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

Authors:
Chris Eijsbouts, Tenghao Zheng, Nicholas A Kennedy, Ferdinando Bonfiglio, Carl A Anderson, Loukas Moutsianas, Joanne Holliday, Jingchunzi Shi, Suyash Shringarpure, Alexandru-Ioan Voda, Gianrico Farrugia, Andre Franke, Matthias Hübenthal, Gonçalo Abecasis, Matthew Zawistowski, Anne Heidi Skogholt, Eivind Ness-Jensen, Kristian Hveem, Tõnu Esko, Maris Teder-Laving, Alexandra Zhernakova, Michael Camilleri, Guy Boeckxstaens, Peter J Whorwell, Robin Spiller, Gil McVean, Mauro D'Amato, Luke Jostins, Miles Parkes
Year of publication:
2021
Volume:
53
Issue:
11
Issn:
1061-4036
Journal title abbreviated:
NAT GENET
Journal title long:
Nature genetics
Impact factor:
41.376
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<sub>g</sub> > 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.