An integrative scoring system for ranking SNPs by their potential deleterious effects
An integrative scoring system for ranking SNPs by their potential deleterious effects
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DOI：
10.1093/bioinformatics/btp103
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发表时间：
2009-04-15
期刊：
影响因子：
5.8
通讯作者：
Shatkay, Hagit
中科院分区：
文献类型：
--
作者：
Lee, Phil Hyoun;Shatkay, Hagit
动机：识别构成常见和复杂人类疾病(如癌症)的单核苷酸多态(SNPs)是当前分子流行病学的主要兴趣。然而，人类基因组上数量巨大的SNPs需要计算方法来根据其对人类健康的潜在有害影响来确定SNPs的优先顺序，并因此加快基因分型和分析。结果：我们提出了一个新的综合评分系统，用于在概率框架内根据SNPs可能的有害影响对其进行优先排序。我们将我们的系统应用于从OMIM(在线孟德尔遗传在人类)数据库中获得的580个疾病易感基因，该数据库是关于人类基因和遗传疾病的最广泛使用的数据库之一。评分结果清楚地表明，已知的疾病相关SNPs的功能意义(FS)得分的分布与中性SNPs的显著不同。此外，我们根据FS评分总结了潜在有害SNPs的不同特征，如它们出现的功能基因组区域或它们主要影响的生物分子功能。我们还通过比较研究证明，我们的系统改进了其他SNPs功能评估系统，为已知的与疾病相关的SNPs赋予比中性SNPs高得多的FS分数。
Motivation: Identifying single nucleotide polymorphisms (SNPs) that underlie common and complex human diseases, such as cancer, is of major interest in current molecular epidemiology. Nevertheless, the tremendous number of SNPs on the human genome requires computational methods for prioritizing SNPs according to their potentially deleterious effects to human health, and as such, for expediting genotyping and analysis. As of yet, little has been done to quantitatively assess the possible deleterious effects of SNPs for effective association studies.Results: We propose a new integrative scoring system for prioritizing SNPs based on their possible deleterious effects within a probabilistic framework. We applied our system to 580 disease-susceptibility genes obtained from the OMIM (Online Mendelian Inheritance in Man) database, which is one of the most widely used databases of human genes and genetic disorders. The scoring results clearly show that the distribution of the functional significance (FS) scores for already known disease-related SNPs is significantly different from that of neutral SNPs. In addition, we summarize distinct features of potentially deleterious SNPs based on their FS score, such as functional genomic regions where they occur or biomolecular functions that they mainly affect. We also demonstrate, through a comparative study, that our system improves upon other function-assessment systems for SNPs, by assigning significantly higher FS scores to already known disease-related SNPs than to neutral SNPs.