Sen Srijan, Burmeister Margit
Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Hum Genomics. 2008 Sep;3(1):36-52. doi: 10.1186/1479-7364-3-1-36.
In genetic association studies, deviation from Hardy-Weinberg equilibrium (HWD) can be due to recent admixture or selection at a locus, but is most commonly due to genotyping errors. In addition to its utility for identifying potential genotyping errors in individual studies, here we report that HWD can be useful in detecting the presence, magnitude and direction of genotyping error across multiple studies. If there is a consistent genotyping error at a given locus, larger studies, in general, will show more evidence for HWD than small studies. As a result, for loci prone to genotyping errors, there will be a correlation between HWD and the study sample size. By contrast, in the absence of consistent genotyping errors, there will be a chance distribution of p- values among studies without correlation with sample size. We calculated the evidence for HWD at 17 separate polymorphic loci investigated in 325 published genetic association studies. In the full set of studies, there was a significant correlation between HWD and locus-standardised sample size ( p = 0.001). For 14/17 of the individual loci, there was a positive correlation between extent of HWD and sample size, with the evidence for two loci ( 5-HTTLPR and CTSD ) rising to the level of statistical significance. Among single nucleotide polymorphisms (SNPs), 15/23 studies that deviated significantly from Hardy-Weinberg equilibrium (HWE) did so because of a deficit of heterozygotes. The inbreeding coefficient (F(is)) is a measure of the degree and direction of deviation from HWE. Among studies investigating SNPs, there was a significant correlation between F(is) and HWD ( R = 0.191; p = 0.002), indicating that the greater the deviation from HWE, the greater the deficit of heterozygotes. By contrast, for repeat variants, only one in five studies that deviated significantly from HWE showed a deficit of heterozygotes and there was no significant correlation between F(is) and HWD. These results indicate the presence of HWD across multiple loci, with the magnitude of the deviation varying substantially from locus to locus. For SNPs, HWD tends to be due to a deficit of heterozygotes, indicating that allelic dropout may be the most prevalent genotyping error.
在基因关联研究中，偏离哈迪-温伯格平衡（HWD）可能是由于近期的基因混合或某个位点的选择，但最常见的原因是基因分型错误。除了有助于识别单个研究中潜在的基因分型错误外，我们在此报告，HWD还可用于检测多个研究中基因分型错误的存在、程度和方向。如果在给定位点存在一致的基因分型错误，一般来说，大型研究比小型研究更能显示出偏离哈迪-温伯格平衡的证据。因此，对于容易出现基因分型错误的位点，HWD与研究样本量之间将存在相关性。相比之下，在不存在一致的基因分型错误的情况下，各研究之间的p值将呈随机分布，与样本量无关。我们计算了在325项已发表的基因关联研究中所调查的17个独立多态性位点的哈迪-温伯格平衡证据。在所有研究中，HWD与位点标准化样本量之间存在显著相关性（p = 0.001）。对于17个单个位点中的14个，哈迪-温伯格平衡程度与样本量呈正相关，其中两个位点（5-HTTLPR和CTSD）的证据达到了统计学显著水平。在单核苷酸多态性（SNP）中，15/23项显著偏离哈迪-温伯格平衡（HWE）的研究是由于杂合子不足。近交系数（F(is)）是衡量偏离哈迪-温伯格平衡的程度和方向的指标。在研究SNP的研究中，F(is)与哈迪-温伯格平衡偏离（HWD）之间存在显著相关性（R = 0.191；p = 0.002），表明偏离哈迪-温伯格平衡的程度越大，杂合子不足越严重。相比之下，对于重复变异，只有五分之一显著偏离哈迪-温伯格平衡的研究显示出杂合子不足，且F(is)与哈迪-温伯格平衡偏离之间无显著相关性。这些结果表明多个位点存在哈迪-温伯格平衡偏离，不同位点的偏离程度差异很大。对于SNP，哈迪-温伯格平衡偏离往往是由于杂合子不足，这表明等位基因缺失可能是最普遍的基因分型错误。
