Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

PRACTICAL Consortium, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative, The Australian Prostrate Cancer BioResource, The UK Genetic Prostate Cancer Study Collaborators, The UK ProtecT Study Collaborators, Andrew A Brown

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Abstract

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

Original languageEnglish
Pages (from-to)5589-5602
Number of pages14
JournalHuman Molecular Genetics
Volume24
Issue number19
Early online date29 May 2015
DOIs
Publication statusPublished - 1 Oct 2015

Keywords

  • Chromosome Mapping/methods
  • European Continental Ancestry Group/genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms/genetics

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    PRACTICAL Consortium, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative, The Australian Prostrate Cancer BioResource, The UK Genetic Prostate Cancer Study Collaborators, The UK ProtecT Study Collaborators, & Brown, A. A. (2015). Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. Human Molecular Genetics, 24(19), 5589-5602. https://doi.org/10.1093/hmg/ddv203