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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 :
AuthorsEmailORCID
Al Olama, AAUNSPECIFIEDUNSPECIFIED
Dadaev, TUNSPECIFIEDUNSPECIFIED
Hazelett, DJUNSPECIFIEDUNSPECIFIED
Li, QUNSPECIFIEDUNSPECIFIED
Leongamornlert, DUNSPECIFIEDUNSPECIFIED
Saunders, EJUNSPECIFIEDUNSPECIFIED
Stephens, SUNSPECIFIEDUNSPECIFIED
Cieza-Borrella, CUNSPECIFIEDUNSPECIFIED
Whitmore, IUNSPECIFIEDUNSPECIFIED
Garcia, SBUNSPECIFIEDUNSPECIFIED
Giles, GGUNSPECIFIEDUNSPECIFIED
Southey, MCUNSPECIFIEDUNSPECIFIED
Fitzgerald, LUNSPECIFIEDUNSPECIFIED
Gronberg, HUNSPECIFIEDUNSPECIFIED
Wiklund, FUNSPECIFIEDUNSPECIFIED
Aly, MUNSPECIFIEDUNSPECIFIED
Henderson, BEUNSPECIFIEDUNSPECIFIED
Schumacher, FUNSPECIFIEDUNSPECIFIED
Haiman, CAUNSPECIFIEDUNSPECIFIED
Schleutker, JUNSPECIFIEDUNSPECIFIED
Wahlfors, TUNSPECIFIEDUNSPECIFIED
Tammela, TLUNSPECIFIEDUNSPECIFIED
Nordestgaard, BGUNSPECIFIEDUNSPECIFIED
Key, TJUNSPECIFIEDUNSPECIFIED
Travis, RCUNSPECIFIEDUNSPECIFIED
Neal, DEUNSPECIFIEDUNSPECIFIED
Donovan, JLUNSPECIFIEDUNSPECIFIED
Hamdy, FCUNSPECIFIEDUNSPECIFIED
Pharoah, PUNSPECIFIEDUNSPECIFIED
Pashayan, NUNSPECIFIEDUNSPECIFIED
Khaw, K-TUNSPECIFIEDUNSPECIFIED
Stanford, JLUNSPECIFIEDUNSPECIFIED
Thibodeau, SNUNSPECIFIEDUNSPECIFIED
Mcdonnell, SKUNSPECIFIEDUNSPECIFIED
Schaid, DJUNSPECIFIEDUNSPECIFIED
Maier, CUNSPECIFIEDUNSPECIFIED
Vogel, WUNSPECIFIEDUNSPECIFIED
Luedeke, MUNSPECIFIEDUNSPECIFIED
Herkommer, KUNSPECIFIEDUNSPECIFIED
Kibel, ASUNSPECIFIEDUNSPECIFIED
Cybulski, CUNSPECIFIEDUNSPECIFIED
Wokolorczyk, DUNSPECIFIEDUNSPECIFIED
Kluzniak, WUNSPECIFIEDUNSPECIFIED
Cannon-Albright, LUNSPECIFIEDUNSPECIFIED
Brenner, HUNSPECIFIEDUNSPECIFIED
Butterbach, KUNSPECIFIEDUNSPECIFIED
Arndt, VUNSPECIFIEDUNSPECIFIED
Park, JYUNSPECIFIEDUNSPECIFIED
Sellers, TUNSPECIFIEDUNSPECIFIED
Lin, H-YUNSPECIFIEDUNSPECIFIED
Slavov, CUNSPECIFIEDUNSPECIFIED
Kaneva, RUNSPECIFIEDUNSPECIFIED
Mitev, VUNSPECIFIEDUNSPECIFIED
Batra, JUNSPECIFIEDUNSPECIFIED
Clements, JAUNSPECIFIEDUNSPECIFIED
Spurdle, AUNSPECIFIEDUNSPECIFIED
Teixeira, MRUNSPECIFIEDUNSPECIFIED
Paulo, PUNSPECIFIEDUNSPECIFIED
Maia, SUNSPECIFIEDUNSPECIFIED
Pandha, HUNSPECIFIEDUNSPECIFIED
Michael, AUNSPECIFIEDUNSPECIFIED
Kierzek, AUNSPECIFIEDUNSPECIFIED
Govindasami, KUNSPECIFIEDUNSPECIFIED
Guy, MUNSPECIFIEDUNSPECIFIED
Lophatonanon, AUNSPECIFIEDUNSPECIFIED
Muir, KUNSPECIFIEDUNSPECIFIED
Vinuela, AUNSPECIFIEDUNSPECIFIED
Brown, AAUNSPECIFIEDUNSPECIFIED
Freedman, MUNSPECIFIEDUNSPECIFIED
Conti, DVUNSPECIFIEDUNSPECIFIED
Easton, DUNSPECIFIEDUNSPECIFIED
Coetzee, GAUNSPECIFIEDUNSPECIFIED
Eeles, RAUNSPECIFIEDUNSPECIFIED
Kote-Jarai, ZUNSPECIFIEDUNSPECIFIED
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 : 06 Jan 2016 16:09
URI: http://epubs.surrey.ac.uk/id/eprint/809646

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