Quantitative Trait Loci Identification by Estimating the Genetic Model based on the Extremal Samples

Background: In genetic association studies with quantitative trait loci (QTL), the association between a candidate genetic marker and the trait of interest is commonly examined by the omnibus F test or by the t-test corresponding to a given genetic model or mode of inheritance. It is known that the t-test with a correct model specification is more powerful than the F test. However, since the underlying genetic model is rarely known in practice, the use of a model-specific t-test may incur substantial power loss. Robustefficient tests, such as the Maximin Efficiency Robust Test (MERT) and MAX3 have been proposed in the literature. Methods: In this paper, we propose a novel two-step robust-efficient approach, namely, the genetic model selection (GMS) method for quantitative trait analysis. GMS selects a genetic model by testing Hardy-Weinberg disequilibrium (HWD) with extremal samples of the population in the first step and then applies the corresponding genetic modelspecific t-test in the second step. Results: Simulations show that GMS is not only more efficient than MERT and MAX3, but also has comparable power to the optimal t-test when the genetic model is known. Conclusion: Application to the data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort demonstrates that the proposed approach can identify meaningful biological SNPs on chromosome 19.