TY - JOUR
T1 - GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome
AU - Bonfiglio, Ferdinando
AU - Liu, Xingrong
AU - Smillie, Christopher
AU - Pandit, Anita
AU - Kurilshikov, Alexander
AU - Bacigalupe, Rodrigo
AU - Zheng, Tenghao
AU - Nim, Hieu
AU - Garcia-Etxebarria, Koldo
AU - Bujanda, Luis
AU - Andreasson, Anna
AU - Agreus, Lars
AU - Walter, Susanna
AU - Abecasis, Gonçalo
AU - Eijsbouts, Chris
AU - Jostins, Luke
AU - Parkes, Miles
AU - Hughes, David A.
AU - Timpson, Nicholas
AU - Raes, Jeroen
AU - Franke, Andre
AU - Kennedy, Nicholas A.
AU - Regev, Aviv
AU - Zhernakova, Alexandra
AU - Simren, Magnus
AU - Camilleri, Michael
AU - D'Amato, Mauro
N1 - Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2021/12/8
Y1 - 2021/12/8
N2 - Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10−8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.
AB - Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10−8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.
KW - enteric nervous system
KW - genetics
KW - gut motility
KW - GWAS
KW - irritable bowel syndrome
KW - peristalsis
KW - polygenic scores
KW - SNP
UR - http://www.scopus.com/inward/record.url?scp=85133862907&partnerID=8YFLogxK
U2 - 10.1016/j.xgen.2021.100069
DO - 10.1016/j.xgen.2021.100069
M3 - Article
C2 - 34957435
AN - SCOPUS:85133862907
SN - 2666-979X
VL - 1
SP - 1-9, e1-e5
JO - Cell Genomics
JF - Cell Genomics
IS - 3
M1 - 100069
ER -