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Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Saunders, Edward J 
Dadaev, Tokhir 
Leongamornlert, Daniel A 
Jugurnauth-Little, Sarah 
Tymrakiewicz, Malgorzata 

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.

Description

Keywords

Alleles, Chromosomes, Human, Pair 17, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Homeodomain Proteins, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Factors

Journal Title

PLoS Genet

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

10

Publisher

Public Library of Science (PLoS)
Sponsorship
Medical Research Council (G0900871)
Medical Research Council (G1000143)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Medical Research Council (G0401527)
Cancer Research Uk (None)
Medical Research Council (G0401527/1)