Test Gene-Environment Interactions for Multiple Traits in Sequencing Association Studies

Abstract The risk of many complex diseases is determined by a complex interplay of genetic and environmental factors. Data on multiple traits is often collected for many complex diseases in order to obtain a better understanding of the diseases. Examination of gene-environment interactions (GxEs) for multiple traits can yield valuable insights about the etiology of the disease and increase power in detecting disease associated genes. Most existing methods focus on testing gene-environment interaction (GxE) for a single trait. In this study, we develop novel approaches to test GxEs for multiple traits in sequencing association studies. We first perform transformation of multiple traits by using either principle component analysis or standardization analysis. Then, we detect the effect of GxE for each transferred phenotypic trait using novel proposed tests: testing the effect of an optimallyweighted combination of GxE (TOW-GE) and/or variable weight TOW-GE (VW-TOW-GE). Finally, we employ the Fisher’s combination test to combine the p-values of TOW-GE and/or VW-TOW-GE. Extensive simulation studies based on the Genetic Analysis Workshop 17 data show that the type I error rates of the proposed methods are well controlled. Compared to the existing interaction sequence kernel association test (ISKAT), TOW-GE is more powerful when there are only rare risk and protective variants; VW-TOW-GE is more powerful when there are both rare and common risk and protective variants. Both TOW-GE and VW-TOW-GE are robust to directions of effects of causal GxEs. Application to the COPDGene Study demonstrates that our proposed methods are very powerful.