Integrative transcriptome imputation reveals tissue-specific and shared biological mechanisms mediating susceptibility to complex traits

Transcriptome-wide association studies integrate gene expression data with common risk variation to identify gene-trait associations. By incorporating epigenome data to estimate the functional importance of genetic variation on gene expression, we improve the accuracy of transcriptome prediction and the power to detect significant expression-trait associations. Joint analysis of 14 large-scale transcriptome datasets and 58 traits identify 13,724 significant expression-trait associations that converge to biological processes and relevant phenotypes in human and mouse phenotype databases. We perform drug repurposing analysis and identify known and novel compounds that mimic or reverse trait-specific changes. We identify genes that exhibit agonistic pleiotropy for genetically correlated traits that converge on shared biological pathways and elucidate distinct processes in disease etiopathogenesis. Overall, this comprehensive analysis provides insight into the specificity and convergence of gene expression on susceptibility to complex traits.