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

Dadaev, T; Saunders, EJ; Newcombe, PJ; Anokian, E; Leongamornlert, DA; Brook, MN; Cieza-Borrella, C; Mijuskovic, M; Wakerell, S; Olama, AAA; et al. 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; Freedman, M; Wiklund, F; Chanock, S; Henderson, BE; Easton, DF; Haiman, CA; Eeles, RA; Conti, DV; Kote-Jarai, Z (2018) Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants. Nature Communications, 9 (1). ISSN 2041-1723 https://doi.org/10.1038/s41467-018-04109-8
SGUL Authors: Cieza-Borrella, Clara Isabel

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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.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2018
Keywords: MD Multidisciplinary
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Nature Communications
ISSN: 2041-1723
Language: en
Dates:
DateEvent
December 2018Published
11 June 2018Published Online
5 April 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
URI: https://openaccess.sgul.ac.uk/id/eprint/111860
Publisher's version: https://doi.org/10.1038/s41467-018-04109-8

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