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

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 (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.

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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.

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ID Code: 77730
Item Type: Journal Article
Refereed: Yes
Keywords: Fine genome mapping, HOXB Region, Rare Coding Allele, Synthetic Association, Prostate Cancer
DOI: 10.1371/journal.pgen.1004129
ISSN: 1553-7404
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Genetics (111203)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Statement: This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Deposited On: 15 Oct 2014 22:31
Last Modified: 17 Oct 2014 00:27

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