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 = 2.62x10(-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. ; Saunders, Edward J Dadaev, Tokhir Leongamornlert, Daniel A Jugurnauth-Little, Sarah Tymrakiewicz, Malgorzata Wiklund, Fredrik Al Olama, Ali Amin Benlloch, Sara Neal, David E Hamdy, Freddie C Donovan, Jenny L Giles, Graham G Severi, Gianluca Gronberg, Henrik Aly, Markus Haiman, Christopher A Schumacher, Fredrick Henderson, Brian E Lindstrom, Sara Kraft, Peter Hunter, David J Gapstur, Susan Chanock, Stephen Berndt, Sonja I Albanes, Demetrius Andriole, Gerald Schleutker, Johanna Weischer, Maren Nordestgaard, Borge G Canzian, Federico Campa, Daniele Riboli, Elio Key, Tim J Travis, Ruth C Ingles, Sue A John, Esther M Hayes, Richard B Pharoah, Paul Khaw, Kay-Tee Stanford, Janet L Ostrander, Elaine A Signorello, Lisa B Thibodeau, Stephen N Schaid, Daniel Maier, Christiane Kibel, Adam S Cybulski, Cezary Cannon-Albright, Lisa Brenner, Hermann Park, Jong Y Kaneva, Radka Batra, Jyotsna Clements, Judith A Teixeira, Manuel R Xu, Jianfeng Mikropoulos, Christos Goh, Chee Govindasami, Koveela Guy, Michelle Wilkinson, Rosemary A Sawyer, Emma J Morgan, Angela COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative UK Genetic Prostate Cancer Study Collaborators UK ProtecT Study Collaborators PRACTICAL Consortium Easton, Douglas F Muir, Ken Eeles, Rosalind A Kote-Jarai, Zsofia C5047/A15007/Cancer Research UK/United Kingdom C8197/A10123/Cancer Research UK/United Kingdom C8197/A10865/Cancer Research UK/United Kingdom Research Support, Non-U.S. Gov't United States PLoS genetics PLoS Genet. 2014 Feb 13;10(2):e1004129. doi: 10.1371/journal.pgen.1004129. eCollection 2014 Feb.