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

E J Saunders; T Dadaev; D A Leongamornlert; S Jugurnauth-Little; M Tymrakiewicz; F Wiklund; A A Al Olama; S Benlloch; D E Neal; F C Hamdy; J L Donovan; G G Giles; G Severi; H Gronberg; M Aly; C A Haiman; F Schumacher; B E Henderson; S Lindstrom; P Kraft; D J Hunter; S Gapstur; S Chanock; S I Berndt; D Albanes; G Andriole; J Schleutker; M Weischer; B G Nordestgaard; F Canzian; D Campa; E Riboli; T J Key; R C Travis; S A Ingles; E M John; R B Hayes; P Pharoah; K T Khaw; J L Stanford; E A Ostrander; L B Signorello; S N Thibodeau; D Schaid; C Maier; A S Kibel; C Cybulski; L Cannon-Albright; H Brenner; J Y Park; R Kaneva; J Batra; J A Clements; M R Teixeira; J Xu; C Mikropoulos; C Goh; K Govindasami; M Guy; R A Wilkinson; E J Sawyer; A Morgan; D F Easton; K Muir; R A Eeles; Z Kote-Jarai

doi:10.1371/journal.pgen.1004129

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

E J Saunders, T Dadaev, D A Leongamornlert, S Jugurnauth-Little, M Tymrakiewicz, F Wiklund, A A Al Olama, S Benlloch, D E Neal, F C Hamdy, J L Donovan, G G Giles, G Severi, H Gronberg, M Aly, C A Haiman, F Schumacher, B E Henderson, S Lindstrom, P KraftD J Hunter, S Gapstur, S Chanock, S I Berndt, D Albanes, G Andriole, J Schleutker, M Weischer, B G Nordestgaard, F Canzian, D Campa, E Riboli, T J Key, R C Travis, S A Ingles, E M John, R B Hayes, P Pharoah, K T Khaw, J L Stanford, E A Ostrander, L B Signorello, S N Thibodeau, D Schaid, C Maier, A S Kibel, C Cybulski, L Cannon-Albright, H Brenner, J Y Park, R Kaneva, J Batra, J A Clements, M R Teixeira, J Xu, C Mikropoulos, C Goh, K Govindasami, M Guy, R A Wilkinson, E J Sawyer, A Morgan, D F Easton, K Muir, R A Eeles, Z Kote-Jarai

Research output: Contribution to journal › Article › peer-review

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 = 2.62x10(-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
Journal	PLoS Genet
Volume	10
Issue number	2
DOIs	https://doi.org/10.1371/journal.pgen.1004129
Publication status	Published - 2014

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Saunders, E. J., Dadaev, T., Leongamornlert, D. A., Jugurnauth-Little, S., Tymrakiewicz, M., Wiklund, F., Al Olama, A. A., Benlloch, S., Neal, D. E., Hamdy, F. C., Donovan, J. L., Giles, G. G., Severi, G., Gronberg, H., Aly, M., Haiman, C. A., Schumacher, F., Henderson, B. E., Lindstrom, S., ... Kote-Jarai, Z. (2014). Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer. PLoS Genet, 10(2). https://doi.org/10.1371/journal.pgen.1004129

@article{ef8b4860438440a09f5fe1cb2f75a351,

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

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 = 2.62x10(-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.",

author = "Saunders, {E J} and T Dadaev and Leongamornlert, {D A} and S Jugurnauth-Little and M Tymrakiewicz and F Wiklund and {Al Olama}, {A A} and S Benlloch and Neal, {D E} and Hamdy, {F C} and Donovan, {J L} and Giles, {G G} and G Severi and H Gronberg and M Aly and Haiman, {C A} and F Schumacher and Henderson, {B E} and S Lindstrom and P Kraft and Hunter, {D J} and S Gapstur and S Chanock and Berndt, {S I} and D Albanes and G Andriole and J Schleutker and M Weischer and Nordestgaard, {B G} and F Canzian and D Campa and E Riboli and Key, {T J} and Travis, {R C} and Ingles, {S A} and John, {E M} and Hayes, {R B} and P Pharoah and Khaw, {K T} and Stanford, {J L} and Ostrander, {E A} and Signorello, {L B} and Thibodeau, {S N} and D Schaid and C Maier and Kibel, {A S} and C Cybulski and L Cannon-Albright and H Brenner and Park, {J Y} and R Kaneva and J Batra and Clements, {J A} and Teixeira, {M R} and J Xu and C Mikropoulos and C Goh and K Govindasami and M Guy and Wilkinson, {R A} and Sawyer, {E J} and A Morgan and Easton, {D F} and K Muir and Eeles, {R A} and Z Kote-Jarai",

