A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer (original) (raw)

References

1. Parkin, D.M. The global burden of urinary bladder cancer. Scand. J. Urol. Nephrol. Suppl. 12–20 (2008).
2. Knowles, M.A. Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis 27, 361–373 (2006).
   Article CAS Google Scholar
3. Murta-Nascimento, C. et al. Risk of bladder cancer associated with family history of cancer: do low-penetrance polymorphisms account for the increase in risk? Cancer Epidemiol. Biomarkers Prev. 16, 1595–1600 (2007).
   Article CAS Google Scholar
4. Aben, K.K. et al. Familial aggregation of urothelial cell carcinoma. Int. J. Cancer 98, 274–278 (2002).
   Article CAS Google Scholar
5. 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
6. Wu, X. et al. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat. Genet. 41, 991–995 (2009).
   Article CAS Google Scholar
7. 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
8. Mostofi, F.K. Histological Typing of Urinary Bladder Tumours (World Health Organization, Geneva, 1973).
9. Union Internationale Contre le Cancer (UICC). Bladder. in TNM Classification of Malignant Tumors 3rd edn. 113–117 (UICC, Geneva, 1978).
10. Billerey, C. et al. Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am. J. Pathol. 158, 1955–1959 (2001).
    Article CAS Google Scholar
11. Hernandez, S. et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J. Clin. Oncol. 24, 3664–3671 (2006).
    Article CAS Google Scholar
12. Thorgeirsson, T.E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008).
    Article CAS Google Scholar
13. Bakkar, A.A. et al. Occupational exposure to polycyclic aromatic hydrocarbons influenced neither the frequency nor the spectrum of FGFR3 mutations in bladder urothelial carcinoma. Mol. Carcinog. 49, 25–31 (2010).
    CAS PubMed Google Scholar
14. Wallerand, H. et al. Mutations in TP53, but not FGFR3, in urothelial cell carcinoma of the bladder are influenced by smoking: contribution of exogenous versus endogenous carcinogens. Carcinogenesis 26, 177–184 (2005).
    Article CAS Google Scholar
15. Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).
    Article CAS Google Scholar
16. Kong, A. et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868–874 (2009).
    Article CAS Google Scholar
17. Tomlinson, D.C., L'Hote, C.G., Kennedy, W., Pitt, E. & Knowles, M.A. Alternative splicing of fibroblast growth factor receptor 3 produces a secreted isoform that inhibits fibroblast growth factor-induced proliferation and is repressed in urothelial carcinoma cell lines. Cancer Res. 65, 10441–10449 (2005).
    Article CAS Google Scholar
18. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).
    Article CAS Google Scholar
19. Tomlinson, D.C., Baldo, O., Harnden, P. & Knowles, M.A. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J. Pathol. 213, 91–98 (2007).
    Article CAS Google Scholar
20. Cappellen, D. et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat. Genet. 23, 18–20 (1999).
    Article CAS Google Scholar
21. Catto, J.W. et al. Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res. 69, 8472–8481 (2009).
    Article CAS Google Scholar
22. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).
    Article CAS Google Scholar
23. Falk, C.T. & Rubinstein, P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann. Hum. Genet. 51, 227–233 (1987).
    Article CAS Google Scholar
24. Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).
    CAS PubMed Google Scholar
25. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
    Article CAS Google Scholar
26. Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).
    Article CAS Google Scholar
27. Epstein, J.I., Amin, M.B., Reuter, V.R. & Mostofi, F.K. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am. J. Surg. Pathol. 22, 1435–1448 (1998).
    Article CAS Google Scholar
28. van Oers, J.M. et al. A simple and fast method for the simultaneous detection of nine fibroblast growth factor receptor 3 mutations in bladder cancer and voided urine. Clin. Cancer Res. 11, 7743–7748 (2005).
    Article CAS Google Scholar

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Acknowledgements

We thank the individuals who participated in the study and whose contribution made this work possible. We also thank the nurses at deCODE's recruitment center and the personnel at the deCODE core facilities. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the Icelandic UBC cases. C.Z. and S.B. are funded by a FP7-MC-IAPP Grant agreement no. 218071 (CancerGene). Collection of samples and data in Iceland and The Netherlands was funded in part by the European Commission (POLYGENE: LSHC-CT-2005) and a research investment grant of the Radboud University Nijmegen Medical Centre. Control samples for the Dutch follow-up group were genotyped with generous support from the 'Prinses Beatrix Fonds', VSB Fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, J.R. van Dijk and the Adessium foundation. The controls from the Dutch Schizophrenia GWA study were genotyped with the support of the US National Institute of Mental Health (R.A.O.). The Leeds Bladder Cancer Study was funded by Cancer Research UK and Yorkshire Cancer Research. The Torino Bladder Cancer Case Control Study was supported by a grant to ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union Sixth Framework Program, Priority 5: 'Food Quality and Safety' (Contract No. 513943), and by grants of the Compagnia di San Paolo, of the Italian Association for Cancer Research and of the Piedmont Region Progetti de Ricerca Sanitaria Finalizzata, Italy. The Belgian case-control study on bladder cancer risk was supported by a grant of the Flemish government, the government of the Belgian province of Limburg and the Limburg Cancer Fund.

