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

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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. et al.
(2014) Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer. PLoS Genetics, Volume 10 (Number 2). Article number e1004129. doi:10.1371/journal.pgen.1004129 ISSN 1553-7390.

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Official URL: http://dx.doi.org/10.1371/journal.pgen.1004129

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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.

Item Type: Journal Article
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Prostate -- Cancer -- Susceptibility, Prostate -- Cancer -- Genetic aspects
Journal or Publication Title: PLoS Genetics
Publisher: Public Library of Science
ISSN: 1553-7390
Official Date: February 2014
Dates:
DateEvent
February 2014Published
Volume: Volume 10
Number: Number 2
Article Number: Article number e1004129
DOI: 10.1371/journal.pgen.1004129
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 26 December 2015
Date of first compliant Open Access: 26 December 2015

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