Title: Powerful Genetic Association Analysis for Common or Rare Variants with High Dimensional Structured Traits Running Title: DKAT for Genetic Association Studies

Many genetic association studies collect a wide range of complex traits. As these traits may be correlated and share a common genetic mechanism, joint analysis can be statistically more powerful and biologically more meaningful. However, most existing tests for multiple traits cannot be used for high-dimensional and possibly structured traits, such as network-structured transcriptomic pathway expressions. To overcome potential limitations, in this paper we propose the dual kernel-based association test (DKAT) for testing the association between multiple traits and multiple genetic variants, both common and rare. In DKAT, two individual kernels are used to describe the phenotypic and genotypic similarity, respectively, between pairwise subjects. Using kernels allows for capturing structure while accommodating dimensionality. Then, the association between traits and genetic variants is summarized by a coefficient which measures the association between two kernel matrices. Finally, DKAT evaluates the hypothesis of non-association with an analytical p-value calculation without any computationally expensive resampling procedures. By collapsing information in both traits and genetic variants using kernels, the proposed DKAT is shown to have correct type I error rate and higher power than other existing methods in both simulation studies and application to a study of genetic regulation of pathway gene expressions.