Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
Chris Eijsbouts, Tenghao Zheng, Nicholas A. Kennedy, Ferdinando Bonfiglio, Carl A. Anderson, Loukas Moutsianas, Jo Holliday, Jingchunzi Shi, Suyash Shringarpure, Michelle Agee, Stella Aslibekyan, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah Clark, Sarah L. Elson, Kipper Fletez‐Brant, Pierre Fontanillas, Nicholas A. Furlotte, Pooja Gandhi, Karl Heilbron, Barry Hicks, David A. Hinds, Karen E. Huber, Ethan M. Jewett, Yunxuan Jiang, Aaron Kleinman, Keng‐Han Lin, Nadia K. Litterman, Marie K. Luff, Jey C. McCreight, Matthew H. McIntyre, Kimberly F. McManus, Joanna L. Mountain, Sahar V. Mozaffari, Priyanka Nandakumar, Elizabeth S. Noblin, Carrie A. M. Northover, Jared O’Connell, Aaron A. Petrakovitz, Steven J. Pitts, G. David Poznik, J. Fah Sathirapongsasuti, Anjali J. Shastri, Janie F. Shelton, Chao Tian, Joyce Y. Tung, Robert J. Tunney, Vladimir Vacic, Xin Wang, Amir S. Zare, Alexandru-Ioan Voda, The Bellygenes Initiative, Purna Kashyap, Lin Chang, Emeran A. Mayer, Margaret Heitkemper, Gregory S. Sayuk, Tamar Ringel‐Kulka, Yehuda Ringel, William D. Chey, Shanti Eswaran, Juanita L. Merchant, Robert J. Shulman, Luís Bujanda, Koldo García‐Etxebarria, Aldona Dlugosz, Greger Lindberg, Peter T. Schmidt, Pontus Karling, Bodil Ohlsson, Susanna Walter, Åshild Faresjö, Magnus Simrén, Jonas Halfvarson, Piero Portincasa, Giovanni Barbara, Paolo Usai–Satta, Matteo Neri, Gerardo Nardone, Rosario Cuomo, Francesca Galeazzi, Massimo Bellini, Anna Latiano, Lesley A. Houghton, Daisy Jonkers, Alexander Kurilshikov, Rinse K. Weersma, Mihai G. Netea, Jonas Tesarz, Annika Gauss, Miriam Goebel‐Stengel, Viola Andresen, Thomas Frieling, Christian Pehl, Rainer Schaefert, Beate Niesler, Wolfgang Lieb, Kurt Hanevik, Nina Langeland
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.