Department of Genitourinary Medical Oncology Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Clin Genet. 2011 Mar;79(3):199-206. doi: 10.1111/j.1399-0004.2010.01535.x. Epub 2010 Sep 10.
The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs.
常见疾病/常见变异假说多年来一直被广泛用于描述常见人类疾病的遗传结构。根据最初的假说，一个或几个具有较大效应大小的常见遗传变异控制着常见疾病的风险。然而，越来越多的证据表明，罕见的单核苷酸多态性（SNP），即等位基因频率小于 5%的 SNP，也是常见人类疾病遗传结构的一个重要组成部分。在这项研究中，我们从进化的角度分析了罕见 SNPs 与常见疾病风险的相关性，发现罕见 SNPs 比常见 SNPs 更有可能具有功能，并且其效应大小往往比常见 SNPs 更强。这一观察结果，以及人类基因组中大多数 SNP 都是罕见的这一事实，表明罕见 SNP 是常见人类疾病遗传结构的关键因素。我们建议下一代基因组研究应侧重于分析罕见 SNPs。此外，针对有疾病家族史、极端表型或疾病早期发病的患者，可能有助于检测到与风险相关的罕见 SNPs。
