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

Research output: Contribution to journalArticle


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.


  • Ferdinando Bonfiglio
  • Tenghao Zheng
  • Koldo Garcia-Etxebarria
  • Fatemeh Hadizadeh
  • Luis Bujanda
  • Francesca Bresso
  • Lars Agreus
  • Anna Andreasson
  • Aldona Dlugosz
  • Greger Lindberg
  • Peter T. Schmidt
  • Pontus Karling
  • Magnus Simren
  • Susanna Walter
  • Gerardo Nardone
  • Rosario Cuomo
  • Paolo Usai-Satta
  • Francesca Galeazzi
  • Matteo Neri
  • Piero Portincasa
  • Massimo Bellini
  • Giovanni Barbara
  • Anna Latiano
  • Matthias Hübenthal
  • Vincent Thijs
  • Mihai G. Netea
  • Daisy Jonkers
  • Lin Chang
  • Emeran A. Mayer
  • Mira M. Wouters
  • Guy Boeckxstaens
  • Michael Camilleri
  • Andre Franke
  • Alexandra Zhernakova
  • Mauro D'Amato
External organisations
  • Biodonostia Health Research Institute
  • Karolinska Institutet
  • University of the Basque Country
  • Karolinska University Hospital
  • Umeå University
  • Skåne University Hospital
  • Sahlgrenska Academy
  • Linköping University
  • University of Naples Federico II
  • Azienda Ospedaliera Brotzu
  • University Hospital of Padua
  • Bari University Hospital
  • University of Pisa
  • St. Orsola-Malpighi University Hospital
  • Casa Sollievo della Sofferenza
  • University of Kiel
  • Radboud University Nijmegen
  • University of Bonn
  • Catholic University of Leuven
  • Mayo Clinic Minnesota
  • University Medical Center Groningen
  • Basque Foundation for Science
  • Stockholm University
  • University of Chieti-Pescara
  • Florey Institute of Neuroscience and Mental Health
  • Maastricht University Medical Centre
  • University of California, Los Angeles
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Gastroenterology and Hepatology
  • Medical Genetics


  • Biobank Research, Bowel Symptoms, Genetics, SNP
Original languageEnglish
Pages (from-to)168-179
Number of pages12
Issue number1
Publication statusPublished - 2018 Jul 1
Publication categoryResearch