Aggregating multiple expression prediction models improves the power of transcriptome-wide association studies.

Transcriptome-wide association study (TWAS) is an important integrative method for identifying genes that are causally associated with phenotypes. A key step of TWAS involves the construction of expression prediction models for every gene in turn using its cis-SNPs as predictors. Different TWAS methods rely on different models for gene expression prediction, and each such model makes a distinct modeling assumption that is often suitable for a particular genetic architecture underlying expression. However, the genetic architectures underlying gene expression vary across genes throughout the transcriptome. Consequently, different TWAS methods may be beneficial in detecting genes with distinct genetic architectures. Here, we develop a new method, HMAT, which aggregates TWAS association evidence obtained across multiple gene expression prediction models by leveraging the harmonic mean P-value combination strategy. Because each expression prediction model is suited to capture a particular genetic architecture, aggregating TWAS associations across prediction models as in HMAT improves accurate expression prediction and enables subsequent powerful TWAS analysis across the transcriptome. A key feature of HMAT is its ability to accommodate the correlations among different TWAS test statistics and produce calibrated P-values after aggregation. Through numerical simulations, we illustrated the advantage of HMAT over commonly used TWAS methods as well as ad hoc P-value combination rules such as Fisher's method. We also applied HMAT to analyze summary statistics of nine common diseases. In the real data applications, HMAT was on average 30.6% more powerful compared to the next best method, detecting many new disease-associated genes that were otherwise not identified by existing TWAS approaches. In conclusion, HMAT represents a flexible and powerful TWAS method that enjoys robust performance across a range of genetic architectures underlying gene expression.