Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Fei Chen; Ravi K. Madduri; Alex A. Rodriguez; Burcu F. Darst; Alisha Chou; Xin Sheng; Anqi Wang; Jiayi Shen; Edward J. Saunders; Suhn K. Rhie; Jeannette T. Bensen; Sue A. Ingles; Rick A. Kittles; Sara S. Strom; Benjamin A. Rybicki; Barbara Nemesure; William B. Isaacs; Janet L. Stanford; Wei Zheng; Maureen Sanderson; Esther M. John; Jong Y. Park; Jianfeng Xu; Ying Wang; Sonja I. Berndt; Chad D. Huff; Edward D. Yeboah; Yao Tettey; Joseph Lachance; Wei Tang; Christopher T. Rentsch; Kelly Cho; Benjamin H. Mcmahon; Richard B. Biritwum; Andrew A. Adjei; Evelyn Tay; Ann Truelove; Shelley Niwa; Thomas A. Sellers; Kosj Yamoah; Adam B. Murphy; Dana C. Crawford; Alpa V. Patel; William S. Bush; Melinda C. Aldrich; Olivier Cussenot; Gyorgy Petrovics; Jennifer Cullen; Christine M. Neslund-Dudas; Mariana C. Stern; Zsofia Kote-Jarai; Koveela Govindasami; Michael B. Cook; Anand P. Chokkalingam; Ann W. Hsing; Phyllis J. Goodman; Thomas J. Hoffmann; Bettina F. Drake; Jennifer J. Hu; Jacob M. Keaton; Jacklyn N. Hellwege; Peter E. Clark; Mohamed Jalloh; Serigne M. Gueye; Lamine Niang; Olufemi Ogunbiyi; Michael O. Idowu; Olufemi Popoola; Akindele O. Adebiyi; Oseremen I. Aisuodionoe-Shadrach; Hafees O. Ajibola; Mustapha A. Jamda; Olabode P. Oluwole; Maxwell Nwegbu; Ben Adusei; Sunny Mante; Afua Darkwa-Abrahams; James E. Mensah; Halimatou Diop; Stephen K. Van Den Eeden; Pascal Blanchet; Jay H. Fowke; Graham Casey; Anselm J. Hennis; Alexander Lubwama; Ian M. Thompson; Robin Leach; Douglas F. Easton; Michael H. Preuss; Ruth J. Loos; Susan M. Gundell; Peggy Wan; James L. Mohler; Elizabeth T. Fontham; Gary J. Smith; Jack A. Taylor; Shiv Srivastava; Rosaline A. Eeles; John D. Carpten; Adam S. Kibel; Luc Multigner; Marie Élise Parent; Florence Menegaux; Geraldine Cancel-Tassin; Eric A. Klein; Caroline Andrews; Timothy R. Rebbeck; Laurent Brureau; Stefan Ambs; Todd L. Edwards; Stephen Watya; Stephen J. Chanock; John S. Witte; William J. Blot; J. Michael Gaziano; Amy C. Justice; David V. Conti; Christopher A. Haiman

doi:10.1016/j.eururo.2023.01.022

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Fei Chen, Ravi K. Madduri, Alex A. Rodriguez, Burcu F. Darst, Alisha Chou, Xin Sheng, Anqi Wang, Jiayi Shen, Edward J. Saunders, Suhn K. Rhie, Jeannette T. Bensen, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Janet L. Stanford, Wei Zheng, Maureen SandersonEsther M. John, Jong Y. Park, Jianfeng Xu, Ying Wang, Sonja I. Berndt, Chad D. Huff, Edward D. Yeboah, Yao Tettey, Joseph Lachance, Wei Tang, Christopher T. Rentsch, Kelly Cho, Benjamin H. Mcmahon, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Thomas A. Sellers, Kosj Yamoah, Adam B. Murphy, Dana C. Crawford, Alpa V. Patel, William S. Bush, Melinda C. Aldrich, Olivier Cussenot, Gyorgy Petrovics, Jennifer Cullen, Christine M. Neslund-Dudas, Mariana C. Stern, Zsofia Kote-Jarai, Koveela Govindasami, Michael B. Cook, Anand P. Chokkalingam, Ann W. Hsing, Phyllis J. Goodman, Thomas J. Hoffmann, Bettina F. Drake, Jennifer J. Hu, Jacob M. Keaton, Jacklyn N. Hellwege, Peter E. Clark, Mohamed Jalloh, Serigne M. Gueye, Lamine Niang, Olufemi Ogunbiyi, Michael O. Idowu, Olufemi Popoola, Akindele O. Adebiyi, Oseremen I. Aisuodionoe-Shadrach, Hafees O. Ajibola, Mustapha A. Jamda, Olabode P. Oluwole, Maxwell Nwegbu, Ben Adusei, Sunny Mante, Afua Darkwa-Abrahams, James E. Mensah, Halimatou Diop, Stephen K. Van Den Eeden, Pascal Blanchet, Jay H. Fowke, Graham Casey, Anselm J. Hennis, Alexander Lubwama, Ian M. Thompson, Robin Leach, Douglas F. Easton, Michael H. Preuss, Ruth J. Loos, Susan M. Gundell, Peggy Wan, James L. Mohler, Elizabeth T. Fontham, Gary J. Smith, Jack A. Taylor, Shiv Srivastava, Rosaline A. Eeles, John D. Carpten, Adam S. Kibel, Luc Multigner, Marie Élise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Eric A. Klein, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stefan Ambs, Todd L. Edwards, Stephen Watya, Stephen J. Chanock, John S. Witte, William J. Blot, J. Michael Gaziano, Amy C. Justice, David V. Conti, Christopher A. Haiman^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility. Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19 378 cases and 61 620 controls of African ancestry. Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40–60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10–1.38, p = 4.4 × 10^–4). Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Original language	English (US)
Pages (from-to)	13-21
Number of pages	9
Journal	European urology
Volume	84
Issue number	1
DOIs	https://doi.org/10.1016/j.eururo.2023.01.022
State	Published - Jul 2023

