Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies.
Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies.
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DOI：
10.1016/j.jmb.2015.04.014
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发表时间：
2015-07-03
影响因子：
5.6
通讯作者：
Moult J
中科院分区：
文献类型：
--
作者：
Pal LR;Moult J
最近的全基因组关联研究已经导致在与特定常见人类疾病的风险增加相关的许多基因座处的SNP的可靠鉴定。每个这样的基因座暗示参与疾病机制的多个可能的候选SNP。多种机制可能将SNP的存在与体内基因产物功能的改变联系起来，从而导致疾病风险。在这里，我们报告了这些机制之一，错义SNPs（msSNPs）在7个复杂性状疾病的蛋白质中的作用的分析。连锁不平衡信息被用来确定可能的候选msSNPs与增加的疾病风险在356个位点的7种疾病。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显著影响。69%的基因座具有至少一个候选msSNP，33%具有至少一个预测的高影响msSNP。在某些情况下，这些SNP存在于公认的疾病相关蛋白质中，例如克罗恩病的MST 1（巨噬细胞刺激1）。在其他情况下，它们存在于GWAS鉴定为疾病相关性的可能候选蛋白质中，但以前没有已知的机制，例如ADAMTS13（ADAM金属肽酶，具有1型血小板反应蛋白基序，13）用于冠状动脉疾病。在其他情况下，错义SNP存在于先前未被建议为疾病候选者的蛋白质中，例如用于高血压的TUBB1（微管蛋白，β 1，VI类）。总之，这些数据支持这类SNP在人类常见疾病易感性中的重要作用。
Recent genome wide association studies have led to the reliable identification of 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 a 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.