Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
Chris Eijsbouts(Centre for Human Genetics), Tenghao Zheng(Karolinska Institutet), Nicholas A. Kennedy(University of Exeter), Ferdinando Bonfiglio(Karolinska Institutet), Carl A. Anderson(Wellcome Sanger Institute), Loukas Moutsianas(Queen Mary University of London), Jo Holliday(University of Oxford), Jingchunzi Shi(23andMe (United States)), Suyash Shringarpure(23andMe (United States)), Michelle Agee(23andMe (United States)), Stella Aslibekyan(23andMe (United States)), Adam Auton(23andMe (United States)), Robert K. Bell(23andMe (United States)), Katarzyna Bryc(23andMe (United States)), Sarah Clark(23andMe (United States)), Sarah L. Elson(23andMe (United States)), Kipper Fletez‐Brant(23andMe (United States)), Pierre Fontanillas(23andMe (United States)), Nicholas A. Furlotte(23andMe (United States)), Pooja Gandhi(23andMe (United States)), Karl Heilbron(23andMe (United States)), Barry Hicks(23andMe (United States)), David A. Hinds(23andMe (United States)), Karen E. Huber(23andMe (United States)), Ethan M. Jewett(23andMe (United States)), Yunxuan Jiang(23andMe (United States)), Aaron Kleinman(23andMe (United States)), Keng‐Han Lin(23andMe (United States)), Nadia K. Litterman(23andMe (United States)), Marie K. Luff(23andMe (United States)), Jey C. McCreight(23andMe (United States)), Matthew H. McIntyre(23andMe (United States)), Kimberly F. McManus(23andMe (United States)), Joanna L. Mountain(23andMe (United States)), Sahar V. Mozaffari(23andMe (United States)), Priyanka Nandakumar(23andMe (United States)), Elizabeth S. Noblin(23andMe (United States)), Carrie A. M. Northover(23andMe (United States)), Jared O’Connell(23andMe (United States)), Aaron A. Petrakovitz(23andMe (United States)), Steven J. Pitts(23andMe (United States)), G. David Poznik(23andMe (United States)), J. Fah Sathirapongsasuti(23andMe (United States)), Anjali J. Shastri(23andMe (United States)), Janie F. Shelton(23andMe (United States)), Chao Tian(23andMe (United States)), Joyce Y. Tung(23andMe (United States)), Robert J. Tunney(23andMe (United States)), Vladimir Vacic(23andMe (United States)), Xin Wang(23andMe (United States)), Amir S. Zare(23andMe (United States)), Alexandru-Ioan Voda(University of Oxford), The Bellygenes Initiative(Mayo Clinic in Arizona), Purna Kashyap(University of California, Los Angeles), Lin Chang(University of California, Los Angeles), Emeran A. Mayer(University of California, Los Angeles), Margaret Heitkemper(University of Washington), Gregory S. Sayuk(University of North Carolina at Chapel Hill), Tamar Ringel‐Kulka(University of North Carolina at Chapel Hill), Yehuda Ringel(University of North Carolina at Chapel Hill), William D. Chey(Michigan Medicine), Shanti Eswaran(University of Arizona), Juanita L. Merchant(University of Arizona), Robert J. Shulman(University of the Basque Country), Luís Bujanda(University of the Basque Country), Koldo García‐Etxebarria(Karolinska University Hospital), Aldona Dlugosz(Karolinska University Hospital), Greger Lindberg(Karolinska University Hospital), Peter T. Schmidt(Karolinska University Hospital), Pontus Karling(Lund University), Bodil Ohlsson(Linköping University), Susanna Walter(Linköping University), Åshild Faresjö(Linköping University), Magnus Simrén(Örebro University), Jonas Halfvarson(Örebro University), Piero Portincasa(IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola), Giovanni Barbara(IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola), Paolo Usai–Satta(University of Chieti-Pescara), Matteo Neri(University of Chieti-Pescara), Gerardo Nardone(Federico II University Hospital), Rosario Cuomo(University of Padua), Francesca Galeazzi(University of Pisa), Massimo Bellini(University of Pisa), Anna Latiano(University of Leeds), Lesley A. Houghton(University of Leeds), Daisy Jonkers(University Medical Center Groningen), Alexander Kurilshikov(University Medical Center Groningen), Rinse K. Weersma(University Medical Center Groningen), Mihai G. Netea(Radboud University Nijmegen), Jonas Tesarz(Heidelberg University), Annika Gauss(Heidelberg University), Miriam Goebel‐Stengel(Krankenhaus vom Roten Kreuz), Viola Andresen(Helios Klinikum Krefeld), Thomas Frieling(Helios Klinikum Krefeld), Christian Pehl(University Hospital of Basel), Rainer Schaefert(University of Basel), Beate Niesler(Heidelberg University), Wolfgang Lieb(Christian-Albrechts-Universität zu Kiel), Kurt Hanevik(University of Bergen), Nina Langeland(NORCE Research AS), Knut‐Arne Wensaas(NORCE Research AS), Sverre Litleskare(Norwegian University of Science and Technology), Maiken E. Gabrielsen(Norwegian University of Science and Technology), Laurent F. Thomas(Norwegian University of Science and Technology), Vincent Thijs(Florey Institute of Neuroscience and Mental Health), Robin Lemmens(KU Leuven), Lukas Van Oudenhove(KU Leuven), Mira M. Wouters(Mayo Clinic in Arizona), Gianrico Farrugia(Christian-Albrechts-Universität zu Kiel), André Franke(Christian-Albrechts-Universität zu Kiel), Matthias Hübenthal(University of Michigan), Gonçalo R. Abecasis(University of Michigan), Matthew Zawistowski(Norwegian University of Science and Technology), Anne Heidi Skogholt(Karolinska University Hospital), Eivind Ness‐Jensen(Karolinska University Hospital), Kristian Hveem(Norwegian University of Science and Technology), Tõnu Esko(University of Tartu), Maris Teder‐Laving(University Medical Center Groningen), Alexandra Zhernakova(Mayo Clinic), Michael Camilleri(Mayo Clinic), Guy E. Boeckxstaens(University of California, Los Angeles), Peter J. Whorwell(Nottingham University Hospitals NHS Trust), Robert E. Spiller(Nottingham University Hospitals NHS Trust), Gil McVean(Ikerbasque), Mauro D’Amato(Ikerbasque), Luke Jostins-Dean(Canterbury Christ Church University), Miles Parkes(Addenbrooke's Hospital)
Cited by 275Open Access
Abstract
Abstract Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1 , CADM2 , PHF2/FAM120A , DOCK9 , CKAP2/TPTE2P3 and BAG6 . The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression ( r g > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS.
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