Funding

Funding/Support and role of the sponsor: This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19CA148537 to Christopher A. Haiman, U19CA214253 to Christopher A. Haiman, and R01CA257328 to Christopher A. Haiman, and T32CA229110 to Fei Chen), the Prostate Cancer Foundation (20CHAS03 to Christopher A. Haiman), and the Million Veteran Program-MVP017. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award MVP017. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. The North Carolina-Louisiana Prostate Cancer Project (PCaP) is carried out as a collaborative study supported by the Department of Defense contract DAMD 17-03-2-0052.

Keywords

African ancestry
Aggressive prostate cancer
Polygenic risk score
Prostate cancer
Susceptibility loci

ASJC Scopus subject areas

Urology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.eururo.2023.01.022

Cite this

Chen, F., Madduri, R. K., Rodriguez, A. A., Darst, B. F., Chou, A., Sheng, X., Wang, A., Shen, J., Saunders, E. J., Rhie, S. K., Bensen, J. T., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Stanford, J. L., Zheng, W., ... Haiman, C. A. (2023). Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry. European urology, 84(1), 13-21. https://doi.org/10.1016/j.eururo.2023.01.022

@article{8d6c53c0596f43dbb7c8544f341d7cbd,

title = "Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry",

abstract = "Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility. Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19 378 cases and 61 620 controls of African ancestry. Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40–60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10–1.38, p = 4.4 × 10–4). Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.",

keywords = "African ancestry, Aggressive prostate cancer, Polygenic risk score, Prostate cancer, Susceptibility loci",

