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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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(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
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Official URL: http://dx.doi.org/10.1371/journal.pgen.1004129
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 | ||||
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| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School |
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| 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: |
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| Date of first compliant deposit: | 26 December 2015 | ||||
| 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 |
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