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

Lookup NU author(s): Dr Ana ViñuelaORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author 2015. Published by Oxford University Press. All rights reserved. Genome-wide association studies (GWAS) have identified numerouscommon 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 variationwas observed at 39 regions; 35 of which are nowdescribed 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-AsianGWAS. 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 nowexplain ~38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reportedGWAS 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.


Publication metadata

Author(s): Al Olama AA, Dadaev T, Hazelett DJ, Li Q, Leongamornlert D, Saunders EJ, Stephens S, Cieza-Borrella C, Whitmore I, Garcia SB, Giles GG, Southey MC, Fitzgerald L, Gronberg H, Wiklund F, Aly M, Henderson BE, Schumacher F, Haiman CA, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw K-T, Stanford JL, Thibodeau SN, Mcdonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright L, Brenner H, Butterbach K, Arndt V, Park JY, Sellers T, Lin H-Y, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, Govindasami K, Guy M, Lophatonanon A, Muir K, Vinuela A, Brown AA, Freedman M, Conti DV, Easton D, Coetzee GA, Eeles RA, Kote-Jarai Z

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2015

Volume: 24

Issue: 19

Pages: 5589-5602

Print publication date: 01/10/2015

Online publication date: 29/05/2015

Acceptance date: 27/05/2015

Date deposited: 29/06/2020

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: https://doi.org/10.1093/hmg/ddv203

DOI: 10.1093/hmg/ddv203

PubMed id: 26025378


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Funding

Funder referenceFunder name
1 U19 CA 148537-01
223175
C1287/A10118
C5047/A10692
C5047/A7357
C16913/A6135
C5047/A3354

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