author = "Fei Chen and Madduri, {Ravi K.} and Rodriguez, {Alex A.} and Darst, {Burcu F.} and Alisha Chou and Xin Sheng and Anqi Wang and Jiayi Shen and Saunders, {Edward J.} and Rhie, {Suhn K.} and Bensen, {Jeannette T.} and Ingles, {Sue A.} and Kittles, {Rick A.} and Strom, {Sara S.} and Rybicki, {Benjamin A.} and Barbara Nemesure and Isaacs, {William B.} and Stanford, {Janet L.} and Wei Zheng and Maureen Sanderson and John, {Esther M.} and Park, {Jong Y.} and Jianfeng Xu and Ying Wang and Berndt, {Sonja I.} and Huff, {Chad D.} and Yeboah, {Edward D.} and Yao Tettey and Joseph Lachance and Wei Tang and Rentsch, {Christopher T.} and Kelly Cho and Mcmahon, {Benjamin H.} and Biritwum, {Richard B.} and Adjei, {Andrew A.} and Evelyn Tay and Ann Truelove and Shelley Niwa and Sellers, {Thomas A.} and Kosj Yamoah and Murphy, {Adam B.} and Crawford, {Dana C.} and Patel, {Alpa V.} and Bush, {William S.} and Aldrich, {Melinda C.} and Olivier Cussenot and Gyorgy Petrovics and Jennifer Cullen and Neslund-Dudas, {Christine M.} and Stern, {Mariana C.} and Zsofia Kote-Jarai and Koveela Govindasami and Cook, {Michael B.} and Chokkalingam, {Anand P.} and Hsing, {Ann W.} and Goodman, {Phyllis J.} and Hoffmann, {Thomas J.} and Drake, {Bettina F.} and Hu, {Jennifer J.} and Keaton, {Jacob M.} and Hellwege, {Jacklyn N.} and Clark, {Peter E.} and Mohamed Jalloh and Gueye, {Serigne M.} and Lamine Niang and Olufemi Ogunbiyi and Idowu, {Michael O.} and Olufemi Popoola and Adebiyi, {Akindele O.} and Aisuodionoe-Shadrach, {Oseremen I.} and Ajibola, {Hafees O.} and Jamda, {Mustapha A.} and Oluwole, {Olabode P.} and Maxwell Nwegbu and Ben Adusei and Sunny Mante and Afua Darkwa-Abrahams and Mensah, {James E.} and Halimatou Diop and {Van Den Eeden}, {Stephen K.} and Pascal Blanchet and Fowke, {Jay H.} and Graham Casey and Hennis, {Anselm J.} and Alexander Lubwama and Thompson, {Ian M.} and Robin Leach and Easton, {Douglas F.} and Preuss, {Michael H.} and Loos, {Ruth J.} and Gundell, {Susan M.} and Peggy Wan and Mohler, {James L.} and Fontham, {Elizabeth T.} and Smith, {Gary J.} and Taylor, {Jack A.} and Shiv Srivastava and Eeles, {Rosaline A.} and Carpten, {John D.} and Kibel, {Adam S.} and Luc Multigner and Parent, {Marie {\'E}lise} and Florence Menegaux and Geraldine Cancel-Tassin and Klein, {Eric A.} and Caroline Andrews and Rebbeck, {Timothy R.} and Laurent Brureau and Stefan Ambs and Edwards, {Todd L.} and Stephen Watya and Chanock, {Stephen J.} and Witte, {John S.} and Blot, {William J.} and {Michael Gaziano}, J. and Justice, {Amy C.} and Conti, {David V.} and Haiman, {Christopher A.}",

note = "Publisher Copyright: {\textcopyright} 2023 European Association of Urology",

year = "2023",

month = jul,

doi = "10.1016/j.eururo.2023.01.022",

language = "English (US)",

volume = "84",

pages = "13--21",

journal = "European urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "1",

}

Chen, F, Madduri, RK, Rodriguez, AA, Darst, BF, Chou, A, Sheng, X, Wang, A, Shen, J, Saunders, EJ, Rhie, SK, Bensen, JT, Ingles, SA, Kittles, RA, Strom, SS, Rybicki, BA, Nemesure, B, Isaacs, WB, Stanford, JL, Zheng, W, Sanderson, M, John, EM, Park, JY, Xu, J, Wang, Y, Berndt, SI, Huff, CD, Yeboah, ED, Tettey, Y, Lachance, J, Tang, W, Rentsch, CT, Cho, K, Mcmahon, BH, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Sellers, TA, Yamoah, K, Murphy, AB, Crawford, DC, Patel, AV, Bush, WS, Aldrich, MC, Cussenot, O, Petrovics, G, Cullen, J, Neslund-Dudas, CM, Stern, MC, Kote-Jarai, Z, Govindasami, K, Cook, MB, Chokkalingam, AP, Hsing, AW, Goodman, PJ, Hoffmann, TJ, Drake, BF, Hu, JJ, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Idowu, MO, Popoola, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Mensah, JE, Diop, H, Van Den Eeden, SK, Blanchet, P, Fowke, JH, Casey, G, Hennis, AJ, Lubwama, A, Thompson, IM, Leach, R, Easton, DF, Preuss, MH, Loos, RJ, Gundell, SM, Wan, P, Mohler, JL, Fontham, ET, Smith, GJ, Taylor, JA, Srivastava, S, Eeles, RA, Carpten, JD, Kibel, AS, Multigner, L, Parent, MÉ, Menegaux, F, Cancel-Tassin, G, Klein, EA, Andrews, C, Rebbeck, TR, Brureau, L, Ambs, S, Edwards, TL, Watya, S, Chanock, SJ, Witte, JS, Blot, WJ, Michael Gaziano, J, Justice, AC, Conti, DV & Haiman, CA 2023, 'Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry', European urology, vol. 84, no. 1, pp. 13-21. https://doi.org/10.1016/j.eururo.2023.01.022

TY - JOUR

T1 - Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

AU - Chen, Fei

AU - Madduri, Ravi K.

AU - Rodriguez, Alex A.

AU - Darst, Burcu F.

AU - Chou, Alisha

AU - Sheng, Xin

AU - Wang, Anqi

AU - Shen, Jiayi

AU - Saunders, Edward J.

AU - Rhie, Suhn K.

AU - Bensen, Jeannette T.

AU - Ingles, Sue A.

