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

Author

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, Le Marchand, Loic, Wilkens, Lynne, Wang, Ying, Schleutker, Johanna, MacInnis, Robert J, Cybulski, Cezary, Neal, David E, Nordestgaard, Børge G, Nielsen, Sune F, Batra, Jyotsna, Clements, Judith A, Cancer BioResource, Australian Prostate, 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, and Cancel-Tassin, Géraldine

Subjects
Male, Prostatic Neoplasms/genetics, Risk Factors, Humans, Black People/genetics, Genetic Predisposition to Disease, Multifactorial Inheritance/genetics, Genome-Wide Association Study
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.

Published
2023

2. Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry

Author

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., 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., 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, 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., and Haiman, Christopher A.

Subjects
Article
Abstract

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 (PRS (269) ). 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 PRS (269) . 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 PRS (269) 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 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 PRS (269) constructed with fine-mapping.

Published
2023

3. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V, Darst, Burcu F, Moss, Lilit C, Saunders, Edward J, Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R, Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N, Sahimi, Ali, Hoffmann, Thomas J, Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bojesen, Stig E, Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M, Ghoussaini, Maya, Travis, Ruth C, Key, Tim J, Riboli, Elio, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J, Mucci, Lorelei A, Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J, Penney, Kathryn L, Turman, Constance, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L, Ostrander, Elaine A, Geybels, Milan S, Koutros, Stella, Freeman, Laura E Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L, Hoover, Robert N, Machiela, Mitchell J, Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J, Zheng, Wei, Yeboah, Edward D, Mensah, James E, and Lu, Yong-Jie

Subjects
Male, Urologic Diseases, Aging, Quantitative Trait Loci, Medical and Health Sciences, Risk Factors, Clinical Research, Odds Ratio, Genetics, Humans, 2.1 Biological and endogenous factors, Neoplasm Invasiveness, Genetic Predisposition to Disease, Aetiology, Cancer, Prevention, Prostate Cancer, Racial Groups, Human Genome, Prostatic Neoplasms, Molecular Sequence Annotation, Genomics, Middle Aged, Biological Sciences, Phenotype, Good Health and Well Being, Genetic Loci, Software, Genome-Wide Association Study, Statistical Distributions, Developmental Biology
Abstract

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Published
2021

4. Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21

Author

Haiman, Christopher A, Chen, Gary K, Blot, William J, Strom, Sara S, Berndt, Sonja I, Kittles, Rick A, Rybicki, Benjamin A, Isaacs, William B, Ingles, Sue A, Stanford, Janet L, Diver, W Ryan, Witte, John S, Hsing, Ann W, Nemesure, Barbara, Rebbeck, Timothy R, Cooney, Kathleen A, Xu, Jianfeng, Kibel, Adam S, Hu, Jennifer J, John, Esther M, Gueye, Serigne M, Watya, Stephen, Signorello, Lisa B, Hayes, Richard B, Wang, Zhaoming, Yeboah, Edward, Tettey, Yao, Cai, Qiuyin, Kolb, Suzanne, Ostrander, Elaine A, Zeigler-Johnson, Charnita, Yamamura, Yuko, Neslund-Dudas, Christine, Haslag-Minoff, Jennifer, Wu, William, Thomas, Venetta, Allen, Glenn O, Murphy, Adam, Chang, Bao-Li, Zheng, S Lilly, Leske, M Cristina, Wu, Suh-Yuh, Ray, Anna M, Hennis, Anselm JM, Thun, Michael J, Carpten, John, Casey, Graham, Carter, Erin N, Duarte, Edder R, Xia, Lucy Y, Sheng, Xin, Wan, Peggy, Pooler, Loreall C, Cheng, Iona, Monroe, Kristine R, Schumacher, Fredrick, Le Marchand, Loic, Kolonel, Laurence N, Chanock, Stephen J, Van Den Berg, David, Stram, Daniel O, and Henderson, Brian E

Subjects
African Americans, Male, Pair 17, Prostatic Neoplasms, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Chromosomes, Humans, Genetic Predisposition to Disease, Polymorphism, Human, Genome-Wide Association Study, Developmental Biology
Abstract

