Abstract

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening.Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA.Analyses identified 41 statistically significant (p 0.5: CCNA2 and HIST1H2BN.Six of the 20 identified genes are not known to impact PCa risk.Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels.Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings.These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.