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Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10−21), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10−10), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10−8) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10−13 and 3.63 × 10−11, respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

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Figure 1: Association results, recombination hotspots and LD plots for the regions newly associated with DLBCL.

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Acknowledgements

We thank C. Allmer, E. Angelucci, A. Bigelow, S. Buehler, K. Butterbach, A. Chabrier, J.M. Conners, M. Corines, M. Cornelis, K. Corsano, H. Dykes, L. Ershler, A. Gabbas, R.P. Gallagher, R.D. Gascoyne, P. Hui, L. Irish, L. Jacobus, L. Klareskog, A.S. Lai, J. Lunde, M. McAdams, R. Montalvan, L. Padyukov, M. Rais, T. Rattle, L. Rigacci, K. Snyder, G. Specchia, M. Stagner, G. Thomas, C. Tornow, G. Wood and M. Yang. The overall GWAS project was supported by the Intramural Program of the US National Institutes of Health/National Cancer Institute. A list of support provided to individual studies appears in the Supplementary Note.

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J.R.C., S.I.B., S.S.W., A.N., A.R.B.-W., Q.L., G. Severi, M. Melbye, L.R.T., M.P.P., C.L., B.M.B., S.L.S., S.d.S., K.E.S., C.F.S., N.R. and S.J.C. organized and designed the study. J.R.C., L.C., L.B., A.H., P.M.B., E.A.H., S.L.S., G. Salles, C.F.S., N.R. and S.J.C. conducted and supervised the genotyping of samples. J.R.C., S.I.B., J. Vijai, Z.W., M.Y., L.C., P.I.W.d.B., D.C., J.G., D. Zhi, Y.W.A., J.H., B.M., J.S., L.L., J.-H.P., C.C.C., N.C., S.d.S., K.E.S., C.F.S., N.R. and S.J.C. contributed to the design and execution of statistical analysis. J.R.C., S.I.B., J. Vijai, H.G., J.M., S.S.W., Z.W., M.Y., L.C., A.N., D.C., A.M., C.R.F., A.J.D.R., C.L., K.E.S., C.F.S., N.R. and S.J.C. wrote the first draft of the manuscript. J.R.C., J. Vijai, H.G., J.M., S.S.W., L.C., A.N., L.B., A.M., A.R.B.-W., Q.L., G. Severi, M. Melbye, J.G., R.D.J., E.K., L.R.T., M.P.P., C.M.V., J.J.S., G.G.G., D.A., R.S.K., M.Z., K.A.B., A.Z.-J., T.M.H., B.K.L., A.J.N., A.D., Y.W.A., M.L., C.A.T., S.M.A., T.E.W., G.J.W., A.S.V., D. Zelenika, H.T., C.H., T.J.M., H.H., B.G., H.-O.A., P.M.B., J.R., M.T.S., E.A.H., W.C., P.H., L.M.M., R.K.S., L.F.T., K.E.N., N.B., Y.B., P. Boffetta, P. Brennan, L.F., M. Maynadie, A. Staines, T.L., S.C., A. Smith, E. Roman, W.R.D., K.O., A.Z., R.J.K., D.J.V., T.Z., Y.Z., T.R.H., A.K., J.T., M.C.S., J.C., J. Virtamo, S.W., E. Riboli, P.V., R.K., D.T., R.C.H.V., H.B., A.T., E.A., S.D.L., M.R., B.M.B., F.L., E.G., P.K., Y.Y., B.C.H.C., D.D.W., N.C., J.F.F., S.L.S., X.W., S.d.S., K.E.S., G. Salles, C.F.S. and N.R. 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 James R Cerhan.

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Integrated supplementary information

Supplementary Figure 1 Schematic of the study design.

Supplementary Figure 2 Quantile-quantile (Q-Q) plot of the association results in the stage 1 DLBCL GWAS (red) and after removing SNPs from the HLA region (green).

Supplementary Figure 3 Manhattan plot showing the statistical significance of the association for all genotyped SNPs in the stage 1 DLBCL GWAS.

SNPs are plotted on the x axis according to their position on each chromosome against the significance of the association on the y axis (shown as –log10 P value). The dotted line denotes P = 5 × 10–8 statistical significance.

Supplementary Figure 4 Association results, recombination hotspots and LD plots for the region 5q31.3 with DLBCL.

Top, association results of GWAS data from the stage 1 DLBCL GWAS (gray diamonds) and combined data of stages 1–3 (red diamond) are shown with –log10 (P values) (left y axis). Overlaid are the likelihood ratio statistics (right y axis) to estimate putative recombination hotspots across the region on the basis of 5 unique sets of 100 randomly selected control samples. Bottom, LD heat map based on r2 values from combined control populations for all SNPs included in the GWAS.

Supplementary Figure 5 Chromatin state dynamics of DLBCL-associated SNPs in nine human cell lines.

For details, see the Online Methods.

Supplementary Figure 6 Plot of estimated admixture for individuals in the NHL GWAS (stage 1).

For details, see the Online Methods. Individuals with <80% European ancestry were excluded.

Supplementary Figure 7 Plot of top eigenvectors from DLBCL GWAS (stage 1) data based on principal-components analysis.

For details, see the Online Methods.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 1–5, 7–11 and 13, and Supplementary Note. (PDF 5307 kb)

Supplementary Tables 6 and 12

Supplementary Tables 6 and 12 (XLSX 113 kb)

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Cerhan, J., Berndt, S., Vijai, J. et al. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet 46, 1233–1238 (2014). https://doi.org/10.1038/ng.3105

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