A robust genome-wide scan statistic of the Wellcome Trust Case-Control Consortium

In genome-wide association (GWA) studies, test statistics that are efficient and robust across various genetic models are preferable, particularly for studying multiple diseases in the Wellcome Trust Case-Control Consortium (WTCCC, 2007, Nature 447, 661-678). A new test statistic, the minimum of the p-values of the trend test and Pearson's test, was considered by the WTCCC. It is referred to here as MIN2. Because the minimum of two p-values is no longer a valid p-value itself, the WTCCC only used it to rank single nucleotide polymorphisms (SNPs) but did not report the p-values of the associated SNPs when MIN2 was used for ranking. Given its importance in practice, we derive the asymptotic null distribution of MIN2, study some of its analytical properties related to GWA studies, and compare it with existing methods (the trend test, Pearson's test, MAX3, and the constrained likelihood ratio test [CLRT]) by simulations across a wide range of possible genetic models: the recessive (REC), additive (ADD), multiplicative (MUL), dominant (DOM), and overdominant models. The results show that MAX3 and CLRT have greater efficiency robustness than other tests when the REC, ADD/MUL, and DOM models are possible, whereas Pearson's test and MIN2 have greater efficiency robustness if the possible genetic models also include the overdominant model. We conclude that robust tests (MAX3, MIN2, CLRT, and Pearson's test) are preferable to a single trend test for initial GWA studies. The four robust tests are applied to more than 100 SNPs associated with 11 common diseases identified by the two WTCCC GWA studies.