Abstract

We report a prostate cancer genome-wide association follow-on study. We discovered four variants associated with susceptibility to prostate cancer in several European populations: rs10934853[A] (OR = 1.12, P = 2.9 × 10−10) on 3q21.3; two moderately correlated (r2 = 0.07) variants, rs16902094[G] (OR = 1.21, P = 6.2 × 10−15) and rs445114[T] (OR = 1.14, P = 4.7 × 10−10), on 8q24.21; and rs8102476[C] (OR = 1.12, P = 1.6 × 10−11) on 19q13.2. We also refined a previous association signal on 11q13 with the SNP rs11228565[A] (OR = 1.23, P = 6.7 × 10−12). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, we estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39, 631–637 (2007).

  2. 2.

    et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat. Genet. 39, 638–644 (2007).

  3. 3.

    et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007).

  4. 4.

    et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat. Genet. 40, 316–321 (2008).

  5. 5.

    et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).

  6. 6.

    et al. Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer. Nat. Genet. 40, 281–283 (2008).

  7. 7.

    et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645–649 (2007).

  8. 8.

    et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

  9. 9.

    et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).

  10. 10.

    et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat. Genet. 39, 984–988 (2007).

  11. 11.

    et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat. Genet. 39, 989–994 (2007).

  12. 12.

    et al. A common genetic risk factor for colorectal and prostate cancer. Nat. Genet. 39, 954–956 (2007).

  13. 13.

    et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).

  14. 14.

    et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J. Natl. Cancer Inst. 100, 962–966 (2008).

  15. 15.

    et al. Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. J. Natl. Cancer Inst. 99, 1836–1844 (2007).

  16. 16.

    et al. Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium. Cancer Epidemiol. Biomarkers Prev. 17, 2052–2061 (2008); erratum 17, 2901 (2008).

  17. 17.

    et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat. Genet. 41, 221–227 (2009).

  18. 18.

    et al. Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12. Nat. Genet. 40, 1153–1155 (2008).

  19. 19.

    et al. Sequence variants at 22q13 are associated with prostate cancer risk. Cancer Res. 69, 10–15 (2009).

  20. 20.

    et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).

  21. 21.

    et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008).

  22. 22.

    et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

  23. 23.

    & Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann. Hum. Genet. 51, 227–233 (1987).

  24. 24.

    & Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

  25. 25.

    et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med. 358, 2355–2365 (2008).

  26. 26.

    et al. Evaluating and improving power in whole-genome association studies using fixed marker sets. Nat. Genet. 38, 663–667 (2006).

  27. 27.

    Testing untyped alleles (TUNA)-applications to genome-wide association studies. Genet. Epidemiol. 30, 718–727 (2006).

  28. 28.

    , , & Leveraging the HapMap correlation structure in association studies. Am. J. Hum. Genet. 80, 683–691 (2007).

  29. 29.

    et al. Cumulative association of five genetic variants with prostate cancer. N. Engl. J. Med. 358, 910–919 (2008).

  30. 30.

    et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

Download references

Acknowledgements

We thank the individuals who participated in the study and whose contribution made this work possible. This project was funded in part by contract number 202059 (PROMARK) from the Seventh Framework Program of the European Union to deCODE Genetics (T.R. and L.A.K.), in part by FP7-MC-IAPP Grant agreement no. 218071 (CancerGene) to deCODE Genetics, in part by a V Foundation award and US Department of Veterans Affairs grants to J.R.S., and in part by Academy of Finland, Sigrid Juselius Foundation, Finnish Cancer Organisations and the Competitive Research Funding of the Pirkanmaa Hospital District, Tampere University Hospital, to J.S.

Author information

Author notes

    • Julius Gudmundsson
    •  & Patrick Sulem

    These authors contributed equally to this work.

Affiliations

  1. deCODE Genetics, Reykjavik, Iceland.

    • Julius Gudmundsson
    • , Patrick Sulem
    • , Daniel F Gudbjartsson
    • , Thorarinn Blondal
    • , Arnaldur Gylfason
    • , Droplaug N Magnusdottir
    • , Gudbjorg Orlygsdottir
    • , Margret Jakobsdottir
    • , Simon N Stacey
    • , Asgeir Sigurdsson
    • , Carlo Zanon
    • , Michael L Frigge
    • , Kristleifur Kristjansson
    • , Jeffrey R Gulcher
    • , Augustine Kong
    • , Unnur Thorsteinsdottir
    • , Thorunn Rafnar
    •  & Kari Stefansson
  2. Department of Pathology, Landspitali–University Hospital, Reykjavik, Iceland.

    • Bjarni A Agnarsson
    • , Kristrun R Benediktsdottir
    •  & Rosa B Barkardottir
  3. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Bjarni A Agnarsson
    • , Kristrun R Benediktsdottir
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  4. Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • Tiina Wahlfors
    •  & Johanna Schleutker
  5. Department of Urology, Tampere University Hospital, University of Tampere, Tampere, Finland.

    • Teuvo Tammela
  6. Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Joan P Breyer
    • , Kate M McReynolds
    • , Kevin M Bradley
    •  & Jeffrey R Smith
  7. Health Science Institute of Aragon, Zaragoza, Spain.

