Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry - UTU Research Portal

A1 Refereed original research article in a scientific journal

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

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

Publication year: 2023

Journal: American Journal of Human Genetics

Journal name in source: American journal of human genetics

Journal acronym: Am J Hum Genet

Volume: 110

Issue: 7

First page : 1200

Last page: 1206

ISSN: 0002-9297

eISSN: 1537-6605

DOI: https://doi.org/10.1016/j.ajhg.2023.05.010

Web address : https://www.sciencedirect.com/science/article/pii/S0002929723001672?via%3Dihub

Preprint address: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246022/

Abstract

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs 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 GWASs and fine-mapping studies (PRS₂₆₉). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously 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 ORs 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. Compared to the GW-PRS, in African and European ancestry men, the PRS₂₆₉ had 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 ORs (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 studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS₂₆₉ developed from multi-ancestry GWASs and fine-mapping.