TY - JOUR
T1 - Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
AU - PRACTICAL Consortium
AU - COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative
AU - The Australian Prostrate Cancer BioResource
AU - The UK Genetic Prostate Cancer Study Collaborators
AU - The UK ProtecT Study Collaborators
AU - Amin Al Olama, Ali
AU - Dadaev, Tokhir
AU - Hazelett, Dennis J
AU - Li, Qiuyan
AU - Leongamornlert, Daniel
AU - Saunders, Edward J
AU - Stephens, Sarah
AU - Cieza-Borrella, Clara
AU - Whitmore, Ian
AU - Benlloch Garcia, Sara
AU - Giles, Graham G
AU - Southey, Melissa C
AU - Fitzgerald, Liesel
AU - Gronberg, Henrik
AU - Wiklund, Fredrik
AU - Aly, Markus
AU - Henderson, Brian E.
AU - Schumacher, Fredrick
AU - Haiman, Christopher A
AU - Schleutker, Johanna
AU - Wahlfors, Tiina
AU - Tammela, Teuvo L
AU - Nordestgaard, Børge G
AU - Key, Tim J
AU - Travis, Ruth C
AU - Neal, David E
AU - Donovan, Jenny L
AU - Hamdy, Freddie C
AU - Pharoah, Paul
AU - Pashayan, Nora
AU - Khaw, Kay-Tee
AU - Stanford, Janet L
AU - Thibodeau, Stephen N
AU - Mcdonnell, Shannon K
AU - Schaid, Daniel J
AU - Maier, Christiane
AU - Vogel, Walther
AU - Luedeke, Manuel
AU - Herkommer, Kathleen
AU - Kibel, Adam S
AU - Cybulski, Cezary
AU - Wokołorczyk, Dominika
AU - Kluzniak, Wojciech
AU - Cannon-Albright, Lisa
AU - Brenner, Hermann
AU - Butterbach, Katja
AU - Arndt, Volker
AU - Park, Jong Y
AU - Sellers, Thomas
AU - Lin, Hui-Yi
AU - Slavov, Chavdar
AU - Kaneva, Radka
AU - Mitev, Vanio
AU - Batra, Jyotsna
AU - Clements, Judith A.
AU - Spurdle, Amanda
AU - Teixeira, Manuel R.
AU - Paulo, Paula
AU - Maia, Sofia
AU - Pandha, Hardev
AU - Michael, Agnieszka
AU - Kierzek, Andrzej M.
AU - Govindasami, Koveela
AU - Guy, Michelle
AU - Lophatonanon, Artitaya
AU - Muir, Kenneth
AU - Viñuela, Ana
AU - Brown, Andrew A
AU - Freedman, Mathew
AU - Conti, David V
AU - Easton, Douglas F.
AU - Coetzee, Gerhard A.
AU - Eeles, Rosalind A.
AU - Kote-Jarai, Zsofia
N1 - © The Author 2015. Published by Oxford University Press.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
KW - Chromosome Mapping/methods
KW - European Continental Ancestry Group/genetics
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Linkage Disequilibrium
KW - Male
KW - Polymorphism, Single Nucleotide
KW - Prostatic Neoplasms/genetics
U2 - 10.1093/hmg/ddv203
DO - 10.1093/hmg/ddv203
M3 - Article
C2 - 26025378
VL - 24
SP - 5589
EP - 5602
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 19
ER -