Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
Authors: Eijsbouts Chris , Zheng Tenghao , Kennedy Nicholas A. , Bonfiglio Ferdinando , Anderson Carl A. , Moutsianas Loukas , Holliday Joanne , Shi Jingchunzi , Shringarpure Suyash ,   23andMe Research Team, Agee Michelle , Aslibekyan Stella , Auton Adam , Bell Robert K. , Bryc Katarzyna , Clark Sarah K. , Elson Sarah L. , Fletez-Brant Kipper , Fontanillas Pierre , Furlotte Nicholas A. , Gandhi Pooja M. , Heilbron Karl , Hicks Barry , Hinds David A. , Huber Karen E. , Jewett Ethan M. , Jiang Yunxuan , Kleinman Aaron , Lin Keng-Han , Litterman Nadia K. , Luff Marie K. , McCreight Jey C. , McIntyre Matthew H. , McManus Kimberly F. , Mountain Joanna L. , Mozaffari Sahar V. , Nandakumar Priyanka , Noblin Elizabeth S. , Northover Carrie A. M. , O’Connell Jared , Petrakovitz Aaron A. , Pitts Steven J. , Poznik G. David , Sathirapongsasuti J. Fah , Shastri Anjali J. , Shelton Janie F. , Tian Chao , Tung Joyce Y. , Tunney Robert J. , Vacic Vladimir , Wang Xin , Zare Amir S. , Voda Alexandru-Ioan ,   The Bellygenes Initiative, Kashyap Purna , Chang Lin , Mayer Emeran , Heitkemper Margaret , Sayuk Gregory S. , Ringel-Kulka Tamar , Ringel Yehuda , Chey William D. , Eswaran Shanti , Merchant Juanita L. , Shulman Robert J. , Bujanda Luis , Garcia-Etxebarria Koldo , Dlugosz Aldona , Lindberg Greger , Schmidt Peter T. , Karling Pontus , Ohlsson Bodil , Walter Susanna , Faresjö Åshild O. , Simren Magnus , Halfvarson Jonas , Portincasa Piero , Barbara Giovanni , Usai-Satta Paolo , Neri Matteo , Nardone Gerardo , Cuomo Rosario , Galeazzi Francesca , Bellini Massimo , Latiano Anna , Houghton Lesley , Jonkers Daisy , Kurilshikov Alexander , Weersma Rinse K. , Netea Mihai , Tesarz Jonas , Gauss Annika , Goebel-Stengel Miriam , Andresen Viola , Frieling Thomas , Pehl Christian , Schaefert Rainer , Niesler Beate , Lieb Wolfgang , Hanevik Kurt , Langeland Nina , Wensaas Knut-Arne , Litleskare Sverre , Gabrielsen Maiken E. , Thomas Laurent , Thijs Vincent , Lemmens Robin , Van Oudenhove Lukas , Wouters Mira , Farrugia Gianrico , Franke Andre , Hübenthal Matthias , Abecasis Gonçalo , Zawistowski Matthew , Skogholt Anne Heidi , Ness-Jensen Eivind , Hveem Kristian , Esko Tõnu , Teder-Laving Maris , Zhernakova Alexandra , Camilleri Michael , Boeckxstaens Guy , Whorwell Peter J. , Spiller Robin , McVean Gil , D’Amato Mauro , Jostins Luke , Parkes Miles 
Published: November 2021

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 (rg > 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.