note = "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, Borge 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 UK Genetic Prostate Cancer Study Collaborators UK ProtecT Study Collaborators PRACTICAL Consortium Easton, Douglas F Muir, Ken Eeles, Rosalind A Kote-Jarai, Zsofia C5047/A15007/Cancer Research UK/United Kingdom C8197/A10123/Cancer Research UK/United Kingdom C8197/A10865/Cancer Research UK/United Kingdom Research Support, Non-U.S. Gov't United States PLoS genetics PLoS Genet. 2014 Feb 13;10(2):e1004129. doi: 10.1371/journal.pgen.1004129. eCollection 2014 Feb.",

year = "2014",

doi = "10.1371/journal.pgen.1004129",

language = "English",

volume = "10",

journal = "PLoS Genet",

issn = "1553-7404",

publisher = "Public Library of Science",

number = "2",

}

Saunders, EJ, Dadaev, T, Leongamornlert, DA, Jugurnauth-Little, S, Tymrakiewicz, M, Wiklund, F, Al Olama, AA, Benlloch, S, Neal, DE, Hamdy, FC, Donovan, JL, Giles, GG, Severi, G, Gronberg, H, Aly, M, Haiman, CA, Schumacher, F, Henderson, BE, Lindstrom, S, Kraft, P, Hunter, DJ, Gapstur, S, Chanock, S, Berndt, SI, Albanes, D, Andriole, G, Schleutker, J, Weischer, M, Nordestgaard, BG, Canzian, F, Campa, D, Riboli, E, Key, TJ, Travis, RC, Ingles, SA, John, EM, Hayes, RB, Pharoah, P, Khaw, KT, Stanford, JL, Ostrander, EA, Signorello, LB, Thibodeau, SN, Schaid, D, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, JY, Kaneva, R, Batra, J, Clements, JA, Teixeira, MR, Xu, J, Mikropoulos, C, Goh, C, Govindasami, K, Guy, M, Wilkinson, RA, Sawyer, EJ, Morgan, A, Easton, DF, Muir, K, Eeles, RA & Kote-Jarai, Z 2014, 'Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer', PLoS Genet, vol. 10, no. 2. https://doi.org/10.1371/journal.pgen.1004129

TY - JOUR

T1 - Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer

AU - Saunders, E J

AU - Dadaev, T

AU - Leongamornlert, D A

AU - Jugurnauth-Little, S

AU - Tymrakiewicz, M

AU - Wiklund, F

AU - Al Olama, A A

AU - Benlloch, S

AU - Neal, D E

AU - Hamdy, F C

AU - Donovan, J L

AU - Giles, G G

AU - Severi, G

AU - Gronberg, H

AU - Aly, M

AU - Haiman, C A

AU - Schumacher, F

AU - Henderson, B E

AU - Lindstrom, S

AU - Kraft, P

AU - Hunter, D J

AU - Gapstur, S

AU - Chanock, S

AU - Berndt, S I

AU - Albanes, D

AU - Andriole, G

AU - Schleutker, J

AU - Weischer, M

AU - Nordestgaard, B G

AU - Canzian, F

AU - Campa, D

AU - Riboli, E

AU - Key, T J

AU - Travis, R C

AU - Ingles, S A

AU - John, E M

AU - Hayes, R B

AU - Pharoah, P

AU - Khaw, K T

AU - Stanford, J L

AU - Ostrander, E A

AU - Signorello, L B

AU - Thibodeau, S N

AU - Schaid, D

AU - Maier, C

AU - Kibel, A S

AU - Cybulski, C

AU - Cannon-Albright, L

AU - Brenner, H

AU - Park, J Y

AU - Kaneva, R

AU - Batra, J

AU - Clements, J A

AU - Teixeira, M R

AU - Xu, J

AU - Mikropoulos, C

AU - Goh, C

AU - Govindasami, K

AU - Guy, M

AU - Wilkinson, R A

AU - Sawyer, E J

AU - Morgan, A

AU - Easton, D F

AU - Muir, K

AU - Eeles, R A

AU - Kote-Jarai, Z

N1 - 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, Borge 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 UK Genetic Prostate Cancer Study Collaborators UK ProtecT Study Collaborators PRACTICAL Consortium Easton, Douglas F Muir, Ken Eeles, Rosalind A Kote-Jarai, Zsofia C5047/A15007/Cancer Research UK/United Kingdom C8197/A10123/Cancer Research UK/United Kingdom C8197/A10865/Cancer Research UK/United Kingdom Research Support, Non-U.S. Gov't United States PLoS genetics PLoS Genet. 2014 Feb 13;10(2):e1004129. doi: 10.1371/journal.pgen.1004129. eCollection 2014 Feb.

PY - 2014

Y1 - 2014

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 = 2.62x10(-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 = 2.62x10(-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.

U2 - 10.1371/journal.pgen.1004129

DO - 10.1371/journal.pgen.1004129

M3 - Article

SN - 1553-7404

VL - 10

JO - PLoS Genet

JF - PLoS Genet

IS - 2

ER -

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

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