Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.
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ICR Authors
Authors
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
PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium,
Freedman, M
Wiklund, F
Chanock, S
Henderson, BE
Easton, DF
Haiman, CA
Eeles, RA
Conti, DV
Kote-Jarai, Z
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
PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium,
Freedman, M
Wiklund, F
Chanock, S
Henderson, BE
Easton, DF
Haiman, CA
Eeles, RA
Conti, DV
Kote-Jarai, Z
Document Type
Journal Article
Date
2018-06-11
Date Accepted
2018-04-05
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.
Citation
Nature communications, 2018, 9 (1), pp. 2256 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Research Team
Oncogenetics