Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.
Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.
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DOI：
10.1053/j.gastro.2018.03.064
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发表时间：
2018-07
期刊：
影响因子：
29.4
通讯作者：
D'Amato M
中科院分区：
文献类型：
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作者：
Bonfiglio F;Zheng T;Garcia-Etxebarria K;Hadizadeh F;Bujanda L;Bresso F;Agreus L;Andreasson A;Dlugosz A;Lindberg G;Schmidt PT;Karling P;Ohlsson B;Simren M;Walter S;Nardone G;Cuomo R;Usai-Satta P;Galeazzi F;Neri M;Portincasa P;Bellini M;Barbara G;Latiano A;Hübenthal M;Thijs V;Netea MG;Jonkers D;Chang L;Mayer EA;Wouters MM;Boeckxstaens G;Camilleri M;Franke A;Zhernakova A;D'Amato M
遗传因素被认为会影响肠易激综合征（IBS）的风险，但还没有足够的动力和足够大的研究。为了确定与IBS风险相关的DNA变异，我们对大型英国生物银行人群队列进行了全基因组关联研究（GWAS），其中包括来自50万参与者的基因型和健康数据。我们研究了7，287，191个高质量的单核苷酸多态性，这些个体自我报告了医生诊断的IBS（病例; m=9576），与队列的其余部分（对照; n= 336，499）相比（研究对象的平均年龄，40-69岁）。在来自三级中心的2045名IBS患者和来自欧洲和美国的7955名人群对照以及来自瑞典的小规模一般人群样本（n=249）中进一步研究了全基因组显著性发现。通过整合来自多个生物库的数据对GWAS结果进行功能注释，以从观察到的关联中获得生物学见解。我们在染色体9q31.2（SNP rs 10512344; P=3.57×10−8）上发现了一个全基因组显著相关性，该区域先前与初潮年龄相关，另外还有13个具有提示意义的位点（P<5.0×10−6）。性别分层分析显示，9q32.1的变异仅影响女性的IBS风险（在英国生物库中P=4.29×10−10），并且还与女性便秘为主的IBS（在第三队列中P= 0.015）和女性粪便变硬（在基于人群的样本中P= 0.0012）相关。9q32.1位点的功能注释鉴定了8个候选基因，包括在家族性自主神经功能障碍患者中突变的延长子复合物蛋白1基因（ELP 1或IKBKAP）。在一个足够有力的IBS GWAS中，我们将9q32.1位点的变异与女性IBS的风险相关联。这一观察结果可能为研究性激素和自主神经功能障碍在IBS中的作用提供了额外的理论依据。
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. 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. 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<5.0×10−6). 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. 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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影响因子：
29.4
作者：
Camilleri M;Carlson P;Zinsmeister AR;McKinzie S;Busciglio I;Burton D;Zucchelli M;D'Amato M
通讯作者：
D'Amato M
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Whorwell, PJ
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作者：
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通讯作者：
Targownik, Laura E.
影响因子：
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