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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References
Cannon-Albright, L.A., Bishop, D.T., Goldgar, C. & Skolnick, M.H. Genetic predisposition to cancer. Important Adv. Oncol. 1991, 39–55 (1991).
Naldi, L. 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).
Titus-Ernstoff, L. et al. Pigmentary characteristics and moles in relation to melanoma risk. Int. J. Cancer 116, 144–149 (2005).
Holly, E.A., Aston, D.A., Cress, R.D., Ahn, D.K. & Kristiansen, J.J. 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).
Holly, E.A., Aston, D.A., Cress, R.D., Ahn, D.K. & Kristiansen, J.J. Cutaneous melanoma in women. II. Phenotypic characteristics and other host-related factors. Am. J. Epidemiol. 141, 934–942 (1995).
Bataille, V. 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).
Chang, Y.M. 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).
Brown, K.M. et al. Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat. Genet. 40, 838–840 (2008).
Bishop, D.T. et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat. Genet. 41, 920–925 (2009).
Gu∂bjartsson, D.F. et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat. Genet. 40, 886–891 (2008).
Barrett, J.H. et al. Genome-wide association study identifies three new melanoma susceptibility loci. Nat. Genet. 43, 1108–1113 (2011).
Bertolotto, C. et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94–98 (2011).
Yokoyama, S. et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480, 99–103 (2011).
Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).
Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).
Scuteri, A. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007).
Zeggini, E. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).
Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007.).
Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat. Genet. 40, 638–645 (2008).
Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).
Hertel, J.K. et al. FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC, and MPP studies. Diabetes 60, 1637–1644 (2011).
Li, H. et al. Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians. Diabetologia 55, 981–995 (2012).
Renehan, A.G., Tyson, M., Egger, M., Heller, R.F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).
Pothiawala, S., Qureshi, A.A., Li, Y. & Han, J. Obesity and the incidence of skin cancer in US Caucasians. Cancer Causes Control 23, 717–726 (2012).
Speliotes, E.K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).
Sällman Almén, M. et al. Determination of the obesity-associated gene variants within the entire FTO gene by ultra-deep targeted sequencing in obese and lean children. Int. J. Obes. (Lond.) advance online publication, doi:10.1038/ijo.2012.57 (24 April 2012).
Boissel, S. et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am. J. Hum. Genet. 85, 106–111 (2009).
Hubacek, J.A. et al. The FTO gene polymorphism is associated with end-stage renal disease: two large independent case-control studies in a general population. Nephrol. Dial. Transplant. 27, 1030–1035 (2012).
Hubacek, J.A. et al. A FTO variant and risk of acute coronary syndrome. Clin. Chim. Acta 411, 1069–1072 (2010).
Doney, A.S. et al. The FTO gene is associated with an atherogenic lipid profile and myocardial infarction in patients with type 2 diabetes: a genetics of diabetes audit and research study in Tayside Scotland (Go-DARTS) study. Circ. Cardiovasc. Genet. 2, 255–259 (2009).
Zimmermann, E. et al. Fatness-associated FTO gene variant increases mortality independent of fatness—in cohorts of Danish men. PLoS ONE 4, e4428 (2009).
Keller, L. et al. The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J. Alzheimers Dis. 23, 461–469 (2011).
arcOGEN Consortium and arcOGEN Collaborators. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet 380, 815–823 (2012).
Brennan, P. et al. Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype. Int. J. Epidemiol. 38, 971–975 (2009).
Lurie, G. et al. The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women. PLoS ONE 6, e16756 (2011).
Boyle, A.P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012).
Schaub, M.A. et al. Linking disease associations with regulatory information in the human genome. Genome Res. 22, 1748–1759 (2012).
Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
Newton-Bishop, J.A. 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).
Newton-Bishop, J.A. 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).
Barrett, J.H. et al. Investigation of interaction between N-acetyltransferase 2 and heterocyclic amines as potential risk factors for colorectal cancer. Carcinogenesis 24, 275–282 (2003).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies via imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies via imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).
Dersimonian, R. & Laird, N. Meta-analysis in clinical trials. Control. Clin. Trials 7, 177–188 (1986).
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.
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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.
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the GenoMEL Consortium. A variant in FTO shows association with melanoma risk not due to BMI. Nat Genet 45, 428–432 (2013). https://doi.org/10.1038/ng.2571
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DOI: https://doi.org/10.1038/ng.2571
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