The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10-14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Autori interni: | |
Autori: | Edward J. Saunders;Tokhir Dadaev; Daniel A. Leongamornlert; Sarah Jugurnauth-Little; Malgorzata Tymrakiewicz; Fredrik Wiklund; Ali Amin Al Olama; Sara Benlloch; David E. Neal; Freddie C. Hamdy; Jenny L. Donovan;Graham G. Giles; Gianluca Severi; Henrik Gronberg;Markus Aly;Christopher A. Haiman;Fredrick Schumacher; Brian E. Henderson; Sara Lindstrom; Peter Kraft;David J. Hunter; Susan Gapstur; Stephen Chanock; Sonja I. Berndt; Demetrius Albanes; Gerald Andriole; Johanna Schleutker; Maren Weischer; Borge G. Nordestgaard; Federico Canzian; Daniele Campa; Elio Riboli; Tim J. Key;Ruth C. Travis; Sue A. Ingles; Esther M. John; Richard B. Hayes; Paul Pharoah; Kay-Tee Khaw; Janet L. Stanford;Elaine A. Ostrander;Lisa B. Signorello;Stephen N. Thibodeau;Daniel Schaid;Christiane Maier;Adam S. Kibel;Cezary Cybulski;Lisa Cannon-Albright;Hermann Brenner;Jong Y. Park;Radka Kaneva;Jyotsna Batra;Judith A. Clements;Manuel R. Teixeira;Jianfeng Xu;Christos Mikropoulos;Chee Goh;Koveela Govindasami;Michelle Guy;Rosemary A. Wilkinson;Emma J. Sawyer;Angela Morgan; COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative; The UK Genetic Prostate Cancer Study Collaborators;The UK ProtecT Study Collaborators;The PRACTICAL Consortium;Douglas F. Easton;Ken Muir;Rosalind A. Eeles;Zsofia Kote-Jarai |
Titolo: | Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer |
Anno del prodotto: | 2014 |
Abstract: | The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10-14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility. |
Digital Object Identifier (DOI): | 10.1371/journal.pgen.1004129 |
Appare nelle tipologie: | 1.1 Articolo in rivista |
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Saunders_HOXB_PLOSGEN_2014.pdf | Versione finale editoriale | ![]() | Open AccessVisualizza/Apri |