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

Bonfiglio, Ferdinando; Zheng, Tenghao; Garcia-Etxebarria, Koldo; Hadizadeh, Fatemeh; Bujanda, Luis; Bresso, Francesca; Agreus, Lars; Andreasson, Anna; Dlugosz, Aldona and Lindberg, Greger, et al. (2018) In Gastroenterology 155(1). p.168-179
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; 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... (More)

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.

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@article{81cce975-7934-4054-a019-d00312f17ba4,
  abstract     = {<p>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 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<sup>–8</sup>) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P &lt; 5.0×10<sup>–6</sup>). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10<sup>–10</sup> 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.</p>},
  author       = {Bonfiglio, Ferdinando and Zheng, Tenghao and Garcia-Etxebarria, Koldo and Hadizadeh, Fatemeh and Bujanda, Luis and Bresso, Francesca and Agreus, Lars and Andreasson, Anna and Dlugosz, Aldona and Lindberg, Greger and Schmidt, Peter T. and Karling, Pontus and Ohlsson, Bodil and Simren, Magnus and Walter, Susanna and Nardone, Gerardo and Cuomo, Rosario and Usai-Satta, Paolo and Galeazzi, Francesca and Neri, Matteo and Portincasa, Piero and Bellini, Massimo and Barbara, Giovanni and Latiano, Anna and Hübenthal, Matthias and Thijs, Vincent and Netea, Mihai G. and Jonkers, Daisy and Chang, Lin and Mayer, Emeran A. and Wouters, Mira M. and Boeckxstaens, Guy and Camilleri, Michael and Franke, Andre and Zhernakova, Alexandra and D'Amato, Mauro},
  issn         = {0016-5085},
  keyword      = {Biobank Research,Bowel Symptoms,Genetics,SNP},
  language     = {eng},
  month        = {07},
  number       = {1},
  pages        = {168--179},
  publisher    = {W B Saunders},
  series       = {Gastroenterology},
  title        = {Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome},
  url          = {http://dx.doi.org/10.1053/j.gastro.2018.03.064},
  volume       = {155},
  year         = {2018},
}