Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility
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ISSN: 1061-4036
ESSN: 1546-1718
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Abstract
Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis
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M.T.L., M.M.I. and M.H.L. conceptualized and designed the project. D.T.B., S. MacGregor, M.T.L. and S.J.C. provided funding support. M.T.L., D.T.B., S. MacGregor, M.J.M., J.S., M.M.I. and M.H.L. interpreted the results and supervized the study. M.J.M., M.T.L., M.M.I., K.B., J.C. and M.H.L. wrote the manuscript. J.S., M.M.I., K.B., T.Z., J.C., D.L.D. and M.H.L. analyzed the data. A.J. Stratigos, P. Ghiorzo, S.P. and E.N. coordinated the study and collected the data. M.T.L., D.T.B., S. MacGregor, M.J.M., A.J. Stratigos, P. Ghiorzo, M.B., D.C., J.C., M.C.F., T.Z., M.R., A.J.T., C.M., J. Martinez, A. Hadjisavvas, L.S., I.S., R.S., X.R.Y., A.M.G., M.P., K.P.K., L.P., P.Q., C.P., L.C., M.Z., P. Gimenez-Xavier, A.R., L.E., S. Manoukian, L.R., B.H.S., M.A.L., L.D.R., D.M., M. Mandala, K.K., L.A.A., C.I.A., P.A.A., M.A., E.A., H.P.S., V.B., B.D., L.M.B., K.P.B., W.V.C., V.C., J.E.C., T.D., M.F., S.F., E.F., S.S., P. Galan, Z.G., E.M.G., S.G., A.G., N.A.G., J. Hansson, M. Harland, J. Harris, P.H., A. Henders, M. Hočevar, V.H., D.H., C.I., R.K., J. Lang, G.M.L., J.E.L., X.L., J. Lubiński, R.M.M., M. Malt, J. Malvehy, K.M., H.M., A.M., E.K.M., R.E.N., S.N., D.R.N., H.O., N.O., L.G.F., J.A.P., A.A.Q., G.L.R., J.R., C. Requena, C. Rowe, N.J.S., M. Sanna, D.S., H.S., L.A.S., M. Smithers, F.S., A.J. Swerdlow, N.V.D.S., N.A.K., A. Visconti, L. Wallace, S.V.W., L. Wheeler, R.A.S., A. Hutchinson, K.J., M. Malasky, A. Vogt, W.Z., K.A.P., D.E.E., J. Han, B.H., N.K.H., P.A.K., C.B., G.W.M., C.M.O., C.H., A.M.D., N.G.M., E.E., G.J.M., G.L., P.D.P.P., D.F.E., J.H.B., A.E.C., G.A., D.L.D., D.C.W., H.G., A.D.N., M.A.T., J.A.N.B., K.P., S.J.C., K.M.B., F.D., S.P., E.N., J.S., M.M.I. and M.H.L. participated in data collection, results interpretation and manuscript review.
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