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Author notes

1. Lambertus A Kiemeney and Patrick Sulem: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Epidemiology, Biostatistics and Health Technology Assessment, Nijmegen, The Netherlands
   Lambertus A Kiemeney, Sita H Vermeulen, Anne J Grotenhuis & Katja K H Aben
2. Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
   Lambertus A Kiemeney, J Alfred Witjes & Gerald W Verhaegh
3. Comprehensive Cancer Center East, Nijmegen, The Netherlands
   Lambertus A Kiemeney & Katja K H Aben
4. deCODE Genetics, Reykjavik, Iceland
   Patrick Sulem, Soren Besenbacher, Asgeir Sigurdsson, Gudmar Thorleifsson, Daniel F Gudbjartsson, Simon N Stacey, Julius Gudmundsson, Carlo Zanon, Jelena Kostic, Gisli Masson, Hjordis Bjarnason, Stefan T Palsson, Oskar B Skarphedinsson, Sigurjon A Gudjonsson, Kristleifur Kristjansson, Augustine Kong, Thorgeir Thorgeirsson, Unnur Thorsteinsdottir, Thorunn Rafnar & Kari Stefansson
5. Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK
   D Timothy Bishop, Faye Elliott & Jennifer H Barrett
6. Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK
   Sei Chung Sak, Carolyn D Hurst & Margaret A Knowles
7. Christie Hospital National Health Service Foundation Trust, Manchester, UK
   Ananya Choudhury
8. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
   Petra J de Verdier & Charlotta Ryk
9. National Institute of Environmental Health, Budapest, Hungary
   Peter Rudnai
10. Environmental Health Centre, Cluj-Napoca, Romania
    Eugene Gurzau
11. State Health Institute, Banska Bystrica, Slovakia
    Kvetoslava Koppova
12. Institute for Scientific Interchange (ISI) Foundation, Torino, Italy
    Paolo Vineis, Silvia Polidoro, Simonetta Guarrera & Giuseppe Matullo
13. Department of Epidemiology and Public Health, Imperial College, London, UK
    Paolo Vineis
14. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
    Silvia Polidoro, Simonetta Guarrera & Giuseppe Matullo
15. Unit of Cancer Epidemiology, University of Torino, Torino, Italy
    Carlotta Sacerdote
16. Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Torino, Italy
    Carlotta Sacerdote
17. Department of Experimental and Applied Medicine, Section of Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy
    Marcello Campagna, Donatella Placidi, Cecilia Arici & Stefano Porru
18. Department of Public Health and Epidemiology, Unit of Genetic Epidemiology, University of Birmingham, Birmingham, UK
    Maurice P Zeegers
19. Department of Complex Genetics, Cluster of Genetics and Cell Biology, Nutrition and Toxicology Research Institute, Maastricht University, Maastricht, The Netherlands
    Maurice P Zeegers
20. Leuven University Centre for Cancer Prevention (LUCK), Leuven, Belgium
    Eliane Kellen
21. Department of Medicine, University of Zaragoza, Zaragoza, Spain
    Berta Saez Gutierrez
22. Division of Urology, San Jorge Hospital, Huesca, Spain
    José I Sanz-Velez
23. Division of Urology, Hospital Clinico, Zaragoza, Spain
    Manuel Sanchez-Zalabardo
24. Department of Urology, University of Zaragoza School of Medicine, Zaragoza, Spain
    Gabriel Valdivia
25. Division of Surgical Pathology, San Jorge Hospital, Huesca, Spain
    Maria D Garcia-Prats
26. Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany
    Jan G Hengstler, Meinolf Blaszkewicz & Klaus Golka
27. Department of Urology, Paul Gerhardt Foundation, Lutherstadt Wittenberg, Germany
    Holger Dietrich
28. Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
    Roel A Ophoff
29. University of California Los Angeles Center for Neurobehavioral Genetics, Los Angeles, USA
    Roel A Ophoff
30. Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
    Leonard H van den Berg & Michael A van Es
31. Department of Medical Oncology, Landspitali–University Hospital, Reykjavik, Iceland
    Kristin Alexiusdottir
32. Department of Urology, Landspitali–University Hospital, Reykjavik, Iceland
    Gudmundur Geirsson & Eirikur Jonsson
33. Department of Pathology, Landspitali–University Hospital, Reykjavik, Iceland
    Sigfus Nikulasson & Vigdis Petursdottir
34. Department of Urology, Zonguldak Karaelmas University, Zonguldak, Turkey
    N Aydin Mungan
35. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
    Annika Lindblom
36. Department of General Practice, Catholic University of Leuven, Leuven, Belgium
    Frank Buntinx
37. Department of General Practice, Maastricht University, Maastricht, The Netherlands
    Frank Buntinx
38. Division of Medical Oncology, University of Zaragoza, Zaragoza, Spain
    José I Mayordomo
39. Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany
    Rajiv Kumar
40. Department of Oncology and Pathology, Section of Clinical Cancer Epidemiology, Karolinska Institutet, Stockholm, Sweden
    Gunnar Steineck
41. Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, Gothenburg, Sweden
    Gunnar Steineck
42. Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK
    Anne E Kiltie
43. Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Unnur Thorsteinsdottir & Kari Stefansson

