Simple SummaryMutation in telomerase reverse transcriptase (TERT) has been reportedly related to risks of prostate cancer (PCa). However, prior genome-wide association studies (GWAS) were limited to inconsistency, small-scale, one-outcome phenotype, or single ancestry. In this study, we used two large-scale population datasets from European and Chinese ancestries to comprehensively estimate the association ofTERTloci polymorphisms with prostate tumorigenesis and severity. Results of this study showed that (1) over half of the risk variants were located at the intron 2 region in both populations; (2) seven novel loci situated at intron 2, intron 6, intron 9, and intron 12 were first identified to be related to PCa risk; (3) SNPs rs2736100 and rs2853677 were significantly associated with aggressive PCa, whereas rs35812074 was marginally related to PCa death; (4) most identified loci were different between Europeans and Chinese. These findings support the evidence regardingTERTpolymorphisms in relation to PCa risk and prognosis, and indicate the heterogeneous genetic architectures of PCa susceptibility loci among distinct ancestries.AbstractBackground: Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association betweenTERTvariants and PCa aggressiveness. Methods: Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics). Results: A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12–1.20,p= 4.12 × 10−16) and rs11291391 (OR = 1.73, 95%CI:1.34–2.25,p= 3.04 × 10−5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31–1.71,p= 2.91 × 10−9) and rs2853677 (OR = 1.74, 95%CI:1.52–1.98,p= 3.52 × 10−16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04–2.49,p= 0.034). Gene-based analysis showed a significant association ofTERTwith PCa (European:p= 3.66 × 10−15, Chinese:p= 0.043) and PCa severity (p= 0.006) but not with PCa death (p= 0.171). Conclusion:TERTpolymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries.