PLoS Genetics (Feb 2014)

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,
  • COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative,
  • UK Genetic Prostate Cancer Study Collaborators,
  • UK ProtecT Study Collaborators,
  • PRACTICAL Consortium,
  • Douglas F Easton,
  • Ken Muir,
  • Rosalind A Eeles,
  • Zsofia Kote-Jarai

DOI
https://doi.org/10.1371/journal.pgen.1004129
Journal volume & issue
Vol. 10, no. 2
p. e1004129

Abstract

Read online

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.