Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
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DOI：
10.1136/gutjnl-2018-317619
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发表时间：
2019-05-01
期刊：
影响因子：
24.5
通讯作者：
Hampe, Jochen
中科院分区：
文献类型：
--
作者：
Schafmayer, Clemens;Harrison, James William;Hampe, Jochen
目的憩室病是一种常见的复杂性疾病，以结肠壁粘膜外露为特征，表现为憩室炎、穿孔、出血等并发症。我们报道了迄今为止规模最大的全基因组关联研究，以确定憩室病的遗传危险因素。设计发现对英国生物库归因于欧洲血统的31 964例病例和419 135名对照进行了设计发现关联研究。在欧洲3893例病例和2829例无憩室对照的欧洲样本中复制了相关关系，并评估了其对憩室炎和无并发症憩室病的风险贡献。用实时定量聚合酶链式反应分析结肠粘膜、粘膜下层和肌层的前20个复制位点的转录本。结果共发现48个易感基因座，其中12个为新发现，具有全基因组意义，在复制样本中具有一致的OR。27个基因座的名义复制(p<；0.05)被观察到，在基于人群的队列的荟萃分析中观察到另外8个。在复制分析中，最显著的新风险变异rs9960286位于CTAGE1附近，p值为2.3×10~(-10)和0.002(OR等位基因=1.14(95%CI1.05~1.24))。PHGR1(OR 1.32，95%CI 1.12~1.56)、FAM155A-2(OR 1.21，95%CI 1.04~1.42)、CALCB(OR 1.17，95%CI 1.03~1.33)和S100A10(OR 1.17，95%CI 1.03~1.33)对憩室炎有较强的易感性。
Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p< 0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10-10 and 0.002 (OR allelic = 1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).Conclusion I n silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.