Letter

A variant in FTO shows association with melanoma risk not due to BMI

Received:
Accepted:
Published online:

Abstract

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10−12, per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.

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Acknowledgements

We thank M.I. McCarthy and C.M. Lindgren for assistance with the results of the GIANT study. The GenoMEL study was funded by the European Commission under the 6th Framework Programme (contract number LSHC-CT-2006-018702), by Cancer Research UK Programme Awards (C588/A4994 and C588/A10589), by a Cancer Research UK Project Grant (C8216/A6129), by the Leeds Cancer Research UK Centre (C37059/A11941) 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, US National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. Genotyping of most of the samples collected in France that were included in GenoMEL was done at Centre National de Génotypage, Institut de Génomique–Commissariat à l'Energie Atomique and was supported by the Ministère de l'Enseignement Supérieur et de la Recherche and Institut National du Cancer (INCa). This study used 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. We thank the EGEA cooperative group for giving access to data of the EGEA study (see URLs). 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. Work in Stockholm was funded by the Swedish Cancer Society and Karolinska Institutet research funds. Work in Lund was funded by the Swedish Cancer Society, the Gunnar Nilsson Foundation and the European Research Council (ERC-2011-AdG 294576-risk factors cancer). Work in Genoa was funded by the Italian Ministry of Education, University and Research Progetti di Ricerca di Interesse Nazionale (2008W8JTPA_002), Intergruppo Melanoma Italiano and Mara Naum foundation. Work in Paris was funded by grants from INCa (INCa-PL016) and Ligue Nationale Contre Le Cancer (PRE05/FD and PRE 09/FD) to F. Demenais, and Programme Hospitalier de Recherche Clinique (AOM-07-195) to M.-F. Avril and F. Demenais. Work in Leiden was funded by a grant provided by European Biobanking and Biomolecular Resources Research Infrastructure Netherlands hub (CO18). Research at the Melanoma Unit in Barcelona is partially funded by grants from Fondo de Investigaciones Sanitarias P.I. 09/01393, Spain and by the Centro de Investigaciones Biomedicas en Red (CIBER) de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; by the Agencia de Gestió d'Ajuts Universitaris i de Recerca 2009 SGR-1337 of the Catalan Government, Spain. Work in Norway was funded by grants from the Comprehensive Cancer Center, Oslo University Hospital (SE0728) and the Norwegian Cancer Society (71512-PR-2006-0356). Work in Vienna was supported by the Jubiläumsfonds of the Österreichische Nationalbank (project numbers 12161 and 13036) and the Hans und Blanca Moser Stiftung. The Italian study was partially supported by a NIH RO1 grant CA65558-02 (to M.T. Landi), Department of Health and Human Services and by the Intramural Research Program of NIH, NCI Division of Cancer Epidemiology and Genetics. Work at the MD Anderson Cancer Center was supported by the NIH NCI (P30CA023108 and 2P50CA093459) and by the Marit Peterson Fund for Melanoma Research. A. Cust is supported by fellowships from the Cancer Institute New South Wales and the National Health and Medical Research Council. Work in Nijmegen, The Netherlands, was funded by the Dutch Cancer Society Koningin Wilhemina Fonds (KWF) Kankerbestrijding and by the Radboud University Medical Centre. The Q-MEGA study was supported by the Melanoma Research Alliance, the NIH NCI (CA88363, CA83115, CA122838, CA87969, CA055075, CA100264, CA133996 and CA49449), the National Health and Medical Research Council of Australia (NHMRC) (200071, 241944, 339462, 380385, 389927,389875, 389891, 389892,389938, 443036, 442915, 442981, 496610, 496675, 496739, 552485, 552498), the Cancer Councils New South Wales, Victoria and Queensland, the Cancer Institute New South Wales, the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne), the Australian Cancer Research Foundation, The Wellcome Trust (WT084766/Z/08/Z) and donations from Neville and Shirley Hawkins. N.K.H. was supported by the NHMRC Fellowships scheme. SM was supported by a Career Development award from the NHMRC (496674, 613705). M.H.L. is supported by Cancer Australia grant 1011143.

Author information

Affiliations

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

    • Mark M Iles
    • , Mark Harland
    • , John C Taylor
    • , Juliette Randerson-Moor
    • , Helen Snowden
    • , D Timothy Bishop
    • , Julia A Newton Bishop
    •  & Jennifer H Barrett
  2. Queensland Institute of Medical Research, Brisbane, Australia.

