Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3


We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAPCDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10−11, OR in combined replication cohorts of 0.89 (95% CI 0.85–0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10−8). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

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Figure 1: Association results for SNPs directly genotyped in all Australian samples.
Figure 2: Discovery sample association results at two loci on chromosome 1 for both SNPs directly genotyped in all Australian samples and imputed SNPs.


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The AMFS and Q-MEGA gratefully acknowledge all their participants and the hard work of all their research interviewers and examiners and especially acknowledge C. Agha-Hamilton for managing the AMFS biospecimens. Q-MEGA thanks A. Baxter, M. de Nooyer, I. Gardner, D. Statham, B. Haddon, M.J. Wright, J. Palmer, J. Symmons, B. Castellano, L. Bardsley, S. Smith, D. Smyth, L. Wallace, M.J. Campbell, A. Caracella, M. Kvaskoff, O. Zheng, B. Chapman and H. Beeby for their input in project management, sample processing and database development. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the QIMR and AMFS collections. We acknowledge with appreciation all the participants in the QIMR and endometriosis studies. We thank Endometriosis Associations for supporting study recruitment. We thank S. Nicolaides and the Queensland Medical Laboratory for the pro bono collection and delivery of blood samples and other pathology services for assistance with blood collection. We thank the following US state cancer registries for their help: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington and Wyoming.

This work was supported by the Melanoma Research Alliance, the National Cancer Institute (NCI) of the US National Institutes of Health (NIH) (CA88363, CA83115, CA122838, CA87969, CA055075, CA100264, CA133996 and CA49449), the National Health and Medical Research Council (NHMRC) of Australia (107359, 200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 402761, 443036, 442915, 442981, 496610, 496675, 496739, 552485 and 552498), the Cancer Councils New South Wales, Victoria and Queensland, the Cancer Institute New South Wales, the Cooperative Research Centre (CRC) for Discovery of Genes for Common Human Diseases, Cerylid Biosciences (Melbourne), the Australian Cancer Research Foundation, The Wellcome Trust and donations from Neville and Shirley Hawkins. Endometriosis sample genotyping was funded by a grant from the Wellcome Trust (WT084766/Z/08/Z). The Australian Twin Registry is supported by an Australian National Health and Medical Research Council (NHMRC) Enabling Grant (2004–2009). D.L.D., N.K.H. and G.W.M. are supported by the NHMRC Fellowships scheme and J.L.H. is an Australia Fellow of the NHMRC. S.M. is the recipient of a Career Development Award from the NHMRC (496674, 613705). D.C.W. is a Future Fellow of the Australian Research Council. K.M.B. is supported by the NCI of the NIH. J.M.T. is supported by the NCI of the NIH (CA109544). B.K.A. is supported by the University of Sydney Medical Foundation. A.E.C. is the recipient of a NHMRC public health postdoctoral fellowship (520018) and a Cancer Institute NSW Early Career Development Fellowship (10/ECF/2-06). A.M.G. and M.T.L. were supported by the Intramural Research Program of the NIH, NCI and DCEG. The GenoMEL replication sample was funded by the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702), by Cancer Research UK Programme Award (C588/A4994) and by the NIH (CA83115). Research at M.D. Anderson Cancer Center (MDACC) was partially supported by NIH grants (CA100264, 2P50CA093459, P30CA016672 and R01CA133996). The Center for Inherited Disease Research performed genotyping for MDACC and is supported by contract (HHSN268200782096C). GENEVA performed data cleaning and is supported by an NIH grant (HG004446). Research by the Barcelona team was supported by Fondo de Investigaciones Sanitarias (09/1393).

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S.M., N.K.H. and K.M.B. wrote the manuscript. G.W.M., N.K.H., K.M.B., J.M.T., A.K.H., Z.Z.Z. and M.S. designed, analyzed and managed the sample preparation and genotyping aspects of the study. S.M. and J.Z.L. performed data analysis. D.C.W., D.L.D., G.W.M., N.K.H., S.M., J.N.P., D.R.N. and N.G.M. oversaw collection of the Queensland samples and contributed to statistical analyses, data interpretation and manuscript preparation. G.J.M., A.E.C., E.A.H., H.S., J.A.M., J.J., M.F., M.A.J., R.F.K., G.G.G., B.K.A., J.F.A. and J.L.H. oversaw sample collection, genotyping and analysis in the AMFS study. D.T.B., J.A.N.-B., M.M.I., H.O., S.P., G.B.-S., J.H., F.D., M.T.L., T.D., R.M., E.A., B.B.-d.P., A.M.G., P.A.K., N.A.G., P.H. and D.E.E. contributed to the collection, genotyping and analysis of the GenoMEL samples. C.I.A., Q.W., L.-E.W. and J.E.L. contributed to the collection, genotyping and analysis of the United States 1–M.D. Anderson Cancer Center samples. A.A.Q., M.Z. and J.H. contributed to the collection, genotyping and analysis of the United States 2–Harvard samples.

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Correspondence to Stuart MacGregor.

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MacGregor, S., Montgomery, G., Liu, J. et al. Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3. Nat Genet 43, 1114–1118 (2011).

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