Evaluation of a Multiethnic Polygenic Risk Score Model for Prostate Cancer

Abstract

Polygenic risk scores (PRSs) of common genetic variants have shown promise in prostate cancer risk stratification, but their validity across populations has yet to be confirmed. We evaluated a multiethnic PRS model based on 269 germline genetic risk variants (261 were available for analysis) using an independent population of 13 628 US men. The PRS was strongly associated with prostate cancer but not with any other disease. Comparing men in the top PRS decile with those at average risk (40%-60%), the odds ratio of prostate cancer was 3.89 (95% confidence interval = 3.24 to 4.68) for men of European ancestry and 3.81 (95% confidence interval = 1.48 to 10.19) for men of African ancestry. By age 85 years, the cumulative incidence of prostate cancer for European American men was 7.1% in the bottom decile and 54.1% in the top decile. This suggests that the PRS can be used to identify a substantial proportion of men at high risk for prostate cancer.

Figure 1.

Polygenic risk score (PRS) phenome-wide association results and absolute lifetime risk of prostate cancer in men of European ancestry. (A) Manhattan plot for phenome-wide association study (PheWAS) of 1093 disease categories (based on billing codes) with the prostate cancer PRS in men of European ancestry. The horizontal line indicates phenome-wide–level significance (2-sided P = 4.6 × 10⁻⁵) using Bonferroni correction. Adjustments were made for age at blood collection, genotyping platform, and the first 10 principal components. Odds ratios (ORs) are reported as per 1-SD increase in the PRS. (B) Cumulative incidence of prostate cancer (overall and by Gleason score) for men of European ancestry included in the cohort analysis, stratified by PRS quartile.