    • Berta Saez
    • , Javier Godino
    •  & Jose I Mayordomo
  8. Nanotechnology Institute of Aragon, Zaragoza, Spain.

    • Berta Saez
    •  & Jose I Mayordomo
  9. Division of Radiation Oncology, Lozano Blesa University Hospital, University of Zaragoza, Zaragoza, Spain.

    • Sebastian Navarrete
    •  & Fernando Fuertes
  10. Division of Medical Oncology, Reina Sofia Hospital, Tudela, Spain.

    • Laura Murillo
  11. Division of Medical Oncology, Ernest Lluch Hospital, Calatayud, Spain.

    • Eduardo Polo
  12. Comprehensive Cancer Center East, Nijmegen, The Netherlands.

    • Katja K Aben
    •  & Lambertus A Kiemeney
  13. Department of Epidemiology, Biostatistics & Health Technology Assessment Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Katja K Aben
  14. Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

    • Inge M van Oort
    •  & Lambertus A Kiemeney
  15. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Brian K Suarez
  16. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    • Brian T Helfand
    • , Donghui Kan
    •  & William J Catalona
  17. Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.

    • Carlo Zanon
  18. Department of Urology, Landspitali–University Hospital, Reykjavik, Iceland.

    • Gudmundur V Einarsson
    •  & Eirikur Jonsson
  19. Division of Medical Oncology, University Hospital, University of Zaragoza, Zaragoza, Spain.

    • Jose I Mayordomo
  20. Medical Research Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA.

    • Jeffrey R Smith

Authors

  1. Search for Julius Gudmundsson in:

  2. Search for Patrick Sulem in:

  3. Search for Daniel F Gudbjartsson in:

  4. Search for Thorarinn Blondal in:

  5. Search for Arnaldur Gylfason in:

  6. Search for Bjarni A Agnarsson in:

  7. Search for Kristrun R Benediktsdottir in:

  8. Search for Droplaug N Magnusdottir in:

  9. Search for Gudbjorg Orlygsdottir in:

  10. Search for Margret Jakobsdottir in:

  11. Search for Simon N Stacey in:

  12. Search for Asgeir Sigurdsson in:

  13. Search for Tiina Wahlfors in:

  14. Search for Teuvo Tammela in:

  15. Search for Joan P Breyer in:

  16. Search for Kate M McReynolds in:

  17. Search for Kevin M Bradley in:

  18. Search for Berta Saez in:

  19. Search for Javier Godino in:

  20. Search for Sebastian Navarrete in:

  21. Search for Fernando Fuertes in:

  22. Search for Laura Murillo in:

  23. Search for Eduardo Polo in:

  24. Search for Katja K Aben in:

  25. Search for Inge M van Oort in:

  26. Search for Brian K Suarez in:

  27. Search for Brian T Helfand in:

  28. Search for Donghui Kan in:

  29. Search for Carlo Zanon in:

  30. Search for Michael L Frigge in:

  31. Search for Kristleifur Kristjansson in:

  32. Search for Jeffrey R Gulcher in:

  33. Search for Gudmundur V Einarsson in:

  34. Search for Eirikur Jonsson in:

  35. Search for William J Catalona in:

  36. Search for Jose I Mayordomo in:

  37. Search for Lambertus A Kiemeney in:

  38. Search for Jeffrey R Smith in:

  39. Search for Johanna Schleutker in:

  40. Search for Rosa B Barkardottir in:

  41. Search for Augustine Kong in:

  42. Search for Unnur Thorsteinsdottir in:

  43. Search for Thorunn Rafnar in:

  44. Search for Kari Stefansson in:

Contributions

The study was designed and results were interpreted by J. Gudmundsson, P.S., A.K., U.T., T.R. and K.S. Statistical analysis was carried out by P.S., D.F.G., J. Gudmundsson, M.L.F. and A.K. Subject recruitment, biological material collection and handling along with genotyping were supervised and carried out by J. Gudmundsson, B.A.A., K.R.B., T.B., A.G., D.N.M., G.O., M.J., S.N.S., A.S., T.W., T.T., J.P.B., K.M.M., K.M.B., B.S., J. Godino, S.N., F.F., L.M., E.P., K.K.A., I.M.v.O., B.K.S., B.T.H., D.K., C.Z., K.K., J.R.G., G.V.E., E.J., W.J.C., J.I.M., L.A.K., J.R.S., J.S., R.B.B., U.T. and T.R. Authors J. Gudmundsson, P.S., D.F.G., T.R. and K.S. drafted the manuscript. All authors contributed to the final version of the paper. Principal investigators and corresponding authors for the respective replication study populations are: The Netherlands, L.A.K.; Spain, J.I.M.; Chicago, W.J.C.; Nashville, Tenn., USA, J.R.S.; Finland, J.S.

Competing interests

The authors from deCODE in Reykjavik, Iceland are shareholders in deCODE Genetics, Inc.

Corresponding authors

Correspondence to Javier Godino or Kari Stefansson.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–6, Supplementary Figure 1 and Supplementary Note.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.448

Further reading