    • Matthew H Law
    • , Stuart MacGregor
    • , Nicholas G Martin
    •  & Nicholas K Hayward
  3. deCODE Genetics, Reykjavik, Iceland.

    • Simon N Stacey
    • , Patrick Sulem
    • , Gudmar Thorleifsson
    •  & Kari Stefansson
  4. Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Jiali Han
    • , Fengju Song
    •  & Mingfeng Zhang
  5. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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

    • Jiali Han
  7. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Shenying Fang
    •  & Christopher I Amos
  8. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Ruth Pfeiffer
    • , Alisa M Goldstein
    •  & Maria Teresa Landi
  9. Comprehensive Cancer Center, The Netherlands, Nijmegen, The Netherlands.

    • Katja K Aben
    •  & Lambertus A Kiemeney
  10. Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands.

    • Katja K Aben
    • , Anne C de Waal
    •  & Lambertus A Kiemeney
  11. Centre for Cancer Biomarkers, The Gade Institute, University of Bergen, Bergen, Norway.

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

    • Lars A Akslen
    •  & Anders Molven
  13. Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France.

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

    • Esther Azizi
  15. Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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

    • Bert Bakker
    •  & Nienke van der Stoep
  17. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Kristrun R Benediktsdottir
    •  & Kari Stefansson
  18. Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.

    • Kristrun R Benediktsdottir
  19. Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Wilma Bergman
    •  & Nelleke A Gruis
  20. Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.

    • Giovanna Bianchi Scarrà
    •  & Paola Ghiorzo
  21. Laboratory of Genetics of Rare Hereditary Cancers, Istituto di Ricovero e Cura a Carattere Scientifico, San Martino-Istituto Scientifico Tumori, Genoa, Italy.

    • Giovanna Bianchi Scarrà
    •  & Paola Ghiorzo
  22. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Gaithersburg, Maryland, USA.

    • Kevin M Brown
  23. Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy.

    • Donato Calista
  24. Institut National de la Santé et de la Recherche Médicale (INSERM), Unite Mixte de Recherche (UMR) 946, Genetic Variation and Human Diseases Unit, Paris, France.

    • Valérie Chaudru
    •  & Florence Demenais
  25. Université d'Evry Val d'Essonne, Evry, France.

    • Valérie Chaudru
  26. Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.

    • Valérie Chaudru
    • , Florence Demenais
    •  & G Mark Lathrop
  27. Department of Dermatology, University of L'Aquila, L'Aquila, Italy.

    • Maria Concetta Fargnoli
    •  & Ketty Peris
  28. Cancer Epidemiology and Services Research, Sydney School of Public Health, The University of Sydney, Australia.

    • Anne E Cust
  29. Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.

    • Florence Demenais
  30. Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands.

    • Anne C de Waal
    •  & Michelle M van Rossum
  31. International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

    • Tadeusz Dębniak
    •  & Jan Lubiński
  32. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • David E Elder
  33. Research Unit on Nutritional Epidemiology, Université Paris 13, Sorbonne, Paris Cité, INSERM (U557), Institut Scientifique de Recherche Agronomique (INRA U1125), Conservatoire National des Arts et Métiers (CNAM), Bobigny, France.

    • Pilar Galan
  34. Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA.

    • Elizabeth M Gillanders
  35. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.

    • Johan Hansson
    • , Veronica Höiom
    •  & Rainer Tuominen
  36. Department of Dermatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Per Helsing
  37. Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

    • Marko Hočevar
  38. Centre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Melbourne School of Population Health, University of Melbourne, Melbourne, Australia.

    • John L Hopper
    •  & Mark A Jenkins
  39. Department of Surgery, Clinical Sciences, Lund University, Lund, Sweden.

    • Christian Ingvar
  40. ServiceXS B.V., Leiden, The Netherlands.

    • Marjolein Janssen
    •  & Suzanne Mulder
  41. Centre for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Peter A Kanetsky
  42. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Peter A Kanetsky
  43. Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
  44. Department of Medical Genetics, University of Glasgow, Glasgow, UK.

    • Julie Lang
  45. Commissariat à l′Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France.

    • G Mark Lathrop
    •  & Diana Zelenika
  46. Department of Dermatology, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA.

    • Sancy Leachman
  47. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Jeffrey E Lee
  48. Department of Public Health, University of Glasgow, UK.

