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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Saunders, Edward J 
Newcombe, Paul J 
Anokian, Ezequiel 
Leongamornlert, Daniel A  ORCID logo  https://orcid.org/0000-0002-3486-3168

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.

Description

Keywords

Algorithms, Bayes Theorem, Black People, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Molecular Sequence Annotation, Multivariate Analysis, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Risk, White People

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

9

Publisher

Springer Science and Business Media LLC
Sponsorship
MRC (1185)
MRC (unknown)
Cancer Research UK (16565)
Medical Research Council (G0401527)
Medical Research Council (G1000143)
Medical Research Council (MR/N003284/1)
Medical Research Council (G0401527/1)