Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

Saunders EJ, Dadaev T, Leongamornlert DA, Jugurnauth-Little S, Tymrakiewicz M, Wiklund F, Al Olama AA, Benlloch S, Neal DE, Hamdy FC, Donovan JL, Giles GG, Severi G, Gronberg H, Aly M, Haiman CA, Schumacher F, Henderson BE, Lindstrom S, Kraft P, Hunter DJ, Gapstur S, Chanock S, Berndt SI, Albanes D, Andriole G, Schleutker J, Weischer M, Nordestgaard BG, Canzian F, Campa D, Riboli E, Key TJ, Travis RC, Ingles SA, John EM, Hayes RB, Pharoah P, Khaw KT, Stanford JL, Ostrander EA, Signorello LB, Thibodeau SN, Schaid D, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park JY, Kaneva R, Batra J, Clements JA, Teixeira MR, Xu J, Mikropoulos C, Goh C, Govindasami K, Guy M, Wilkinson RA, Sawyer EJ, Morgan A, Initiative C-CG-E, Collaborators UKGPCS, Collaborators UKPS, Consortium P, Easton DF, Muir K, Eeles RA, Kote-Jarai Z (2014) Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer. PLoS Genet 10:e1004129

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.