A Genome-Wide Meta-Analysis of Functional Dyspepsia in 1,168,899 Individuals Implicates Immune Pathways in Disease Susceptibility.
19 affiliations
- 1Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.
- 2Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
- 3Department of Molecular Medicine Medical Biotechnology, University of Naples Federico II, Naples, Italy.
- 4CEINGE Biotecnologie Avanzate Franco Salvatore s.c.a.r.l., Naples, Italy.
- 5Department of Gastroenterology, AZ Sint-Lucas Brugge, Brugge, Belgium.
- 6Gastroenterology Clinic, University Hospital in Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic.
- 7Department 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.
- 8Department of Gastroenterology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania.
- 92nd Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
- 10Department of Physiology, CHU Rouen, UMR INSERM 1073 - CIC-CRB1404, Univ Rouen Normandie, Rouen, France.
- 11Department of Gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
- 12Clinic of Internal Medicine-Gastroenterology, Jessenius Faculty of Medicine in Martin, University Hospital in Martin, Comenius University, Martin, Slovakia.
- 13Department of Gastroenterology, CHU Rouen, ADEN INSERM UMR 1073 - CIC-CRB1404, Univ Rouen Normandie, Rouen, France.
- 14Digestive System Research Unit, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.
- 15Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
- 16Department of Gastroenterology, Athens Naval Hospital, Athens, Greece.
- 17Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.
- 18Department of Medicine and Surgery, LUM University, Casamassima, Italy.
- 19Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
Abstract
Background
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-powered genetic studies remain limited. We aimed to identify FD genetic risk factors and implicated biological pathways.Methods
We 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
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-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
This 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.
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BibTeX
@article{diazmunoz2026genomewide,
title = {{A Genome-Wide Meta-Analysis of Functional Dyspepsia in 1,168,899 Individuals Implicates Immune Pathways in Disease Susceptibility.}},
author = {Cristian Díaz-Muñoz and Bert Broeders and Ferdinando Bonfiglio and Andreea Zamfir-Taranu and Joris Arts and Peter Banovcin and Luis Bujanda and Vasile Drug and Dan Dumitrascu and Guillaume Gourcerol and Sébastien Kindt and Peter Lipták and Chloé Melchior and Carolina Malagelada and Edoardo Vincenzo Savarino and Artemis Trikola and Jara Lehoucq and Florencia Carbone and Jan Tack and Mauro D'Amato},
journal = {Neurogastroenterology and motility},
year = {2026},
month = oct,
doi = {10.1111/nmo.70469},
url = {https://europepmc.org/article/MED/42897685},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A Genome-Wide Meta-Analysis of Functional Dyspepsia in 1,168,899 Individuals Implicates Immune Pathways in Disease Susceptibility.
AU - Cristian Díaz-Muñoz
AU - Bert Broeders
AU - Ferdinando Bonfiglio
AU - Andreea Zamfir-Taranu
AU - Joris Arts
AU - Peter Banovcin
AU - Luis Bujanda
AU - Vasile Drug
AU - Dan Dumitrascu
AU - Guillaume Gourcerol
AU - Sébastien Kindt
AU - Peter Lipták
AU - Chloé Melchior
AU - Carolina Malagelada
AU - Edoardo Vincenzo Savarino
AU - Artemis Trikola
AU - Jara Lehoucq
AU - Florencia Carbone
AU - Jan Tack
AU - Mauro D'Amato
PY - 2026
DA - 2026/10/01
JO - Neurogastroenterology and motility
DO - 10.1111/nmo.70469
UR - https://europepmc.org/article/MED/42897685
AB - Background 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-powered genetic studies remain limited. We aimed to identify FD genetic risk factors and implicated biological pathways.Methods We 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 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-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 This 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.
SN - 1350-1925
SN - 1365-2982
ER -