Joint analysis of multiple phenotypes in association studies using allele-based clustering approach for non-normal distributions

In the study of complex diseases, several correlated phenotypes are usually measured. There is also increasing evidence showing that testing the association between a single-nucleotide polymorphism (SNP) and multiple-dependent phenotypes jointly is often more powerful than analyzing only one phenotype at a time. Therefore, developing statistical methods to test for genetic association with multiple phenotypes has become increasingly important. In this paper, we develop an Allele-based Clustering Approach (ACA) for the joint analysis of multiple non-normal phenotypes in association studies. In ACA, we consider the alleles at a SNP of interest as a dependent variable with two classes, and the correlated phenotypes as predictors to predict the alleles at the SNP of interest. We perform extensive simulation studies to evaluate the performance of ACA and compare the power of ACA with the powers of Adaptive Fisher's Combination test, Trait-based Association Test that uses Extended Simes procedure, Fisher's Combination test, the standard MANOVA, and the joint model of Multiple Phenotypes. Our simulation studies show that the proposed method has correct type I error rates and is much more powerful than other methods for some non-normal distributions.