","family":"D\u00edaz\u2010Mu\u00f1oz","sequence":"first","affiliation":[{"name":"Gastrointestinal Genetics Lab, CIC bioGUNE \u2013 BRTA Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6050-8461","authenticated-orcid":false,"given":"Bert","family":"Broeders","sequence":"additional","affiliation":[{"name":"Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2488-3867","authenticated-orcid":false,"given":"Ferdinando","family":"Bonfiglio","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Medical Biotechnology University of Naples Federico II Naples Italy"},{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore s.c.a.r.l. Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7087-6735","authenticated-orcid":false,"given":"Andreea","family":"Zamfir\u2010Taranu","sequence":"additional","affiliation":[{"name":"Gastrointestinal Genetics Lab, CIC bioGUNE \u2013 BRTA Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4372-6701","authenticated-orcid":false,"given":"Joris","family":"Arts","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology AZ Sint\u2010Lucas Brugge Brugge Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6694-9364","authenticated-orcid":false,"given":"Peter","family":"Banovcin","sequence":"additional","affiliation":[{"name":"Gastroenterology Clinic, University Hospital in Martin, Jessenius Faculty of Medicine in Martin Comenius University in Bratislava Martin Slovak Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4353-9968","authenticated-orcid":false,"given":"Luis","family":"Bujanda","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute Donostia University Hospital, University of the Basque Country (UPV\/EHU), CIBERehd \u2013Networked Biomedical Research Centre in Hepatic and Digestive Diseases San Sebastian Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7596-2656","authenticated-orcid":false,"given":"Vasile","family":"Drug","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Faculty of Medicine Grigore T. Popa University of Medicine and Pharmacy Iasi Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5404-7662","authenticated-orcid":false,"given":"Dan","family":"Dumitrascu","sequence":"additional","affiliation":[{"name":"2nd Department of Internal Medicine \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy Cluj\u2010Napoca Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8220-9155","authenticated-orcid":false,"given":"Guillaume","family":"Gourcerol","sequence":"additional","affiliation":[{"name":"Department of Physiology, CHU Rouen, UMR INSERM 1073 \u2013 CIC\u2010CRB1404 Univ Rouen Normandie Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4282-4230","authenticated-orcid":false,"given":"S\u00e9bastien","family":"Kindt","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8257-8567","authenticated-orcid":false,"given":"Peter","family":"Lipt\u00e1k","sequence":"additional","affiliation":[{"name":"Clinic of Internal Medicine\u2010Gastroenterology, Jessenius Faculty of Medicine in Martin University Hospital in Martin, Comenius University Martin Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8146-1540","authenticated-orcid":false,"given":"Chlo\u00e9","family":"Melchior","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, CHU Rouen, ADEN INSERM UMR 1073 \u2013 CIC\u2010CRB1404 Univ Rouen Normandie Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7097-1492","authenticated-orcid":false,"given":"Carolina","family":"Malagelada","sequence":"additional","affiliation":[{"name":"Digestive System Research Unit Vall d'Hebron University Hospital, Autonomous University of Barcelona Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3187-2894","authenticated-orcid":false,"given":"Edoardo Vincenzo","family":"Savarino","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology University of Padua Padua Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9550-8417","authenticated-orcid":false,"given":"Artemis","family":"Trikola","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Athens Naval Hospital Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1556-8129","authenticated-orcid":false,"given":"Jara","family":"Lehoucq","sequence":"additional","affiliation":[{"name":"Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1790-7904","authenticated-orcid":false,"given":"Florencia","family":"Carbone","sequence":"additional","affiliation":[{"name":"Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"},{"name":"Department of Gastroenterology and Hepatology University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3206-6704","authenticated-orcid":false,"given":"Jan","family":"Tack","sequence":"additional","affiliation":[{"name":"Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"},{"name":"Department of Gastroenterology and Hepatology University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2743-5197","authenticated-orcid":false,"given":"Mauro","family":"D'Amato","sequence":"additional","affiliation":[{"name":"Gastrointestinal Genetics Lab, CIC bioGUNE \u2013 BRTA Derio Spain"},{"name":"Department of Medicine and Surgery LUM University Casamassima Italy"},{"name":"Ikerbasque, Basque Foundation for Science Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1053\/j.gastro.2020.04.014","article-title":"Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study","volume":"160","author":"Sperber A. D.","year":"2021","journal-title":"Gastroenterology"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"259","DOI":"10.15403\/jgld-3325","article-title":"Association of Functional Dyspepsia With Depression and Anxiety: A Systematic Review","volume":"30","author":"Esterita T.","year":"2021","journal-title":"Journal of Gastrointestinal and Liver Diseases"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/ueg2.12061","article-title":"United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) Consensus on Functional Dyspepsia","volume":"9","author":"Wauters L.","year":"2021","journal-title":"United European Gastroenterology Journal"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/j.1365-2036.2010.04328.x","article-title":"Meta\u2010Analysis: Factors Affecting Placebo Response Rate in the Irritable Bowel Syndrome","volume":"32","author":"Ford A. C.","year":"2010","journal-title":"Alimentary Pharmacology & Therapeutics"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1111\/apt.17414","article-title":"Review Article: Functional Dyspepsia\u2014A Gastric Disorder, a Duodenal Disorder or a Combination of Both?","volume":"57","author":"Broeders B. W. L. C. M.","year":"2023","journal-title":"Alimentary Pharmacology & Therapeutics"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","DOI":"10.1111\/nmo.12913","article-title":"Functional Dyspepsia Susceptibility Is Related to \n CD 14, \n GNB 3, \n MIF\n , and \n TRPV 1 Gene Polymorphisms in the Greek Population","volume":"29","author":"Triantafyllou K.","year":"2017","journal-title":"Neurogastroenterology and Motility"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1111\/jgh.12596","article-title":"The Association of SLC6A4 5\u2010HTTLPR and TRPV1 945G>C With Functional Dyspepsia in Korea","volume":"29","author":"Hwang S. 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