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

Tokhir Dadaev, Edward J. Saunders, Paul J. Newcombe, Ezequiel Anokian, Daniel A. Leongamornlert, Mark N. Brook, Clara Cieza-Borrella, Martina Mijuskovic, Sarah Wakerell, Ali Amin Al Olama, Fredrick R. Schumacher, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Chee Goh, Xin Sheng, Zhuo Zhang, Kenneth Muir, Koveela Govindasami, Artitaya Lophatananon & 172 others Victoria L. Stevens, Susan M. Gapstur, Brian D. Carter, Catherine M. Tangen, Phyllis Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne Chambers, Leire Moya, Judith Clements, Lisa Horvath, Wayne Tilley, Gail Risbridger, Henrik Gronberg, Markus Aly, Tobias Nordström, Paul Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L.J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Niclas Hakansson, Catharine West, Alison M. Dunning, Neil Burnet, Lorelei Mucci, Edward Giovannucci, Gerald Andriole, Olivier Cussenot, Géraldine Cancel-Tassin, Stella Koutros, Laura E.Beane Freeman, Karina Dalsgaard Sorensen, Torben Falck Orntoft, Michael Borre, Lovise Maehle, Eli Marie Grindedal, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Tim J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue Ann Ingles, Mariana C. Stern, Barry Rosenstein, Sarah Kerns, Harry Ostrer, Yong Jie Lu, Hong Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. Fitzgerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez-Caamaño, Laura Fachal, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Kathryn L. Penney, Meir Stampfer, Jong Y. Park, Thomas A. Sellers, Hui Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokolorczyk, Jan Lubinski, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weisher, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Razack, Jasmine Lim, Soo Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kulis, Radka Kaneva, Nawaid Usmani, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Sandeep Singhal, Frank Claessens, Steven Joniau, Thomas Van Den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago-Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Monique J. Roobol, Guido Jenster, Ron H.N. Van Schaik, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindstrom, Constance Turman, Jing Ma, David J. Hunter, Elio Riboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loic Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Peter Kraft, Margaret Cook, Matthew L Freedman, Fredrik Wiklund, Stephen J Chanock, Brian E Henderson, Douglas F Easton, Christopher A Haiman, Rosalind A Eeles, David V Conti, Zsofia Kote-Jarai, The PRACTICAL consortium

