Letter | Published:

Genome-wide association study identifies three new melanoma susceptibility loci

Nature Genetics volume 43, pages 11081113 (2011) | Download Citation


We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10−3: an SNP in ATM (rs1801516, overall P = 3.4 × 10−9), an SNP in MX2 (rs45430, P = 2.9 × 10−9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10−10). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10−7 under a fixed-effects model and P = 1.2 × 10−3 under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , & Genetic predisposition to cancer. Important Adv. Oncol. 39–55 (1991).

  2. 2.

    et al. Cutaneous malignant melanoma in women. Phenotypic characteristics, sun exposure, and hormonal factors: a case-control study from Italy. Ann. Epidemiol. 15, 545–550 (2005).

  3. 3.

    et al. Pigmentary characteristics and moles in relation to melanoma risk. Int. J. Cancer 116, 144–149 (2005).

  4. 4.

    , , , & Cutaneous melanoma in women. I. Exposure to sunlight, ability to tan, and other risk factors related to ultraviolet light. Am. J. Epidemiol. 141, 923–933 (1995).

  5. 5.

    , , , & Cutaneous melanoma in women. II. Phenotypic characteristics and other host-related factors. Am. J. Epidemiol. 141, 934–942 (1995).

  6. 6.

    et al. Risk of cutaneous melanoma in relation to the numbers, types and sites of naevi: a case-control study. Br. J. Cancer 73, 1605–1611 (1996).

  7. 7.

    et al. A pooled analysis of melanocytic nevus phenotype and the risk of cutaneous melanoma at different latitudes. Int. J. Cancer 124, 420–428 (2009).

  8. 8.

    et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat. Genet. 41, 920–925 (2009).

  9. 9.

    et al. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int. J. Cancer 122, 2753–2760 (2008).

  10. 10.

    et al. Population-based study of natural variation in the melanocortin-1 receptor gene and melanoma. Cancer Res. 66, 9330–9337 (2006).

  11. 11.

    et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat. Genet. 40, 886–891 (2008).

  12. 12.

    et al. Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat. Genet. 41, 915–919 (2009).

  13. 13.

    et al. Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat. Genet. 40, 838–840 (2008).

  14. 14.

    et al. IRF4 variants have age-specific effects on nevus count and predispose to melanoma. Am. J. Hum. Genet. 87, 6–16 (2010).

  15. 15.

    et al. Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J. Invest. Dermatol. 130, 520–528 (2010).

  16. 16.

    et al. Variants of the MATP/SLC45A2 gene are protective for melanoma in the French population. Hum. Mutat. 29, 1154–1160 (2008).

  17. 17.

    , , & Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians. Int. J. Cancer 125, 909–917 (2009).

  18. 18.

    et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat. Genet. 41, 221–227 (2009).

  19. 19.

    et al. A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet. 4, e1000074 (2008).

  20. 20.

    et al. SLC45A2: a novel malignant melanoma-associated gene. Hum. Mutat. 29, 1161–1167 (2008).

  21. 21.

    Variation at the TERT locus and predisposition for cancer. Expert Rev. Mol. Med. 12, e16 (2010).

  22. 22.

    , , & CASP8 polymorphisms contribute to cancer susceptibility: evidence from a meta-analysis of 23 publications with 55 individual studies. Carcinogenesis 31, 850–857 (2010).

  23. 23.

    Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat. Rev. Mol. Cell Biol. 9, 759–769 (2008).

  24. 24.

    Upward bias in odds ratio estimates from genome-wide association studies. Genet. Epidemiol. 31, 288–295 (2007).

  25. 25.

    et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005).

  26. 26.

    et al. Melanocytic nevi, nevus genes, and melanoma risk in a large case-control study in the United Kingdom. Cancer Epidemiol. Biomarkers Prev. 19, 2043–2054 (2010).

  27. 27.

    et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

  28. 28.

    , & Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

  29. 29.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  30. 30.

    Testing for association on the X chromosome. Biostatistics 9, 593–600 (2008).

  31. 31.

    & Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

  32. 32.

    & Meta-analysis in clinical trials. Control. Clin. Trials 7, 177–188 (1986).

  33. 33.

    et al. Relationship between sun exposure and melanoma risk for tumours in different body sites in a large case-control study in a temperate climate. Eur. J. Cancer 47, 732–741 (2011).

  34. 34.

    et al. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. J. Clin. Oncol. 27, 5439–5444 (2009).

  35. 35.

    & QUANTO 1.1: A Computer Program for Power and Sample Size Calculations for Genetic-Epidemiology Studies. (2006). Available from .

