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


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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Figure 1: Study design of a multi-stage GWAS of bladder cancer.
Figure 2: Association results, recombination and linkage disequilibrium plots for four regions on chromosomes 22q13.1, 19q12, 2q37.1 and 8p22.


  1. 1

    Silverman, D.T., Devesa, S.S., Moore, L.E. & Rothman, N. Bladder cancer. in Cancer Epidemiology and Prevention (eds. Schottenfeld, D. and Fraumeni, J.F. Jr.) 1101–1127 (Oxford University Press, New York, 2006).

  2. 2

    Kantor, A.F., Hartge, P., Hoover, R.N. & Fraumeni, J.F. Jr. Familial and environmental interactions in bladder cancer risk. Int. J. Cancer 35, 703–706 (1985).

    Google Scholar 

  3. 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).

    Google Scholar 

  4. 4

    Aben, K.K. et al. Segregation analysis of urothelial cell carcinoma. Eur. J. Cancer 42, 1428–1433 (2006).

    Google Scholar 

  5. 5

    Lower, G.M. Jr. et al. N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark. Environ. Health Perspect. 29, 71–79 (1979).

    Google Scholar 

  6. 6

    Bell, D.A. et al. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J. Natl. Cancer Inst. 85, 1159–1164 (1993).

    Google Scholar 

  7. 7

    García-Closas, M. et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 366, 649–659 (2005).

    Google Scholar 

  8. 8

    Rothman, N., Garcia-Closas, M. & Hein, D.W. Commentary: Reflections on G.M. Lower and colleagues' 1979 study associating slow acetylator phenotype with urinary bladder cancer: meta-analysis, historical refinements of the hypothesis, and lessons learned. Int. J. Epidemiol. 36, 23–28 (2007).

    Google Scholar 

  9. 9

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

    Google Scholar 

  10. 10

    Kiemeney, L.A. et al. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat. Genet. 42, 415–419 (2010).

    Google Scholar 

  11. 11

    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).

    Google Scholar 

  12. 12

    Eeles, R.A. et al. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat. Genet. 41, 1116–1121 (2009).

    Google Scholar 

  13. 13

    Yeager, M. et al. Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat. Genet. 41, 1055–1057 (2009).

    Google Scholar 

  14. 14

    Crowther-Swanepoel, D. et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42, 132–136 (2010).

    Google Scholar 

  15. 15

    Tomlinson, I.P. et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat. Genet. 40, 623–630 (2008).

    Google Scholar 

  16. 16

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

    Google Scholar 

  17. 17

    Zanke, B.W. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat. Genet. 39, 989–994 (2007).

    Google Scholar 

  18. 18

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

    Google Scholar 

  19. 19

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

    Google Scholar 

  20. 20

    Stacey, S.N. et al. New common variants affecting susceptibility to basal cell carcinoma. Nat. Genet. 41, 909–914 (2009).

    Google Scholar 

  21. 21

    Landi, M.T. et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am. J. Hum. Genet. 85, 679–691 (2009).

    Google Scholar 

  22. 22

    Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899–904 (2009).

    Google Scholar 

  23. 23

    Petersen, G.M. et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat. Genet. 42, 224–228 (2010).

    Google Scholar 

  24. 24

    Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).

    Google Scholar 

  25. 25

    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  26. 26

    García-Closas, M. et al. A single nucleotide polymorphism identified in a genome-wide scan tags variation in the N-acetyltransferase 2 phenotype in populations of European background. Pharmacogenet. Genomics published online, doi:10.1097/FPC.0b013e32833e1b54 (25 August 2010).

  27. 27

    Conticello, S.G. The AID/APOBEC family of nucleic acid mutators. Genome Biol. 9, 229 (2008).

    Google Scholar 

  28. 28

    Malumbres, M. & Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nat. Rev. Cancer 1, 222–231 (2001).

    Google Scholar 

  29. 29

    Richter, J. et al. High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer. Am. J. Pathol. 157, 787–794 (2000).

