Journal Article

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

Vega, Ana, Hamilton, Robert J., Cybulski, Cezary, Geybels, Milan S., Weisher, Maren, Mitev, Vanio, Aukim-Hastie, Claire, Sun, Zan, Razack, Azad, Cardoso, Marta, Steele, Linda, Stern, Mariana C., FitzGerald, Liesel M., Cannon-Albright, Lisa, Travis, Ruth C., Kibel, Adam S., Khaw, Kay-Tee, Teixeira, Manuel R., Nordström, Tobias, Goodman, Phyllis, Risbridger, Gail, Andriole, Gerald, Hamdy, Freddie C., Teo, Soo-Hwang, Benlloch, Sara, Van den Broeck, Thomas, De Ruyck, Kim, Wolk, Alicja, Kerns, Sarah, Schleutker, Johanna, Donovan, Jenny L., Ahmed, Mahbubl, Kraft, Peter, Zhang, Zhuo, Maehle, Lovise, Gapstur, Susan M., Drake, Bettina F., Orntoft, Torben Falck, Bisbjerg, Rasmus, Parliament, Matthew, Sheng, Xin, Feng, Ninghan, Rosenstein, Barry, Iversen, Peter, Berndt, Sonja I., Giles, Graham G., Wokolorczyk, Dominika, Thibodeau, Stephen N., Canzian, Federico, Gamulin, Marija, Kierzek, Andrzej, Zhang, Hong-Wei, Wang, Guomin, Fachal, Laura, Park, Jong Y., Stanford, Janet L., Freeman, Laura E. Beane, Kaneva, Radka, Koutros, Stella, Logothetis, Christopher J., Conti, David V., Ostrander, Elaine A., McDonnell, Shannon K.

2018

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/43 / 631/67/589/466 / 692/308/2056 / Algorithms / Annotations / Bayes Theorem / Bayesian analysis / Binding sites / Black People - genetics / Chromosome Mapping / Genetic Predisposition to Disease / Genome-Wide Association Study / Health risk assessment / Health risks / Humanities and Social Sciences / Humans / Life Sciences / Loci / Male / Mapping / Meta-analysis / Molecular Sequence Annotation / multidisciplinary / Multivariate Analysis / Polymorphism, Single Nucleotide / Prostate cancer / Prostatic Neoplasms - genetics / Quantitative Trait Loci / Risk / Science / Science (multidisciplinary) / White People - genetics