Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants
Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants
复制标题
DOI：
10.1073/pnas.1114759108
复制
发表时间：
2011-11-01
影响因子：
11.1
通讯作者：
Chatterjee, Nilanjan
中科院分区：
文献类型：
--
作者：
Park, Ju-Hyun;Gail, Mitchell H.;Chatterjee, Nilanjan
最近从全基因组关联研究中发现的数百个常见易感性 SNP 为检查复杂性状的群体遗传模型提供了独特的机会。在本报告中，我们利用对一系列定性和定量性状中约 400 个易感性 SNP 的等位基因频率和效应大小参数的估计，研究了各种群体遗传参数的分布及其相互关系。我们通过 SNP 检测的统计功效来校准我们的分析，以解释当前已知的 SNP 中具有较大效应量的变异的过度代表性，这些变异是由于发现的统计功效而预期的。在所有定性疾病特征中，次要等位基因更多地赋予“风险”而不是“保护”。在所有性状中，“回归效应”和等位基因频率之间存在反比关系。这两种趋势对于 I 型糖尿病（这一特征最有可能受到选择的影响）来说非常强烈，但对于其他特征（例如人类身高或晚发疾病（例如 II 型糖尿病和癌症））来说则不太明显。在所有性状中，估计的效应大小分布表明存在越来越多的易感性 SNP，而效应却越来越小。对于大多数性状，具有中等次要等位基因频率 (5-20%) 的 SNP 组包含异常少量的易感位点，与一般人群中 SNP 分布的预期相比，解释了相对较小部分的遗传力。这些趋势可能对未来常见和不常见变异的研究产生多种影响。
Recent discoveries of hundreds of common susceptibility SNPs from genome-wide association studies provide a unique opportunity to examine population genetic models for complex traits. In this report, we investigate distributions of various population genetic parameters and their interrelationships using estimates of allele frequencies and effect-size parameters for about 400 susceptibility SNPs across a spectrum of qualitative and quantitative traits. We calibrate our analysis by statistical power for detection of SNPs to account for overrepresentation of variants with larger effect sizes in currently known SNPs that are expected due to statistical power for discovery. Across all qualitative disease traits, minor alleles conferred "risk" more often than "protection." Across all traits, an inverse relationship existed between "regression effects" and allele frequencies. Both of these trends were remarkably strong for type I diabetes, a trait that is most likely to be influenced by selection, but were modest for other traits such as human height or late-onset diseases such as type II diabetes and cancers. Across all traits, the estimated effect-size distribution suggested the existence of increasingly large numbers of susceptibility SNPs with decreasingly small effects. For most traits, the set of SNPs with intermediate minor allele frequencies (5-20%) contained an unusually small number of susceptibility loci and explained a relatively small fraction of heritability compared with what would be expected from the distribution of SNPs in the general population. These trends could have several implications for future studies of common and uncommon variants.