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Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Published version
Peer-reviewed

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Authors

Zheng, Tenghao 
Kennedy, Nicholas A. 
Bonfiglio, Ferdinando 

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 (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.

Description

Funder: Kennedy Trust Rheumatology Research Prize Studentship


Funder: DFG Cluster of Excellence “Precision Medicine in Chronic In-flammation” (PMI; ID: EXC2167)


Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772


Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL


Funder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421

Keywords

Article, /631/208/205/2138, /692/699/1503/1502/2071, /692/699/476, /38/43, article

Journal Title

Nature Genetics

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

53

Publisher

Nature Publishing Group US
Sponsorship
Wellcome Trust (Wellcome) (280750/Z/17/Z, 203141/Z/16/Z, 098051)
DH | National Institute for Health Research (NIHR) (BRC-1215-20008, BRC-1215-20007, BRC-1215-20003, BRC-1215-20014)
U.S. Department of Health & Human Services | National Institutes of Health (NIH) (R01 DK 92179 and 115950)
Vetenskapsrådet (Swedish Research Council) (2017-02403)