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

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.

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Item Type:	Article
Authors/Creators:	Eijsbouts, C Zheng, T Kennedy, NA Bonfiglio, F Anderson, CA Moutsianas, L Holliday, J Shi, J Shringarpure, S 23andMe Research Team Voda, A-I The Bellygenes Initiative Farrugia, G Franke, A Hübenthal, M Abecasis, G Zawistowski, M Skogholt, AH Ness-Jensen, E Hveem, K Esko, T Teder-Laving, M Zhernakova, A Camilleri, M Boeckxstaens, G Whorwell, PJ Spiller, R McVean, G D’Amato, M Jostins, L Parkes, M
Copyright, Publisher and Additional Information:	© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: November 2021 Published (online): 5 November 2021 Accepted: 8 September 2021
Institution:	The University of Leeds
Depositing User:	Symplectic Publications
Date Deposited:	11 Jan 2023 13:40
Last Modified:	11 Jan 2023 14:41
Published Version:	http://dx.doi.org/10.1038/s41588-021-00950-8
Status:	Published
Publisher:	Springer Science and Business Media LLC
Identification Number:	10.1038/s41588-021-00950-8
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:194611

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

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