title: Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
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.
authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
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authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
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authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
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authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
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authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
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authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
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mesh_terms: D000483:Alleles; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors
chemical_list: C484414:HOXB13 protein, human; D018398:Homeodomain Proteins