Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

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; Douglas F. Easton; Ken Muir; Rosalind A. Eeles; Zsofia 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

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 KraftDavid 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, Douglas F. Easton, Ken Muir, Rosalind A. Eeles, Zsofia Kote-Jarai

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28 Scopus citations

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 (US)
Article number	e1004129
Journal	PLoS genetics
Volume	10
Issue number	2
DOIs	https://doi.org/10.1371/journal.pgen.1004129
State	Published - Feb 2014

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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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 genetics, 10(2), Article e1004129. https://doi.org/10.1371/journal.pgen.1004129

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 genetics, vol. 10, no. 2, e1004129. https://doi.org/10.1371/journal.pgen.1004129

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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 = 2.62×10-14). 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.",

author = "Saunders, {Edward J.} and Tokhir Dadaev and Leongamornlert, {Daniel A.} and Sarah Jugurnauth-Little and Malgorzata Tymrakiewicz and Fredrik Wiklund and {Al Olama}, {Ali Amin} and Sara Benlloch and Neal, {David E.} and Hamdy, {Freddie C.} and Donovan, {Jenny L.} and Giles, {Graham G.} and Gianluca Severi and Henrik Gronberg and Markus Aly and Haiman, {Christopher A.} and Fredrick Schumacher and Henderson, {Brian E.} and Sara Lindstrom and Peter Kraft and Hunter, {David J.} and Susan Gapstur and Stephen Chanock and Berndt, {Sonja I.} and Demetrius Albanes and Gerald Andriole and Johanna Schleutker and Maren Weischer and Nordestgaard, {B{\o}rge G.} and Federico Canzian and Daniele Campa and Elio Riboli and Key, {Tim J.} and Travis, {Ruth C.} and Ingles, {Sue A.} and John, {Esther M.} and Hayes, {Richard B.} and Paul Pharoah and Khaw, {Kay Tee} and Stanford, {Janet L.} and Ostrander, {Elaine A.} and Signorello, {Lisa B.} and Thibodeau, {Stephen N.} and Daniel Schaid and Christiane Maier and Kibel, {Adam S.} and Cezary Cybulski and Lisa Cannon-Albright and Hermann Brenner and Park, {Jong Y.} and Radka Kaneva and Jyotsna Batra and Clements, {Judith A.} and Teixeira, {Manuel R.} and Jianfeng Xu and Christos Mikropoulos and Chee Goh and Koveela Govindasami and Michelle Guy and Wilkinson, {Rosemary A.} and Sawyer, {Emma J.} and Angela Morgan and Easton, {Douglas F.} and Ken Muir and Eeles, {Rosalind A.} and Zsofia Kote-Jarai",

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month = feb,

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

language = "English (US)",

volume = "10",

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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 - Easton, Douglas F.

AU - Muir, Ken

AU - Eeles, Rosalind A.

AU - Kote-Jarai, Zsofia

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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.

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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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