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

Burcu F. Darst; Jiayi Shen; NC-LA PCaP Investigators; Canary PASS Investigators; 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; Loic Le Marchand; 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; Australian Prostate Cancer BioResource; 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; Monique J. Roobol

doi:10.1016/j.ajhg.2023.05.010

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

Burcu F. Darst^*
, Jiayi Shen
, NC-LA PCaP Investigators
, Canary PASS Investigators
, 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
, Loic Le Marchand
, 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, Australian Prostate Cancer BioResource, 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, Monique J. Roobol

^*Corresponding author for this work

Urology

University of North Carolina at Chapel Hill
Epidemiology Branch
National Institute of Environmental Health Sciences (NIEHS)
Fred Hutchinson Cancer Research Center
University of Washington
Keck School of Medicine of USC
Argonne National Laboratory
Institute of Cancer Research (ICR), London
University of California at San Francisco
University of Manchester
University of Hawaii Cancer Center
University of Turku
Cancer Council Victoria
University of Melbourne
Pomeranian Medical University in Szczecin
University of Oxford
University of Cambridge
Cancer Research UK
University of Copenhagen
Copenhagen University Hospital (Nordvest)
Queensland University of Technology
Translational Research Institute
Monash University
University of Adelaide
Kinghorn Cancer Centre
Karolinska Institutet
H. Lee Moffitt Cancer Center and Research Institute
National Cancer Institute (Bethesda, Md)
Harvard T.H. Chan School of Public Health
Harvard Medical School
Princess Margaret Hospital Cancer Centre
University of Toronto
Institut national de la recherche scientifique
University of Montreal
Uppsala University
Aarhus University Hospital
Aarhus University
Vanderbilt University School of Medicine
International Epidemiology Institute
University of Ghana
Korle Bu Teaching Hospital
Barts and The London School of Medicine and Dentistry
Mayo Clinic Rochester, MN
Humangenetik Tuebingen
University College London
American Cancer Society

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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.

Original language	English
Pages (from-to)	1200-1206
Number of pages	7
Journal	American Journal of Human Genetics
Volume	110
Issue number	7
DOIs	https://doi.org/10.1016/j.ajhg.2023.05.010
Publication status	Published - 6 Jul 2023

Bibliographical note

Funding Information:
This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., R01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., and R00 CA246063 to B.F.D.), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), an award from the Andy Hill Cancer Research Endowment Distinguished Researchers Program (B.F.D.), a Fred Hutchinson Cancer Center/ University of Washington SPORE Career Enhancement Program award (B.F.D.), and the Million Veteran Program -MVP017. This research has been conducted with the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

Publisher Copyright:
© 2023 American Society of Human Genetics

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10.1016/j.ajhg.2023.05.010

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestryFinal published version, 1.69 MBLicence: Article 25fa Dutch Copyright Act

Cite this

Darst, B. F., Shen, J., NC-LA PCaP Investigators, Canary PASS Investigators, Madduri, R. K., Rodriguez, A. A., Xiao, Y., Sheng, X., Saunders, E. J., Dadaev, T., Brook, M. N., Hoffmann, T. J., Muir, K., Wan, P., Le Marchand, L., Wilkens, L., Wang, Y., Schleutker, J., MacInnis, R. J., ... Roobol, M. J. (2023). Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry. American Journal of Human Genetics, 110(7), 1200-1206. https://doi.org/10.1016/j.ajhg.2023.05.010

@article{ee0339fd53024e9a8e6b2d5ace1a9aa3,

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

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{\textendash}0.677) in African and 0.844 (95\% CI = 0.840{\textendash}0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95\% CI = 1.67{\textendash}2.00) and 2.19 (95\% CI = 2.14{\textendash}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{\textendash}0.700 and AUC = 0.845, 95\% CI = 0.841{\textendash}0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95\% CI = 1.87{\textendash}2.26 and OR = 2.21, 95\% CI = 2.16{\textendash}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.",

author = "Darst, \{Burcu F.\} and Jiayi Shen and \{NC-LA PCaP Investigators\} and \{Canary PASS Investigators\} and Madduri, \{Ravi K.\} and Rodriguez, \{Alexis A.\} and Yukai Xiao and Xin Sheng and Saunders, \{Edward J.\} and Tokhir Dadaev and Brook, \{Mark N.\} and Hoffmann, \{Thomas J.\} and Kenneth Muir and Peggy Wan and \{Le Marchand\}, Loic and Lynne Wilkens and Ying Wang and Johanna Schleutker and MacInnis, \{Robert J.\} and Cezary Cybulski and Neal, \{David E.\} and Nordestgaard, \{B{\o}rge G.\} and Nielsen, \{Sune F.\} and Jyotsna Batra and Clements, \{Judith A.\} and \{Cancer BioResource\}, \{Australian Prostate\} and Henrik Gr{\"o}nberg and Nora Pashayan and Travis, \{Ruth C.\} and Park, \{Jong Y.\} and Demetrius Albanes and Stephanie Weinstein and Mucci, \{Lorelei A.\} and Hunter, \{David J.\} and Penney, \{Kathryn L.\} and Tangen, \{Catherine M.\} and Hamilton, \{Robert J.\} and Parent, \{Marie {\'E}lise\} and Stanford, \{Janet L.\} and Stella Koutros and Alicja Wolk and S{\o}rensen, \{Karina D.\} and Blot, \{William J.\} and Yeboah, \{Edward D.\} and Mensah, \{James E.\} and Lu, \{Yong Jie\} and Schaid, \{Daniel J.\} and Thibodeau, \{Stephen N.\} and West, \{Catharine M.\} and Christiane Maier and Kibel, \{Adam S.\} and Roobol, \{Monique J.\}",