Download references


The authors are extremely grateful for the contributions of D. Seminara to the work of GenoMEL and also for the support of G. Cross (University of Leeds) for maintaining the study wiki. Overall, the GenoMEL Consortium is indebted to the organizational skills of P. Affleck.

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 is available from their website (see URLs). Funding for the project was provided by the Wellcome Trust under award 076113.

The authors thank the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) cooperative group for giving access to data of the EGEA study. We acknowledge that the biological specimens of the French Familial Melanoma Study Group were obtained from the Institut Gustave Roussy and Fondation Jean Dausset–CEPH Biobanks.

The GenoMEL study was funded by the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702), by Cancer Research UK Programme Awards (C588/A4994 and C588/A10589), by a Cancer Research UK Project grant (C8216/A6129) and by a grant from the US National Institutes of Health (NIH; CA83115). This research was also supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. Funding specific to particular locations is acknowledged below.

Australia: Melanoma Research Alliance, US NCI (CA088363, CA083115, CA122838, CA87969, CA055075, CA100264, CA133996 and CA49449), the National Health and Medical Research Council of Australia (NHMRC) (107359, 200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 402761, 443036, 442915, 442981, 496610, 496675, 520018, 496739, 552485 and 552498), the Cancer Councils NSW, 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) and the Australian Cancer Research Foundation.

Cambridge: D.F.E. is a Principal Research Fellow of Cancer Research UK. SEARCH is funded by grants from Cancer Research UK (C8197/A10123, C8197/A10123 and C490/A10124). A.M.D. has been supported by a Cancer Research UK grant (C8197/A10865) and by the Joseph Mitchell Fund.

Emilia-Romagna: US NCI grant to M.T. Landi (CA5558).

Genoa: IRCSS 2007 Italian Ministry of Health (DGRST4/4235-P1.9.A.B.) and Fondazione CARIGE, PRIN 2008 to G. Bianchi-Scarrà.

Houston: NIH grants to the M.D. Anderson Cancer Center (CA100264 and CA33996).

Leeds: Cancer Research UK Programme grants for Genetic epidemiology of cancer (C588/A10589 and C588/A4994) and Cancer Research UK Project grant (C8216/A6129) and Leeds Cancer Research UK Centre (C37059/A11941).

Leiden: Grant provided by European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)–Netherlands hub (CO18).

Lund: Funding by the Swedish Cancer Society, Swedish Research Council, Region Skåne funds, Kamprad Foundation.

Norway: Grants from the Comprehensive Cancer Center, Oslo University Hospital (SE0728) and the Norwegian Cancer Society (71512-PR-2006-0356).

Paris: Grants from Institut National du Cancer (INCa-PL016) and Ligue Nationale Contre Le Cancer (PRE05/FD and PRE 09/FD) to F. Demenais, Programme Hospitalier de Recherche Clinique (AOM-07-195) to M.-F. Avril and F. Demenais, Institut National du Cancer (Melanoma Network RS 13), Association pour la Recherche sur le Cancer (ARC A09/5/5003) and Société Française de Dermatologie (SFD2009) to B.B.-deP. B.B.-deP. has been awarded an INSERM Research Fellowship for hospital-based scientists.

Stockholm: Grants were provided by the Swedish Cancer Society (100279), the Swedish Research Council (K2006-74X-20141-01-3), Radiumhemmet Research Funds (101152) and Karolinska Institutet Research Funds (2010Fobi0450).

Utah: NIH award to L.A. Cannon-Albright (CA102422).

Author information

Author notes

    • Jennifer H Barrett
    •  & Mark M Iles

    These authors contributed equally to this work.


  1. Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds Cancer Research UK Centre, St James's University Hospital, Leeds, UK.

    • Jennifer H Barrett
    • , Mark M Iles
    • , Mark Harland
    • , John C Taylor
    • , Juliette Randerson-Moor
    • , Helen Snowden
    • , Julia A Newton Bishop
    •  & D Timothy Bishop
  2. Viertel Centre for Research in Cancer Control, The Cancer Council, Queensland, Spring Hill, Brisbane, Queensland, Australia.

    • Joanne F Aitken
  3. Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Per Arne Andresen
  4. The Gade Institute, University of Bergen, Bergen, Norway.

    • Lars A Akslen
    •  & Anders Molven
  5. Deptartment of Pathology, Haukeland University Hospital, Bergen, Norway.

    • Lars A Akslen
    •  & Anders Molven
  6. Westmead Millennium Institute, Westmead, New South Wales, Australia.

    • Bruce K Armstrong
    • , Richard F Kefford
    •  & Graham J Mann
  7. Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Descartes, Paris, France.

