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

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 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.

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Acknowledgements

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.

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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.

Corresponding author

Correspondence to Montserrat Garcia-Closas.

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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). https://doi.org/10.1038/ng.687

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