Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

Saunders, Edward J.; Tokhir, Dadaev; Leongamornlert, Daniel A.; Sarah Jugurnauth Little,; Malgorzata, Tymrakiewicz; Fredrik, Wiklund; Ali Amin Al Olama,; Sara, Benlloch; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Giles, Graham G.; Gianluca, Severi; Henrik, Gronberg; Markus, Aly; Haiman, Christopher A.; Fredrick, Schumacher; Henderson, Brian E.; Sara, Lindstrom; Peter, Kraft; Hunter, David J.; Susan, Gapstur; Stephen, Chanock; Berndt, Sonja I.; Demetrius, Albanes; Gerald, Andriole; Johanna, Schleutker; Maren, Weischer; Nordestgaard, Borge G.; Federico, Canzian; Campa, Daniele; Elio, Riboli; Key, Tim J.; Travis, Ruth C.; Ingles, Sue A.; John, Esther M.; Hayes, Richard B.; Paul, Pharoah; Kay Tee Khaw,; Stanford, Janet L.; Ostrander, Elaine A.; Signorello, Lisa B.; Thibodeau, Stephen N.; Daniel, Schaid; Christiane, Maier; Kibel, Adam S.; Cezary, Cybulski; Lisa Cannon Albright,; Hermann, Brenner; Park, Jong Y.; Radka, Kaneva; Jyotsna, Batra; Clements, Judith A.; Teixeira, Manuel R.; Jianfeng, Xu; Christos, Mikropoulos; Chee, Goh; Koveela, Govindasami; Michelle, Guy; Wilkinson, Rosemary A.; Sawyer, Emma J.; Angela, Morgan; COGS CRUK GWAS ELLIPSE Initiative,; The UK Genetic Prostate Cancer Study Collaborators,; The UK ProtecT Study Collaborators,; The PRACTICAL Consortium,; Easton, Douglas F.; Ken, Muir; Eeles, Rosalind A.; Zsofia Kote Jarai,

doi:10.1371/journal.pgen.1004129

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.

Autori interni:	Edward J. Saunders Tokhir Dadaev Daniel A. Leongamornlert Sarah Jugurnauth Little Malgorzata Tymrakiewicz Fredrik Wiklund Ali Amin Al Olama Sara Benlloch David E. Neal Freddie C. Hamdy Jenny L. Donovan Graham G. Giles Gianluca Severi Henrik Gronberg Markus Aly Christopher A. Haiman Fredrick Schumacher Brian E. Henderson Sara Lindstrom Peter Kraft David J. Hunter Susan Gapstur Stephen Chanock Sonja I. Berndt Demetrius Albanes Gerald Andriole Johanna Schleutker Maren Weischer Borge G. Nordestgaard Federico Canzian CAMPA, DANIELE Elio Riboli Tim J. Key Ruth C. Travis Sue A. Ingles Esther M. John Richard B. Hayes Paul Pharoah Kay Tee Khaw Janet L. Stanford Elaine A. Ostrander Lisa B. Signorello Stephen N. Thibodeau Daniel Schaid Christiane Maier Adam S. Kibel Cezary Cybulski Lisa Cannon Albright Hermann Brenner Jong Y. Park Radka Kaneva Jyotsna Batra Judith A. Clements Manuel R. Teixeira Jianfeng Xu Christos Mikropoulos Chee Goh Koveela Govindasami Michelle Guy Rosemary A. Wilkinson Emma J. Sawyer Angela Morgan COGS CRUK GWAS ELLIPSE Initiative The UK Genetic Prostate Cancer Study Collaborators The UK ProtecT Study Collaborators The PRACTICAL Consortium Douglas F. Easton Ken Muir Rosalind A. Eeles Zsofia Kote Jarai mostra contributor esterni nascondi contributor esterni
Autori:	Edward J. Saunders;Tokhir Dadaev; Daniel A. Leongamornlert; Sarah Jugurnauth-Little; Malgorzata Tymrakiewicz; Fredrik Wiklund; Ali Amin Al Olama; Sara Benlloch; David E. Neal; Freddie C. Hamdy; Jenny L. Donovan;Graham G. Giles; Gianluca Severi; Henrik Gronberg;Markus Aly;Christopher A. Haiman;Fredrick Schumacher; Brian E. Henderson; Sara Lindstrom; Peter Kraft;David J. Hunter; Susan Gapstur; Stephen Chanock; Sonja I. Berndt; Demetrius Albanes; Gerald Andriole; Johanna Schleutker; Maren Weischer; Borge G. Nordestgaard; Federico Canzian; Daniele Campa; Elio Riboli; Tim J. Key;Ruth C. Travis; Sue A. Ingles; Esther M. John; Richard B. Hayes; Paul Pharoah; Kay-Tee Khaw; Janet L. Stanford;Elaine A. Ostrander;Lisa B. Signorello;Stephen N. Thibodeau;Daniel Schaid;Christiane Maier;Adam S. Kibel;Cezary Cybulski;Lisa Cannon-Albright;Hermann Brenner;Jong Y. Park;Radka Kaneva;Jyotsna Batra;Judith A. Clements;Manuel R. Teixeira;Jianfeng Xu;Christos Mikropoulos;Chee Goh;Koveela Govindasami;Michelle Guy;Rosemary A. Wilkinson;Emma J. Sawyer;Angela Morgan; COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative; The UK Genetic Prostate Cancer Study Collaborators;The UK ProtecT Study Collaborators;The PRACTICAL Consortium;Douglas F. Easton;Ken Muir;Rosalind A. Eeles;Zsofia Kote-Jarai
Titolo:	Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer
Anno del prodotto:	2014
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.
Digital Object Identifier (DOI):	10.1371/journal.pgen.1004129
Appare nelle tipologie:	1.1 Articolo in rivista

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