Improving Power for Testing Genetic Association in Case–Control Studies by Reducing the Alternative Space

Summary .  To detect association between a genetic marker and a disease in case–control studies, the Cochran–Armitage trend test is typically used. The trend test is locally optimal when the genetic model is correctly specified. However, in practice, the underlying genetic model, and hence the optimal trend test, are usually unknown. In this case, Pearson's chi-squared test, the maximum of three trend test statistics (optimal for the recessive, additive, and dominant models), and the test based on genetic model selection (GMS) are useful. In this article, we first modify the existing GMS method so that it can be used when the risk allele is unknown. Then we propose a new approach by excluding a genetic model that is not supported by the data. Using either the model selection or exclusion, the alternative space is reduced conditional on the observed data, and hence the power to detect a true association can be increased. Simulation results are reported and the proposed methods are applied to the genetic markers identified from the genome-wide association studies conducted by the Wellcome Trust Case–Control Consortium. The results demonstrate that the genetic model exclusion approach usually performs better than existing methods under its worst situation across scientifically plausible genetic models we considered.