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

Author

Paul A. Townsend, Edward J. Saunders, Hidewaki Nakagawa, Manuel R. Teixeira, Graham Casey, Demetrius Albanes, Christine Neslund-Dudas, Sara Lindström, William S. Bush, Maren Weischer, Lisa A. Cannon-Albright, Rick A. Kittles, Peggy Wan, Martin Eklund, Stephen N. Thibodeau, Burcu F. Darst, Fredrik Wiklund, Nicholas Mancuso, Jeri Kim, Jong Y. Park, Johanna Schleutker, Maureen Sanderson, Samantha E.T. Larkin, Radka Kaneva, Hongwei Zhang, Daniel J. Schaid, Luc Multigner, Marie-Élise Parent, Robert Szulkin, Fredrick R. Schumacher, Geraldine Cancel-Tassin, Jianfeng Xu, Gill Barnett, Melissa C. Southey, Yuan Chun Ding, Alexander Lubwama, Maria Elena Martinez, Manolis Kogevinas, Linda Steele, Laurent Brureau, Shiv Srivastava, Maya Ghoussaini, Alison M. Dunning, Adam B. Murphy, Kenneth Muir, Edward Giovannucci, Mitchell J. Machiela, James L. Mohler, Jack A. Taylor, Robert N. Hoover, Sandeep Singhal, Chavdar Slavov, Guido Jenster, Frank Claessens, Neil Fleshner, Sara Benlloch, Gert De Meerleer, Michael B. Cook, Zan Sun, Harry Ostrer, Pascal Blanchet, Lynne R. Wilkens, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jay H. Fowke, Agnieszka Michael, Yves Akoli Koudou, Victoria L. Stevens, Kathryn L. Penney, Ana Vega, Xin Sheng, Ron H.N. van Schaik, Zsofia Kote-Jarai, Kim De Ruyck, Christopher A. Haiman, Atushi Takahashi, Florence Menegaux, Judith A. Clements, Stephen K. Van Den Eeden, Brian D. Carter, Wayne D. Tilley, Antonio Finelli, Jennifer J. Hu, Hermann Brenner, Thomas Van den Broeck, Shan Chao Zhao, Azad Hassan Abdul Razack, Edward D. Yeboah, Sonja I. Berndt, Barbara Nemesure, Mark N. Brook, David V. Conti, Katarina Cuk, Teuvo L.J. Tammela, Ali Sahimi, Stephen J. Chanock, Loic Le Marchand, Gemma Castaño-Vinyals, Sune F. Nielsen, Sara S. Strom, Ann W. Hsing, Roberta McKean-Cowdin, David J. Hunter, Ian M. Thompson, Børge G. Nordestgaard, Jyotsna Batra, Paula Paulo, Masashi Fujita, Jennifer Cullen, Susan M. Gapstur, Sarah L. Kerns, Lorelei A. Mucci, Neil G. Burnet, Xueying Mao, Hui Yi Lin, Rohit Varma, Marija Gamulin, Wei Zheng, Thomas A. Sellers, Adam S. Kibel, Robert J. Hamilton, Leire Moya, Ninghan Feng, Laura E. Beane Freeman, James E. Mensah, Catherine M. Tangen, Shannon K. McDonnell, Matthew Parliament, Davor Lessel, Gail P. Risbridger, Mina Torres, Janet L. Stanford, Bettina F. Drake, Soo-Hwang Teo, Robert J. MacInnis, Stig E. Bojesen, Jeannette T. Bensen, William J. Blot, Stella Koutros, Robin J. Leach, Graham G. Giles, Piet Ost, Artitaya Lophatananon, Laura Fachal, Tomislav Kuliš, Peter Kraft, Monique J. Roobol, Elaine A. Ostrander, Niclas Håkansson, Anselm Hennis, Yukihide Momozawa, Anssi Auvinen, Koichi Matsuda, Steven Joniau, Lisa G. Horvath, Javier Llorca, Claire Aukim-Hastie, Bernd Holleczek, Daniel W. Lin, Gerald L. Andriole, John D. Carpten, Eli Marie Grindedal, Rosalind A. Eeles, Elio Riboli, Constance Turman, Martin Andreas Røder, Yong-Jie Lu, Tobias Nordström, Kai Uwe Saum, Esther M. John, Melinda C. Aldrich, Peter Iversen, Henrik Grönberg, John S. Witte, Andreia Brandão, Eric A. Klein, Olivier Cussenot, Barry S. Rosenstein, Stephen Watya, Jan Lubinski, Douglas F. Easton, Dana C. Crawford, Gyorgy Petrovics, Thomas J. Schnoeller, Richard M. Martin, Stephanie J. Weinstein, Jose Esteban Castelao, Suzanne K. Chambers, Tokhir Dadaev, Karina Dalsgaard Sørensen, Antonio Gómez-Caamaño, Lisa F. Newcomb, Csilla Sipeky, Lovise Maehle, Brandi Weaver, Susan L. Neuhausen, Christiane Maier, Alicja Wolk, Vanio Mitev, Thérèse Truong, Manuel Luedeke, Jenny L Donovan, Mariana C. Stern, Catharine M L West, Manuela Gago-Dominguez, Elizabeth T. H. Fontham, William B. Isaacs, David E. Neal, Christopher J. Logothetis, Alisha Chou, Jasmine Lim, Benjamin A. Rybicki, Kay-Tee Khaw, Meir J. Stampfer, Chad D. Huff, Thomas J. Hoffmann, Michael Borre, Freddie C. Hamdy, Nawaid Usmani, Cezary Cybulski, Craig C. Teerlink, Milan S. Geybels, Nora Pashayan, Timothy J. Key, Phyllis J. Goodman, Hardev Pandha, Ruth C. Travis, Yudong Wu, Dominika Wokołorczyk, Lilit C. Moss, University of Southern California (USC), Keck School of Medicine [Los Angeles], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], The institute of cancer research [London], U01CA194393, National Institutes of Health, NA, Achievement Rewards for College Scientists Foundation, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Urology, Clinical Chemistry, Darst, Burcu F [0000-0002-6205-4632], Chou, Alisha [0000-0001-7521-6373], Schumacher, Fredrick R [0000-0002-3073-7463], Dadaev, Tokhir [0000-0002-8268-0438], Brook, Mark N [0000-0002-8969-2378], Hoffmann, Thomas J [0000-0001-6893-4449], Takahashi, Atushi [0000-0001-7099-8767], Matsuda, Koichi [0000-0001-7292-2686], Fujita, Masashi [0000-0002-1457-6233], Muir, Kenneth [0000-0001-6429-988X], Stevens, Victoria L [0000-0003-0259-4407], Schleutker, Johanna [0000-0002-1863-0305], Sipeky, Csilla [0000-0002-8853-4722], Auvinen, Anssi [0000-0003-1125-4818], Giles, Graham G [0000-0003-4946-9099], Martin, Richard M [0000-0002-7992-7719], Nordestgaard, Børge G [0000-0002-1954-7220], Bojesen, Stig E [0000-0002-4061-4133], Røder, Martin Andreas [0000-0002-0019-5333], Batra, Jyotsna [0000-0003-4646-6247], Tilley, Wayne [0000-0003-1893-2626], Risbridger, Gail P [0000-0003-3089-4028], Gronberg, Henrik [0000-0002-1073-2753], Eklund, Martin [0000-0001-5032-5266], Nordström, Tobias [0000-0003-4915-7546], Pashayan, Nora [0000-0003-0843-2468], Dunning, Alison M [0000-0001-6651-7166], Travis, Ruth C [0000-0002-9571-0763], Riboli, Elio [0000-0001-6795-6080], Park, Jong Y [0000-0002-6384-6447], Weinstein, Stephanie J [0000-0002-3834-1535], Kraft, Peter [0000-0002-4472-8103], Ostrander, Elaine A [0000-0001-6075-9738], Wolk, Alicja [0000-0001-7387-6845], Håkansson, Niclas [0000-0001-7673-5554], Machiela, Mitchell J [0000-0001-6538-9705], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Zheng, Wei [0000-0003-1226-070X], Mensah, James E [0000-0003-4133-1722], Lu, Yong-Jie [0000-0001-6174-6621], West, Catharine ML [0000-0002-0839-3449], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Truong, Thérèse [0000-0002-2943-6786], Vega, Ana [0000-0002-7416-5137], Gómez-Caamaño, Antonio [0000-0002-9773-4590], Fachal, Laura [0000-0002-7256-9752], Kerns, Sarah L [0000-0002-6503-0011], Ostrer, Harry [0000-0002-2209-5376], Teixeira, Manuel R [0000-0002-4896-5982], Brandão, Andreia [0000-0003-0938-1543], Cannon-Albright, Lisa [0000-0003-2602-3668], Multigner, Luc [0000-0003-3205-8568], Klein, Eric A [0000-0002-1783-0698], Murphy, Adam B [0000-0001-9977-3473], Michael, Agnieszka [0000-0002-7262-6227], Ost, Piet [0000-0002-2203-4848], Xu, Jianfeng [0000-0002-1343-8752], Teo, Soo-Hwang [0000-0002-0444-590X], Lessel, Davor [0000-0003-4496-244X], Kulis, Tomislav [0000-0002-0895-5691], Joniau, Steven [0000-0003-3195-9890], Bush, William S [0000-0002-9729-6519], Crawford, Dana C [0000-0002-6437-6248], Roobol, Monique J [0000-0001-6967-1708], Jenster, Guido [0000-0002-8658-2552], Van Den Eeden, Stephen K [0000-0002-5599-8387], Easton, Douglas F [0000-0003-2444-3247], Chanock, Stephen J [0000-0002-2324-3393], Wiklund, Fredrik [0000-0002-4623-0544], Eeles, Rosalind A [0000-0002-3698-6241], Haiman, Christopher A [0000-0002-0097-9971], and Apollo - University of Cambridge Repository

Subjects
Male, 8Q24, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Prostate cancer, 0302 clinical medicine, Risk Factors, Epidemiology, IMPUTATION, Odds Ratio, Prostatic Neoplasms/diagnosis, 0303 health sciences, education.field_of_study, Continental Population Groups, Manchester Cancer Research Centre, Middle Aged, Càncer--Aspectes genètics, 3. Good health, ODDS RATIOS, 06 Biological Sciences, 11 Medical and Health Sciences, medicine.medical_specialty, Population, Biology, prostate cancer, meta-analysis, SEQUENCE, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetics, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, education, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, ResearchInstitutes_Networks_Beacons/mcrc, Racial Groups, Prostatic Neoplasms, Molecular Sequence Annotation, Odds ratio, medicine.disease, BRCA2, Pròstata--Càncer, Genetic Loci, 030217 neurology & neurosurgery, Imputation (genetics), Genètica, Demography, Developmental Biology, Genome-Wide Association Study
Abstract

International audience; 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

2. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author

Dadaev, T, Saunders, EJ, Newcombe, PJ, Anokian, E, Leongamornlert, DA, Brook, MN, Cieza-Borrella, C, Mijuskovic, M, Wakerell, S, Olama, AAA, Schumacher, FR, Berndt, SI, Benlloch, S, Ahmed, M, Goh, C, Sheng, X, Zhang, Z, Muir, K, Govindasami, K, Lophatananon, A, Stevens, VL, Gapstur, SM, Carter, BD, Tangen, CM, Goodman, P, Thompson, IM, Batra, J, Chambers, S, Moya, L, Clements, J, Horvath, L, Tilley, W, Risbridger, G, Gronberg, H, Aly, M, Nordström, T, Pharoah, P, Pashayan, N, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Albanes, D, Weinstein, S, Wolk, A, Hakansson, N, West, C, Dunning, AM, Burnet, N, Mucci, L, Giovannucci, E, Andriole, G, Cussenot, O, Cancel-Tassin, G, Koutros, S, Freeman, LEB, Sorensen, KD, Orntoft, TF, Borre, M, Maehle, L, Grindedal, EM, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Travis, RC, Key, TJ, Hamilton, RJ, Fleshner, NE, Finelli, A, Ingles, SA, Stern, MC, Rosenstein, B, Kerns, S, Ostrer, H, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Guo, X, Wang, G, Sun, Z, Giles, GG, Southey, MC, Macinnis, RJ, Fitzgerald, LM, Kibel, AS, Drake, BF, Vega, A, Gómez-Caamaño, A, Fachal, L, Szulkin, R, Eklund, M, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Penney, KL, Stampfer, M, Park, JY, Sellers, TA, Lin, H-Y, Stanford, JL, Cybulski, C, Wokolorczyk, D, Lubinski, J, Ostrander, EA, Geybels, MS, Nordestgaard, BG, Nielsen, SF, Weisher, M, Bisbjerg, R, Røder, MA, Iversen, P, Brenner, H, Cuk, K, Holleczek, B, Maier, C, Luedeke, M, Schnoeller, T, Kim, J, Logothetis, CJ, John, EM, Teixeira, MR, Paulo, P, Cardoso, M, Neuhausen, SL, Steele, L, Ding, YC, De Ruyck, K, De Meerleer, G, Ost, P, Razack, A, Lim, J, Teo, S-H, Lin, DW, Newcomb, LF, Lessel, D, Gamulin, M, Kulis, T, Kaneva, R, Usmani, N, Slavov, C, Mitev, V, Parliament, M, Singhal, S, Claessens, F, Joniau, S, Van