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

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 usin...

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Autores principales:	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, Børge 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, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, PRACTICAL Consortium, Douglas F Easton, Ken Muir, Rosalind A Eeles, Zsofia Kote-Jarai
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/ef4e48a676e14b05b1bb979807ceb684
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spelling	oai:doaj.org-article:ef4e48a676e14b05b1bb979807ceb6842021-11-18T06:21:12ZFine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.1553-73901553-740410.1371/journal.pgen.1004129https://doaj.org/article/ef4e48a676e14b05b1bb979807ceb6842014-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24550738/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The 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.Edward J SaundersTokhir DadaevDaniel A LeongamornlertSarah Jugurnauth-LittleMalgorzata TymrakiewiczFredrik WiklundAli Amin Al OlamaSara BenllochDavid E NealFreddie C HamdyJenny L DonovanGraham G GilesGianluca SeveriHenrik GronbergMarkus AlyChristopher A HaimanFredrick SchumacherBrian E HendersonSara LindstromPeter KraftDavid J HunterSusan GapsturStephen ChanockSonja I BerndtDemetrius AlbanesGerald AndrioleJohanna SchleutkerMaren WeischerBørge G NordestgaardFederico CanzianDaniele CampaElio RiboliTim J KeyRuth C TravisSue A InglesEsther M JohnRichard B HayesPaul PharoahKay-Tee KhawJanet L StanfordElaine A OstranderLisa B SignorelloStephen N ThibodeauDaniel SchaidChristiane MaierAdam S KibelCezary CybulskiLisa Cannon-AlbrightHermann BrennerJong Y ParkRadka KanevaJyotsna BatraJudith A ClementsManuel R TeixeiraJianfeng XuChristos MikropoulosChee GohKoveela GovindasamiMichelle GuyRosemary A WilkinsonEmma J SawyerAngela MorganCOGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) InitiativeUK Genetic Prostate Cancer Study CollaboratorsUK ProtecT Study CollaboratorsPRACTICAL ConsortiumDouglas F EastonKen MuirRosalind A EelesZsofia Kote-JaraiPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 10, Iss 2, p e1004129 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 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 Børge 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 UK Genetic Prostate Cancer Study Collaborators UK ProtecT Study Collaborators PRACTICAL Consortium Douglas F Easton Ken Muir Rosalind A Eeles Zsofia Kote-Jarai Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
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.
format	article
author	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 Børge 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 UK Genetic Prostate Cancer Study Collaborators UK ProtecT Study Collaborators PRACTICAL Consortium Douglas F Easton Ken Muir Rosalind A Eeles Zsofia Kote-Jarai
author_facet	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 Børge 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 UK Genetic Prostate Cancer Study Collaborators UK ProtecT Study Collaborators PRACTICAL Consortium Douglas F Easton Ken Muir Rosalind A Eeles Zsofia Kote-Jarai
author_sort	Edward J Saunders
title	Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
title_short	Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
title_full	Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
title_fullStr	Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
title_full_unstemmed	Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
title_sort	fine-mapping the hoxb region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/ef4e48a676e14b05b1bb979807ceb684
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Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

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