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number2256
Number of pages19
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Dadaev, T., Saunders, E. J., Newcombe, P. J., Anokian, E., Leongamornlert, D. A., Brook, M. N., ... The PRACTICAL consortium (2018). Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants. Nature Communications, 9(1), [2256]. https://doi.org/10.1038/s41467-018-04109-8
Dadaev, Tokhir ; Saunders, Edward J. ; Newcombe, Paul J. ; Anokian, Ezequiel ; Leongamornlert, Daniel A. ; Brook, Mark N. ; Cieza-Borrella, Clara ; Mijuskovic, Martina ; Wakerell, Sarah ; Olama, Ali Amin Al ; Schumacher, Fredrick R. ; Berndt, Sonja I. ; Benlloch, Sara ; Ahmed, Mahbubl ; Goh, Chee ; Sheng, Xin ; Zhang, Zhuo ; Muir, Kenneth ; Govindasami, Koveela ; Lophatananon, Artitaya ; Stevens, Victoria L. ; Gapstur, Susan M. ; Carter, Brian D. ; Tangen, Catherine M. ; Goodman, Phyllis ; Thompson, Ian M. ; Batra, Jyotsna ; Chambers, Suzanne ; Moya, Leire ; Clements, Judith ; Horvath, Lisa ; Tilley, Wayne ; Risbridger, Gail ; Gronberg, Henrik ; Aly, Markus ; Nordström, Tobias ; Pharoah, Paul ; Pashayan, Nora ; Schleutker, Johanna ; Tammela, Teuvo L.J. ; Sipeky, Csilla ; Auvinen, Anssi ; Albanes, Demetrius ; Weinstein, Stephanie ; Wolk, Alicja ; Hakansson, Niclas ; West, Catharine ; Dunning, Alison M. ; Burnet, Neil ; Mucci, Lorelei ; Giovannucci, Edward ; Andriole, Gerald ; Cussenot, Olivier ; Cancel-Tassin, Géraldine ; Koutros, Stella ; Freeman, Laura E.Beane ; Sorensen, Karina Dalsgaard ; Orntoft, Torben Falck ; Borre, Michael ; Maehle, Lovise ; Grindedal, Eli Marie ; Neal, David E. ; Donovan, Jenny L. ; Hamdy, Freddie C. ; Martin, Richard M. ; Travis, Ruth C. ; Key, Tim J. ; Hamilton, Robert J. ; Fleshner, Neil E. ; Finelli, Antonio ; Ingles, Sue Ann ; Stern, Mariana C. ; Rosenstein, Barry ; Kerns, Sarah ; Ostrer, Harry ; Lu, Yong Jie ; Zhang, Hong Wei ; Feng, Ninghan ; Mao, Xueying ; Guo, Xin ; Wang, Guomin ; Sun, Zan ; Giles, Graham G. ; Southey, Melissa C. ; MacInnis, Robert J. ; Fitzgerald, Liesel M. ; Kibel, Adam S. ; Drake, Bettina F. ; Vega, Ana ; Gómez-Caamaño, Antonio ; Fachal, Laura ; Szulkin, Robert ; Eklund, Martin ; Kogevinas, Manolis ; Llorca, Javier ; Castaño-Vinyals, Gemma ; Penney, Kathryn L. ; Stampfer, Meir ; Park, Jong Y. ; Sellers, Thomas A. ; Lin, Hui Yi ; Stanford, Janet L. ; Cybulski, Cezary ; Wokolorczyk, Dominika ; Lubinski, Jan ; Ostrander, Elaine A. ; Geybels, Milan S. ; Nordestgaard, Børge G. ; Nielsen, Sune F. ; Weisher, Maren ; Bisbjerg, Rasmus ; Røder, Martin Andreas ; Iversen, Peter ; Brenner, Hermann ; Cuk, Katarina ; Holleczek, Bernd ; Maier, Christiane ; Luedeke, Manuel ; Schnoeller, Thomas ; Kim, Jeri ; Logothetis, Christopher J. ; John, Esther M. ; Teixeira, Manuel R. ; Paulo, Paula ; Cardoso, Marta ; Neuhausen, Susan L. ; Steele, Linda ; Ding, Yuan Chun ; De Ruyck, Kim ; De Meerleer, Gert ; Ost, Piet ; Razack, Azad ; Lim, Jasmine ; Teo, Soo Hwang ; Lin, Daniel W. ; Newcomb, Lisa F. ; Lessel, Davor ; Gamulin, Marija ; Kulis, Tomislav ; Kaneva, Radka ; Usmani, Nawaid ; Slavov, Chavdar ; Mitev, Vanio ; Parliament, Matthew ; Singhal, Sandeep ; Claessens, Frank ; Joniau, Steven ; Van Den Broeck, Thomas ; Larkin, Samantha ; Townsend, Paul A. ; Aukim-Hastie, Claire ; Gago-Dominguez, Manuela ; Castelao, Jose Esteban ; Martinez, Maria Elena ; Roobol, Monique J. ; Jenster, Guido ; Van Schaik, Ron H.N. ; Menegaux, Florence ; Truong, Thérèse ; Koudou, Yves Akoli ; Xu, Jianfeng ; Khaw, Kay Tee ; Cannon-Albright, Lisa ; Pandha, Hardev ; Michael, Agnieszka ; Kierzek, Andrzej ; Thibodeau, Stephen N. ; McDonnell, Shannon K. ; Schaid, Daniel J. ; Lindstrom, Sara ; Turman, Constance ; Ma, Jing ; Hunter, David J. ; Riboli, Elio ; Siddiq, Afshan ; Canzian, Federico ; Kolonel, Laurence N. ; Le Marchand, Loic ; Hoover, Robert N. ; Machiela, Mitchell J. ; Kraft, Peter ; Cook, Margaret ; Freedman, Matthew L ; Wiklund, Fredrik ; Chanock, Stephen J ; Henderson, Brian E ; Easton, Douglas F ; Haiman, Christopher A ; Eeles, Rosalind A ; Conti, David V ; Kote-Jarai, Zsofia ; The PRACTICAL consortium. / Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants. In: Nature Communications. 2018 ; Vol. 9, No. 1.
@article{6088135ce6cd4b2da6d71c2fec62c079,
title = "Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants",
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.",
