TY - JOUR
T1 - Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
AU - Eijsbouts, Chris
AU - Zheng, Tenghao
AU - Kennedy, Nicholas A.
AU - Bonfiglio, Ferdinando
AU - Anderson, Carl A.
AU - Moutsianas, Loukas
AU - Holliday, Joanne
AU - Shi, Jingchunzi
AU - Shringarpure, Suyash
AU - Agee, Michelle
AU - Aslibekyan, Stella
AU - Auton, Adam
AU - Bell, Robert K.
AU - Bryc, Katarzyna
AU - Clark, Sarah K.
AU - Elson, Sarah L.
AU - Fletez-Brant, Kipper
AU - Fontanillas, Pierre
AU - Furlotte, Nicholas A.
AU - Gandhi, Pooja M.
AU - Heilbron, Karl
AU - Hicks, Barry
AU - Hinds, David A.
AU - Huber, Karen E.
AU - Jewett, Ethan M.
AU - Jiang, Yunxuan
AU - Kleinman, Aaron
AU - Lin, Keng Han
AU - Litterman, Nadia K.
AU - Luff, Marie K.
AU - McCreight, Jey C.
AU - McIntyre, Matthew H.
AU - McManus, Kimberly F.
AU - Mountain, Joanna L.
AU - Mozaffari, Sahar V.
AU - Nandakumar, Priyanka
AU - Noblin, Elizabeth S.
AU - Northover, Carrie A.M.
AU - O’Connell, Jared
AU - Petrakovitz, Aaron A.
AU - Pitts, Steven J.
AU - Poznik, G. David
AU - Sathirapongsasuti, J. Fah
AU - Shastri, Anjali J.
AU - Shelton, Janie F.
AU - Tian, Chao
AU - Tung, Joyce Y.
AU - Tunney, Robert J.
AU - Vacic, Vladimir
AU - Jonkers, Daisy
AU - 23andMe Research team
AU - Bellygenes Initiative
AU - Parkes, Miles
N1 - Funding Information:
This research was conducted using the UK Biobank resource under application no. 17670. We acknowledge the contribution made by all participants in the cohorts studied. We also thank all 23andMe employees and participants involved in its research. The research leading to these results received funding from the European Union Seventh Framework Programme under grant no. 313010 (Biobanking and Biomolecular Research Infrastructure—Large Prospective Cohorts). We received funding support from the National Institute for Health Research Biomedical Research Centres based at Cambridge University Hospital NHS Trust and the University of Cambridge (no. BRC-1215-20014); the University of Oxford (no. BRC-1215-20008); Nottingham University Hospitals NHS Trust and the University of Nottingham (no. BRC-1215-20003); and the University Hospital of South Manchester and University of Manchester (no. BRC-1215-20007). This research was funded in whole, or in part, by Wellcome Trust grant nos. 215097/Z/18/Z, 203141/Z/16/Z, 093885/Z/10/Z, 098051, 100956/Z/13/Z and 280750/Z/17/Z. For the purpose of open access, we have applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. Additional support was received from the Li Ka Shing Foundation and the Kennedy Trust for Rheumatology Research. M.C. received past and current support from the National Institutes of Health (NIH) for genetic studies in IBS (nos. R01 DK 92179 and 115950). A.-I.V.’s contribution was supported by a Kennedy Trust Prize Studentship. This work received support from European Research Council Starting Grant no. 715772, a Nederlandse Organisatie voor Wetenschappelijk (NOW)-VIDI grant, Netherlands Heart Foundation CVON grant no. 2018-27 and NWO Gravitation grant Exposome-NL. The study was supported by grants from the Swedish Research Council (VR project no. 2017-02403), the Health Department of the Basque Government (grant no. 2015111133) and the Spanish Ministry of Economy and Competitiveness (Instituto Salud Carlos III grant no. FIS PI17/00308) to M.D.A. This work received infrastructure support from the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (no. EXC2167). The GTEx Project was supported by the Common Fund of the Office of the Director of the NIH and by the National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. The data used for the colocalization analyses were obtained from the GTEx Portal on 16 June 2019. The Lifelines Biobank initiative has been made possible by funds from Fonds Economische Structuurversterking, Samenwerkingsverband Noord Nederland and Ruimtelijk Economisch Programma. The UK Household Longitudinal Study, a source of UK controls in this work, is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website (https://www.understandingsociety. ac.uk/). The Nord-Trøndelag Health Study (HUNT study) is a collaboration between the HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology), Trøndelag County Council, the Central Norway Regional Health Authority and the Norwegian Institute of Public Health. We are grateful to D. Levy and all Million Veteran Program (MVP) staff, researchers and volunteers, who provided anxiety association summary statistics for this work, and especially participants who previously served their country in the military and now generously agreed to enroll in the MVP study. We thank S. Berens, F. Kraus, E. Stroe-Kunold and W. Herzog of the Heidelberg outpatient clinic and the supporting staff of each site of the IBS Net Germany. The data and analyses presented in the current publication are based on the use of study data downloaded from the database of Genotypes and Phenotypes (dbGaP) website (https://www.ncbi.nlm.nih.gov/gap/) under phs000674.v2.p2 (now superseded by phs000674.v3.p3) and under phs000428.v2.p2.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
U2 - 10.1038/s41588-021-00950-8
DO - 10.1038/s41588-021-00950-8
M3 - Article
SN - 1061-4036
VL - 53
SP - 1543
EP - 1552
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -