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Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome
Biodonostia Hlth Res Inst, Spain; Karolinska Inst, Sweden.
Karolinska Inst, Sweden; Karolinska Inst, Sweden.
Biodonostia Hlth Res Inst, Spain; Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
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2018 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 155, no 1, p. 168-179Article in journal (Refereed) Published
Abstract [en]

BACKGROUND amp; 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 doctors 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 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P amp;lt; 5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also [GRAPHICS] 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 IKB-KAP), 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.

Place, publisher, year, edition, pages
W B SAUNDERS CO-ELSEVIER INC , 2018. Vol. 155, no 1, p. 168-179
Keywords [en]
SNP; Biobank Research; Genetics; Bowel Symptoms
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-150283DOI: 10.1053/j.gastro.2018.03.064ISI: 000439705600056PubMedID: 29626450OAI: oai:DiVA.org:liu-150283DiVA, id: diva2:1239694
Note

Funding Agencies|Swedish Research Council (Vetenskapsradet project) [2013-03862, 2017-02403]; Health Department of the Basque Government [2015111133]; Spanish Ministry of Economy and Competitiveness (Instituto Salud Carlos III grant) [FIS PI17/00308]; National Institutes of Health [P50 DK64539, R01 DK048351, P30 DK 41301]; EU [313010]; European Research Council [310372]; Spinoza Grant of the Netherlands Organization for Scientific Research

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-08-17

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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Gastroentorology
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