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<h5 class="section-title" id="d8814801e565">Background & Aims</h5>
<p id="P1">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.
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<h5 class="section-title" id="d8814801e570">Methods</h5>
<p id="P2">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.
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<h5 class="section-title" id="d8814801e575">Results</h5>
<p id="P3">We identified a genome-wide significant association on chromosome 9q31.2
(SNP rs10512344;
<i>P</i>=3.57×10
<sup>−8</sup>), in a region previously linked to age at menarche, and 13 additional
loci of suggestive
significance (P<5.0×10
<sup>−6</sup>). Sex-stratified analyses revealed that the variants at 9q32.1 affect
risk of IBS
in only women (P=4.29×10
<sup>−10</sup> in UK Biobank) and also associate with constipation-predominant IBS
in women (
<i>P</i>=.015 in the tertiary cohort) and harder stools in women (
<i>P</i>=.0012 in the population-based sample). Functional annotation of the 9q32.1
locus
identified 8 candidate genes, including the elongator complex protein 1 gene (
<i>ELP1</i> or
<i>IKBKAP</i>), which is mutated in patients with familial dysautonomia.
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<h5 class="section-title" id="d8814801e605">Conclusions</h5>
<p id="P4">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.
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