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

Ferdinando Bonfiglio, Xingrong Liu, Christopher Smillie, Anita Pandit, Alexander Kurilshikov, Rodrigo Bacigalupe, Tenghao Zheng, Hieu Nim, Koldo Garcia-Etxebarria, Luis Bujanda, Anna Andreasson, Lars Agreus, Susanna Walter, Gonçalo Abecasis, Chris Eijsbouts, Luke Jostins, Miles Parkes, David A. Hughes, Nicholas Timpson, Jeroen RaesAndre Franke, Nicholas A. Kennedy, Aviv Regev, Alexandra Zhernakova, Magnus Simren, Michael Camilleri, Mauro D'Amato*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)
29 Downloads (Pure)


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.

Original languageEnglish
Article number100069
Pages (from-to)1-9, e1-e5
Number of pages15
JournalCell Genomics
Issue number3
Publication statusPublished - 8 Dec 2021
Externally publishedYes

Bibliographical note

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.


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


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