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 & 46 others 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 J 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

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 languageEnglish (US)
Article numbere1004129
JournalPLoS Genetics
Volume10
Issue number2
DOIs
StatePublished - Feb 2014

Fingerprint

tagging
prostatic neoplasms
cancer
Prostatic Neoplasms
allele
Alleles
alleles
Single Nucleotide Polymorphism
genotyping
gene
penetrance
Genetic Loci
Penetrance
Genome-Wide Association Study
genetic variation
relative risk
Haplotypes
Genes
haplotypes
genes

ASJC Scopus subject areas

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

Cite this

Saunders, E. J., Dadaev, T., Leongamornlert, D. A., Jugurnauth-Little, S., Tymrakiewicz, M., Wiklund, F., ... 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), [e1004129]. https://doi.org/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. / 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 J; 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; 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 journalArticle

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, DJ, 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
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 J ; 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 ; Easton, Douglas F. ; Muir, Ken ; Eeles, Rosalind A. ; Kote-Jarai, Zsofia. / Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele : Evidence for Synthetic Association in Prostate Cancer. In: PLoS Genetics. 2014 ; Vol. 10, No. 2.
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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.",
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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

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AU - Weischer, Maren

AU - Nordestgaard, Børge G.

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AU - Hayes, Richard B.

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AU - Thibodeau, Stephen N

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AU - Maier, Christiane

AU - Kibel, Adam S.

AU - Cybulski, Cezary

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AU - Brenner, Hermann

AU - Park, Jong Y.

AU - Kaneva, Radka

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AU - Clements, Judith A.

AU - Teixeira, Manuel R.

AU - Xu, Jianfeng

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AU - Wilkinson, Rosemary A.

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