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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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cam.issuedOnline2014-02-13
dc.contributor.authorSaunders, Edward J
dc.contributor.authorDadaev, Tokhir
dc.contributor.authorLeongamornlert, Daniel A
dc.contributor.authorJugurnauth-Little, Sarah
dc.contributor.authorTymrakiewicz, Malgorzata
dc.contributor.authorWiklund, Fredrik
dc.contributor.authorAl Olama, Ali Amin
dc.contributor.authorBenlloch, Sara
dc.contributor.authorNeal, David E
dc.contributor.authorHamdy, Freddie C
dc.contributor.authorDonovan, Jenny L
dc.contributor.authorGiles, Graham G
dc.contributor.authorSeveri, Gianluca
dc.contributor.authorGronberg, Henrik
dc.contributor.authorAly, Markus
dc.contributor.authorHaiman, Christopher A
dc.contributor.authorSchumacher, Fredrick
dc.contributor.authorHenderson, Brian E
dc.contributor.authorLindstrom, Sara
dc.contributor.authorKraft, Peter
dc.contributor.authorHunter, David J
dc.contributor.authorGapstur, Susan
dc.contributor.authorChanock, Stephen
dc.contributor.authorBerndt, Sonja I
dc.contributor.authorAlbanes, Demetrius
dc.contributor.authorAndriole, Gerald
dc.contributor.authorSchleutker, Johanna
dc.contributor.authorWeischer, Maren
dc.contributor.authorNordestgaard, Børge G
dc.contributor.authorCanzian, Federico
dc.contributor.authorCampa, Daniele
dc.contributor.authorRiboli, Elio
dc.contributor.authorKey, Tim J
dc.contributor.authorTravis, Ruth C
dc.contributor.authorIngles, Sue A
dc.contributor.authorJohn, Esther M
dc.contributor.authorHayes, Richard B
dc.contributor.authorPharoah, Paul
dc.contributor.authorKhaw, Kay-Tee
dc.contributor.authorStanford, Janet L
dc.contributor.authorOstrander, Elaine A
dc.contributor.authorSignorello, Lisa B
dc.contributor.authorThibodeau, Stephen N
dc.contributor.authorSchaid, Daniel
dc.contributor.authorMaier, Christiane
dc.contributor.authorKibel, Adam S
dc.contributor.authorCybulski, Cezary
dc.contributor.authorCannon-Albright, Lisa
dc.contributor.authorBrenner, Hermann
dc.contributor.authorPark, Jong Y
dc.contributor.authorKaneva, Radka
dc.contributor.authorBatra, Jyotsna
dc.contributor.authorClements, Judith A
dc.contributor.authorTeixeira, Manuel R
dc.contributor.authorXu, Jianfeng
dc.contributor.authorMikropoulos, Christos
dc.contributor.authorGoh, Chee
dc.contributor.authorGovindasami, Koveela
dc.contributor.authorGuy, Michelle
dc.contributor.authorWilkinson, Rosemary A
dc.contributor.authorSawyer, Emma J
dc.contributor.authorMorgan, Angela
dc.contributor.authorCOGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative
dc.contributor.authorUK Genetic Prostate Cancer Study Collaborators
dc.contributor.authorUK ProtecT Study Collaborators
dc.contributor.authorPRACTICAL Consortium
dc.contributor.authorEaston, Douglas F
dc.contributor.authorMuir, Ken
dc.contributor.authorEeles, Rosalind A
dc.contributor.authorKote-Jarai, Zsofia
dc.contributor.orcidPharoah, Paul [0000-0001-8494-732X]
dc.contributor.orcidKhaw, Kay-Tee [0000-0002-8802-2903]
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.date.accessioned2018-09-10T22:17:47Z
dc.date.available2018-09-10T22:17:47Z
dc.date.issued2014-02
dc.description.abstractThe 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.
dc.format.mediumElectronic-eCollection
dc.identifier.doi10.17863/CAM.27451
dc.identifier.eissn1553-7404
dc.identifier.issn1553-7390
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280087
dc.languageeng
dc.language.isoeng
dc.publisherPublic Library of Science (PLoS)
dc.publisher.urlhttp://dx.doi.org/10.1371/journal.pgen.1004129
dc.rightsAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAlleles
dc.subjectChromosomes, Human, Pair 17
dc.subjectGenetic Predisposition to Disease
dc.subjectGenetic Variation
dc.subjectGenome-Wide Association Study
dc.subjectGenotype
dc.subjectHomeodomain Proteins
dc.subjectHumans
dc.subjectMale
dc.subjectPolymorphism, Single Nucleotide
dc.subjectProstatic Neoplasms
dc.subjectRisk Factors
dc.titleFine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
dc.typeArticle
dcterms.dateAccepted2013-12-06
prism.issueIdentifier2
prism.publicationDate2014
prism.publicationNamePLoS Genet
prism.startingPagee1004129
prism.volume10
pubs.funder-project-idMedical Research Council (G0900871)
pubs.funder-project-idMedical Research Council (G1000143)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idMedical Research Council (G0401527)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idMedical Research Council (G0401527/1)
rioxxterms.licenseref.startdate2014-02-13
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1371/journal.pgen.1004129

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