Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. (29th May 2015)

• Record Type: Journal Article
• Authors: Amin Al Olama, Ali; Dadaev, Tokhir; Hazelett, Dennis J.; Li, Qiuyan; Leongamornlert, Daniel; Saunders, Edward J.; Stephens, Sarah; Cieza-Borrella, Clara; Whitmore, Ian; Benlloch Garcia, Sara; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schumacher, Fredrick; Haiman, Christopher A.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; Mcdonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokołorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Park, Jong Y.; Sellers, Thomas; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Clements, Judith A.; Spurdle, Amanda; Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Govindasami, Koveela; Guy, Michelle; Lophatonanon, Artitaya; Muir, Kenneth; Viñuela, Ana; Brown, Andrew A.; Freedman, Mathew; Conti, David V.; Easton, Douglas; Coetzee, Gerhard A.; Eeles, Rosalind A.; Kote-Jarai, Zsofia;
• Other Names: author non-byline.; Easton Douglas F. author non-byline.; Pharoah Paul author non-byline.; Michailidou Kyriaki author non-byline.; Bolla Manjeet K. author non-byline.; Wang Qin author non-byline.; Berchuck Andrew author non-byline.; Eeles Rosalind A. author non-byline.; Easton Douglas F. author non-byline.; Kote-Jarai Zsofia author non-byline.; Al Olama Ali Amin author non-byline.; Benlloch Sara author non-byline.; Chenevix-Trench Georgia author non-byline.; Antoniou Antonis author non-byline.; McGuffog Lesley author non-byline.; Couch Fergus author non-byline.; Offit Ken author non-byline.; Dennis Joe author non-byline.; Dunning Alison M. author non-byline.; Lee Andrew author non-byline.; Dicks Ed author non-byline.; Luccarini Craig author non-byline.; Benitez Javier author non-byline.; Gonzalez-Neira Anna author non-byline.; Simard Jacques author non-byline.; Tessier Daniel C. author non-byline.; Bacot Francois author non-byline.; Vincent Daniel author non-byline.; LaBoissière Sylvie author non-byline.; Robidoux Frederic author non-byline.; Bojesen Stig E. author non-byline.; Nielsen Sune F. author non-byline.; Nordestgaard Borge G. author non-byline.; Cunningham Julie M. author non-byline.; Windebank Sharon A. author non-byline.; Hilker Christopher A. author non-byline.; Meyer Jeffrey author non-byline.;
• Is Part Of: Human molecular genetics. Volume 24:Number 19(2015:Oct. 01)
• Page Start: 5589
• Page End: 5602
• Publication Date: 2015-05-29
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddv203
• Languages: English
• ISSNs: 0964-6906

Abstract

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.