Cell Genomics
Volume 1, Issue 3, 8 December 2021, 100069
Journal home page for Cell Genomics

Short article
GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome

https://doi.org/10.1016/j.xgen.2021.100069Get rights and content
Under a Creative Commons license
open access

Highlights

  • Genetics of gut motility via data on stool frequency in 167,875 individuals

  • GWAS identifies 14 loci associated with stool frequency

  • Candidate genes enriched in neurotransmitter signaling and enteric motor neurons

  • Polygenic scores predict increased risk of irritable bowel syndrome

Summary

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.

Keywords

gut motility
GWAS
SNP
irritable bowel syndrome
polygenic scores
genetics
peristalsis
enteric nervous system

Data and code availability

The stool frequency GWAS meta-analysis summary statistics have been deposited in the GWAS Catalog (https://www.ebi.ac.uk/gwas/) with the study accession ID GCST90002250. Stool frequency PGS is deposited in the PGS Catalog (https://www.pgscatalog.org/), under an ID associated with the publication. Publicly available analysis software and code were used as described in the method details.

Cited by (0)

28

Present address: Genentech, South San Francisco, CA, USA

29

Lead contact

30

These authors contributed equally

31

These authors contributed equally