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Cited by 76Gastrointestinal motility and disordersGenetic Associations and EpidemiologyGut microbiota and health

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

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Bonfiglio, Ferdinando, Zheng, Tenghao, Garcia-Etxebarria, Koldo, Hadizadeh, Fatemeh, Bujanda, Luis, Bresso, Francesca, Agreus, Lars, Andreasson, Anna +28 more·2018·Gastroenterology
DOI 10.1053/j.gastro.2018.03.064PMC PMC6035117
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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.

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  • The biopsychosocial model conceptualises a genetic predisposition, where adverse events in early life, psychological factors, or gastrointestinal infections then trigger alterations in the enteric nervous system, which controls gastrointestinal motor, sensory, mucosal barrier, and secretory responses.

    “The biopsychosocial model to explain symptoms of abdominal pain and disordered bowel habit in IBS conceptualised a genetic predisposition, where adverse events in early life, psychological factors, or gastrointestinal infections then trigger alterations in the enteric nervous system, which controls gastrointestinal motor, sensory, mucosal barrier, and secretory responses (Figure 3). 21”

    From Irritable bowel syndrome (2020) · cites this paper as [21]

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Authors
Bonfiglio, F., Zheng, T., Garcia-Etxebarria, K., Hadizadeh, F., Bujanda, L., Bresso, F., Agreus, L., Andreasson, A., Dlugosz, A., Lindberg, G., Schmidt, P. T., Karling, P., Ohlsson, B., Simren, M., Walter, S., Nardone, G., Cuomo, R., Usai-Satta, P., Galeazzi, F., Neri, M., Portincasa, P., Bellini, M., Barbara, G., Latiano, A., Hübenthal, M., Thijs, V., Netea, M. G., Jonkers, D., Chang, L., Mayer, E. A., Wouters, M. M., Boeckxstaens, G., Camilleri, M., Franke, A., Zhernakova, A., & D’Amato, M.
Affiliations
  • Karolinska Institutet (SE)
  • Karolinska University Hospital (SE)
  • Umeå University (SE)
  • Lund University (SE)
  • Linköping University (SE)
  • Federico II University Hospital (IT)
  • University of Padua (IT)
  • University of Chieti-Pescara (IT)
  • University of Bari Aldo Moro (IT)
  • University of Pisa (IT)
  • IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
  • Casa Sollievo della Sofferenza (IT)
  • Christian-Albrechts-Universität zu Kiel (DE)
  • Florey Institute of Neuroscience and Mental Health (AU)
  • University of Bonn (DE)
  • Maastricht University Medical Centre (NL)
  • University of California, Los Angeles (US)
  • KU Leuven (BE)
  • Mayo Clinic (US)
  • University Medical Center Groningen (NL)
  • Ikerbasque (ES)
Corresponding author
D’Amato, Mauro
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2018-07
Volume
155
Issue
1
Pages
168-179
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2018.03.064
PMC
PMC6035117
OpenAlex
W2796338032
Cited by
76
References
7
Citations by year
2026: 3 · 2025: 11 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 11 · 2020: 11 · 2019: 9 · 2018: 1
FWCI
7.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (acceptedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Lirias (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • University of Essex
  • Wellcome Trust (EU-FP7-)
  • Understanding Society
  • Eusko Jaurlaritza (2015111133)
  • Ministerio de Economía y Competitividad (FIS PI17/00308)
  • Vetenskapsrådet (2017-02403, 2013-03862)
  • National Institutes of Health (41301, P30 DK, DK64539)
  • Medical Research Council (MC_PC_17228)
  • Economic and Social Research Council
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048351, P50DK064539, P30DK041301)
Topics
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
irritable bowel syndrome, sex differences, women, irritable bowel syndrome with constipation, hard stools, age at menarche, ELP1, IKBKAP, familial dysautonomia, sex hormones, autonomic dysfunction, genetic risk variants
MeSH terms
Adult, Aged, Chromosomes, Human, Pair 9, Constipation, Europe, Female, Genotype, Humans, Male, Menarche, Middle Aged, Sex Factors, Sweden, United States, Genetic Variation, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Irritable Bowel Syndrome, Genome-Wide Association Study, Self Report

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