Cell Genomics (Dec 2021)
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
Affiliations
- Ferdinando Bonfiglio
- School of Biological Sciences, Monash University, Clayton, VIC, Australia; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Xingrong Liu
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Christopher Smillie
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
- Anita Pandit
- Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA
- Alexander Kurilshikov
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Rodrigo Bacigalupe
- Department of Microbiology and Immunology, Rega Instituut, KU Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven 3000, Belgium
- Tenghao Zheng
- School of Biological Sciences, Monash University, Clayton, VIC, Australia; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Hieu Nim
- School of Biological Sciences, Monash University, Clayton, VIC, Australia
- Koldo Garcia-Etxebarria
- Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastian, Spain
- Luis Bujanda
- Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastian, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Universidad del País Vasco (UPV/EHU), San Sebastian, Spain
- Anna Andreasson
- Division of Clinical Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Lars Agreus
- Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Susanna Walter
- Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
- Gonçalo Abecasis
- Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA
- Chris Eijsbouts
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
- Luke Jostins
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK; Christ Church, University of Oxford, Oxford, UK
- Miles Parkes
- Division of Gastroenterology, Department of Medicine, University of Cambridge, Cambridge, UK
- David A. Hughes
- MRC Integrative Epidemiology Unit at University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Nicholas Timpson
- MRC Integrative Epidemiology Unit at University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Jeroen Raes
- Department of Microbiology and Immunology, Rega Instituut, KU Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven 3000, Belgium
- Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
- Nicholas A. Kennedy
- IBD Pharmacogenetics, College of Medicine and Health, University of Exeter, Exeter, UK
- Aviv Regev
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
- Alexandra Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Magnus Simren
- Dept of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Mauro D’Amato
- School of Biological Sciences, Monash University, Clayton, VIC, Australia; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastian, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain; Corresponding author
- Journal volume & issue
-
Vol. 1,
no. 3
p. 100069
Abstract
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.
