Genome-wide association study identifies five new breast cancer susceptibility loci

Journal name:
Nature Genetics
Volume:
42,
Pages:
504–507
Year published:
DOI:
doi:10.1038/ng.586
Received
Accepted
Published online

Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 × 10−7 to P = 3.2 × 10−15). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 × 10−6), 8q24 (rs1562430, P = 5.8 × 10−7) and LSP1 (rs909116, P = 7.3 × 10−7) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.

References

  1. Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 10871093 (2007).
  2. Hunter, D.J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870874 (2007).
  3. Stacey, S.N. et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat. Genet. 39, 865869 (2007).
  4. Stacey, S.N. et al. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat. Genet. 40, 703706 (2008).
  5. Ahmed, S. et al. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat. Genet. 41, 585590 (2009).
  6. Thomas, G. et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat. Genet. 41, 579584 (2009).
  7. Zheng, W. et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat. Genet. 41, 324328 (2009).
  8. Cox, A. et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat. Genet. 39, 352358 (2007).
  9. Antoniou, A.C. & Easton, D.F. Polygenic inheritance of breast cancer: implications for design of association studies. Genet. Epidemiol. 25, 190202 (2003).
  10. Milne, R.L. et al. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042. J. Natl. Cancer Inst. 101, 10121018 (2009).
  11. Kamb, A. et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436440 (1994).
  12. Kamb, A. et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat. Genet. 8, 2326 (1994).
  13. Bishop, D.T. et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat. Genet. 41, 920925 (2009).
  14. Falchi, M. et al. Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat. Genet. 41, 915919 (2009).
  15. Stacey, S.N. et al. New common variants affecting susceptibility to basal cell carcinoma. Nat. Genet. 41, 909914 (2009).
  16. Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899904 (2009).
  17. Wrensch, M. et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat. Genet. 41, 905908 (2009).
  18. Zeggini, E. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 13361341 (2007).
  19. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661678 (2007).
  20. Liu, Y. et al. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One 4, e5027 (2009).
  21. Karlseder, J. et al. Patterns of DNA amplification at band q13 of chromosome 11 in human breast cancer. Genes Chromosom. Cancer 9, 4248 (1994).
  22. Ornitz, D.M. et al. Receptor specificity of the fibroblast growth factor family. J. Biol. Chem. 271, 1529215297 (1996).
  23. Gianfrancesco, F. et al. Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate. Am. J. Hum. Genet. 72, 14791491 (2003).
  24. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955962 (2008).
  25. Udler, M.S. et al. FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation. Hum. Mol. Genet. 18, 16921703 (2009).
  26. Power, C. & Elliott, J. Cohort profile: 1958 British birth cohort (National Child Development Study). Int. J. Epidemiol. 35, 3441 (2006).
  27. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661678 (2007).
  28. Teo, Y.Y. et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23, 27412746 (2007).
  29. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904909 (2006).
  30. Schaid, D.J., Rowland, C.M., Tines, D.E., Jacobson, R.M. & Poland, G.A. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am. J. Hum. Genet. 70, 425434 (2002).
  31. Aulchenko, Y.S., Ripke, S., Isaacs, A. & van Duijn, C.M. GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 12941296 (2007).

Download references

Author information

Affiliations

  1. Section of Cancer Genetics, The Institute of Cancer Research, Sutton, Surrey, UK.

    • The Breast Cancer Susceptibility Collaboration,
    • Clare Turnbull,
    • David Pernet,
    • Anthony Renwick,
    • Sheila Seal,
    • Sarah Hines,
    • Deborah Hughes,
    • Margaret Warren-Perry,
    • Richard Houlston,
    • Michael R Stratton &
    • Nazneen Rahman
  2. Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Shahana Ahmed,
    • Mel Maranian,
    • Maya Ghoussaini,
    • Catherine S Healey,
    • Paul D P Pharoah,
    • Alison M Dunning &
    • Douglas F Easton
  3. Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Jonathan Morrison,
    • Paul D P Pharoah &
    • Douglas F Easton
  4. Academic Unit of Genetic Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

    • William Tapper &
    • Diana Eccles
  5. Department of Genetic Medicine, St. Mary's Hospital, Manchester, UK.

    • D Gareth Evans
  6. Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Maartje Hooning &
    • Mieke Schutte
  7. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Ans van den Ouweland
  8. Breast Cancer Unit, Royal Marsden National Health Service Foundation Trust, London, UK.

    • Gillian Ross
  9. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Cordelia Langford &
    • Michael R Stratton
  10. A full list of members is provided in the Supplementary Note.

    • The Breast Cancer Susceptibility Collaboration

Consortia

  1. The Breast Cancer Susceptibility Collaboration (UK)

Contributions

D.F.E., N.R., M.R.S., P.D.P.P. and A.M.D. obtained funding for the study. D.F.E. designed the study and drafted the manuscript. D.F.E. and C.T. conducted the statistical analyses. J.M. provided data management and bioinformatics support. C.T. and N.R. coordinated the Familial Breast Cancer Study (FBCS). D.P., A.R., S.S., S.H., D.H., M.W.-P., C.T. and N.R. coordinated the FBCS genotyping. P.D.P.P. and D.F.E. coordinated Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH). S.A., M.M., M.G., C.S.H. and A.M.D. coordinated the stage 2 genotyping of the SEARCH and RBCS samples. M.H., M.S. and A.v.d.O. coordinated and provided samples and data from RBCS. C.L. coordinated the stage 1 genotyping. G.R. and R.H. provided data and samples from the Royal Marsden Hospital (RMH) study. W.T. and D.E. provided data and samples from the Prospective study of Outcomes in Sporadic vs. Hereditary breast cancer (POSH) study. D.E. and D.G.E. provided data and samples for FBCS. All authors provided critical review of the manuscript.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Author details

Supplementary information

PDF files

  1. Supplementary Text and Figures (124K)

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

Excel files

  1. Supplementary Table 3 (32K)

    Genotype counts in cases and controls for all SNPs tested in stages 1 and 2

Additional data