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Title: Female-specific Association Between Variants on Chromosome 9 and Self-reported Diagnosis of Irritable Bowel Syndrome.
Austin Authors: Bonfiglio, Ferdinando;Zheng, Tenghao;Garcia-Etxebarria, Koldo;Hadizadeh, Fatemeh;Bujanda, Luis;Bresso, Francesca;Agreus, Lars;Andreasson, Anna;Dlugosz, Aldona;Lindberg, Greger;Schmidt, Peter T;Karling, Pontus;Ohlsson, Bodil;Simren, Magnus;Walter, Susanna;Nardone, Gerardo;Cuomo, Rosario;Usai-Satta, Paolo;Galeazzi, Francesca;Neri, Matteo;Portincasa, Piero;Bellini, Massimo;Barbara, Giovanni;Latiano, Anna;Hübenthal, Matthias;Thijs, Vincent N ;Netea, Mihai G;Jonkers, Daisy;Chang, Lin;Mayer, Emeran A;Wouters, Mira M;Boeckxstaens, Guy;Camilleri, Michael;Franke, Andre;Zhernakova, Alexandra;D'Amato, Mauro
Affiliation: IKERBASQUE, Basque Science Foundation, Bilbao, Spain
G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, CA, USA
The Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia
Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
Translational Research Center for Gastro Intestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
Unit of Gastrointestinal Genetics, Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Universidad del País Vasco (UPV/EHU), San Sebastián, Spain.
Gastoenterology Unit, Tema inflammation and infection, Karolinska University Hospital, Stockholm, Sweden
Division for Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
Stress Research Institute, Stockholm University, Stockholm, Sweden
Department of Medicine Solna, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden
Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy
S.C. Gastroenterologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy
UOC Gastroenterologia, Padova University Hospital, Padova, Italy
Department of Medicine and Aging Sciences and CESI, G. D'Annunzio University & Foundation, Chieti, Italy
Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy
Department of Medical and Surgical Sciences, University of Bologna, St. Orsola - Malpighi Hospital, Bologna, Italy
Division of Gastroenterology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy
Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
Lund University, Skåne University Hospital, Department of Internal Medicine, Lund, Sweden
Department of Biomedical Sciences and Human Oncology (DIMO), Clinica Medica "A. Murri", University of Bari Medical School, Bari, Italy
Issue Date: Jul-2018 2018-04-05
Publication information: Gastroenterology 2018; 155(1): 168-179
Abstract: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. We studied 7,287,191 high-quality single-nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; m=9576) compared to the remainder of the cohort (controls; n=336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n=249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories, to obtain biological insights from the observed associations. We identified a genome-wide significant association on chromosome 9q31.2 (SNP rs10512344; P=3.57×10-8), in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P<5.0×10-6). Sex-stratified analyses revealed that the variants at 9q32.1 affect risk of IBS in only women (P=4.29×10-10in UK Biobank) and also associate with constipation-predominant IBS in women (P=.015 in the tertiary cohort) and harder stools in women (P=.0012 in the population-based sample). Functional annotation of the 9q32.1 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q32.1 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
DOI: 10.1053/j.gastro.2018.03.064
ORCID: 0000-0002-6614-8417
PubMed URL: 29626450
Type: Journal Article
Subjects: SNP
biobank research
bowel symptoms
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