TIGAR: An Improved Bayesian Tool for Transcriptomic Data Imputation Enhances Gene Mapping of Complex Traits

The transcriptome-wide association studies (TWAS) that test for association between the study trait and the imputed gene expression levels from cis-acting expression quantitative trait loci (cis-eQTL) genotypes have successfully enhanced the discovery of genetic risk loci for complex traits. By using the gene expression imputation models fitted from reference datasets that have both genetic and transcriptomic data, TWAS facilitates gene-based tests with GWAS data while accounting for the reference transcriptomic data. The existing TWAS tools like PrediXcan and FUSION use parametric imputation models that have limitations for modeling the complex genetic architecture of transcriptomic data. Therefore, to improve on this, we propose to use a Bayesian method that assumes a data-driven nonparametric prior to impute gene expression. The nonparametric Bayesian method is flexible and general because it includes both of the parametric imputation models used by PrediXcan and FUSION as special cases. Our simulation studies showed that the nonparametric Bayesian model improved both imputation R2 for transcriptomic data and the TWAS power over PrediXcan. In real applications, our nonparametric Bayesian method fitted transcriptomic imputation models for 57.6% more genes over PrediXcan, thus improving the power of follow-up TWAS. Hence, the nonparametric Bayesian model is preferred for modeling the complex genetic architecture of transcriptomes and is expected to enhance transcriptome-integrated genetic association studies. We implement our Bayesian approach in a convenient software tool “TIGAR” (Transcriptome-Integrated Genetic Association Resource), which imputes transcriptomic data and performs subsequent TWAS using individual-level or summary-level GWAS data.