Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry
Authors: Darst Burcu F. , Shen Jiayi , Madduri Ravi K. , Rodriguez Alexis A. , Xiao Yukai , Sheng Xin , Saunders Edward J. , Dadaev Tokhir , Brook Mark N. , Hoffmann Thomas J. , Muir Kenneth , Wan Peggy , Marchand Loic Le , Wilkens Lynne , Wang Ying , Schleutker Johanna , MacInnis Robert J. , Cybulski Cezary , Neal David E. , G. Nordestgaard Børge , Nielsen Sune F. , Batra Jyotsna , Clements Judith A. ,   Australian Prostate Cancer BioResource, Grönberg Henrik , Pashayan Nora , Travis Ruth C. , Park Jong Y. , Albanes Demetrius , Weinstein Stephanie , Mucci Lorelei A. , Hunter David J. , Penney Kathryn L. , Tangen Catherine M. , Hamilton Robert J. , Parent Marie-Élise , Stanford Janet L. , Koutros Stella , Wolk Alicja , Sørensen Karina D. , Blot William J. , Yeboah Edward D. , Mensah James E. , Lu Yong-Jie , Schaid Daniel J. , Thibodeau Stephen N. , West Catharine M. , Maier Christiane , Kibel Adam S. , Cancel-Tassin Géraldine , Menegaux Florence , John Esther M. , Grindedal Eli Marie , Khaw Kay-Tee , Ingles Sue A. , Vega Ana , Rosenstein Barry S. , Teixeira Manuel R. ,   NC-LA PCaP Investigators, Kogevinas Manolis , Cannon-Albright Lisa , Huff Chad , Multigner Luc , Kaneva Radka , Leach Robin J. , Brenner Hermann , Hsing Ann W. , Kittles Rick A. , Murphy Adam B. , Logothetis Christopher J. , Neuhausen Susan L. , Isaacs William B. , Nemesure Barbara , Hennis Anselm J. , Carpten John , Pandha Hardev , De Ruyck Kim , Xu Jianfeng , Razack Azad , Teo Soo-Hwang ,   Canary PASS Investigators, Newcomb Lisa F. , Fowke Jay H. , Neslund-Dudas Christine , Rybicki Benjamin A. , Gamulin Marija , Usmani Nawaid , Claessens Frank , Gago-Dominguez Manuela , Castelao Jose Esteban , Townsend Paul A. , Crawford Dana C. , Petrovics Gyorgy , Casey Graham , Roobol Monique J. , Hu Jennifer F. , Berndt Sonja I. , Van Den Eeden Stephen K. , Easton Douglas F. , Chanock Stephen J. , Cook Michael B. , Wiklund Fredrik , Witte John S. , Eeles Rosalind A. , Kote-Jarai Zsofia , Watya Stephen , Gaziano John M. , Justice Amy C. , Conti David V. , Haiman Christopher A. 
Published: May 2023

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS269). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had 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 and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS269had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS269constructed with fine-mapping.