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 Raes; Andre Franke; Nicholas A. Kennedy; Aviv Regev; Alexandra Zhernakova; Magnus Simren; Michael Camilleri; Mauro D'Amato

doi:10.1016/j.xgen.2021.100069

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

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Abstract

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 language	English
Article number	100069
Pages (from-to)	1-9, e1-e5
Number of pages	15
Journal	Cell Genomics
Volume	1
Issue number	3
DOIs	https://doi.org/10.1016/j.xgen.2021.100069
Publication status	Published - 8 Dec 2021
Externally published	Yes

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.

Keywords

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

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Publisher version (open access)Final published version, 1.93 MBLicence: CC BY-NC-ND

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Bonfiglio, F., Liu, X., Smillie, C., Pandit, A., Kurilshikov, A., Bacigalupe, R., Zheng, T., Nim, H., Garcia-Etxebarria, K., Bujanda, L., Andreasson, A., Agreus, L., Walter, S., Abecasis, G., Eijsbouts, C., Jostins, L., Parkes, M., Hughes, D. A., Timpson, N., ... D'Amato, M. (2021). GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome. Cell Genomics, 1(3), 1-9, e1-e5. Article 100069. https://doi.org/10.1016/j.xgen.2021.100069

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abstract = "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 = "enteric nervous system, genetics, gut motility, GWAS, irritable bowel syndrome, peristalsis, polygenic scores, SNP",

author = "Ferdinando Bonfiglio and Xingrong Liu and Christopher Smillie and Anita Pandit and Alexander Kurilshikov and Rodrigo Bacigalupe and Tenghao Zheng and Hieu Nim and Koldo Garcia-Etxebarria and Luis Bujanda and Anna Andreasson and Lars Agreus and Susanna Walter and Gon{\c c}alo Abecasis and Chris Eijsbouts and Luke Jostins and Miles Parkes and Hughes, \{David A.\} and Nicholas Timpson and Jeroen Raes and Andre Franke and Kennedy, \{Nicholas A.\} and Aviv Regev and Alexandra Zhernakova and Magnus Simren and Michael Camilleri and Mauro D'Amato",

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.",

year = "2021",

month = dec,

day = "8",

doi = "10.1016/j.xgen.2021.100069",

language = "English",

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Bonfiglio, F, Liu, X, Smillie, C, Pandit, A, Kurilshikov, A, Bacigalupe, R, Zheng, T, Nim, H, Garcia-Etxebarria, K, Bujanda, L, Andreasson, A, Agreus, L, Walter, S, Abecasis, G, Eijsbouts, C, Jostins, L, Parkes, M, Hughes, DA, Timpson, N, Raes, J, Franke, A, Kennedy, NA, Regev, A, Zhernakova, A, Simren, M, Camilleri, M & D'Amato, M 2021, 'GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome', Cell Genomics, vol. 1, no. 3, 100069, pp. 1-9, e1-e5. https://doi.org/10.1016/j.xgen.2021.100069

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 - https://www.scopus.com/pages/publications/85133862907

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 -

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

Abstract

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