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

TY - JOUR

T1 - Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome

AU - Bonfiglio, Ferdinando

AU - Zheng, Tenghao

AU - Garcia-Etxebarria, Koldo

AU - Hadizadeh, Fatemeh

AU - Bujanda, Luis

AU - Bresso, Francesca

AU - Agreus, Lars

AU - Andreasson, Anna

AU - Dlugosz, Aldona

AU - Lindberg, Greger

AU - Schmidt, Peter T.

AU - Karling, Pontus

AU - Ohlsson, Bodil

AU - Simren, Magnus

AU - Walter, Susanna

AU - Nardone, Gerardo

AU - Cuomo, Rosario

AU - Usai-Satta, Paolo

AU - Galeazzi, Francesca

AU - Neri, Matteo

AU - Portincasa, Piero

AU - Bellini, Massimo

AU - Barbara, Giovanni

AU - Latiano, Anna

AU - Hübenthal, Matthias

AU - Thijs, Vincent

AU - Netea, Mihai G.

AU - Jonkers, Daisy

AU - Chang, Lin

AU - Mayer, Emeran A.

AU - Wouters, Mira M.

AU - Boeckxstaens, Guy

AU - Camilleri, Michael

AU - Franke, Andre

AU - Zhernakova, Alexandra

AU - D'Amato, Mauro

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

KW - Biobank Research

KW - Bowel Symptoms

KW - Genetics

KW - SNP

UR - http://www.scopus.com/inward/record.url?scp=85049316459&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049316459&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2018.03.064

DO - 10.1053/j.gastro.2018.03.064

M3 - Article

C2 - 29626450

AN - SCOPUS:85049316459

VL - 155

SP - 168

EP - 179

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 1

ER -