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

Authors
  • 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
  • And 50 more
Type
Published Article
Journal
PLoS Genetics
Publisher
Public Library of Science
Publication Date
Feb 01, 2014
Volume
10
Issue
2
Identifiers
DOI: 10.1371/journal.pgen.1004129
PMID: 24550738
Source
Medline
License
Unknown

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.

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