Abstract PO-163: Genome-wide polygenic risk score of prostate cancer in African and European ancestry men
Authors: Darst Burcu F. , Madduri Ravi K , Rodriguez Alexis A. , Sheng Xin , Eeles Rosalind A. , Kote-Jarai Zsofia , Gaziano John M. , Justice Amy C. , Conti David V. , Haiman Christopher A. 
Published: January 2022

Abstract
Genome-wide polygenic risk scores (PRS) are reported to have higher performance than standard genome-wide significant PRS across numerous complex traits. We evaluated the ability of genome-wide PRS to evaluate prostate cancer risk compared to our recently developed and highly predictive multi-ancestry PRS of 269 fine-mapped and established prostate cancer risk variants. Genome-wide PRS approaches included LDpred2, PRS-CSx, and EB-PRS. Models were trained using the largest and most diverse prostate cancer GWAS to date of 107,247 cases and 127,006 controls, which was previously used to develop the multi-ancestry PRS of 269 variants. For each approach, we constructed the PRS using population-specific weights (i.e., African or European) and multi-ancestry weights, which were calculated across men from African, European, East Asian, and Hispanic populations in our previous GWAS. Resulting models were tested in independent samples of 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,045 cases and 191,835 controls of European ancestry from the UK Biobank. Across all approaches, multi-ancestry weighted PRS had either similar or stronger performance compared to population-specific weighted PRS, both in terms of area under the curve (AUC) and odds of prostate cancer. Among the genome-wide PRS approaches, PRS-CSx constructed with multi-ancestry weights had the best performance, with AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men. Based on PRS-CSx, African and European ancestry men in the top 90-100% PRS decile relative to men in the median 40-60% PRS category had odds of prostate cancer of 2.67 (95% CI=2.00-3.55) and 4.17 (95% CI=3.87-4.50), respectively. However, the PRS constructed using 269 fine-mapped variants had larger AUCs in both African (0.679, 95% CI=0.659-0.700) and European ancestry men (0.845, 95% CI=0.841-0.849), with African and European ancestry men in the top PRS decile having larger odds of prostate cancer (3.53, 95% CI=2.66-4.69 and 4.20, 95% CI=3.89-4.53, respectively). We are currently further validating these findings in diverse men from Million Veteran's Program. This investigation suggests that genome-wide PRS may not improve the ability to distinguish prostate cancer compared to our genome-wide significant PRS and that a multi-ancestry approach to constructing PRS leads to similar or better performance than a population-specific approach.
Citation Format: Burcu F. Darst, Ravi K Madduri, Alexis A. Rodriguez, Xin Sheng, Rosalind A. Eeles, Zsofia Kote-Jarai, John M. Gaziano, Amy C. Justice, David V. Conti, Christopher A. Haiman. Genome-wide polygenic risk score of prostate cancer in African and European ancestry men [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-163.