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
N1 - Funding Information:
This research has been conducted using the UK Biobank Resource under Application Number 17435. The UK Household Longitudinal Study (Understanding Society) is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website www.understandingsociety.ac.uk/ . Author contributions: MDA and AZ: study concept and design. LB, F Bresso, LA, AA, AD, GL, PTS, PK, BO, MS, SW, GN, RC, PU-S, FG, MN, PP, MB, G Barbara, AL, VT, MGN, DJ, LC, EAM, MMW, G Boeckxstaens, MC: patients characterization, data acquisition. F Bonfiglio, TZ, KG-E, FH: statistical analyses. F Bonfiglio, TZ, MDA, MH, AF: data analysis and interpretation. MDA: obtained funding, administrative and technical support, and study supervision. F Bonfiglio and MDA: drafted the manuscript, with input and critical revision from all other authors. All authors approved the final draft of the manuscript.
Publisher Copyright:
© 2018 AGA Institute
PY - 2018/7
Y1 - 2018/7
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
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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 -