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Gastroenterology. 2018 Jul;155(1):168-179. doi: 10.1053/j.gastro.2018.03.064. Epub 2018 Apr 5.

Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.

Author information

1
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.
2
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
3
Unit of Gastrointestinal Genetics, Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
4
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
5
Unit of Gastrointestinal Genetics, Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Universidad del País Vasco, San Sebastián, Spain.
6
Gastoenterology Unit, Tema inflammation and infection, Karolinska University Hospital, Stockholm, Sweden.
7
Division for Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
8
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.
9
Department of Medicine Solna, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
10
Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
11
Lund University, Skåne University Hospital, Department of Internal Medicine, Lund, Sweden.
12
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
13
Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
14
Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.
15
Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy.
16
SC Gastroenterologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy.
17
UOC Gastroenterologia, Padova University Hospital, Padova, Italy.
18
Department of Medicine and Aging Sciences and Center for Excellence on Aging, G. D'Annunzio University and Foundation, Chieti, Italy.
19
Department of Biomedical Sciences and Human Oncology, Clinica Medica A. Murri, University of Bari Medical School, Bari, Italy.
20
Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy.
21
Department of Medical and Surgical Sciences, University of Bologna, St. Orsola, Malpighi Hospital, Bologna, Italy.
22
Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
23
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
24
Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia.
25
Department of Internal Medicine and Radboud Center of Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department for Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
26
Department of Internal Medicine, Nutrition and Toxicology Research Institute Maastricht, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands.
27
G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California.
28
Translational Research Center for Gastro Intestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium.
29
Clinical Enteric Neuroscience Translational and Epidemiological Research, and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
30
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
31
Unit of Gastrointestinal Genetics, Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Ikerbasque, Basque Science Foundation, Bilbao, Spain. Electronic address: mauro.damato@ki.se.

Abstract

BACKGROUND & AIMS:

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.

METHODS:

We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 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.

RESULTS:

We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism 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 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in 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 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia.

CONCLUSIONS:

In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

KEYWORDS:

Biobank Research; Bowel Symptoms; Genetics; SNP

PMID:
29626450
PMCID:
PMC6035117
[Available on 2019-07-01]
DOI:
10.1053/j.gastro.2018.03.064
[Indexed for MEDLINE]

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