Article open access publication

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

PLOS Genetics, Public Library of Science (PLoS), ISSN 1553-7390

Volume 10, 2, 2014

DOI:10.1371/journal.pgen.1004129, Dimensions: pub.1042472911, PMC: PMC3923678, PMID: 24550738,

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  1. (1) Institute of Cancer Research, grid.18886.3f
  2. (2) Karolinska Institute, grid.4714.6
  3. (3) University of Cambridge, grid.5335.0
  4. (4) University of Oxford, grid.4991.5
  5. (5) University of Bristol, grid.5337.2
  6. (6) Cancer Council Victoria, grid.3263.4
  7. (7) University of Melbourne, grid.1008.9
  8. (8) University of Southern California, grid.42505.36
  9. (9) Harvard University, grid.38142.3c
  10. (10) American Cancer Society, grid.422418.9
  11. (11) National Institute of Arthritis and Musculoskeletal and Skin Diseases, grid.420086.8
  12. (12) Washington University in St. Louis, grid.4367.6
  13. (13) University of Turku, grid.1374.1
  14. (14) Herlev Hospital, grid.411900.d, Capital Region
  15. (15) German Cancer Research Center, grid.7497.d
  16. (16) Imperial College London, grid.7445.2
  17. (17) Cancer Prevention Institute of California, grid.280669.3
  18. (18) Stanford University, grid.168010.e
  19. (19) New York University Langone Medical Center, grid.240324.3
  20. (20) Fred Hutchinson Cancer Research Center, grid.270240.3
  21. (21) National Human Genome Research Institute, grid.280128.1
  22. (22) International Epidemiology Institute, grid.419344.f
  23. (23) Mayo Clinic, grid.66875.3a
  24. (24) University Hospital Ulm, grid.410712.1
  25. (25) Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
  26. (26) Pomeranian Medical University, grid.107950.a
  27. (27) University of Utah, grid.223827.e
  28. (28) Moffitt Cancer Center, grid.468198.a
  29. (29) Medical University of Sofia, grid.410563.5
  30. (30) Queensland University of Technology, grid.1024.7
  31. (31) University of Porto, grid.5808.5
  32. (32) Wake Forest University, grid.241167.7
  33. (33) University of Warwick, grid.7372.1

Description

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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Times Cited: 30

Field Citation Ratio (FCR): 3.43

Relative Citation ratio (RCR): 0.83

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