The effect of minor allele frequency on the likelihood of obtaining false positives.
The effect of minor allele frequency on the likelihood of obtaining false positives.
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DOI：
10.1186/1753-6561-3-s7-s41
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发表时间：
2009-12-15
期刊：
影响因子：
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通讯作者：
Martin LJ
中科院分区：
文献类型：
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作者：
Tabangin ME;Woo JG;Martin LJ
确定最有希望的单核苷酸多态性（SNPs）在全基因组关联研究中提出了一个挑战，当进行数十万个关联测试时。检测遗传效应的能力取决于次要等位基因频率（MAF），全基因组关联研究的SNP阵列包括具有广泛分布的MAF的SNP。因此，了解MAF对假阳性率的影响是至关重要的。来自弗雷明汉心脏研究模拟数据（问题3，带答案）的数据被用来检验不同maf对假阳性可能性的影响。复制集1用于在不相关的个体中生成100万个病例/对照状态的排列。使用加性模型使用逻辑回归来检验每个SNP与心肌梗死之间的关联。我们报告了MAF在α = 10- 4,10 -5和10-6时“显著”试验的数量。常见snp的假阳性比预期的要少。在α = 10-4时，MAF为25%和50%的snp分别导致69.2 [95%CI: 62.8-75.6]和70.8 [95%CI: 61.3-80.4]假阳性，而预期为100。罕见的snp表现出更多的变异性，但没有显示出比偶然预期更多的假阳性结果。然而，在α = 10-4时，MAF = 5%比MAF = 25%和50%表现出更多的假阳性（105.5 [95%CI: 81-130.1]）。在其他alpha值上也可以看到类似的结果。这些结果表明，由于担心虚增的假阳性结果，从分析中去除低MAF snp可能不合适。
Determining the most promising single-nucleotide polymorphisms (SNPs) presents a challenge in genome-wide association studies, when hundreds of thousands of association tests are conducted. The power to detect genetic effects is dependent on minor allele frequency (MAF), and genome-wide association studies SNP arrays include SNPs with a wide distribution of MAFs. Therefore, it is critical to understand MAF's effect on the false positive rate. Data from the Framingham Heart Study simulated data (Problem 3, with answers) was used to examine the effects of varying MAFs on the likelihood of false positives. Replication set 1 was used to generate 1 million permutations of case/control status in unrelated individuals. Logistic regression was used to test for the association between each SNP and myocardial infarction using an additive model. We report the number of "significant" tests by MAF at α = 10-4, 10-5, and 10-6. Common SNPs exhibited fewer false positives than expected. At α = 10-4, SNPs with MAF 25% and 50% resulted in 69.2 [95%CI: 62.8-75.6] and 70.8 [95%CI: 61.3-80.4] false positives, respectively, compared to 100 expected. Rare SNPs exhibited more variability but did not show more false-positive results than expected by chance. However, at α = 10-4, MAF = 5% exhibited significantly more false positives (105.5 [95%CI: 81-130.1]) than MAF = 25% and 50%. Similar results were seen at the other alpha values. These results suggest that removal of low MAF SNPs from analysis due to concerns about inflated false-positive results may not be appropriate.