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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-02-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1004129 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850161476676878336 |
|---|---|
| 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 |
| collection | DOAJ |
| 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 |
| id | doaj-art-ef4e48a676e14b05b1bb979807ceb684 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2014-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-ef4e48a676e14b05b1bb979807ceb6842025-08-20T02:22:49ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-02-01102e100412910.1371/journal.pgen.1004129Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.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-JaraiThe 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.https://doi.org/10.1371/journal.pgen.1004129 |
| spellingShingle | 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. PLoS Genetics |
| title | 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_short | 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 |
| url | https://doi.org/10.1371/journal.pgen.1004129 |
| work_keys_str_mv | AT edwardjsaunders finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT tokhirdadaev finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT danielaleongamornlert finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT sarahjugurnauthlittle finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT malgorzatatymrakiewicz finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT fredrikwiklund finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT aliaminalolama finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT sarabenlloch finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT davideneal finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT freddiechamdy finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT jennyldonovan finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT grahamggiles finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT gianlucaseveri finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT henrikgronberg finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT markusaly finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT christopherahaiman finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT fredrickschumacher finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT brianehenderson finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT saralindstrom finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT peterkraft finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT davidjhunter finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT susangapstur finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT stephenchanock finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT sonjaiberndt finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT demetriusalbanes finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT geraldandriole finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT johannaschleutker finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT marenweischer finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT børgegnordestgaard finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT federicocanzian finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT danielecampa finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT elioriboli finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT timjkey finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT ruthctravis finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT sueaingles finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT esthermjohn finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT richardbhayes finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT paulpharoah finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT kayteekhaw finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT janetlstanford finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT elaineaostrander finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT lisabsignorello finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT stephennthibodeau finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT danielschaid finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT christianemaier finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT adamskibel finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT cezarycybulski finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT lisacannonalbright finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT hermannbrenner finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT jongypark finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT radkakaneva finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT jyotsnabatra finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT judithaclements finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT manuelrteixeira finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT jianfengxu finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT christosmikropoulos finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT cheegoh finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT koveelagovindasami finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT michelleguy finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT rosemaryawilkinson finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT emmajsawyer finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT angelamorgan finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT cogscrukgwasellipsepartofgameoninitiative finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT ukgeneticprostatecancerstudycollaborators finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT ukprotectstudycollaborators finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT practicalconsortium finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT douglasfeaston finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT kenmuir finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT rosalindaeeles finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer AT zsofiakotejarai finemappingthehoxbregiondetectscommonvariantstaggingararecodingalleleevidenceforsyntheticassociationinprostatecancer |