Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genome-wide association study identifies five susceptibility loci for glioma

Nature Genetics volume 41, pages 899–904 (2009)Cite this article

This article has been updated

Abstract

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 × 10−17), 8q24.21 (rs4295627, CCDC26; P = 2.34 × 10−18), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 × 10−15), 20q13.33 (rs6010620, RTEL1; P = 2.52 × 10−12) and 11q23.3 (rs498872, PHLDB1; P = 1.07 × 10−8). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2: LD structure and association results for the five confirmed glioma-associated regions.
Figure 3: Cumulative effects of glioma risk alleles.

Change history

  • 20 July 2009

    In the version of this article initially published online, there were two errors in the author affiliations. For footnote 3, the correct affiliation is “Service de Neurologie Mazarin and UMR 975 INSERM-UPMC, GH Pitié-Salpêtrière, APHP, Paris, France,” rather than “Service de Neurologie Mazarin et INSERM U 711, Hôpital de la Salpêtrière 47, Paris, France.” For author Anders Ahlbom, the correct affiliation is footnote 8 rather than 7. These errors have been corrected for the print, PDF and HTML versions of this article.

References

  1. Bondy, M.L. et al. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 113, 1953–1968 (2008).

    Article  Google Scholar 

  2. Hemminki, K. & Li, X. Familial risks in nervous system tumors. Cancer Epidemiol. Biomarkers Prev. 12, 1137–1142 (2003).

    PubMed  Google Scholar 

  3. Cardis, E. et al. The INTERPHONE study: design, epidemiological methods, and description of the study population. Eur. J. Epidemiol. 22, 647–664 (2007).

    Article  Google Scholar 

  4. Power, C. & Elliott, J. Cohort profile: 1958 British birth cohort (National Child Development Study). Int. J. Epidemiol. 35, 34–41 (2006).

    Article  Google Scholar 

  5. 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, 870–874 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Clayton, D.G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat. Genet. 37, 1243–1246 (2005).

    Article  CAS  Google Scholar 

  8. Yin, W., Rossin, A., Clifford, J.L. & Gronemeyer, H. Co-resistance to retinoic acid and TRAIL by insertion mutagenesis into RAM. Oncogene 25, 3735–3744 (2006).

    Article  CAS  Google Scholar 

  9. Jiang, M., Zhu, K., Grenet, J. & Lahti, J.M. Retinoic acid induces caspase-8 transcription via phospho-CREB and increases apoptotic responses to death stimuli in neuroblastoma cells. Biochim. Biophys. Acta 1783, 1055–1067 (2008).

    Article  CAS  Google Scholar 

  10. Das, A., Banik, N.L. & Ray, S.K. Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-γ and taxol for apoptosis. Neurochem. Res. 32, 2167–2183 (2007).

    Article  CAS  Google Scholar 

  11. Tomlinson, I. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Birnbaum, S. et al. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat. Genet. 41, 473–477 (2009).

    Article  CAS  Google Scholar 

  15. Bille, C. et al. Cancer risk in persons with oral cleft—a population-based study of 8,093 cases. Am. J. Epidemiol. 161, 1047–1055 (2005).

    Article  Google Scholar 

  16. Wager, M. et al. Prognostic molecular markers with no impact on decision-making: the paradox of gliomas based on a prospective study. Br. J. Cancer 98, 1830–1838 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  19. Parsons, D.W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Article  CAS  Google Scholar 

  20. Randerson-Moor, J.A. et al. A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumor syndrome family. Hum. Mol. Genet. 10, 55–62 (2001).

    Article  CAS  Google Scholar 

  21. Bahuau, M. et al. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res. 58, 2298–2303 (1998).

    CAS  PubMed  Google Scholar 

  22. Simon, M., Voss, D., Park-Simon, T.W., Mahlberg, R. & Koster, G. Role of p16 and p14ARF in radio- and chemosensitivity of malignant gliomas. Oncol. Rep. 16, 127–132 (2006).

    CAS  PubMed  Google Scholar 

  23. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Article  CAS  Google Scholar 

  24. McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).

    Article  CAS  Google Scholar 

  25. Harder, T., Plagemann, A. & Harder, A. Birth weight and subsequent risk of childhood primary brain tumors: a meta-analysis. Am. J. Epidemiol. 168, 366–373 (2008).

    Article  Google Scholar 

  26. Ferrie, J.E., Langenberg, C., Shipley, M.J. & Marmot, M.G. Birth weight, components of height and coronary heart disease: evidence from the Whitehall II study. Int. J. Epidemiol. 35, 1532–1542 (2006).

    Article  Google Scholar 

  27. Whincup, P.H. et al. Birth weight and risk of type 2 diabetes: a systematic review. J. Am. Med. Assoc. 300, 2886–2897 (2008).

