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

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; 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. Results We identified a genome-wide significant association on chromosome 9q31.2 (SNP rs10512344; P =3.57×10 –8 ), in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P –6 ). Sex-stratified analyses revealed that the variants at 9q32.1 affect risk of IBS in only women (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 9q32.1 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 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.