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Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Abstract

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10−8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

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Figure 1: Manhattan plot of the stage 1 meta-analysis of GWAS of CMM from Europe, the United States and Australia.
Figure 2: Regional association plots for the new genome-wide significant loci at 2p22.2, 6p22.3, 7p21.1, 9q31.2 and 10q24.33 and the newly confirmed region at 15q13.1 (OCA2).

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Acknowledgements

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M.M.I. and M.H.L. led, designed and carried out the statistical analyses and wrote the manuscript. M. Harland was involved in the Leeds genotyping design. J.C.T. carried out statistical analyses. J.R.-M. and N.v.d.S. carried out genotyping and contributed to the interpretation of genotyping data. J.A.N.B. led the GenoMEL Consortium and contributed to study design. N.A.G. was deputy lead of the consortium and contributed to study design. S.M., N.K.H., D.T.B. and J.H.B. designed and led the overall study. J. Han supervised and carried out statistical analysis of the Harvard GWAS data. F.S. and A.A.Q. carried out statistical analysis of the Harvard GWAS data. C.I.A. led and carried out statistical analysis of the MD Anderson GWAS data. W.V.C., J.E.L. and S.F. contributed to the analysis and interpretation of the MD Anderson GWAS data. F.D. led, designed and contributed to the sample collection, analysis and interpretation of the French MELARISK GWAS and advised on the overall statistical analysis. M.B. contributed to the analysis and interpretation of the French MELARISK GWAS data. M.-F.A. led, designed and contributed to the sample collection of the French MELARISK GWAS. G.M.L. led and contributed to the genotyping and interpretation in the French MELARISK GWAS. R.K. and D.S. led and contributed to the sample collection and analysis for the Heidelberg data set. H.-J.S. contributed to the sample collection and analysis for the Heidelberg data set. S.V.W. led and contributed to the sample collection for the WAMHS study. E.K.M. provided coordination and oversight for the WAMHS study. D.C.W. led, designed and contributed to the sample collection for the SDH data set. J.E.C. led and designed the Glaucoma study. K.P.B. contributed to the analysis and interpretation of the Glaucoma data set. G.L.R.-S. led and contributed to the analysis and interpretation of the IBD data set. L.A.S. contributed to the analysis and interpretation of the IBD data set. G.J.M. led and contributed to the sample collection, analysis and interpretation of the AMFS study. A.E.C. contributed to the sample collection, analysis and interpretation of the AMFS study. D.R.N. contributed to the sample collection and analysis of the Q-MEGA, Endometriosis and QTWIN data sets. N.G.M. led the sample collection and analysis for the Q-MEGA and QTWIN data sets. G.W.M. led the sample collection and analysis for the Endometriosis data sets and contributed to the sample collection and analysis for the Q-MEGA, Endometriosis and QTWIN data sets. D.L.D. contributed to the sample collection and analysis for the Q-MEGA, Endometriosis and QTWIN data sets. K.M.B. contributed to the sample collection and analysis for the Q-MEGA and QTWIN data sets. A.J. Stratigos and K.P.K. interpreted and contributed genotype data for the Athens stage 2 data set. A.M.G., P.A.K. and E.M.G. advised on statistical analysis. D.E.E. contributed to the design of the GenoMEL GWAS. A.J. Swerdlow and N.O. interpreted and contributed genotype data for the Breakthrough Generations Study. L.A.A., P.A.A., E.A., G.B.S., T.D., E.F., P. Ghiorzo, J. Hansson, P.H., M. Hocˇevar, V.H., C.I., M.T.L., J. Lang, R.M.M., A.M., J. Lubin´ski, S.N., H.O., S.P., J.A.P.-B. and R.v.D. contributed to sample collection, analysis and interpretation for the GenoMEL data sets. K.A.P., A.M.D., P.D.P.P. and D.F.E. interpreted and contributed genotype data for the Cambridge stage 2 data set. P. Galan contributed to the collection, analysis and interpretation of the SU.VI.Max French control data set. All authors provided critical review of the manuscript.

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Correspondence to Matthew H Law or Mark M Iles.

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A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

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Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–3, 5–8 and 10, and Supplementary Note. (PDF 4182 kb)

Supplementary Table 4

List of SNPs reaching P < 1 × 10–7. (XLSX 115 kb)

Supplementary Table 9

SNPs used in bioinformatics annotation. (XLSX 19 kb)

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Law, M., Bishop, D., Lee, J. et al. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma. Nat Genet 47, 987–995 (2015). https://doi.org/10.1038/ng.3373

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