结合功能预测值与Variable Threshold检验法研究非同义SNP

Incorporating predicted functions with variable threshold test to study non-synonymous single nucleotide polymorphisms

背景:目前,随着全基因组关联分析的开展,成千上万的SNP基因型测序已经使遗传流行病学的研究进入一个新的阶段。通常,识别疾病相关的遗传位点依赖于DNA序列的单个碱基改变,而其中的一些改变可能影响蛋白质的结构和功能。因此出现在编码区域并导致氨基酸替代或插入的非同义SNP由于改变了氨基酸序列,更倾向于影响与复杂疾病易感性相关的蛋白质功能。目的:结合非同义SNP的功能预测分数和Variable Threshold(VT)检验提高复杂疾病易感基因识别的准确率。方法:文中首先对非同义SNP,计算它们的SIFT分数值和Polyphen-2分数值。然后筛选了35个疾病基因,对这些基因采用加权的VT检验进行分析,并与传统的关联分析进行了比较。结果与结论:结果显示结合了SNP功能预测分数的VT检验,检验效能要高于传统的关联分析,提高了风险基因识别的准确率。

BACKGROUND：As the development of genome-wide association study, the simultaneous genotyping of thousands of single nucleotide polymorphisms have made genetic epidemiology studies come into a new phase. Generally, identification of genetic variants associated with human diseases is based on single base changes in the DNA sequence, some of which lead to alterations in protein structure and function. Therefore, those non-synonymous single nucleotide polymorphisms occurring in coding regions and causing an amino acid substitution or insertion of a stop codon are likely to affect the function of the proteins accounting for susceptibility to complex disease for altering the encoded amino acid sequence. OBJECTIVE：To combine incorporating predicted function scores of non-synonymous single nucleotide polymorphisms with variable threshold test to improve the identification accuracy of susceptibility genes associated with complex diseases. METHODS：Firstly, for non-synonymous single nucleotide polymorphisms, we computed their scale invariant feature transform and Polyphen-2 scores. Then weighted variable threshold tests were performed for 35 selected genes. The comparison with general association analysis was also performed. RESULTS AND CONCLUSION：The results showed that the test power of our method was higher than general association test, and the identification accuracy of susceptibility genes was improved.