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Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
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(2015) Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. Human molecular genetics, 24 (19). pp. 5589-5602. doi:10.1093/hmg/ddv203 ISSN 0964-6906.
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Official URL: https://doi.org/10.1093/hmg/ddv203
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, whilst the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed 2 association signals in Europeans that had been previously reported only in East-Asian GWAS.Based on statistical evidence and 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 approximately 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.
Item Type: | Journal Article | ||||||||
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Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Population, Evidence & Technologies (PET) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Prostate -- Cancer, Cancer -- Susceptibility | ||||||||
Journal or Publication Title: | Human molecular genetics | ||||||||
Publisher: | Oxford University Press | ||||||||
ISSN: | 0964-6906 | ||||||||
Official Date: | 1 October 2015 | ||||||||
Dates: |
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Volume: | 24 | ||||||||
Number: | 19 | ||||||||
Page Range: | pp. 5589-5602 | ||||||||
DOI: | 10.1093/hmg/ddv203 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Date of first compliant deposit: | 29 December 2015 | ||||||||
Date of first compliant Open Access: | 29 December 2015 | ||||||||
Funder: | Seventh Framework Programme (European Commission) (FP7), Cancer Research UK (CRUK), National Institutes of Health (U.S.) (NIH) | ||||||||
Grant number: | 223175 (FP7), C5047/A7357 (CRUK), C1287/A10118 (CRUK), C5047/A3354 (CRUK), C5047/A10692 (CRUK), C16913/A6135 (CRUK), 1 U19 CA 148537-01 (NIH) | ||||||||
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