학술논문
Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer.
Document Type
Article
Author
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
Source
Subject
*HUMAN genetic variation
*HAPLOTYPES
*GENE mapping
*PROSTATE cancer
*DISEASE susceptibility
*
*
*
*
Language
ISSN
1553-7390
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. [ABSTRACT FROM AUTHOR]