author = "Tokhir Dadaev and Saunders, {Edward J.} and Newcombe, {Paul J.} and Ezequiel Anokian and Leongamornlert, {Daniel A.} and Brook, {Mark N.} and Clara Cieza-Borrella and Martina Mijuskovic and Sarah Wakerell and Olama, {Ali Amin Al} and Schumacher, {Fredrick R.} and Berndt, {Sonja I.} and Sara Benlloch and Mahbubl Ahmed and Chee Goh and Xin Sheng and Zhuo Zhang and Kenneth Muir and Koveela Govindasami and Artitaya Lophatananon and Stevens, {Victoria L.} and Gapstur, {Susan M.} and Carter, {Brian D.} and Tangen, {Catherine M.} and Phyllis Goodman and Thompson, {Ian M.} and Jyotsna Batra and Suzanne Chambers and Leire Moya and Judith Clements and Lisa Horvath and Wayne Tilley and Gail Risbridger and Henrik Gronberg and Markus Aly and Tobias Nordstr{\"o}m and Paul Pharoah and Nora Pashayan and Johanna Schleutker and Tammela, {Teuvo L.J.} and Csilla Sipeky and Anssi Auvinen and Demetrius Albanes and Stephanie Weinstein and Alicja Wolk and Niclas Hakansson and Catharine West and Dunning, {Alison M.} and Neil Burnet and Lorelei Mucci and Edward Giovannucci and Gerald Andriole and Olivier Cussenot and G{\'e}raldine Cancel-Tassin and Stella Koutros and Freeman, {Laura E.Beane} and Sorensen, {Karina Dalsgaard} and Orntoft, {Torben Falck} and Michael Borre and Lovise Maehle and Grindedal, {Eli Marie} and Neal, {David E.} and Donovan, {Jenny L.} and Hamdy, {Freddie C.} and Martin, {Richard M.} and Travis, {Ruth C.} and Key, {Tim J.} and Hamilton, {Robert J.} and Fleshner, {Neil E.} and Antonio Finelli and Ingles, {Sue Ann} and Stern, {Mariana C.} and Barry Rosenstein and Sarah Kerns and Harry Ostrer and Lu, {Yong Jie} and Zhang, {Hong Wei} and Ninghan Feng and Xueying Mao and Xin Guo and Guomin Wang and Zan Sun and Giles, {Graham G.} and Southey, {Melissa C.} and MacInnis, {Robert J.} and Fitzgerald, {Liesel M.} and Kibel, {Adam S.} and Drake, {Bettina F.} and Ana Vega and Antonio G{\'o}mez-Caama{\~n}o and Laura Fachal and Robert Szulkin and Martin Eklund and Manolis Kogevinas and Javier Llorca and Gemma Casta{\~n}o-Vinyals and Penney, {Kathryn L.} and Meir Stampfer and Park, {Jong Y.} and Sellers, {Thomas A.} and Lin, {Hui Yi} and Stanford, {Janet L.} and Cezary Cybulski and Dominika Wokolorczyk and Jan Lubinski and Ostrander, {Elaine A.} and Geybels, {Milan S.} and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune F.} and Maren Weisher and Rasmus Bisbjerg and R{\o}der, {Martin Andreas} and Peter Iversen and Hermann Brenner and Katarina Cuk and Bernd Holleczek and Christiane Maier and Manuel Luedeke and Thomas Schnoeller and Jeri Kim and Logothetis, {Christopher J.} and John, {Esther M.} and Teixeira, {Manuel R.} and Paula Paulo and Marta Cardoso and Neuhausen, {Susan L.} and Linda Steele and Ding, {Yuan Chun} and {De Ruyck}, Kim and {De Meerleer}, Gert and Piet Ost and Azad Razack and Jasmine Lim and Teo, {Soo Hwang} and Lin, {Daniel W.} and Newcomb, {Lisa F.} and Davor Lessel and Marija Gamulin and Tomislav Kulis and Radka Kaneva and Nawaid Usmani and Chavdar Slavov and Vanio Mitev and Matthew Parliament and Sandeep Singhal and Frank Claessens and Steven Joniau and {Van Den Broeck}, Thomas and Samantha Larkin and Townsend, {Paul A.} and Claire Aukim-Hastie and Manuela Gago-Dominguez and Castelao, {Jose Esteban} and Martinez, {Maria Elena} and Roobol, {Monique J.} and Guido Jenster and {Van Schaik}, {Ron H.N.} and Florence Menegaux and Th{\'e}r{\`e}se Truong and Koudou, {Yves Akoli} and Jianfeng Xu and Khaw, {Kay Tee} and Lisa Cannon-Albright and Hardev Pandha and Agnieszka Michael and Andrzej Kierzek and Thibodeau, {Stephen N.} and McDonnell, {Shannon K.} and Schaid, {Daniel J.} and Sara Lindstrom and Constance Turman and Jing Ma and Hunter, {David J.} and Elio Riboli and Afshan Siddiq and Federico Canzian and Kolonel, {Laurence N.} and {Le Marchand}, Loic and Hoover, {Robert N.} and Machiela, {Mitchell J.} and Peter Kraft and Margaret Cook and Freedman, {Matthew L} and Fredrik Wiklund and Chanock, {Stephen J} and Henderson, {Brian E} and Easton, {Douglas F} and Haiman, {Christopher A} and Eeles, {Rosalind A} and Conti, {David V} and Zsofia Kote-Jarai and {The PRACTICAL consortium} and Renea Taylor and Melissa Papargiris",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-04109-8",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
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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, YJ, Zhang, HW, 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, HY, 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, SH, 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, KT, 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, Cook, M, Freedman, ML, Wiklund, F, Chanock, SJ, Henderson, BE, Easton, DF, Haiman, CA, Eeles, RA, Conti, DV, Kote-Jarai, Z & The PRACTICAL consortium 2018, 'Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants' Nature Communications, vol. 9, no. 1, 2256. https://doi.org/10.1038/s41467-018-04109-8

