Exome sequencing directly implicates 68 genes in inflammatory bowel disease
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.
Source: medRxiv
Authors: Ruifei Zhu, Qian Zhang, Kai Yuan, Rui Zhang, Alexandra K. Turvey, Christine R. Stevens, Laura Fachal, Tariq Ahmad, Klaartje Bel Kok, Charles N. Bernstein, Bernd Bokemeyer, Steven R. Brant, Johanne Brooks, Jeffrey Butterworth, Judy H. Cho, Katie Clark, Fraser Cummings, Richard H. Duerr, Sarah Ennis, Martti Farkkila, William A. Faubion, Stephen Foley, Denis Franchimont, Andre Franke, Laura Hancock, Ailsa Hart, Patricia Hooper, Peter Irving, Mark Jarvis, Emma Johnston, Elizabeth W. Karlson, Cheryl Kemp, Nick Kennedy, Juozas Kupcinskas, Christopher A. Lamb, Charlie Lees, James D. Lewis, Andy Li, Jimmy Limdi, Britt-Sabina Loescher, Edouard Louis, Jacob L. McCauley, Dermot P.B. McGovern, John McLaughlin, Paul Moayyedi, Gordon Moran, Rodney D. Newberry, Arabis Oglesby, Aarno Palotie, Joel Pekow, Kate J. Perez, Richard Pollok, Natalie Prescott, Tim Raine, Arvind Ramadas, Subramaniam Ramakrishnan, Ksenija Sabic, Bruce Sands, Jack Satsangi, Aleksejs Sazonovs, Stefan Schreiber, Christian Selinger, Sophy Shedwell, Mark S. Silverberg, Salil Singh, Harry Sokol, Helen Steed, Alan Steel, Holm H. Uhlig, Ajay Verma, Séverine Vermeire, Rinse K. Weersma, Ramnik J. Xavier, Mingrui Yu, Miles Parkes, John D. Rioux, Mark J. Daly, Hailiang Huang, Carl A. Anderson
Institutions: Broad Institute, Stanley Center for Psychiatric Research, Wellcome Sanger Institute, Royal Devon & Exeter NHS Foundation Trust, Royal Devon and Exeter Hospital, Queen Mary University of London, University of Manitoba, University Hospital Schleswig-Holstein, Rutgers, The State University of New Jersey, Lister Hospital, Royal Shrewsbury Hospital, Icahn School of Medicine at Mount Sinai, Southampton General Hospital, University of Pittsburgh, University of Southampton, Helsinki University Hospital, Mayo Clinic in Arizona, Kings Mill Hospital, Erasmus Hospital, Christian-Albrechts-Universität zu Kiel, Wythenshawe Hospital, St Mark's Hospital, Leicester General Hospital, Guy's Hospital, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, Basildon Hospital, West Middlesex University Hospital, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard University, Mass General Brigham, Watford General Hospital, Lithuanian University of Health Sciences, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne Hospital, Newcastle University, Western General Hospital, Crohn's and Colitis Foundation, University of Pennsylvania, Worthing Hospital, Fairfield General Hospital, University of Liège, Centre Hospitalier Universitaire de Liège, University of Miami, Dr. John T. Macdonald Foundation, Cedars-Sinai Medical Center, F. Widjaja Inflammatory Bowel Disease Institute, Salford Royal NHS Foundation Trust, Salford Royal Hospital, McMaster University, University of Nottingham, National Institute for Health and Care Research, Queen's Medical Centre, Nottingham Biomedical Research Centre, Washington University in St. Louis, Dorset County Hospital NHS Foundation Trust, Dorset County Hospital, University of Helsinki, Massachusetts General Hospital, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, University of Chicago, University of Chicago Medical Center, Cambridge University Hospitals NHS Foundation Trust, St George’s University Hospitals NHS Foundation Trust, James Cook University Hospital, Warrington and Halton Teaching Hospitals NHS Foundation Trust, Warrington Hospital, John Radcliffe Hospital, St James's University Hospital, Queen Elizabeth Hospital King's Lynn NHS Foundation Trust, Queen Elizabeth Hospital, Mount Sinai Hospital, Royal Bolton Hospital, Inserm, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Recherche Saint-Antoine, New Cross Hospital, The Royal Wolverhampton NHS Trust, Royal Liverpool University Hospital, University of Oxford, Kettering General Hospital, Kettering General Hospital NHS Trust, KU Leuven, University Medical Center Groningen, University of Groningen, Center for Computational and Integrative Biology, Massachusetts General Hospital, Montreal Heart Institute, Université de Montréal
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: Genetics and gene regulation in the inflammatory bowel diseases, Center for Common Disease Genetics, IBD: Role of Genetic and Immunopathologic Mechanisms, Large Scale Sequencing and Analysis of Genomes, An integrative approach to understanding the genetic basis of very early onset inflammatory bowel disease, INNATE IMMUNE PATHWAYS AND THE MICROBIOME IN HISPANICS WITH INFLAMMATORY BOWEL DISEASE, Identifying Microbial, Epithelial and Immune Cell Interactions that Mediate Mucosal Homeostasis and Determine IBD Phenotypes, Gene discoveries in subjects with Crohn's disease of African descent, The impact of diet patterns and PUFA-related polymorphisms on ulcerative colitis in Hispanics, SOFTWARE FOR LARGE-SCALE INFERENCE OF THE GENETICS OF LIFESTYLE MEASURES, BIOMARKERS, AND COMMON AND RARE DISEASES, NIDDK IBD Genetics Consortium Genetic Research Center, Center for Multi- and Trans-ethnic Mapping of Mendelian and Complex Diseases, Precision IBD via genetics and genomics: integrating International and multi-omic datasets, expanding studies in diverse populations, and defining mechanisms of unmet clinical needs in IBD, Determining genomic and host-environment contributions to IBD phenotypes, Mount Sinai NYC Genetics Research Center: Multi-omic integration across data-types, cell niches and populations, University of Miami IBD Genetic Research Center: Understanding the Genetic Architecture of IBD in the South Florida community, Montreal-Boston Collaborative GRC, Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital, Medical Scientist Training Program, IBD Gene Mapping by Clinical and Population Subset, Genomic and Immunologic Characterization of Inflammatory Bowel Disease and its Phenotypes, Identification and characterization of inflammatory bowel disease causal variants
OpenAlex ID: W7160895620