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首页> 外文期刊>Journal of Molecular Biology >Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies
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Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies

机译：常见人类疾病的遗传基础：从基因组范围的关联研究中了解错义SNP的作用

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Recent genome-wide association studies (GWAS) have led to the reliable identification of single nucleotide polymorphisms (SNPs) at a number of loci associated with increased risk of specific common human diseases. Each such locus implicates multiple possible candidate SNPs for involvement in disease mechanism. A variety of mechanisms may link the presence of an SNP to altered in vivo gene product function and hence contribute to disease risk. Here, we report an analysis of the role of one of these mechanisms, missense SNPs (msSNPs) in proteins in seven complex trait diseases. Linkage disequilibrium information was used to identify possible candidate msSNPs associated with increased disease risk at each of 356 loci for the seven diseases. Two computational methods were used to estimate which of these SNPs has a significant impact on in vivo protein function. 69% of the loci have at least one candidate msSNP and 33% have at least one predicted high-impact msSNP. In some cases, these SNPs are in well-established disease-related proteins, such as MST1 (macrophage stimulating 1) for Crohn's disease. In others, they are in proteins identified by GWAS as likely candidates for disease relevance, but previously without known mechanism, such as ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13) for coronary artery disease. In still other cases, the missense SNPs are in proteins not previously suggested as disease candidates, such as TUBB1 (tubulin, beta 1, class VI) for hypertension. Together, these data support a substantial role for this class of SNPs in susceptibility to common human disease. (C) 2015 Elsevier Ltd. All rights reserved.
机译：最近的全基因组关联研究（GWAS）已导致在与特定人类常见疾病风险增加相关的多个基因座上可靠鉴定单核苷酸多态性（SNP）。每个这样的基因座都牵涉多个可能的候选SNP参与疾病机制。多种机制可以将SNP的存在与体内基因产物功能的改变联系起来，从而增加疾病风险。在这里，我们报告分析这些机制之一的作用，七种复杂性状疾病中的蛋白质中的错义SNP（msSNPs）。连锁不平衡信息被用来识别与这七个疾病的356个基因座中的每一个基因座的疾病风险增加相关的可能候选msSNP。使用两种计算方法来估计这些SNP中的哪一个对体内蛋白质功能具有重要影响。 69％的基因座具有至少一种候选msSNP，33％的基因具有至少一种预测的高影响msSNP。在某些情况下，这些SNP位于成熟的疾病相关蛋白质中，例如克罗恩氏病的MST1（巨噬细胞刺激物1）。在其他情况下，它们存在于被GWAS鉴定为可能与疾病相关的候选蛋白中，但以前没有已知的机制，例如ADAMTS13（ADAMTS13（具有血小板反应蛋白1型基序的ADAM金属肽酶，13）用于冠心病。在其他情况下，错义单核苷酸多态性存在于以前没有被建议作为疾病候选者的蛋白质中，例如用于高血压的TUBB1（微管蛋白，β1，VI类）。总之，这些数据支持此类SNP在常见人类疾病易感性中的重要作用。 （C）2015 Elsevier Ltd.保留所有权利。

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