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants. / Dadaev, Tokhir; Saunders, Edward J.; Newcombe, Paul J.; Anokian, Ezequiel; Leongamornlert, Daniel A.; Brook, Mark N.; Cieza-Borrella, Clara; Mijuskovic, Martina; Wakerell, Sarah; Olama, Ali Amin Al; Schumacher, Fredrick R.; Berndt, Sonja I.; Benlloch, Sara; Ahmed, Mahbubl; Goh, Chee; Sheng, Xin; Zhang, Zhuo; Muir, Kenneth; Govindasami, Koveela; Lophatananon, Artitaya; Stevens, Victoria L.; Gapstur, Susan M.; Carter, Brian D.; Tangen, Catherine M.; Goodman, Phyllis; Thompson, Ian M.; Batra, Jyotsna; Chambers, Suzanne; Moya, Leire; Clements, Judith; Horvath, Lisa; Tilley, Wayne; Risbridger, Gail; Gronberg, Henrik; Aly, Markus; Nordström, Tobias; Pharoah, Paul; Pashayan, Nora; Schleutker, Johanna; Tammela, Teuvo L.J.; Sipeky, Csilla; Auvinen, Anssi; Albanes, Demetrius; Weinstein, Stephanie; Wolk, Alicja; Hakansson, Niclas; West, Catharine; Dunning, Alison M.; Burnet, Neil; Mucci, Lorelei; Giovannucci, Edward; Andriole, Gerald; Cussenot, Olivier; Cancel-Tassin, Géraldine; Koutros, Stella; Freeman, Laura E.Beane; Sorensen, Karina Dalsgaard; Orntoft, Torben Falck; Borre, Michael; Maehle, Lovise; Grindedal, Eli Marie; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Martin, Richard M.; Travis, Ruth C.; Key, Tim J.; Hamilton, Robert J.; Fleshner, Neil E.; Finelli, Antonio; Ingles, Sue Ann; Stern, Mariana C.; Rosenstein, Barry; Kerns, Sarah; Ostrer, Harry; Lu, Yong Jie; Zhang, Hong Wei; Feng, Ninghan; Mao, Xueying; Guo, Xin; Wang, Guomin; Sun, Zan; Giles, Graham G.; Southey, Melissa C.; MacInnis, Robert J.; Fitzgerald, Liesel M.; Kibel, Adam S.; Drake, Bettina F.; Vega, Ana; Gómez-Caamaño, Antonio; Fachal, Laura; Szulkin, Robert; Eklund, Martin; Kogevinas, Manolis; Llorca, Javier; Castaño-Vinyals, Gemma; Penney, Kathryn L.; Stampfer, Meir; Park, Jong Y.; Sellers, Thomas A.; Lin, Hui Yi; Stanford, Janet L.; Cybulski, Cezary; Wokolorczyk, Dominika; Lubinski, Jan; Ostrander, Elaine A.; Geybels, Milan S.; Nordestgaard, Børge G.; Nielsen, Sune F.; Weisher, Maren; Bisbjerg, Rasmus; Røder, Martin Andreas; Iversen, Peter; Brenner, Hermann; Cuk, Katarina; Holleczek, Bernd; Maier, Christiane; Luedeke, Manuel; Schnoeller, Thomas; Kim, Jeri; Logothetis, Christopher J.; John, Esther M.; Teixeira, Manuel R.; Paulo, Paula; Cardoso, Marta; Neuhausen, Susan L.; Steele, Linda; Ding, Yuan Chun; De Ruyck, Kim; De Meerleer, Gert; Ost, Piet; Razack, Azad; Lim, Jasmine; Teo, Soo Hwang; Lin, Daniel W.; Newcomb, Lisa F.; Lessel, Davor; Gamulin, Marija; Kulis, Tomislav; Kaneva, Radka; Usmani, Nawaid; Slavov, Chavdar; Mitev, Vanio; Parliament, Matthew; Singhal, Sandeep; Claessens, Frank; Joniau, Steven; Van Den Broeck, Thomas; Larkin, Samantha; Townsend, Paul A.; Aukim-Hastie, Claire; Gago-Dominguez, Manuela; Castelao, Jose Esteban; Martinez, Maria Elena; Roobol, Monique J.; Jenster, Guido; Van Schaik, Ron H.N.; Menegaux, Florence; Truong, Thérèse; Koudou, Yves Akoli; Xu, Jianfeng; Khaw, Kay Tee; Cannon-Albright, Lisa; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Lindstrom, Sara; Turman, Constance; Ma, Jing; Hunter, David J.; Riboli, Elio; Siddiq, Afshan; Canzian, Federico; Kolonel, Laurence N.; Le Marchand, Loic; Hoover, Robert N.; Machiela, Mitchell J.; Kraft, Peter; Cook, Margaret; Freedman, Matthew L; Wiklund, Fredrik; Chanock, Stephen J; Henderson, Brian E; Easton, Douglas F; Haiman, Christopher A; Eeles, Rosalind A; Conti, David V; Kote-Jarai, Zsofia; The PRACTICAL consortium.

