EJ Saunders, T Dadaev, DA Leongamornlert, S Jugurnauth-Little, M Tymrakiewicz, F Wiklund, AA Al Olama, S Benlloch, DE Neal, FC Hamdy, JL Donovan, GG Giles, G Severi, H Gronberg, M Aly, CA Haiman, F Schumacher, BE Henderson, S Lindstrom, P Kraft, DJ Hunter, S Gapstur, S Chanock, SI Berndt, D Albanes, G Andriole, J Schleutker, M Weischer, BG Nordestgaard, F Canzian, D Campa, E Riboli, TJ Key, RC Travis, SA Ingles, EM John, RB Hayes, P Pharoah, K-T Khaw, JL Stanford, EA Ostrander, LB Signorello, SN Thibodeau, D Schaid, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, H Brenner, JY Park, R Kaneva, J Batra, JA Clements, MR Teixeira, J Xu, C Mikropoulos, C Goh, K Govindasami, M Guy, RA Wilkinson, EJ Sawyer, A Morgan, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, PRACTICAL Consortium, DF Easton, K Muir, RA Eeles, Z Kote-Jarai
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.