    Article  CAS  Google Scholar 

  28. Barber, L.J. et al. RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135, 261–271 (2008).

    Article  CAS  Google Scholar 

  29. Arakawa, Y. et al. Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma. Acta Neuropathol. 109, 294–298 (2005).

    Article  CAS  Google Scholar 

  30. Guo, C. et al. Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene 18, 4948–4957 (1999).

    Article  CAS  Google Scholar 

  31. Hercberg, S. et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch. Intern. Med. 164, 2335–2342 (2004).

    Article  CAS  Google Scholar 

  32. Hallmans, G. et al. Cardiovascular disease and diabetes in the Northern Sweden Health and Disease Study Cohort—evaluation of risk factors and their interactions. Scand. J. Public Health Suppl. 61, 18–24 (2003).

    Article  Google Scholar 

  33. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  34. Stranger, B.E. et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005).

    Article  Google Scholar 

  35. Stranger, B.E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

    Article  CAS  Google Scholar 

  36. Myers, A.J. et al. A survey of genetic human cortical gene expression. Nat. Genet. 39, 1494–1499 (2007).

    Article  CAS  Google Scholar 

  37. Wu, J. et al. Integrated network analysis platform for protein-protein interactions. Nat. Methods 6, 75–77 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The Wellcome Trust provided principal funding for the study. In the UK, additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the European Union (CPRB LSHC-CT-2004-503465). The UK and Swedish INTERPHONE studies were supported by the European Union Fifth Framework Program “Quality of Life and Management of Living Resources” (contract number QLK4-CT-1999-01563) and the International Union against Cancer (UICC). The UICC received funds for this purpose from the Mobile Manufacturers' Forum and Groupe Speciale Mobile (GSM) Association. Provision of funds via the UICC was governed by agreements that guaranteed INTERPHONE's complete scientific independence. These agreements are publicly available at http://www.iarc.fr/en/research-groups/RAD/RCAd.html. The Swedish centre was also supported by the Swedish Research Council, the Cancer Foundation of Northern Sweden, the Swedish Cancer Society, and the Nordic Cancer Union and the UK centre by the Mobile Telecommunications and Health Research (MTHR) Programme and the Health and Safety Executive, Department of Health and Safety Executive and the UK Network Operators (O2, Orange, T-Mobile, Vodafone and '3'). The views expressed in the publication are those of the authors and not necessarily those of the funding bodies. In the United States, funding was provided by US National Institutes of Health grants 5R01 CA119215 and 5R01 CA070917. Additional support was obtained from the American Brain Tumor Association and the National Brain Tumor Society. The University of Texas M.D. Anderson Cancer Center acknowledges the work of P. Adatto, F. Morice, H. Zhang, V. Levin, A. Yung, M. Gilbert, R. Sawaya, V. Puduvalli, C. Conrad, F. Lang and J. Weinberg from the Brain and Spine Center. In France, funding was provided by the Délégation à la Recherche Clinique (MUL03012), the Association pour la Recherche sur les Tumeurs Cérébrales (ARTC), the Institut National du Cancer (INCa; PL 046) and the French Ministry of Higher Education and Research. In Germany, funding was provided to M. Simon, J.S. and M. Linnebank by the Deutsche Forschungsgemeinschaft (Si 552, Schr 285), the Deutsche Krebshilfe (70-2385-Wi2, 70-3163-Wi3, 10-6262) and BONFOR. In Sweden, the collection of samples from the Northern Sweden Health of disease study were collected with support from Umeå University Hospital and NIH funded part of GLIOGENE collection (R01 CA119215). B.M. was supported by Acta Oncologica Foundation as a research fellow at Royal Swedish Academy of Science. In the UK we acknowledge NHS funding to the NIHR Biomedical Research Centre. The UK-GWA study made use of genotyping data on the 1958 Birth Cohort. Genotyping data on controls was generated and generously supplied to us by P. Deloukas (Wellcome Trust Sanger Institute). A full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk. The US-GWA study made use of control genotypes from the CGEMS prostate and breast cancer studies. A full list of the investigators who contributed to the generation of the data are available from http://cgems.cancer.gov/. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas pilot project established by the National Cancer Institute and National Human Genome Research Institute. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov. Finally, we are grateful to all the study subjects for their participation. We also thank the clinicians and other hospital staff, cancer registries and study staff who contributed to the blood sample and data collection for this study.

