TY - JOUR
T1 - Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
AU - 23andMe Research Team
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 - Voda, Alexandru-Ioan
AU - Farrugia, Gianrico
AU - Franke, Andre
AU - Hübenthal, Matthias
AU - Abecasis, Gonçalo
AU - Zawistowski, Matthew
AU - Skogholt, Anne Heidi
AU - Ness-Jensen, Eivind
AU - Hveem, Kristian
AU - Esko, Tõnu
AU - Teder-Laving, Maris
AU - Zhernakova, Alexandra
AU - Camilleri, Michael
AU - Boeckxstaens, Guy
AU - Whorwell, Peter J
AU - Spiller, Robin
AU - McVean, Gil
AU - D'Amato, Mauro
AU - Jostins, Luke
AU - Parkes, Miles
N1 - © 2021. The Author(s).
PY - 2021/11/5
Y1 - 2021/11/5
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.
KW - Aged
KW - Anxiety Disorders/genetics
KW - CD56 Antigen/genetics
KW - Cell Adhesion Molecules/genetics
KW - Cytoskeletal Proteins/genetics
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Guanine Nucleotide Exchange Factors/genetics
KW - Homeodomain Proteins/genetics
KW - Humans
KW - Irritable Bowel Syndrome/epidemiology
KW - Male
KW - Middle Aged
KW - Molecular Chaperones/genetics
KW - Mood Disorders/genetics
KW - Polymorphism, Single Nucleotide
KW - United Kingdom/epidemiology
U2 - 10.1038/s41588-021-00950-8
DO - 10.1038/s41588-021-00950-8
M3 - Article
C2 - 34741163
SN - 1061-4036
VL - 53
SP - 1543
EP - 1552
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -