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; COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative

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, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative

Institut for Klinisk Medicin

28 Citationer (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.

Originalsprog	Engelsk
Artikelnummer	e1004129
Tidsskrift	P L o S Genetics
Vol/bind	10
Udgave nummer	2
Sider (fra-til)	1-8
Antal sider	8
ISSN	1553-7390
DOI	https://doi.org/10.1371/journal.pgen.1004129
Status	Udgivet - feb. 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., ... COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative (2014). Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer. P L o S Genetics, 10(2), 1-8. [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, K-T, Stanford, JL, Ostrander, EA, Signorello, LB, Thibodeau, SN, Schaid, D, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, JY & COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative 2014, 'Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer', P L o S Genetics, bind 10, nr. 2, e1004129, s. 1-8. https://doi.org/10.1371/journal.pgen.1004129

@article{617c305b48174e66abcf02bb56e177ae,

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.",

keywords = "Alleles, Chromosomes, Human, Pair 17, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Homeodomain Proteins, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Factors",

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 Kay-Tee Khaw 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 {COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative}",

year = "2014",

month = feb,

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

language = "English",

volume = "10",

pages = "1--8",

journal = "P L o S Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "2",

}

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 - COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative

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.

KW - Alleles

KW - Chromosomes, Human, Pair 17

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genotype

KW - Homeodomain Proteins

KW - Humans

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Prostatic Neoplasms

KW - Risk Factors

U2 - 10.1371/journal.pgen.1004129

DO - 10.1371/journal.pgen.1004129

M3 - Journal article

C2 - 24550738

SN - 1553-7390

VL - 10

SP - 1

EP - 8

JO - P L o S Genetics

JF - P L o S Genetics

IS - 2

M1 - e1004129

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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