Increase of Rejection Rate in Case-Control Studies with the Differential Genotyping Error Rates

Genotyping error adversely affects the statistical power of case-control association studies and introduces bias in the estimated parameters when the same error mechanism and probabilities apply to both affected and unaffected individuals; that is, when there is non-differential genotype misclassification. Simulation studies have shown that differential genotype misclassification leads to a rejection rate that is higher than the nominal significance level (type I error rate) for some tests of association. This study extends previous work by examining this issue analytically using the non-centrality parameter of the asymptotic distribution of the chi-squared test and linear trend test (LTT) when there is no difference between case and control genotype frequencies, but there is differential misclassification with SNP data. The parameters examined are the minor allele frequency (MAF) and sample size. When MAF is less than 0.2, differential genotyping errors lead to a rejection rate much larger than the nominal significance level. As the MAF decreases to zero, the increase in the rejection rate becomes larger. The errors that most increase the rejection rate are differential recording of the more common homozygote as the other homozygote and differential recording of the more common homozygote as the heterozygote. The rejection rate increases as the sample size increases for fixed differential genotyping error rates and nominal significance level for each test.