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

Cell Genom. 2021 Dec 8;1(3):None. doi: 10.1016/j.xgen.2021.100069.

Authors

Ferdinando Bonfiglio^{1

2}, Xingrong Liu^{2

3}, Christopher Smillie⁴, Anita Pandit⁵, Alexander Kurilshikov⁶, Rodrigo Bacigalupe^{7

8}, Tenghao Zheng^{1

2

3}, Hieu Nim¹, Koldo Garcia-Etxebarria⁹, Luis Bujanda^{9

10

11}, Anna Andreasson¹², Lars Agreus¹³, Susanna Walter¹⁴, Gonçalo Abecasis⁵, Chris Eijsbouts^{15

16}, Luke Jostins^{17

18}, Miles Parkes¹⁹, David A Hughes^{20

21}, Nicholas Timpson^{20

21}, Jeroen Raes^{7

8}, Andre Franke²², Nicholas A Kennedy²³, Aviv Regev⁴, Alexandra Zhernakova⁶, Magnus Simren²⁴, Michael Camilleri²⁵, Mauro D'Amato^{1

2

9

26

27}

Affiliations

¹ School of Biological Sciences, Monash University, Clayton, VIC, Australia.
² Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
³ Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴ Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA.
⁵ Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA.
⁶ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁷ Department of Microbiology and Immunology, Rega Instituut, KU Leuven, Leuven, Belgium.
⁸ Center for Microbiology, VIB, Leuven 3000, Belgium.
⁹ Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastian, Spain.
¹⁰ Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
¹¹ Universidad del País Vasco (UPV/EHU), San Sebastian, Spain.
¹² Division of Clinical Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
¹³ Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
¹⁵ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁶ Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
¹⁷ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
¹⁸ Christ Church, University of Oxford, Oxford, UK.
¹⁹ Division of Gastroenterology, Department of Medicine, University of Cambridge, Cambridge, UK.
²⁰ MRC Integrative Epidemiology Unit at University of Bristol, Bristol, UK.
²¹ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
²² Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
²³ IBD Pharmacogenetics, College of Medicine and Health, University of Exeter, Exeter, UK.
²⁴ Dept of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁵ Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
²⁶ IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
²⁷ Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.

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

Abstract

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