    • Marie-Francoise Avril
  8. Department of Dermatology and the Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Esther Azizi
    •  & Eitan Friedman
  9. Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

    • Bert Bakker
    •  & Nienke van der Stoep
  10. Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Wilma Bergman
    • , Frans A van Nieuwpoort
    •  & Nelleke A Gruis
  11. Department of Internal Medicine, University of Genoa, Genoa, Italy.

    • Giovanna Bianchi-Scarrà
    • , Paola Ghiorzo
    •  & Lorenza Pastorino
  12. INSERM, U946, Fondation Jean-Dausset–CEPH, Paris, France.

    • Brigitte Bressac-de Paillerets
    • , Eve Corda
    •  & Florence Demenais
  13. Département de Biopathologie, Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France.

    • Brigitte Bressac-de Paillerets
  14. Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy.

    • Donato Calista
    •  & Giorgio Landi
  15. Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Lisa A Cannon-Albright
  16. Fondation Jean Dausset–CEPH, Paris, France.

    • Eve Corda
    • , G Mark Lathrop
    •  & Florence Demenais
  17. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Victoria, Australia.

    • Anne E Cust
    • , Graham G Giles
    • , John L Hopper
    •  & Mark A Jenkins
  18. Cancer Epidemiology and Services Research, Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.

    • Anne E Cust
  19. International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

    • Tadeusz Dębniak
    •  & Jan Lubiński
  20. Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • David Duffy
    • , Nicholas G Martin
    • , Grant W Montgomery
    • , David C Whiteman
    • , Stuart MacGregor
    •  & Nicholas K Hayward
  21. Department of Oncology, University of Cambridge, Cambridge, UK.

    • Alison M Dunning
    •  & Douglas F Easton
  22. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Douglas F Easton
  23. Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Eitan Friedman
  24. UMR U557 Inserm; U1125 Institut national de la Recherche Agronomique, Conservatoire national des arts et métiers, Centre de Recherche en Nutrition Humaine, Ile de France, Bobigny, France.

    • Pilar Galan
  25. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

    • Graham G Giles
  26. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

    • Johan Hansson
    • , Veronica Höiom
    •  & Rainer Tuominen
  27. Institute of Oncology Ljubljana, Ljubljana, Slovenia.

    • Marko Hocevar
    •  & Srdjan Novakovic
  28. Department of Surgery, University Hospital Lund, Lund, Sweden.

    • Christian Ingvar
  29. ServiceXS, Leiden, The Netherlands.

    • Bart Janssen
  30. Department of Oncology, University Hospital Lund, Lund, Sweden.

    • Göran Jönsson
    •  & Håkan Olsson
  31. Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Maria Teresa Landi
    •  & Alisa M Goldstein
  32. Department of Medical Genetics, University of Glasgow, Glasgow, UK.

    • Julie Lang
    •  & Rona Mackie
  33. Public Health and Health Policy, University of Glasgow, Glasgow, UK.

    • Rona Mackie
  34. Melanoma Unit, Dermatology Department, Hospital Clinic, Institut de Investigacó Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain.

    • Josep Malvehy
    • , Susana Puig
    •  & Joan Anton Puig-Butille
  35. Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.

    • Susana Puig
    •  & Joan Anton Puig-Butille
  36. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Patricia Van Belle
    •  & David E Elder
  37. Commissariat à l′Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France.

    • Diana Zelenika
    •  & G Mark Lathrop
  38. Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Jiali Han
  39. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Jiali Han
  40. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Jiali Han
  41. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Shenying Fang
  42. Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Jeffrey E Lee
  43. Department of Epidemiology Unit 1365, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Qingyi Wei
  44. Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, USA.

    • Elizabeth M Gillanders
  45. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Gaithersburg, Maryland, USA.

    • Kevin M Brown
  46. Centre for Clinical Epidemiology & Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Peter A Kanetsky
  47. Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Peter A Kanetsky
  48. Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Christopher I Amos
  49. Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie, Paris, France.

