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A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

Nature Genetics volume 42, pages 978984 (2010) | Download Citation


We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10−12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10−11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10−7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10−11) and a tag SNP for NAT2 acetylation status (P = 4 × 10−11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.

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The bladder cancer GWAS was supported by the intramural research program of the US National Institutes of Health, National Cancer Institute.

This project has been funded in part with federal funds from the National Cancer Institute, US National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

Please see Supplementary Note for information on support for individual studies that participated in the effort.

Author information

Author notes

    • Nathaniel Rothman
    • , Montserrat Garcia-Closas
    • , Nilanjan Chatterjee
    • , Nuria Malats
    •  & Xifeng Wu

    These authors contributed equally to this work.

    • Jonine D Figueroa
    • , Francisco X Real
    • , David Van Den Berg
    • , Giuseppe Matullo
    • , Dalsu Baris
    • , Michael Thun
    • , Lambertus A Kiemeney
    • , Paolo Vineis
    • , Immaculata De Vivo
    • , Demetrius Albanes
    • , Mark P Purdue
    • , Thorunn Rafnar
    • , Michelle A T Hildebrandt
    • , Anne E Kiltie
    • , Olivier Cussenot
    • , Klaus Golka
    • , Rajiv Kumar
    • , Jack A Taylor
    • , Jose I Mayordomo
    • , Kevin B Jacobs
    •  & Manolis Kogevinas

    These authors are the designated representatives of the participating studies.

    • Debra T Silverman
    •  & Stephen J Chanock

    These authors jointly directed this work.


  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Nathaniel Rothman
    • , Montserrat Garcia-Closas
    • , Nilanjan Chatterjee
    • , Jonine D Figueroa
    • , Dalsu Baris
    • , Demetrius Albanes
    • , Mark P Purdue
    • , Yi-Ping Fu
    • , Ludmila Prokunina-Olsson
    • , Amanda Black
    • , Stephanie J Weinstein
    • , Neil Caporaso
    • , Maria Teresa Landi
    • , Robert N Hoover
    • , Joseph F Fraumeni Jr
    • , Debra T Silverman
    •  & Stephen J Chanock
  2. Spanish National Cancer Research Centre, Madrid, Spain.

    • Nuria Malats
    •  & Francisco X Real
  3. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Xifeng Wu
    • , Michelle A T Hildebrandt
    • , Meng Chen
    •  & Hushan Yang
  4. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

    • Francisco X Real
  5. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • David Van Den Berg
    • , Victoria K Cortessis
    • , Manuela Gago-Dominguez
    • , Malcolm C Pike
    •  & Mariana C Stern
  6. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.

    • Giuseppe Matullo
    •  & Fulvio Ricceri
  7. Human Genetics Foundation (HuGeF), Torino, Italy.

    • Giuseppe Matullo
    • , Paolo Vineis
    • , Simonetta Guarrera
    • , Silvia Polidoro
    • , Fulvio Ricceri
    • , Carlotta Sacerdote
    •  & Alessandra Allione
  8. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.

    • Michael Thun
    • , Eric J Jacobs
    • , W Ryan Diver
    •  & Susan M Gapstur
  9. Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
    • , Sita H Vermeulen
    •  & Katja K Aben
  10. Comprehensive Cancer Center East, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
    •  & Katja K Aben
  11. Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
    •  & J Alfred Witjes
  12. Imperial College London, London, UK.

    • Paolo Vineis
    •  & Elio Riboli
  13. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Immaculata De Vivo
  14. deCODE Genetics, Reykjavik, Iceland.

    • Thorunn Rafnar
    • , Patrick Sulem
    • , Soren Besenbacher
    •  & Kari Stefansson
  15. Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.

    • Anne E Kiltie
  16. Department of Urology, Assistance Publique-Hôpitaux de Paris, Tenon Hospital, Paris, France.

    • Olivier Cussenot
  17. Centre de Recherche sur les Pathologies Prostatiques, Paris, France.

    • Olivier Cussenot
    •  & Geraldine Cancel-Tassin
  18. Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany.

    • Klaus Golka
    • , Silvia Selinski
    •  & Jan G Hengstler
  19. Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.

    • Rajiv Kumar
  20. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

    • Jack A Taylor
    • , Sophia C E Bolick
    • , Ashley Godfrey
    •  & Zongli Xu
  21. University of Zaragoza, Zaragoza, Spain.

    • Jose I Mayordomo
    • , Manuel Sanchez
    •  & Gabriel Valdivia
  22. Core Genotype Facility, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA.

    • Kevin B Jacobs
    • , Amy Hutchinson
    • , Zhaoming Wang
    • , Laurie Burdett
    •  & Meredith Yeager
  23. Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.

    • Manolis Kogevinas
  24. Municipal Institute of Medical Research, Barcelona, Spain.

    • Manolis Kogevinas
  25. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.

    • Manolis Kogevinas
    • , Adonina Tardón
    •  & Carmen Navarro
  26. National School of Public Health, Athens, Greece.

    • Manolis Kogevinas
  27. Information Management Services, Inc., Rockville, Maryland, USA.

    • William Wheeler
  28. Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.

    • Adonina Tardón
  29. Universitat Pompeu Fabra, Barcelona, Spain.

    • Consol Serra
  30. Ramón y Cajal University Hospital, Madrid, Spain.

    • Alfredo Carrato
  31. Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain.

