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.
| Original language | English |
|---|---|
| Article number | e1004129 |
| Number of pages | 8 |
| Journal | PLoS Genetics |
| Volume | 10 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2014 |
| Externally published | Yes |
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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; COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative; The UK Genetic Prostate Cancer Study Collaborators; The UK ProtecT Study Collaborators; The PRACTICAL consortium; Easton, Douglas F.; Muir, Ken; Eeles, Rosalind A.; Kote-Jarai, Zsofia.
In: PLoS Genetics, Vol. 10, No. 2, e1004129, 02.2014.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele
T2 - Evidence for Synthetic Association in Prostate Cancer
AU - Saunders, Edward J.
AU - Dadaev, Tokhir
AU - Leongamornlert, Daniel A.
AU - Jugurnauth-Little, Sarah
AU - Tymrakiewicz, Malgorzata
AU - Wiklund, Fredrik
AU - Al Olama, Ali Amin
AU - Benlloch, Sara
AU - Neal, David E.
AU - Hamdy, Freddie C.
AU - Donovan, Jenny L.
AU - Giles, Graham G.
AU - Severi, Gianluca
AU - Gronberg, Henrik
AU - Aly, Markus
AU - Haiman, Christopher A.
AU - Schumacher, Fredrick
AU - Henderson, Brian E.
AU - Lindstrom, Sara
AU - Kraft, Peter
AU - Hunter, David J.
AU - Gapstur, Susan
AU - Chanock, Stephen
AU - Berndt, Sonja I.
AU - Albanes, Demetrius
AU - Andriole, Gerald
AU - Schleutker, Johanna
AU - Weischer, Maren
AU - Nordestgaard, Børge G.
AU - Canzian, Federico
AU - Campa, Daniele
AU - Riboli, Elio
AU - Key, Tim J.
AU - Travis, Ruth C.
AU - Ingles, Sue A.
AU - John, Esther M.
AU - Hayes, Richard B.
AU - Pharoah, Paul
AU - Khaw, Kay Tee
AU - Stanford, Janet L.
AU - Ostrander, Elaine A.
AU - Signorello, Lisa B.
AU - Thibodeau, Stephen N.
AU - Schaid, Daniel
AU - Maier, Christiane
AU - Kibel, Adam S.
AU - Cybulski, Cezary
AU - Cannon-Albright, Lisa
AU - Brenner, Hermann
AU - Park, Jong Y.
AU - Kaneva, Radka
AU - Batra, Jyotsna
AU - Clements, Judith A.
AU - Teixeira, Manuel R.
AU - Xu, Jianfeng
AU - Mikropoulos, Christos
AU - Goh, Chee
AU - Govindasami, Koveela
AU - Guy, Michelle
AU - Wilkinson, Rosemary A.
AU - Sawyer, Emma J.
AU - Morgan, Angela
AU - COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative
AU - The UK Genetic Prostate Cancer Study Collaborators
AU - The UK ProtecT Study Collaborators
AU - The PRACTICAL consortium
AU - Easton, Douglas F.
AU - Muir, Ken
AU - Eeles, Rosalind A.
AU - Kote-Jarai, Zsofia
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84901741339&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1004129
DO - 10.1371/journal.pgen.1004129
M3 - Article
C2 - 24550738
AN - SCOPUS:84901741339
VL - 10
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 2
M1 - e1004129
ER -