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Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi

Nature Genetics volume 41, pages 915–919 (2009)Cite this article

Abstract

A high melanocytic nevi count is the strongest known risk factor for cutaneous melanoma. We conducted a genome-wide association study for nevus count using 297,108 SNPs in 1,524 twins, with validation in an independent cohort of 4,107 individuals. We identified strongly associated variants in MTAP, a gene adjacent to the familial melanoma susceptibility locus CDKN2A on 9p21 (rs4636294, combined P = 3.4 × 10−15), as well as in PLA2G6 on 22q13.1 (rs2284063, combined P = 3.4 × 10−8). In addition, variants in these two loci showed association with melanoma risk in 3,131 melanoma cases from two independent studies, including rs10757257 at 9p21, combined P = 3.4 × 10−8, OR = 1.23 (95% CI = 1.15–1.30) and rs132985 at 22q13.1, combined P = 2.6 × 10−7, OR = 1.23 (95% CI = 1.15–1.30). This provides the first report of common variants associated to nevus number and demonstrates association of these variants with melanoma susceptibility.

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Figure 1: Genome-wide association plot for total nevus count in the TwinsUK sample.
Figure 2: Regional plots.
Figure 3
Figure 4: Relative positions of genes in the vicinity of the 9p21 association signal (not drawn to scale).

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Acknowledgements

The KCL authors acknowledge financial support from the Wellcome Trust, the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, EC Framework 7 Health-2007-A ENGAGE project and the Chronic Disease Research Foundation (CDRF). T.D.S. is an NIHR senior investigator. We would also like to thank all the nurses and research assistants who collected the skin data, including U. Perks, G. Clement, D. Glass and E. Qweitin as well as the volunteer twins who gave their time.

The Leeds case-control study and genotyping was supported by Cancer Research UK Programme Award (C588/A4994), NIH (R01 CA83115) and EU FP6 to GenoMEL (LSHC-CT-2006-018702).

This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. The Leeds second control series were recruited through an award from the Department of Health in conjunction with I. dos Santos Silva and A. Swerdlow. We would like to thank J. Taylor for statistical analyses relating to the Leeds dataset. T.P. holds a Canada Research Chair and is supported by Genome Canada/Quebec and the CIHR.

The Australian Studies were supported by the National Institutes of Health/National Cancer Institute (CA88363), the National Health and Medical Research Council of Australia (NHMRC) and the Cancer Council Queensland. D.L.D., G.W.M. and N.K.H. are supported by the NHMRC Fellowships scheme. We thank D. Whiteman, A. Green, J. Aitken, A. Henders, M. Campbell, M. Stark, A. Baxter, M. de Nooyer, I. Gardner, D. Statham, B. Haddon, J. Palmer, L. Bardsley, D. Smyth and H. Beeby for their input into project management, sample processing, database and questionnaire development. We are grateful to all the participants of the BTNS and Q-MEGA as well as the research interviewers and examiners for these studies.

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Author notes

  1. Mario Falchi, Veronique Bataille, Nicholas K Hayward, D Timothy Bishop, Grant W Montgomery and Timothy D Spector: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Twin Research & Genetic Epidemiology, Kings College London, St. Thomas' Hospital Campus, London, UK

    Mario Falchi, Veronique Bataille, Alessandra Cervino, Nicole Soranzo & Timothy D Spector

  2. Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK

    Mario Falchi

  3. Dermatology Department, West Hertfordshire NHS Trust, Hemel Hempstead General Hospital, Herts, UK

    Veronique Bataille

  4. Oncogenomics, Queensland Institute of Medical Research, Brisbane, Australia

    Nicholas K Hayward

  5. Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia

    David L Duffy & Nicholas G Martin

  6. Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK

    Julia A Newton Bishop, Jennifer H Barrett & D Timothy Bishop

  7. Department of Human and Medical Genetics, McGill University, Montréal, Canada

    Tomi Pastinen

  8. McGill University and Genome Québec Innovation Centre, Montréal, Canada

    Tomi Pastinen

  9. Molecular Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia

    Zhen Z Zhao & Grant W Montgomery

  10. Human Genetics Department, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Panos Deloukas & Nicole Soranzo

  11. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    David E Elder

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Contributions

M.F., T.D.S., N.G.M., D.T.B. and N.K.H. designed the study. M.F., D.L.D., J.H.B. and A.C. analysed the data. V.B., N.G.M. and J.A.N.B. contributed to data collection and phenotype definitions. T.D.S., P.D., D.E.E., N.G.M., N.K.H. and J.A.N.B. obtained funding. Z.Z.Z., P.D., N.S. and G.W.M. contributed to genotyping. M.F., V.B. and T.D.S. wrote the first draft of the paper. All authors made important contributions to the final version of the paper.

Corresponding authors

Correspondence to Mario Falchi or Timothy D Spector.

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Falchi, M., Bataille, V., Hayward, N. et al. Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat Genet 41, 915–919 (2009). https://doi.org/10.1038/ng.410

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