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Title: 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;Hunter, David J.;Gapstur, Susan;Chanock, Stephen;Berndt, Sonja I.;Albanes, Demetrius;Andriole, Gerald;Schleutker, Johanna;Weischer, Maren;Nordestgaard, Børge G.;Canzian, Federico;Campa, Daniele;Riboli, Elio;Key, Tim J.;Travis, Ruth C.;Ingles, Sue A.;John, Esther M.;Hayes, Richard B.;Pharoah, Paul;Khaw, Kay-Tee;Stanford, Janet L.;Ostrander, Elaine A.;Signorello, Lisa B.;Thibodeau, Stephen N.;Schaid, Daniel;Maier, Christiane;Kibel, Adam S.;Cybulski, Cezary;Cannon-Albright, Lisa;Brenner, Hermann;Park, Jong Y.;Kaneva, Radka;Batra, Jyotsna;Clements, Judith A.;Teixeira, Manuel R.;Xu, Jianfeng;Mikropoulos, Christos;Goh, Chee;Govindasami, Koveela;Guy, Michelle;Wilkinson, Rosemary A.;Sawyer, Emma J.;Morgan, Angela;Easton, Douglas F.;Muir, Ken;Eeles, Rosalind A.;Kote-Jarai, Zsofia
subject: Biology;Genetics;Cancer genetics
Year: 2014
Publisher: Public Library of Science
Description: 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.
Standard no: Saunders, E. J., T. Dadaev, D. A. Leongamornlert, S. Jugurnauth-Little, M. Tymrakiewicz, F. Wiklund, A. A. Al Olama, 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 10 (2): e1004129. doi:10.1371/journal.pgen.1004129.
Appears in Collections:HSPH Scholarly Articles

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