1AbstractTranscriptome-Wide Association Studies discover SNP effects mediated by gene expression through a two-stage process: a typically small reference panel is used to infer SNP-expression effects, and then these are applied to discover associations between imputed expression and phenotypes. We investigate whether the accuracy of SNP-expression and expression-phenotype associations can be increased by performing inference on both the reference panel and independent GWAS cohorts simultaneously. We develop EMBER (Estimation of Mediated Binary Effects in Regression) to re-estimate these effects using a liability threshold model with an adjustment to variance components accounting for imputed expression from GWAS data. In simulated data with only gene-mediated effects, EMBER more than doubles the performance of SNP-expression linear regression, increasing mean r2 from 0.3 to 0.65 with a gene-mediated variance explained of 0.01. EMBER also improves estimation accuracy when the fraction of cis-SNP variance mediated by genes is as low as 30%. We apply EMBER to genotype and gene expression data in schizophrenia by combining 512 samples from the CommonMind Consortium and 56,081 samples from the Psychiatric Genomic Consortium. We evaluate performance of EMBER in 36 genes suggested by TWAS by concordance of inferred effects with effects reported independently for frontal cortex expression. Applying the EMBER framework to a baseline linear regression model increases performance in 26 out of 36 genes (sign test p-value .0020) with an increase in mean r2 from 0.200 to 0.235.