1. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
- Author
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Eijsbouts, Chris, Zheng, Tenghao, Kennedy, Nicholas A, Bonfiglio, Ferdinando, Anderson, Carl A, Moutsianas, Loukas, Holliday, Joanne, Shi, Jingchunzi, Shringarpure, Suyash, Voda, Alexandru-Ioan, 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, and Parkes, Miles
- Subjects
Human Genome ,Behavioral and Social Science ,Mental Health ,Neurosciences ,Chronic Pain ,Genetics ,Pain Research ,Digestive Diseases ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Oral and gastrointestinal ,Mental health ,Neurological ,Aged ,Anxiety Disorders ,CD56 Antigen ,Cell Adhesion Molecules ,Cytoskeletal Proteins ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Guanine Nucleotide Exchange Factors ,Homeodomain Proteins ,Humans ,Irritable Bowel Syndrome ,Male ,Middle Aged ,Molecular Chaperones ,Mood Disorders ,Polymorphism ,Single Nucleotide ,United Kingdom ,23andMe Research Team ,Bellygenes Initiative ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - 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.
- Published
- 2021