ABSTRACT 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

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BEING VIEWED BY OTHERS TRANSCRIPTOME-WIDE ASSOCIATION STUDY IDENTIFIES GENES ASSOCIATED WITH BLADDER CANCER RISK Article Open access 09 January 2025 IDENTIFICATION OF LOW-FREQUENCY VARIANTS

OF _UGT1A3_ ASSOCIATED WITH BLADDER CANCER RISK BY NEXT-GENERATION SEQUENCING Article 03 March 2021 PAN-CANCER AND CROSS-POPULATION GENOME-WIDE ASSOCIATION STUDIES DISSECT SHARED GENETIC

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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 and 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 and Manolis Kogevinas: These authors are the

designated representatives of the participating studies. * Debra T Silverman and Stephen J Chanock: These authors jointly directed this work. AUTHORS AND AFFILIATIONS * 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 * Spanish National Cancer Research Centre, Madrid, Spain Nuria Malats & Francisco X Real * Department of Epidemiology, The University of Texas MD Anderson Cancer

Center, Houston, Texas, USA Xifeng Wu, Michelle A T Hildebrandt, Meng Chen & Hushan Yang * Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona,

Spain Francisco X Real * 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 * Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy Giuseppe Matullo & Fulvio Ricceri *

Human Genetics Foundation (HuGeF), Torino, Italy Giuseppe Matullo, Paolo Vineis, Simonetta Guarrera, Silvia Polidoro, Fulvio Ricceri, Carlotta Sacerdote & Alessandra Allione *

Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA Michael Thun, Eric J Jacobs, W Ryan Diver & Susan M Gapstur * 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 * Comprehensive Cancer Center

East, Nijmegen, The Netherlands Lambertus A Kiemeney & Katja K Aben * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Lambertus A Kiemeney 

& J Alfred Witjes * Imperial College London, London, UK Paolo Vineis & Elio Riboli * Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston,

Massachusetts, USA Immaculata De Vivo * deCODE Genetics, Reykjavik, Iceland Thorunn Rafnar, Patrick Sulem, Soren Besenbacher & Kari Stefansson * Gray Institute for Radiation Oncology and

Biology, University of Oxford, Oxford, UK Anne E Kiltie * Department of Urology, Assistance Publique-Hôpitaux de Paris, Tenon Hospital, Paris, France Olivier Cussenot * Centre de Recherche

sur les Pathologies Prostatiques, Paris, France Olivier Cussenot & Geraldine Cancel-Tassin * Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany Klaus

Golka, Silvia Selinski & Jan G Hengstler * Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany Rajiv Kumar * National Institute of

Environmental Health Sciences, Research Triangle Park, North Carolina, USA Jack A Taylor, Sophia C E Bolick, Ashley Godfrey & Zongli Xu * University of Zaragoza, Zaragoza, Spain Jose I

Mayordomo, Manuel Sanchez & Gabriel Valdivia * Core Genotype Facility, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA Kevin B Jacobs, Amy Hutchinson,

 Zhaoming Wang, Laurie Burdett & Meredith Yeager * Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain Manolis Kogevinas * Municipal Institute of Medical

Research, Barcelona, Spain Manolis Kogevinas * CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Manolis Kogevinas, Adonina Tardón & Carmen Navarro * National School of

Public Health, Athens, Greece Manolis Kogevinas * Information Management Services, Inc., Rockville, Maryland, USA William Wheeler * Instituto Universitario de Oncología, Universidad de

Oviedo, Oviedo, Spain Adonina Tardón * Universitat Pompeu Fabra, Barcelona, Spain Consol Serra * Ramón y Cajal University Hospital, Madrid, Spain Alfredo Carrato * Unidad de Investigación,

Hospital Universitario de Canarias, La Laguna, Spain Reina García-Closas * Hospital del Mar-Institut Municipal d'Investigació Mèdica (IMIM), Universitat Pompeu Fabra, Barcelona, Spain

Josep Lloreta * Vermont Cancer Registry, Burlington, Vermont, USA Alison Johnson * Maine Cancer Registry, Augusta, Maine, USA Molly Schwenn * Dartmouth Medical School, Hanover, New

Hampshire, USA Margaret R Karagas & Alan Schned * Department of Urology, Washington University School of Medicine, St. Louis, Missouri, USA Gerald Andriole Jr & Robert Grubb III *

National Institute for Health and Welfare, Helsinki, Finland Jarmo Virtamo * Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Malcolm C Pike * Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA Jian-Min Yuan * Department of Epidemiology, Program in Molecular and Genetic Epidemiology,

Harvard School of Public Health, Boston, Massachusetts, USA David J Hunter & Monica McGrath * Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas,

USA Colin P Dinney * Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Bogdan Czerniak * Department of Human Genetics, Radboud University

Nijmegen Medical Centre, Nijmegen, The Netherlands Sita H Vermeulen & Remco R Makkinje * Faculty of Medicine, University of Iceland, Reykjavik, Iceland Kari Stefansson * International

Agency for Research on Cancer, Lyon, France Paul Brennan * Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy Salvatore Panico * Department of

Epidemiology, Murcia Regional Health Council, Murcia, Spain Carmen Navarro * Nuffield Department of Clinical Medicine, Cancer Epidemiology Unit, University of Oxford, Oxford, UK Naomi E

Allen * National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands H Bas Bueno-de-Mesquita * Department of Epidemiology, Harvard School of Public Health,

Boston, Massachusetts, USA Dimitrios Trichopoulos * Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece Dimitrios Trichopoulos * Genomic Epidemiology Group, German Cancer

Research Center, Heidelberg, Germany Federico Canzian * Department of Surgical and Perioperative Sciences, University of Umea, Umea, Sweden Borje Ljungberg * Danish Cancer Society, Institute

of Cancer Epidemiology, Copenhagen, Denmark Anne Tjonneland * Centre for Research in Epidemiology and Population Health, Institute Gustave-Roussy, Paris South University, Villejuif, France

Francoise Clavel-Chapelon * 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

* Unit of Cancer Epidemiology, University of Torino, Torino, Italy Carlotta Sacerdote * Department of Urology, Paul Gerhardt Foundation, Wittenberg, Germany Holger Dietrich * Institute of

Hygiene and Tropical Medicine, London, UK Tony Fletcher * National Institute of Environmental Health, Budapest, Hungary Peter Rudnai * Babes Bolyai University, Environmental Health Center,

Cluj-Napoca, Romania Eugen Gurzau * State Health Institute, Banská Bystrica, Slovakia Kvetoslava Koppova * San Jorge University Hospital, Huesca, Spain José I Sanz-Velez & María D

García-Prats * Department of Experimental and Applied Medicine, Section of Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy Stefano Porru * 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 * Centre National de la

Recherche Scientifique, UMR8200, Institut Gustave-Roussy, Villejuif, France Simone Benhamou Authors * Nathaniel Rothman View author publications You can also search for this author inPubMed 

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CONTRIBUTIONS 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. CORRESPONDING AUTHOR Correspondence to Montserrat Garcia-Closas. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–7, Supplementary Tables 1–4 and

Supplementary Note (PDF 4458 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Rothman, N., Garcia-Closas, M., Chatterjee, N. _et al._ A multi-stage

genome-wide association study of bladder cancer identifies multiple susceptibility loci. _Nat Genet_ 42, 978–984 (2010). https://doi.org/10.1038/ng.687 Download citation * Received: 10 May

2010 * Accepted: 19 August 2010 * Published: 24 October 2010 * Issue Date: November 2010 * DOI: https://doi.org/10.1038/ng.687 SHARE THIS ARTICLE Anyone you share the following link with

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