    • Reina García-Closas
  32. Hospital del Mar-Institut Municipal d'Investigació Mèdica (IMIM), Universitat Pompeu Fabra, Barcelona, Spain.

    • Josep Lloreta
  33. Vermont Cancer Registry, Burlington, Vermont, USA.

    • Alison Johnson
  34. Maine Cancer Registry, Augusta, Maine, USA.

    • Molly Schwenn
  35. Dartmouth Medical School, Hanover, New Hampshire, USA.

    • Margaret R Karagas
    •  & Alan Schned
  36. Department of Urology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Gerald Andriole Jr
    •  & Robert Grubb III
  37. National Institute for Health and Welfare, Helsinki, Finland.

    • Jarmo Virtamo
  38. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Malcolm C Pike
  39. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.

    • Jian-Min Yuan
  40. Department of Epidemiology, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • David J Hunter
    •  & Monica McGrath
  41. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Colin P Dinney
  42. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Bogdan Czerniak
  43. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Sita H Vermeulen
    •  & Remco R Makkinje
  44. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Kari Stefansson
  45. International Agency for Research on Cancer, Lyon, France.

    • Paul Brennan
  46. Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.

    • Salvatore Panico
  47. Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain.

    • Carmen Navarro
  48. Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

    • Naomi E Allen
  49. National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

    • H Bas Bueno-de-Mesquita
  50. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Dimitrios Trichopoulos
  51. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece.

    • Dimitrios Trichopoulos
  52. Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.

    • Federico Canzian
  53. Department of Surgical and Perioperative Sciences, University of Umea, Umea, Sweden.

    • Borje Ljungberg
  54. Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark.

    • Anne Tjonneland
  55. Centre for Research in Epidemiology and Population Health, Institute Gustave-Roussy, Paris South University, Villejuif, France.

    • Francoise Clavel-Chapelon
  56. Leeds Institute of Molecular Medicine, St. James's University Hospital, University of Leeds, Leeds, UK.

    • David T Bishop
    • , Mark T W Teo
    •  & Margaret A Knowles
  57. Unit of Cancer Epidemiology, University of Torino, Torino, Italy.

    • Carlotta Sacerdote
  58. Department of Urology, Paul Gerhardt Foundation, Wittenberg, Germany.

    • Holger Dietrich
  59. Institute of Hygiene and Tropical Medicine, London, UK.

    • Tony Fletcher
  60. National Institute of Environmental Health, Budapest, Hungary.

    • Peter Rudnai
  61. Babes Bolyai University, Environmental Health Center, Cluj-Napoca, Romania.

    • Eugen Gurzau
  62. State Health Institute, Banská Bystrica, Slovakia.

    • Kvetoslava Koppova
  63. San Jorge University Hospital, Huesca, Spain.

    • José I Sanz-Velez
    •  & María D García-Prats
  64. Department of Experimental and Applied Medicine, Section of Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy.

    • Stefano Porru
  65. Institut national de la santé et de la recherche médicale, U946, Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.

    • Simone Benhamou
  66. Centre National de la Recherche Scientifique, UMR8200, Institut Gustave-Roussy, Villejuif, France.

    • Simone Benhamou


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N.R., M.G.-C., N.C., J.D.F., D.T.S. and S.J.C. organized and designed the study.S.J.C., K.B.J., A.H., Z.W., Y.-P.F., .L.P.-O., L.B., X.W., M.A.T.H., M.C., D.V.D.B., S.G., S.P., R.R.M., I.D.V., T.R., D.T.B., G.C.-T., J.G.H., R.K., S.C.E.B. and A.G. conducted and supervised genotyping of samples.

M.G.-C., N.C., N.R., K.B.J., M.Y., N.M., D.T.S. and S.J.C. contributed to the design and execution of statistical analysis.

M.G.-C., N.R., N.C., N.M., J.D.F., F.X.R., J.F.F., D.T.S. and S.J.C. wrote the first draft of the manuscript.N.R., M.G.-C., N.M., X.W., J.D.F., F.X.R., D.V.D.B., F.X.R., G.M., D.B., M.T., L.A.K., P.V., I.D.V., D.A., M.P.P., T.R., M.A.T.H., A.E.K., O.C., K.G., R.K., J.A.T., J.I.M., M.K., A.T., C.S., A.C., R.G.-C., J.L., A.J., M.S., M.R.K., A.S., G.A., R.G., A.B., E.J.J., W.R.D., S.M.G., S.J.W., J.V., V.K.C., M.G.-D., M.C.P., M.C.S., J.-M.Y., D.J.H., M.M., C.P.D., B.C., M.C., H.Y., S.H.V., K.K.A., J.A.W., R.R.M., P.S., S.B., K.S., E.R., P.B., S.P., C.N., N.E.A., H.B.B., D.T., N.C., M.T.L., F.C., B.L., A.T., F.C.-C., D.T.B., M.T.W.T., M.A.K., S.G., S.P., F.R., C.S., A.A., G.C.-T., S.S., J.G.H., H.D., T.F., P.R., E.G., K.K., S.C.E.B., A.G., Z.X., J.I.S.-V., M.D.G.-P., M.S., G.V., S.P., S.B., R.N.H., J.F.F., D.T.S. and S.J.C. conducted the epidemiologic studies and contributed samples to the bladder cancer GWAS and/or replication.

All authors contributed to the writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Montserrat Garcia-Closas.

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