note = "Funding Information: This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., R01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., and R00 CA246063 to B.F.D.), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), an award from the Andy Hill Cancer Research Endowment Distinguished Researchers Program (B.F.D.), a Fred Hutchinson Cancer Center/ University of Washington SPORE Career Enhancement Program award (B.F.D.), and the Million Veteran Program -MVP017. This research has been conducted with the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. Publisher Copyright: {\textcopyright} 2023 American Society of Human Genetics",

year = "2023",

month = jul,

day = "6",

doi = "10.1016/j.ajhg.2023.05.010",

language = "English",

volume = "110",

pages = "1200--1206",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "7",

}

Darst, BF, Shen, J, NC-LA PCaP Investigators, Canary PASS Investigators, Madduri, RK, Rodriguez, AA, Xiao, Y, Sheng, X, Saunders, EJ, Dadaev, T, Brook, MN, Hoffmann, TJ, Muir, K, Wan, P, Le Marchand, L, Wilkens, L, Wang, Y, Schleutker, J, MacInnis, RJ, Cybulski, C, Neal, DE, Nordestgaard, BG, Nielsen, SF, Batra, J, Clements, JA, Cancer BioResource, AP, Grönberg, H, Pashayan, N, Travis, RC, Park, JY, Albanes, D, Weinstein, S, Mucci, LA, Hunter, DJ, Penney, KL, Tangen, CM, Hamilton, RJ, Parent, MÉ, Stanford, JL, Koutros, S, Wolk, A, Sørensen, KD, Blot, WJ, Yeboah, ED, Mensah, JE, Lu, YJ, Schaid, DJ, Thibodeau, SN, West, CM, Maier, C, Kibel, AS & Roobol, MJ 2023, 'Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry', American Journal of Human Genetics, vol. 110, no. 7, pp. 1200-1206. https://doi.org/10.1016/j.ajhg.2023.05.010

TY - JOUR

T1 - Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

AU - Darst, Burcu F.

AU - Shen, Jiayi

AU - NC-LA PCaP Investigators

AU - Canary PASS Investigators

AU - Madduri, Ravi K.

AU - Rodriguez, Alexis A.

AU - Xiao, Yukai

AU - Sheng, Xin

AU - Saunders, Edward J.

AU - Dadaev, Tokhir

AU - Brook, Mark N.

AU - Hoffmann, Thomas J.

AU - Muir, Kenneth

AU - Wan, Peggy

AU - Le Marchand, Loic

AU - Wilkens, Lynne

AU - Wang, Ying

AU - Schleutker, Johanna

AU - MacInnis, Robert J.

AU - Cybulski, Cezary

AU - Neal, David E.

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Batra, Jyotsna

AU - Clements, Judith A.

AU - Cancer BioResource, Australian Prostate

AU - Grönberg, Henrik

AU - Pashayan, Nora

AU - Travis, Ruth C.

AU - Park, Jong Y.

AU - Albanes, Demetrius

AU - Weinstein, Stephanie

AU - Mucci, Lorelei A.

AU - Hunter, David J.

AU - Penney, Kathryn L.

AU - Tangen, Catherine M.

AU - Hamilton, Robert J.

AU - Parent, Marie Élise

AU - Stanford, Janet L.

AU - Koutros, Stella

AU - Wolk, Alicja

AU - Sørensen, Karina D.

AU - Blot, William J.

AU - Yeboah, Edward D.

AU - Mensah, James E.

AU - Lu, Yong Jie

AU - Schaid, Daniel J.

AU - Thibodeau, Stephen N.

AU - West, Catharine M.

AU - Maier, Christiane

AU - Kibel, Adam S.

AU - Roobol, Monique J.

N1 - Funding Information: This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., R01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., and R00 CA246063 to B.F.D.), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), an award from the Andy Hill Cancer Research Endowment Distinguished Researchers Program (B.F.D.), a Fred Hutchinson Cancer Center/ University of Washington SPORE Career Enhancement Program award (B.F.D.), and the Million Veteran Program -MVP017. This research has been conducted with the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. Publisher Copyright: © 2023 American Society of Human Genetics

PY - 2023/7/6

Y1 - 2023/7/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85165069171

U2 - 10.1016/j.ajhg.2023.05.010

DO - 10.1016/j.ajhg.2023.05.010

M3 - Article

C2 - 37311464

AN - SCOPUS:85165069171

SN - 0002-9297

VL - 110

SP - 1200

EP - 1206

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 7

ER -

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

Abstract

Bibliographical note

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