    • Florence Demenais


  1. Search for Jennifer H Barrett in:

  2. Search for Mark M Iles in:

  3. Search for Mark Harland in:

  4. Search for John C Taylor in:

  5. Search for Joanne F Aitken in:

  6. Search for Per Arne Andresen in:

  7. Search for Lars A Akslen in:

  8. Search for Bruce K Armstrong in:

  9. Search for Marie-Francoise Avril in:

  10. Search for Esther Azizi in:

  11. Search for Bert Bakker in:

  12. Search for Wilma Bergman in:

  13. Search for Giovanna Bianchi-Scarrà in:

  14. Search for Brigitte Bressac-de Paillerets in:

  15. Search for Donato Calista in:

  16. Search for Lisa A Cannon-Albright in:

  17. Search for Eve Corda in:

  18. Search for Anne E Cust in:

  19. Search for Tadeusz Dębniak in:

  20. Search for David Duffy in:

  21. Search for Alison M Dunning in:

  22. Search for Douglas F Easton in:

  23. Search for Eitan Friedman in:

  24. Search for Pilar Galan in:

  25. Search for Paola Ghiorzo in:

  26. Search for Graham G Giles in:

  27. Search for Johan Hansson in:

  28. Search for Marko Hocevar in:

  29. Search for Veronica Höiom in:

  30. Search for John L Hopper in:

  31. Search for Christian Ingvar in:

  32. Search for Bart Janssen in:

  33. Search for Mark A Jenkins in:

  34. Search for Göran Jönsson in:

  35. Search for Richard F Kefford in:

  36. Search for Giorgio Landi in:

  37. Search for Maria Teresa Landi in:

  38. Search for Julie Lang in:

  39. Search for Jan Lubiński in:

  40. Search for Rona Mackie in:

  41. Search for Josep Malvehy in:

  42. Search for Nicholas G Martin in:

  43. Search for Anders Molven in:

  44. Search for Grant W Montgomery in:

  45. Search for Frans A van Nieuwpoort in:

  46. Search for Srdjan Novakovic in:

  47. Search for Håkan Olsson in:

  48. Search for Lorenza Pastorino in:

  49. Search for Susana Puig in:

  50. Search for Joan Anton Puig-Butille in:

  51. Search for Juliette Randerson-Moor in:

  52. Search for Helen Snowden in:

  53. Search for Rainer Tuominen in:

  54. Search for Patricia Van Belle in:

  55. Search for Nienke van der Stoep in:

  56. Search for David C Whiteman in:

  57. Search for Diana Zelenika in:

  58. Search for Jiali Han in:

  59. Search for Shenying Fang in:

  60. Search for Jeffrey E Lee in:

  61. Search for Qingyi Wei in:

  62. Search for G Mark Lathrop in:

  63. Search for Elizabeth M Gillanders in:

  64. Search for Kevin M Brown in:

  65. Search for Alisa M Goldstein in:

  66. Search for Peter A Kanetsky in:

  67. Search for Graham J Mann in:

  68. Search for Stuart MacGregor in:

  69. Search for David E Elder in:

  70. Search for Christopher I Amos in:

  71. Search for Nicholas K Hayward in:

  72. Search for Nelleke A Gruis in:

  73. Search for Florence Demenais in:

  74. Search for Julia A Newton Bishop in:

  75. Search for D Timothy Bishop in:


J.H.B. and M.M.I. led and carried out the statistical analysis, contributed to the design of the study and were members of the writing team. M. Harland contributed to the design of the study and provided genotyping information. J.C.T. carried out statistical analyses and was a member of the writing team. J.F.A., P.A.A., L.A.A., B.K.A., M.-F.A., E.A., W.B., D.C., A.E.C., D.D., A.M.D., D.F.E., E.F., P. Ghiorzo, G.G.G., M. Hocevar, V.H., C.I., M.A.J., G.J., G.L., M.T.L., J. Lang, R.M., J.M., N.G.M., A.M., G.W.M., S.N., L.P., J.A.P.-B., R.T., N.v.d.S., J. Hansson and D.C.W. contributed to the identification of suitable samples for the study. B.B. contributed to the design of the study and supervised the initial processing of samples. G.B.-S., K.M.B., B.B.-deP., L.A.C.-A., T.D., D.E.E., J. Hansson, J.L.H., R.F.K., J. Lubiński, F.A.v.N., H.O., S.P. and P.V.B. contributed to the design of the study. H.S. and B.J. carried out genotyping and contributed to the interpretation of genotyping data. P. Galan, J.R.-M. and D.Z. contributed to the interpretation of genotyping data. J. Han contributed results of a confirmatory study. C.I.A., S.F., J.E.L. and Q.W. led and contributed analyses from the Houston study. N.K.H., G.J.M. and S.M. led and contributed results from the Australian study. G.M.L. provided genotyping information and contributed to the interpretation of genotype data. F.D., P.A.K., E.C., A.M.G. and E.M.G. advised on statistical analysis and contributed to the design of the study. N.A.G. was consortium deputy lead and contributed to the design of the study. J.A.N.B. was overall consortium lead and contributed to the design of the study. D.T.B. led the analysis group, contributed to the design of the study and was a member of the writing team.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to D Timothy Bishop.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4, Supplementary Tables 1–3 and Supplementary Note

About this article

Publication history






Further reading