    Google Scholar 

  30. 30

    Strassburg, C.P., Lankisch, T.O., Manns, M.P. & Ehmer, U. Family 1 uridine-5′-diphosphate glucuronosyltransferases (UGT1A): from Gilbert's syndrome to genetic organization and variability. Arch. Toxicol. 82, 415–433 (2008).

    Google Scholar 

  31. 31

    Ando, Y. et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 60, 6921–6926 (2000).

    Google Scholar 

  32. 32

    Strassburg, C.P., Manns, M.P. & Tukey, R.H. Differential down-regulation of the UDP-glucuronosyltransferase 1A locus is an early event in human liver and biliary cancer. Cancer Res. 57, 2979–2985 (1997).

    Google Scholar 

  33. 33

    Strassburg, C.P., Nguyen, N., Manns, M.P. & Tukey, R.H. Polymorphic expression of the UDP-glucuronosyltransferase UGT1A gene locus in human gastric epithelium. Mol. Pharmacol. 54, 647–654 (1998).

    Google Scholar 

  34. 34

    Giuliani, L. et al. Can down-regulation of UDP-glucuronosyltransferases in the urinary bladder tissue impact the risk of chemical carcinogenesis? Int. J. Cancer 91, 141–143 (2001).

    Google Scholar 

  35. 35

    Iida, K. et al. Suppression of AhR signaling pathway is associated with the down-regulation of UDP-glucuronosyltransferases during BBN-induced urinary bladder carcinogenesis in mice. J. Biochem. 147, 353–360 (2010).

    Google Scholar 

  36. 36

    Calado, R.T. & Young, N.S. Telomere maintenance and human bone marrow failure. Blood 111, 4446–4455 (2008).

    Google Scholar 

  37. 37

    Armanios, M.Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).

    Google Scholar 

  38. 38

    Tsakiri, K.D. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl. Acad. Sci. USA 104, 7552–7557 (2007).

    Google Scholar 

  39. 39

    Calado, R.T. et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc. Natl. Acad. Sci. USA 106, 1187–1192 (2009).

    Google Scholar 

  40. 40

    Park, J.H. et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat. Genet. 42, 570–575 (2010).

    Google Scholar 

  41. 41

    Hein, D.W. N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene 25, 1649–1658 (2006).

    Google Scholar 

  42. 42

    Wigginton, J.E., Cutler, D.J. & Abecasis, G.R. A note on exact tests of Hardy-Weinberg equilibrium. Am. J. Hum. Genet. 76, 887–893 (2005).

    Google Scholar 

  43. 43

    Pritchard, J.K., Stephens, M. & Donnelly, P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).

    Google Scholar 

  44. 44

    Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    Google Scholar 

  45. 45

    Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Google Scholar 

  46. 46

    Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    Google Scholar 

  47. 47

    Yu, K. et al. Population substructure and control selection in genome-wide association studies. PLoS ONE 3, e2551 (2008).

    Google Scholar 

  48. 48

    de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122–R128 (2008).

    Google Scholar 

  49. 49

    Sun, L., Wilder, K. & McPeek, M.S. Enhanced pedigree error detection. Hum. Hered. 54, 99–110 (2002).

    Google Scholar 

  50. 50

    Clayton, D. Testing for association on the X chromosome. Biostatistics 9, 593–600 (2008).

    Google Scholar 

  51. 51

    Fearnhead, P. SequenceLDhot: detecting recombination hotspots. Bioinformatics 22, 3061–3066 (2006).

    Google Scholar 

  52. 52

    Fearnhead, P., Harding, R.M., Schneider, J.A., Myers, S. & Donnelly, P. Application of coalescent methods to reveal fine-scale rate variation and recombination hotspots. Genetics 167, 2067–2081 (2004).

    Google Scholar 

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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




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.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7, Supplementary Tables 1–4 and Supplementary Note (PDF 4458 kb)

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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).

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