Authors

1. Lambertus A Kiemeney
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2. Patrick Sulem
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3. Soren Besenbacher
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4. Sita H Vermeulen
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5. Asgeir Sigurdsson
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6. Gudmar Thorleifsson
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7. Daniel F Gudbjartsson
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8. Simon N Stacey
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9. Julius Gudmundsson
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10. Carlo Zanon
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11. Jelena Kostic
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12. Gisli Masson
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13. Hjordis Bjarnason
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14. Stefan T Palsson
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15. Oskar B Skarphedinsson
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16. Sigurjon A Gudjonsson
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17. J Alfred Witjes
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18. Anne J Grotenhuis
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19. Gerald W Verhaegh
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20. D Timothy Bishop
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21. Sei Chung Sak
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22. Ananya Choudhury
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23. Faye Elliott
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24. Jennifer H Barrett
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25. Carolyn D Hurst
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26. Petra J de Verdier
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27. Charlotta Ryk
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28. Peter Rudnai
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29. Eugene Gurzau
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30. Kvetoslava Koppova
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31. Paolo Vineis
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32. Silvia Polidoro
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33. Simonetta Guarrera
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34. Carlotta Sacerdote
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35. Marcello Campagna
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36. Donatella Placidi
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37. Cecilia Arici
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38. Maurice P Zeegers
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39. Eliane Kellen
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40. Berta Saez Gutierrez
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41. José I Sanz-Velez
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42. Manuel Sanchez-Zalabardo
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43. Gabriel Valdivia
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44. Maria D Garcia-Prats
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45. Jan G Hengstler
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46. Meinolf Blaszkewicz
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47. Holger Dietrich
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48. Roel A Ophoff
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49. Leonard H van den Berg
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50. Kristin Alexiusdottir
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51. Kristleifur Kristjansson
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52. Sigfus Nikulasson
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53. Vigdis Petursdottir
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54. Augustine Kong
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55. N Aydin Mungan
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56. Annika Lindblom
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57. Michael A van Es
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58. Stefano Porru
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59. Frank Buntinx
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60. Klaus Golka
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61. José I Mayordomo
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62. Rajiv Kumar
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63. Giuseppe Matullo
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64. Gunnar Steineck
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65. Anne E Kiltie
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66. Katja K H Aben
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67. Eirikur Jonsson
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68. Unnur Thorsteinsdottir
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69. Margaret A Knowles
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70. Thorunn Rafnar
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71. Kari Stefansson
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Contributions

The study was designed and results were interpreted by L.A.K., P.S., U.T., M.A.K., T.R. and K.S. Statistical analysis was carried out by L.A.K., P.S., S.B., G.T., D.F.G., G. Masson and A.K. Subject ascertainment, recruitment, biological material collection and collection of clinical and lifestyle information was organized and carried out by S.H.V., J.A.W., A.J.G., G.W.V., D.T.B., S.C.S., A.C., F.E., J.H.B., C.D.H., P.J.d.V., C.R., P.R., E.G., K. Koppova, P.V., S. Polidoro, S.G., C.S., M.C., D.P., C.A., M.P.Z., E.K., B.S.G., J.I.S.-V., M.S.-Z., G.V., M.D.G.-P., J.G.H., M.B., H.D., R.A.O., L.H.v.d.B., K.A., K. Kristjansson, G.G., S.N., V.P., N.A.M., A.L., M.A.v.E., S. Porru, F.B., K.G., J.I.M., R.K., G. Matullo, G.S., A.E.K., K.K.H.A., T.T., E.J. and M.A.K. Principal investigators for the UBC follow-up populations were A.E.K. (UK), G. Matullo and P.V. (Torino), S. Porru (Brescia), M.P.Z. and F.B. (Belgium), R.K. (Eastern Europe), J.I.M. (Spain), G.S. (Sweden), K.G. (Germany) and L.A.K. (The Netherlands, group 2). Genotyping and laboratory experiments were carried out by A.S., S.N.S., J.G., J.K., H.B., S.T.P., O.B.S. and C.D.H. Bioinformatics analysis was carried out by P.S., A.S., G.T., C.Z. and S.A.G. L.A.K., P.S., U.T., M.A.K., T.R. and K.S. drafted the manuscript. All authors contributed to the final version of the paper.

Corresponding authors

Correspondence toLambertus A Kiemeney or Kari Stefansson.

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Competing interests

The authors from deCODE genetics are shareholders in deCODE Genetics Inc.

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Kiemeney, L., Sulem, P., Besenbacher, S. et al. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.Nat Genet 42, 415–419 (2010). https://doi.org/10.1038/ng.558

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• Received: 30 December 2009
• Accepted: 03 March 2010
• Published: 28 March 2010
• Issue Date: May 2010
• DOI: https://doi.org/10.1038/ng.558