Author information

Author notes

  1. Sanjay Shete and Fay J Hosking: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Sanjay Shete, Georgina Armstrong, Yanhong Liu, Xiangjun Gu, Robert Yu & Melissa Bondy

  2. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK

    Fay J Hosking, Lindsay B Robertson, Sara E Dobbins, Amy Price & Richard S Houlston

  3. Service de Neurologie Mazarin and UMR 975 INSERM-UPMC, GH Pitié-Salpêtrière, APHP, Paris, France

    Marc Sanson, Yannick Marie, Blandine Boisselier, Jean-Yves Delattre, Khe Hoang-Xuan, Soufiane El Hallani & Ahmed Idbaih

  4. Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

    Beatrice Malmer, Ulrika Andersson & Roger Henriksson

  5. Neurochirurgische Universitätsklinik, Bonn, Germany

    Matthias Simon & Johannes Schramm

  6. Centre National de Génotypage, IG/CEA, Evry Cedex, France

    Diana Zelenika & Mark Lathrop

  7. Department of Clinical Neuroscience, Umeå University, Umeå, Sweden

    A Tommy Bergenheim

  8. Institute of Environmental Medicine, Karolinska Institutet, Sweden

    Maria Feychting & Anders Ahlbom

  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Stefan Lönn

  10. Department of Neurology, University Hospital Zurich, Zurich, Switzerland

    Michael Linnebank

  11. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg, Germany

    Kari Hemminki & Rajiv Kumar

  12. Centre for Epidemiology and Biostatistics, Faculty of Medicine and Health, University of Leeds, Leeds, UK

    Sarah J Hepworth

  13. Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA

    Ching Lau

  14. Section of Epidemiology, Institute of Cancer Research, Sutton, UK

    Minouk Schoemaker & Anthony Swerdlow

  15. Division of Epidemiology and Public Health, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK

    Kenneth Muir

  16. Foundation Jean Dausett-CEPH, Paris, France

    Mark Lathrop

Authors
  1. Sanjay Shete
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fay J Hosking
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lindsay B Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara E Dobbins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marc Sanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Beatrice Malmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthias Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yannick Marie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Blandine Boisselier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Yves Delattre
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Khe Hoang-Xuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Soufiane El Hallani
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ahmed Idbaih
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Diana Zelenika
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ulrika Andersson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Roger Henriksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. A Tommy Bergenheim
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Maria Feychting
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Stefan Lönn
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Anders Ahlbom
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Johannes Schramm
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Michael Linnebank
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Kari Hemminki
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Rajiv Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Sarah J Hepworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Amy Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Georgina Armstrong
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Yanhong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Xiangjun Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Robert Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Ching Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Minouk Schoemaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Kenneth Muir
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Anthony Swerdlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Mark Lathrop
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Melissa Bondy
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Richard S Houlston
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.S.H. and M.B. designed the study. R.S.H. drafted the manuscript, with extensive contributions from F.J.H. and S.S. F.J.H. and S.S. performed statistical analyses. S.E.D., F.J.H. and S.S. performed bioinformatics analyses. L.B.R. performed laboratory management and oversaw genotyping of UK cases and with A.P. performed genotyping of German and Swedish case-control series. In the UK, A.S., M. Schoemaker, K.M., S.J.H. and R.S.H. developed patient recruitment, sample acquisition and performed sample collection of cases. In the US, M.B. and C.L. developed protocols, M.B. and G.A. developed patient recruitment, G.A., X.G. and R.Y. performed curation and organization of samples and data, and Y.L. performed management of genotyping. In Germany, M. Simon and J.S. developed patient recruitment and blood sample collection, M. Simon oversaw DNA isolation and storage, K.H. and M. Linnebank collected control samples, M. Simon and M. Linnebank performed case ascertainment and supervision of DNA extractions, and K.H. and R.K. procured German control samples. In France, M. Sanson, J.-Y.D., K.H.-X. and A.I. developed patient recruitment, and Y.M., B.B. and S. El-H. developed sample acquisition and performed sample collection of cases. M. Lathrop and D.Z. performed laboratory management and oversaw genotyping of the French samples. In Sweden, for the Swedish INTERPHONE Study, M.F., S.L. and A.A. developed study design and conducted patient recruitment and control selection, M.F., S.L., A.A., B.M. and R.H. organized sample acquisition and performed sample collection of case and controls, U.A. coordinated sample collection and complied information into data files of cases and controls for statistical analyses, and B.M. and R.H. performed laboratory management and oversaw DNA extraction. The NSHDS samples were collected by Umeå University (Principal Investigator Göran Hallmans), and the additional samples were collected at the neurosurgery department in Umeå from 2005 and onwards (A.T.B. and R.H.) and through the national GLIOGENE study (Principal Investigator B.M.). All authors contributed to the final paper.

Corresponding authors

Correspondence to Melissa Bondy or Richard S Houlston.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 and Supplementary Tables 1–5 (PDF 638 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shete, S., Hosking, F., Robertson, L. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 41, 899–904 (2009). https://doi.org/10.1038/ng.407

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.407

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing