Here we train
cis
-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated
TMPRSS2
expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the
TMPRSS2
:
ERG
fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes,
HOXA4
,
KLK1
, and
TIMM23
, additionally replicate in the RPGEH cohort. Furthermore, 4 genes,
MSMB
,
NCOA4
,
PCAT1
, and
PPP1R14A
, are associated with PrCa in a trans-ethnic meta-analysis (
N
= 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.