In: Nature Communications, Vol. 9, No. 1, 2256, 01.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

AU - Dadaev, Tokhir

AU - Saunders, Edward J.

AU - Newcombe, Paul J.

AU - Anokian, Ezequiel

AU - Leongamornlert, Daniel A.

AU - Brook, Mark N.

AU - Cieza-Borrella, Clara

AU - Mijuskovic, Martina

AU - Wakerell, Sarah

AU - Olama, Ali Amin Al

AU - Schumacher, Fredrick R.

AU - Berndt, Sonja I.

AU - Benlloch, Sara

AU - Ahmed, Mahbubl

AU - Goh, Chee

AU - Sheng, Xin

AU - Zhang, Zhuo

AU - Muir, Kenneth

AU - Govindasami, Koveela

AU - Lophatananon, Artitaya

AU - Stevens, Victoria L.

AU - Gapstur, Susan M.

AU - Carter, Brian D.

AU - Tangen, Catherine M.

AU - Goodman, Phyllis

AU - Thompson, Ian M.

AU - Batra, Jyotsna

AU - Chambers, Suzanne

AU - Moya, Leire

AU - Clements, Judith

AU - Horvath, Lisa

AU - Tilley, Wayne

AU - Risbridger, Gail

AU - Gronberg, Henrik

AU - Aly, Markus

AU - Nordström, Tobias

AU - Pharoah, Paul

AU - Pashayan, Nora

AU - Schleutker, Johanna

AU - Tammela, Teuvo L.J.

AU - Sipeky, Csilla

AU - Auvinen, Anssi

AU - Albanes, Demetrius

AU - Weinstein, Stephanie

AU - Wolk, Alicja

AU - Hakansson, Niclas

AU - West, Catharine

AU - Dunning, Alison M.

AU - Burnet, Neil

AU - Mucci, Lorelei

AU - Giovannucci, Edward

AU - Andriole, Gerald

AU - Cussenot, Olivier

AU - Cancel-Tassin, Géraldine

AU - Koutros, Stella

AU - Freeman, Laura E.Beane

AU - Sorensen, Karina Dalsgaard

AU - Orntoft, Torben Falck

AU - Borre, Michael

AU - Maehle, Lovise

AU - Grindedal, Eli Marie

AU - Neal, David E.

AU - Donovan, Jenny L.

AU - Hamdy, Freddie C.

AU - Martin, Richard M.

AU - Travis, Ruth C.

AU - Key, Tim J.

AU - Hamilton, Robert J.

