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

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.

SUBMITTER: Amin Al Olama A

PROVIDER: S-EPMC4572072 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Amin Al Olama Ali A Dadaev Tokhir T Hazelett Dennis J DJ Li Qiuyan Q Leongamornlert Daniel D Saunders Edward J EJ Stephens Sarah S Cieza-Borrella Clara C Whitmore Ian I Benlloch Garcia Sara S Giles Graham G GG Southey Melissa C MC Fitzgerald Liesel L Gronberg Henrik H Wiklund Fredrik F Aly Markus M Henderson Brian E BE Schumacher Fredrick F Haiman Christopher A CA Schleutker Johanna J Wahlfors Tiina T Tammela Teuvo L TL Nordestgaard Børge G BG Key Tim J TJ Travis Ruth C RC Neal David E DE Donovan Jenny L JL Hamdy Freddie C FC Pharoah Paul P Pashayan Nora N Khaw Kay-Tee KT Stanford Janet L JL Thibodeau Stephen N SN Mcdonnell Shannon K SK Schaid Daniel J DJ Maier Christiane C Vogel Walther W Luedeke Manuel M Herkommer Kathleen K Kibel Adam S AS Cybulski Cezary C Wokołorczyk Dominika D Kluzniak Wojciech W Cannon-Albright Lisa L Brenner Hermann H Butterbach Katja K Arndt Volker V Park Jong Y JY Sellers Thomas T Lin Hui-Yi HY Slavov Chavdar C Kaneva Radka R Mitev Vanio V Batra Jyotsna J Clements Judith A JA Spurdle Amanda A Teixeira Manuel R MR Paulo Paula P Maia Sofia S Pandha Hardev H Michael Agnieszka A Kierzek Andrzej A Govindasami Koveela K Guy Michelle M Lophatonanon Artitaya A Muir Kenneth K Viñuela Ana A Brown Andrew A AA Freedman Mathew M Conti David V DV Easton Douglas D Coetzee Gerhard A GA Eeles Rosalind A RA Kote-Jarai Zsofia Z

Human molecular genetics 20150529 19

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 va ...[more]

PMID: 26025378

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Project description:Recent genome-wide association studies have identified 78 loci associated with Parkinson's disease susceptibility but the underlying mechanisms remain largely unclear. To identify likely causal variants for disease risk, we fine-mapped these Parkinson's-associated loci using four different fine-mapping methods. We then integrated multi-assay cell type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus single nucleotide polymorphism (SNPs) that disrupt LRRK2 and FCGR2A regulatory elements in microglia, an MBNL2 enhancer in oligodendrocytes, and a DYRK1A enhancer in neurons. This genome-wide functional fine-mapping investigation of Parkinson's disease substantially advances our understanding of the causal mechanisms underlying this complex disease while avoiding focus on spurious, non-causal mechanisms. Together, these results provide a robust, comprehensive list of the likely causal variants, genes and cell-types underlying Parkinson's disease risk as demonstrated by consistently greater enrichment of our fine-mapped SNPs relative to lead GWAS SNPs across independent functional impact annotations. In addition, our approach prioritized an average of 3/85 variants per locus as putatively causal, making downstream experimental studies both more tractable and more likely to yield disease-relevant, actionable results. Large-scale studies comparing individuals with Parkinson's disease to age-matched controls have identified many regions of the genome associated with the disease. However, there is widespread correlation between different parts of the genome, making it difficult to tell which genetic variants cause Parkinson's and which are simply co-inherited with causal variants. We therefore applied a suite of statistical models to identify the most likely causal genetic variants (i.e. fine-mapping). We then linked these genetic variants with epigenomic and gene expression signatures across a wide variety of tissues and cell types to identify how these variants cause disease. Therefore, this study provides a comprehensive and robust list of cellular and molecular mechanisms that may serve as targets in the development of more effective Parkinson's therapeutics.

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

Publications

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

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