AU - Kittles, Rick A.

AU - Strom, Sara S.

AU - Rybicki, Benjamin A.

AU - Nemesure, Barbara

AU - Isaacs, William B.

AU - Stanford, Janet L.

AU - Zheng, Wei

AU - Sanderson, Maureen

AU - John, Esther M.

AU - Park, Jong Y.

AU - Xu, Jianfeng

AU - Wang, Ying

AU - Berndt, Sonja I.

AU - Huff, Chad D.

AU - Yeboah, Edward D.

AU - Tettey, Yao

AU - Lachance, Joseph

AU - Tang, Wei

AU - Rentsch, Christopher T.

AU - Cho, Kelly

AU - Mcmahon, Benjamin H.

AU - Biritwum, Richard B.

AU - Adjei, Andrew A.

AU - Tay, Evelyn

AU - Truelove, Ann

AU - Niwa, Shelley

AU - Sellers, Thomas A.

AU - Yamoah, Kosj

AU - Murphy, Adam B.

AU - Crawford, Dana C.

AU - Patel, Alpa V.

AU - Bush, William S.

AU - Aldrich, Melinda C.

AU - Cussenot, Olivier

AU - Petrovics, Gyorgy

AU - Cullen, Jennifer

AU - Neslund-Dudas, Christine M.

AU - Stern, Mariana C.

AU - Kote-Jarai, Zsofia

AU - Govindasami, Koveela

AU - Cook, Michael B.

AU - Chokkalingam, Anand P.

AU - Hsing, Ann W.

AU - Goodman, Phyllis J.

AU - Hoffmann, Thomas J.

AU - Drake, Bettina F.

AU - Hu, Jennifer J.

AU - Keaton, Jacob M.

AU - Hellwege, Jacklyn N.

AU - Clark, Peter E.

AU - Jalloh, Mohamed

AU - Gueye, Serigne M.

AU - Niang, Lamine

AU - Ogunbiyi, Olufemi

AU - Idowu, Michael O.

AU - Popoola, Olufemi

AU - Adebiyi, Akindele O.

AU - Aisuodionoe-Shadrach, Oseremen I.

AU - Ajibola, Hafees O.

AU - Jamda, Mustapha A.

AU - Oluwole, Olabode P.

AU - Nwegbu, Maxwell

AU - Adusei, Ben

AU - Mante, Sunny

AU - Darkwa-Abrahams, Afua

AU - Mensah, James E.

AU - Diop, Halimatou

AU - Van Den Eeden, Stephen K.

AU - Blanchet, Pascal

AU - Fowke, Jay H.

AU - Casey, Graham

AU - Hennis, Anselm J.

AU - Lubwama, Alexander

AU - Thompson, Ian M.

AU - Leach, Robin

AU - Easton, Douglas F.

AU - Preuss, Michael H.

AU - Loos, Ruth J.

AU - Gundell, Susan M.

AU - Wan, Peggy

AU - Mohler, James L.

AU - Fontham, Elizabeth T.

AU - Smith, Gary J.

AU - Taylor, Jack A.

AU - Srivastava, Shiv

AU - Eeles, Rosaline A.

AU - Carpten, John D.

AU - Kibel, Adam S.

AU - Multigner, Luc

AU - Parent, Marie Élise

AU - Menegaux, Florence

AU - Cancel-Tassin, Geraldine

AU - Klein, Eric A.

AU - Andrews, Caroline

AU - Rebbeck, Timothy R.

AU - Brureau, Laurent

AU - Ambs, Stefan

AU - Edwards, Todd L.

AU - Watya, Stephen

AU - Chanock, Stephen J.

AU - Witte, John S.

AU - Blot, William J.

AU - Michael Gaziano, J.

AU - Justice, Amy C.

AU - Conti, David V.

AU - Haiman, Christopher A.

PY - 2023/7

Y1 - 2023/7

N2 - Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility. Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19 378 cases and 61 620 controls of African ancestry. Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40–60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10–1.38, p = 4.4 × 10–4). Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

AB - Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility. Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19 378 cases and 61 620 controls of African ancestry. Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40–60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10–1.38, p = 4.4 × 10–4). Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

KW - African ancestry

KW - Aggressive prostate cancer

KW - Polygenic risk score

KW - Prostate cancer

KW - Susceptibility loci

UR - http://www.scopus.com/inward/record.url?scp=85150933098&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85150933098&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2023.01.022

DO - 10.1016/j.eururo.2023.01.022

M3 - Article

C2 - 36872133

AN - SCOPUS:85150933098

SN - 0302-2838

VL - 84

SP - 13

EP - 21

JO - European urology

JF - European urology

IS - 1

ER -

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this