Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Abstract

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10−14), 18q21.33 (BCL2, P = 7.76 × 10−11), 11p15.5 (C11orf21, P = 2.15 × 10−10), 4q25 (LEF1, P = 4.24 × 10−10), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 × 10−9), 9p21.3 (CDKN2B-AS1, P = 1.27 × 10−8), 18q21.32 (PMAIP1, P = 2.51 × 10−8), 15q15.1 (BMF, P = 2.71 × 10−10) and 2p22.2 (QPCT, P = 1.68 × 10−8), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 × 10−18). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 × 10−8) and 5p15.33 (TERT, P = 1.92 × 10−7). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.

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Figure 1: Association results, recombination hotspots and LD plots for the regions newly associated with CLL.
Figure 2: Association results, recombination hotspots and LD plot for the new independent CLL susceptibility SNP in the established 2q13 locus.

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Acknowledgements

We thank C. Allmer, E. Angelucci, A. Bigelow, I. Brock, K. Butterbach, A. Chabrier, D. Chan-Lam, J.M. Conners, D. Connley, M. Cornelis, K. Corsano, C. Dalley, D. Cox, H. Cramp, R. Cutting, H. Dykes, L. Ershler, A. Gabbas, R.P. Gallagher, R.D. Gascoyne, P. Hui, L. Irish, L. Jacobus, S. Kaul, J. Lunde, M. McAdams, R. Montalvan, M. Rais, T. Rattle, L. Rigacci, K. Snyder, G. Specchia, M. Stagner, P. Taylor, G. Thomas, C. Tornow, G. Wood, M. Yang and M. Zucca for their assistance. The overall GWAS project was supported by the intramural program of the Division of Cancer Epidemiology and Genetics, NCI, US National Institutes of Health. A full list of acknowledgments is provided in the Supplementary Note.

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S.I.B., C.F.S., N.J.C., A.N., W.C., S.S.W., L.R.T., A.R.B.-W., P.H., M.P.P., B.M.B., B.K.A., P.C., Y.Z., G.S., A.Z.-J., C.L., K.E.S., J.M., P.V., J.J.S., A.K., S.d.S., H.H., J.R.C., S.J.C., N.R. and S.L.S. organized and designed the study. C.F.S., N.J.C., B.J., L.B., J.Y., A.H., L.C., P.M.B., E.A.H., J.M.C., J.R.C., S.J.C. and S.L.S. conducted and supervised the genotyping of samples. S.I.B., C.F.S., V.J., N.J.C., Z.W., N.C., C.C.C., M.Y., K.B.J., L.L., J.S., J.-H.P., J.R.C., L.C., S.J.C., N.R. and S.L.S. contributed to the design and execution of statistical analyses. S.I.B., C.F.S., V.J., N.J.C., A.N., Z.W., W.C., A.M., R.S.K., N.C., C.C.C., M.Y., C.L., H.H., J.R.C., S.J.C., N.R. and S.L.S. wrote the first draft of the manuscript. S.I.B., C.F.S., V.J., N.J.C., A.N., W.C., A.M., S.S.W., R.S.K., Q.L., L.R.T., A.R.B.-W., P.H., M.P.P., B.M.B., B.K.A., P.C., Y.Z., G.S., A.Z.-J., T.G.C., T.D.S., A.J.N., N.E.K., M.L., A.H.W., K.E.S., H.-O.A., M. Melbye, B.G., E.T.C., M.G., K.C., L.A.C.-A., B.J., W.R.D., B.K.L., G.J.W., L.C., P.M.B., J.R., E.A.H., M.T.S., R.D.J., L.F.T., S.d.S., Y.B., N.B., P. Boffetta, P. Brennan, L.F., M. Maynadie, J.M., A.S., K.G.R., S.J.A., C.M. Vachon, L.R.G., S.S.S., M.C.L., L.G.S., J.F.L., J.M.C., J.B.W., V.A.M., N.E.C., A.D.N., M.S.L., A.J.D.R., L.M.M., R.K.S., E.R., P.V., R.K., D.T., G.M., E.W., M.-D.C., R.C.H.V., R.C.T., G.G.G., D.A., J.V., S.W., J.C., T.Z., T.R.H., K.O., A.Z., R.J.K., J.J.S., K.A.B., F.L., E.G., P.K., A.K., J.T., C.M. Vajdic, M.G.E., G.M.F., L.M., L.L., J.A.S., S.C., J.F.F., K.E.N., A. Cox, J.S., J.W., A. Carracedo, C.L.-O., S.B., I.S., D.M.-G., E.C., H.H., J.R.C., N.R. and S.L.S. conducted the epidemiological studies and contributed samples to the GWAS and/or follow-up genotyping. All authors contributed to the writing of the manuscript.

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Correspondence to Susan L Slager.

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Berndt, S., Skibola, C., Joseph, V. et al. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nat Genet 45, 868–876 (2013). https://doi.org/10.1038/ng.2652

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