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

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 and Kote-Jarai, Z (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.

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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

Item Type: Article
Divisions : Faculty of Health and Medical Sciences
Authors :
NameEmailORCID
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
Date : 1 October 2015
Identification Number : 10.1093/hmg/ddv203
Uncontrolled Keywords : Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Genetics & Heredity, GENOME-WIDE ASSOCIATION, ANDROGEN RECEPTOR, GENE-EXPRESSION, BREAST-CANCER, HNF1B GENE, VARIANTS, NGEP, PREDISPOSITION, TRANSCRIPTOME, METAANALYSIS
Related URLs :
Additional Information : © The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Depositing User : Symplectic Elements
Date Deposited : 06 Jan 2016 16:09
Last Modified : 31 Oct 2017 17:58
URI: http://epubs.surrey.ac.uk/id/eprint/809646

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