AU - Fleshner, Neil E.

AU - Finelli, Antonio

AU - Ingles, Sue Ann

AU - Stern, Mariana C.

AU - Rosenstein, Barry

AU - Kerns, Sarah

AU - Ostrer, Harry

AU - Lu, Yong Jie

AU - Zhang, Hong Wei

AU - Feng, Ninghan

AU - Mao, Xueying

AU - Guo, Xin

AU - Wang, Guomin

AU - Sun, Zan

AU - Giles, Graham G.

AU - Southey, Melissa C.

AU - MacInnis, Robert J.

AU - Fitzgerald, Liesel M.

AU - Kibel, Adam S.

AU - Drake, Bettina F.

AU - Vega, Ana

AU - Gómez-Caamaño, Antonio

AU - Fachal, Laura

AU - Szulkin, Robert

AU - Eklund, Martin

AU - Kogevinas, Manolis

AU - Llorca, Javier

AU - Castaño-Vinyals, Gemma

AU - Penney, Kathryn L.

AU - Stampfer, Meir

AU - Park, Jong Y.

AU - Sellers, Thomas A.

AU - Lin, Hui Yi

AU - Stanford, Janet L.

AU - Cybulski, Cezary

AU - Wokolorczyk, Dominika

AU - Lubinski, Jan

AU - Ostrander, Elaine A.

AU - Geybels, Milan S.

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Weisher, Maren

AU - Bisbjerg, Rasmus

AU - Røder, Martin Andreas

AU - Iversen, Peter

AU - Brenner, Hermann

AU - Cuk, Katarina

AU - Holleczek, Bernd

AU - Maier, Christiane

AU - Luedeke, Manuel

AU - Schnoeller, Thomas

AU - Kim, Jeri

AU - Logothetis, Christopher J.

AU - John, Esther M.

AU - Teixeira, Manuel R.

AU - Paulo, Paula

AU - Cardoso, Marta

AU - Neuhausen, Susan L.

AU - Steele, Linda

AU - Ding, Yuan Chun

AU - De Ruyck, Kim

AU - De Meerleer, Gert

AU - Ost, Piet

AU - Razack, Azad

AU - Lim, Jasmine

AU - Teo, Soo Hwang

AU - Lin, Daniel W.

AU - Newcomb, Lisa F.

AU - Lessel, Davor

AU - Gamulin, Marija

AU - Kulis, Tomislav

AU - Kaneva, Radka

AU - Usmani, Nawaid

AU - Slavov, Chavdar

AU - Mitev, Vanio

AU - Parliament, Matthew

AU - Singhal, Sandeep

AU - Claessens, Frank

AU - Joniau, Steven

AU - Van Den Broeck, Thomas

AU - Larkin, Samantha

AU - Townsend, Paul A.

AU - Aukim-Hastie, Claire

AU - Gago-Dominguez, Manuela

AU - Castelao, Jose Esteban

AU - Martinez, Maria Elena

AU - Roobol, Monique J.

AU - Jenster, Guido

AU - Van Schaik, Ron H.N.

AU - Menegaux, Florence

AU - Truong, Thérèse

AU - Koudou, Yves Akoli

AU - Xu, Jianfeng

AU - Khaw, Kay Tee

AU - Cannon-Albright, Lisa

AU - Pandha, Hardev

AU - Michael, Agnieszka

AU - Kierzek, Andrzej

AU - Thibodeau, Stephen N.

AU - McDonnell, Shannon K.

AU - Schaid, Daniel J.

AU - Lindstrom, Sara

AU - Turman, Constance

AU - Ma, Jing

AU - Hunter, David J.

AU - Riboli, Elio

AU - Siddiq, Afshan

AU - Canzian, Federico

AU - Kolonel, Laurence N.

AU - Le Marchand, Loic

AU - Hoover, Robert N.

AU - Machiela, Mitchell J.

AU - Kraft, Peter

AU - Cook, Margaret

AU - Freedman, Matthew L

AU - Wiklund, Fredrik

AU - Chanock, Stephen J

AU - Henderson, Brian E

AU - Easton, Douglas F

AU - Haiman, Christopher A

AU - Eeles, Rosalind A

AU - Conti, David V

AU - Kote-Jarai, Zsofia

AU - The PRACTICAL consortium

AU - Taylor, Renea

AU - Papargiris, Melissa

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048420948&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-04109-8

DO - 10.1038/s41467-018-04109-8

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2256

ER -