Den Broeck, T, Larkin, S, Townsend, PA, Aukim-Hastie, C, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Roobol, MJ, Jenster, G, Van Schaik, RHN, Menegaux, F, Truong, T, Koudou, YA, Xu, J, Khaw, K-T, Cannon-Albright, L, Pandha, H, Michael, A, Kierzek, A, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Lindstrom, S, Turman, C, Ma, J, Hunter, DJ, Riboli, E, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Hoover, RN, Machiela, MJ, Kraft, P, Consortium, Practical (Prostate Cancer Association Group To Investigate Cancer-Associated Alterations In The Genome), Freedman, M, Wiklund, F, Chanock, S, Henderson, BE, Easton, DF, Haiman, CA, Eeles, RA, Conti, DV, Kote-Jarai, Z, Dadaev, Tokhir [0000-0002-8268-0438], Leongamornlert, Daniel A [0000-0002-3486-3168], Brook, Mark N [0000-0002-8969-2378], Olama, Ali Amin Al [0000-0002-7178-3431], Schumacher, Fredrick R [0000-0002-3073-7463], Muir, Kenneth [0000-0001-6429-988X], Batra, Jyotsna [0000-0003-4646-6247], Nordström, Tobias [0000-0003-4915-7546], Pharoah, Paul [0000-0001-8494-732X], Pashayan, Nora [0000-0003-0843-2468], Schleutker, Johanna [0000-0002-1863-0305], Sipeky, Csilla [0000-0002-8853-4722], Wolk, Alicja [0000-0001-7387-6845], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Sorensen, Karina Dalsgaard [0000-0002-4902-5490], Kerns, Sarah [0000-0002-6503-0011], Ostrer, Harry [0000-0002-2209-5376], Fachal, Laura [0000-0002-7256-9752], Kogevinas, Manolis [0000-0002-9605-0461], Nordestgaard, Børge G [0000-0002-1954-7220], Lim, Jasmine [0000-0002-7501-1834], Truong, Thérèse [0000-0002-2943-6786], Xu, Jianfeng [0000-0002-1343-8752], Easton, Douglas F [0000-0003-2444-3247], Eeles, Rosalind A [0000-0002-3698-6241], Apollo - University of Cambridge Repository, National Institutes of Health, Urology, and Clinical Chemistry

Subjects
Male, Risk, Science, GENETIC, Quantitative Trait Loci, Black People, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, urologic and male genital diseases, ANNOTATION, Polymorphism, Single Nucleotide, Article, White People, REGION, GENETIC ASSOCIATION, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Medicine and Health Sciences, ELEMENTS, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, lcsh:Science, Medicinsk genetik, MODEL SELECTION, BAYESIAN FRAMEWORK, Cancer och onkologi, Science & Technology, Chromosome Mapping, Prostatic Neoplasms, Bayes Theorem, Molecular Sequence Annotation, ASSOCIATION, JOINT ANALYSIS, RISK LOCI, STATISTICS, Multidisciplinary Sciences, Cancer and Oncology, Multivariate Analysis, Science & Technology - Other Topics, lcsh:Q, Medical Genetics, Algorithms, VARIABLE-SELECTION, Genome-Wide Association Study
Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling., Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

Published
2018

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