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首页> 外文期刊>BMC Medical Genomics >eMERGE Phenome-Wide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants
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eMERGE Phenome-Wide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants

机译：eMERGE现象广泛关联研究（PheWAS）确定了终止增益变异体的临床关联和多效性

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Background We explored premature stop-gain variants to test the hypothesis that variants, which are likely to have a consequence on protein structure and function, will reveal important insights with respect to the phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover potential pleiotropy. Results In this study, we selected 25 stop-gain variants: 5 stop-gain variants with previously reported phenotypic associations, and a set of 20 putative stop-gain variants identified using dbSNP. For the PheWAS, we used data from the electronic MEdical Records and GEnomics (eMERGE) Network across 9 sites with a total of 41,057 unrelated patients. We divided all these samples into two datasets by equal proportion of eMERGE site, sex, race, and genotyping platform. We calculated single effect associations between these 25 stop-gain variants and ICD-9 defined case-control diagnoses. We also performed stratified analyses for samples of European and African ancestry. Associations were adjusted for sex, site, genotyping platform and the first three principal components to account for global ancestry. We identified previously known associations, such as variants in LPL associated with hyperglyceridemia indicating that our approach was robust. We also found a total of three significant associations with?p?discovery?=?2.59x10-6, preplicating?=?2.7x10-4). The other two significant replicated associations identified by this study are: variant rs1137617 in KCNH2 gene associated with ICD-9 code category 244 “Acquired Hypothyroidism” (pdiscovery?=?5.31x103, preplicating?=?1.15x10-3) and variant rs12060879 in DPT gene associated with ICD-9 code category 996 “Complications peculiar to certain specified procedures” (pdiscovery?=?8.65x103, preplicating?=?4.16x10-3). Conclusion In conclusion, this PheWAS revealed novel associations of stop-gained variants with interesting phenotypes (ICD-9 codes) along with pleiotropic effects.
机译：背景我们探讨了过早的终止增益变异体，以检验以下假设：变异体可能对蛋白质的结构和功能产生影响，该变异体将揭示有关其相关表型的重要见解。我们进行了一项全现象组关联研究（PheWAS），研究了功能停止增益遗传变异的选定列表（导致蛋白质被截断或无义介导的衰变的变异）与大量诊断之间的关联，以识别新的关联并发现潜在的多效性。结果在这项研究中，我们选择了25个终止增益变体：5个具有先前报道的表型关联的终止增益变体，以及使用dbSNP鉴定的20个假定的终止增益变体集。对于PheWAS，我们使用了来自9个站点的电子医学记录和基因组学（eMERGE）网络的数据，共有41,057名无关患者。我们按eMERGE网站，性别，种族和基因分型平台的相等比例将所有这些样本分为两个数据集。我们计算了这25种停止增益变型与ICD-9定义的病例对照诊断之间的单效关联。我们还对欧洲和非洲血统的样本进行了分层分析。对协会进行了性别，地点，基因分型平台和前三个主要组成部分的调整，以说明全球血统。我们确定了先前已知的关联，例如与高甘油血症相关的LPL变体，表明我们的方法是可靠的。我们还发现总共有三个显着的关联，它们的关联度分别为？p？discovery ？=？2.59x10-6，p replicating ？=？2.7x10-4）。这项研究确定的其他两个重要的复制关联是：与ICD-9代码类别244“后天性甲状腺功能减退”相关的KCNH2基因的变体rs1137617（p discovery ？=？5.31x103，p replicating ？=？1.15x10-3）和与ICD-9代码类别996“某些特定程序所特有的并发症”相关的DPT基因中的变体rs12060879（p discovery ？=？8.65x103， p replicating ？=？4.16x10-3）。结论总之，该PheWAS揭示了终止获得的变体与有趣的表型（ICD-9代码）以及多效性效应之间的新型关联。

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