    • Rona M Mackie
  49. Westmead Institute of Cancer Research, University of Sydney at Westmead Millennium Institute and Melanoma Institute Australia, Sydney, Australia.

    • Graham J Mann
  50. University of Zaragoza, Zaragoza, Spain.

    • Jose I Mayordomo
    •  & Maria Pilar Grasa
  51. Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

    • Eduardo Nagore
    •  & Celia Requena
  52. Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

    • Srdjan Novaković
  53. Department of Dermatology, Medical University of Vienna, Vienna, Austria.

    • Ichiro Okamoto
    •  & Judith Wendt
  54. Department of Dermatology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Jon H Olafsson
    • , Bardur Sigurgeirsson
    •  & Kristin Thorisdottir
  55. Departments of Oncology and Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.

    • Håkan Olsson
  56. Laboratory of Histocompatibility–Molecular Biology, Center for Blood Transfusion, Valencia, Spain.

    • Hubert Pehamberger
    •  & Dolores Planelles
  57. Melanoma Unit, Dermatology Department, Hospital Clinic, Institut de Investigacó Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain.

    • Susana Puig
    •  & Joan Anton Puig-Butille
  58. Centro de Investigaciones Biomedicas en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.

    • Susana Puig
    •  & Joan Anton Puig-Butille
  59. Immunotherapy of Human Tumors Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale deiTumori, Milan, Italy.

    • Licia Rivoltini
    •  & Monica Rodolfo
  60. Melanoma and Sarcoma Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

    • Mario Santinami
  61. Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

    • Fengju Song
  62. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Patricia Van Belle
  63. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Qingyi Wei
  64. Department of Community and Family Medicine, Geisel College of Medicine, Dartmouth College, Hanover, New Hampshire, USA.

    • Christopher I Amos

Consortia

  1. the GenoMEL Consortium

    A full list of members is provided in the Supplementary Note.

    Q-MEGA and AMFS Investigators

Authors

    Contributions

    M.M.I. led, designed and carried out the statistical analysis and wrote the manuscript. M. Harland was involved in the Leeds replication genotyping design. J.C.T. carried out statistical analysis. H.S., J.R.-M., M.J., S. Mulder and N.v.d.S. carried out genotyping and contributed to the interpretation of genotyping data. B.B. contributed to the design of the GWAS and supervised processing of GWAS samples. J.A.N.B. led the overall consortium and contributed to study design. N.A.G. was deputy lead of the consortium and contributed to study design. D.T.B. and J.H.B. designed and led the overall study. N.K.H., S. MacGregor and M.H.L. led and carried out statistical analysis of the Australian replication data. K.S., S.N.S., P.S. and G.T. led and carried out statistical analysis of the Icelandic, Dutch, Viennese, Milanese, Valencian and Zaragozan replication data. J. Han carried out statistical analysis of the Harvard replication data. C.I.A. and S.F. led and carried out statistical analysis of the Houston replication data. M.T.L. and R.P. led and carried out statistical analysis of the Italian replication data. D.Z. and G.M.L. interpreted and contributed genotype data. A.M.G., P.A.K., E.M.G. and F.D. advised on statistical analysis. F.D. and G.M.L. contributed to the design of the study of the French component of GenoMEL. K.M.B. and D.E.E. contributed to the design of the GWAS. K.K.A., L.A.A., M.-F.A., E.A., K.R.B., W.B., G.B.S., D.C., V.C., M.C.F., A.E.C., A.C.d.W., T.D., E.F., P. Galan, P. Ghiorzo, J. Hansson, P.H., Marko Hočevar, V.H., J.L.H., C.I., M.A.J., L.A.K., J. Lang, S.L., J.E.L., J. Lubiński, R.M.M., G.J.M., N.G.M., J.I.M., A.M., E.N., S.N., I.O., J.H.O., H.O., H.P., K.P., M.P.G., D.P., S.P., J.A.P.-B., C.R., L.R., M.R., M.S., B.S., F.S., K.T., R.T., P.V.B., M.M.v.R., Q.W., J.W. and M.Z. contributed to the design and sample collection of either the initial GWAS or one of the replication studies.

    Competing interests

    The authors declare no competing financial interests.

    Corresponding author

    Correspondence to Mark M Iles.

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

      Supplementary Tables 1–2, Supplementary Figures 1–7, Supplementary Note