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (

Published
2011

5. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer

Author

Haiman, Christopher A. Chen, Gary K. Vachon, Celine M. and Canzian, Federico Dunning, Alison Millikan, Robert C. Wang, Xianshu Ademuyiwa, Foluso Ahmed, Shahana Ambrosone, Christine B. Baglietto, Laura Balleine, Rosemary Bandera, Elisa V. Beckmann, Matthias W. Berg, Christine D. Bernstein, Leslie Blomqvist, Carl Blot, William J. Brauch, Hiltrud and Buring, Julie E. Carey, Lisa A. Carpenter, Jane E. and Chang-Claude, Jenny Chanock, Stephen J. Chasman, Daniel I. and Clarke, Christine L. Cox, Angela Cross, Simon S. Deming, Sandra L. Diasio, Robert B. Dimopoulos, Athanasios M. and Driver, W. Ryan Duennebier, Thomas Durcan, Lorraine Eccles, Diana Edlund, Christopher K. Ekici, Arif B. Fasching, Peter A. Feigelson, Heather S. Flesch-Janys, Dieter Fostira, Florentia Foersti, Asta Fountzilas, George Gerty, Susan M. and Giles, Graham G. Godwin, Andrew K. Goodfellow, Paul and Graham, Nikki Greco, Dario Hamann, Ute Hankinson, Susan E. and Hartmann, Arndt Hein, Rebecca Heinz, Judith Holbrook, Andrea Hoover, Robert N. Hu, Jennifer J. Hunter, David J. and Ingles, Sue A. Irwanto, Astrid Ivanovich, Jennifer John, Esther M. Johnson, Nicola Jukkola-Vuorinen, Arja Kaaks, Rudolf Ko, Yon-Dschun Kolonel, Laurence N. Konstantopoulou, Irene Kosma, Veli-Matti Kulkarni, Swati Lambrechts, Diether and Lee, Adam M. Le Marchand, Loic Lesnick, Timothy Liu, Jianjun Lindstrom, Sara Mannermaa, Arto Margolin, Sara and Martin, Nicholas G. Miron, Penelope Montgomery, Grant W. and Nevanlinna, Heli Nickels, Stephan Nyante, Sarah Olswold, Curtis Palmer, Julie Pathak, Harsh Pectasides, Dimitrios and Perou, Charles M. Peto, Julian Pharoah, Paul D. P. Pooler, Loreall C. Press, Michael F. Pylkas, Katri Rebbeck, Timothy R. Rodriguez-Gil, Jorge L. Rosenberg, Lynn Ross, Eric and Ruediger, Thomas Silva, Isabel dos Santos Sawyer, Elinor and Schmidt, Marjanka K. Schulz-Wendtland, Ruediger Schumacher, Fredrick Severi, Gianluca Sheng, Xin Signorello, Lisa B. and Sinn, Hans-Peter Stevens, Kristen N. Southey, Melissa C. and Tapper, William J. Tomlinson, Ian Hogervorst, Frans B. L. and Wauters, Els Weaver, JoEllen Wildiers, Hans Winqvist, Robert and Van Den Berg, David Wan, Peggy Xia, Lucy Y. Yannoukakos, Drakoulis Zheng, Wei Ziegler, Regina G. Siddiq, Afshan and Slager, Susan L. Stram, Daniel O. Easton, Douglas Kraft, Peter Henderson, Brian E. Couch, Fergus J. Gene Environm Interaction Breast C

Abstract

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (

Published
2011

6. A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

Author

Kolonel, Laurence N., Ziegler, Regina G., Haiman, Chris A., Zheng, Wei, Deming, Sandra L., Millikan, Robert C., Van Den Berg, David J., Bernstein, Leslie, Sheng, Xin, Nyante, Sarah, Bandera, Elisa V., Stram, Daniel O., Ingles, Sue A., Chanock, Stephen J., Song, Chi, Pooler, Loreall C., Henderson, Brian E., Chen, Gary K., John, Esther M., Le Marchand, Loic, Ambrosone, Christine B., Hu, Jennifer J., Rodriguez-Gil, Jorge L., Wan, Peggy, and Press, Michael F.

Subjects
3. Good health
Abstract

Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

7. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V, Darst, Burcu F, Moss, Lilit C, Saunders, Edward J, Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R, Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N, Sahimi, Ali, Hoffmann, Thomas J, Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bojesen, Stig E, Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M, Ghoussaini, Maya, Travis, Ruth C, Key, Tim J, Riboli, Elio, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J, Mucci, Lorelei A, Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J, Penney, Kathryn L, Turman, Constance, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L, Ostrander, Elaine A, Geybels, Milan S, Koutros, Stella, Freeman, Laura E Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L, Hoover, Robert N, Machiela, Mitchell J, Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J, Zheng, Wei, Yeboah, Edward D, Mensah, James E, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, West, Catharine ML, Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M, Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A, Stern, Mariana C, Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S, Kerns, Sarah L, Ostrer, Harry, Teixeira, Manuel R, Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T, Fontham, Elizabeth TH, Mohler, James, Taylor, Jack A, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C, Huff, Chad D, Strom, Sara S, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J, Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A, Hsing, Ann W, Kittles, Rick A, Murphy, Adam B, Logothetis, Christopher J, Kim, Jeri, Neuhausen, Susan L, Steele, Linda, Ding, Yuan Chun, Isaacs, William B, Nemesure, Barbara, Hennis, Anselm JM, Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F, Lin, Daniel W, Fowke, Jay H, Neslund-Dudas, Christine, Rybicki, Benjamin A, Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van Den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A, Aukim-Hastie, Claire, Bush, William S, Aldrich, Melinda C, Crawford, Dana C, Srivastava, Shiv, Cullen, Jennifer C, Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J, Jenster, Guido, Van Schaik, Ron HN, Hu, Jennifer J, Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I, Van Den Eeden, Stephen K, Easton, Douglas F, Chanock, Stephen J, Cook, Michael B, Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S, Eeles, Rosalind A, Kote-Jarai, Zsofia, and Haiman, Christopher A

Subjects
Male, Genetic Loci, Risk Factors, Racial Groups, Odds Ratio, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Molecular Sequence Annotation, Neoplasm Invasiveness, Middle Aged, 3. Good health, Genome-Wide Association Study
Abstract

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

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