To provide another layer of insight into the results of the 19 proteins identified by PWAS, we asked whether the cis-regulated mRNA levels of these genes were also associated with depression in a transcriptome-wide association study (TWAS) of depression using 888 reference human brain transcriptomes and the discovery depression GWAS (N=500,199). The brain transcriptomes were predominantly profiled from the frontal cortex of post-mortem brain samples of 783 participants of European descent from ROS/MAP, Mayo, and Mount Sinai Brain Bank studies30. Of the 13,650 mRNAs that passed quality control, 6735 had significant SNP-based heritability and were included in the TWAS. The TWAS of depression using FUSION identified 73 genes whose cis-regulated brain mRNA expression was associated with depression at FDR q<0.05 (Supplementary Table 13). Among these, 47 genes passed both the SMR (i.e., SMR p<0.05) and HEIDI test (i.e., HEIDI p ≥ 0.05; Supplementary Table 14). These 47 genes contribute to depression pathogenesis by modulating their genetically controlled brain mRNA expression.
