OBJECTIVE: A number of susceptibility genes in prostate tissue have been identified to be associated with prostate cancer (PCa) risk. However, the reported genes based on assessing prostate tissue could not fully explain PCa genetic susceptibility. It is believed that genes functioning in the immune system may fill in the gap of some missing heritability. METHODS: To study potential susceptibility genes acting in such pathways, we performed a transcriptome-wide association study (TWAS) of 79,194 PCa cases and 61,112 control of European ancestry by using three sets of gene expression prediction models of blood tissue. RESULTS: A total of 470 genes were associated at false discovery rates-corrected p-value <
0.05, of which 51 were implicated as likely causal genes based on fine-mapping analysis. Compared with previous literature, 133 novel genes were reported for the first time. Of the identified genes, five (CREB3L4, GSTP1, MAPK3, NKX3-1, and PIK3C2B) were enriched in a PCa signaling pathway, and 128 genes were enriched in five PCa categories. Importantly, 13 genes (SCP2, LMNA, ZNF148, H2AFV, TACC1, FLII, SUPT4H1, CD300LF, MYO9B, COX6B1, CTSA, EP300, and TSPO) showed consistent effect directions for the measured levels in circulating immune cells between PCa cases and controls, and 14 genes (SLC39A1, ZBTB7B, TRIM59, NCEH1, N4BP2, TAGAP, TACC1, TRAF1, AIP, SECTM1, C18orf54, ZNF793, YIF1B, and TSPO) showed consistency for levels in blood exosomes between PCa patients and controls. CONCLUSION: The identified blood-based candidate susceptibility genes provide further insights into the genetic basis of PCa risk.