Skip to main content
SpringerLink
Log in

Obesity-related genetic variants, human pigmentation, and risk of melanoma

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles = 0.12, P value = 4 × 10−5). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R 2 quality metric >0.8 using the 1,000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Adan RAH, Hillebrand JJG, Rijke C, Nijenhuis W, Vink T, Garner KM, Kas MJH (2003) Melanocortin system and eating disorders. Ann NY Acad Sci 994:267–274

    Article  PubMed  CAS  Google Scholar 

  • Cone RD (2006) Studies on the physiological functions of the melanocortin system. Endocr Rev 27:736–749

    PubMed  CAS  Google Scholar 

  • Danforth C (2012) Hereditary adiposity in mice. Obes Res 4:96–100

    Google Scholar 

  • Dickies MM (1962) A new viable yellow mutation in the house mouse. J Hered 53:84–86

    PubMed  CAS  Google Scholar 

  • Fawcett KA, Barroso I (2010) The genetics of obesity: FTO leads the way. Trends Genet 26:266–274

    Article  PubMed  CAS  Google Scholar 

  • Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JRB, Elliott KS, Lango H, Rayner NW (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889

    Article  PubMed  CAS  Google Scholar 

  • Frisancho AR, Wainwright R, Way A (1981) Heritability and components of phenotypic expression in skin reflectance of Mestizos from the Peruvian lowlands. Am J Phys Anthropol 55:203–208

    Article  PubMed  CAS  Google Scholar 

  • Gantz I, Fong TM (2003) The melanocortin system. Am J Physiol Endocrinol Metab 284:E468–E474

    PubMed  CAS  Google Scholar 

  • Gerken T, Girard CA, Tung YCL, Webby CJ, Saudek V, Hewitson KS, Yeo GSH, McDonough MA, Cunliffe S, McNeill LA (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318:1469

    Article  PubMed  CAS  Google Scholar 

  • Gerstenblith MR, Shi J, Landi MT (2010) Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis. Pigment Cell Melanoma Res 23:587–606

    Article  PubMed  CAS  Google Scholar 

  • Getting SJ (2006) Targeting melanocortin receptors as potential novel therapeutics. Pharmacol Ther 111:1–15

    Article  PubMed  CAS  Google Scholar 

  • Harrison GA, Owen J (1964) Studies on the inheritance of human skin colour. Ann Hum Genet 28:27–37

    Article  PubMed  CAS  Google Scholar 

  • He M, Cornelis MC, Franks PW, Zhang C, Hu FB, Qi L (2010) Obesity genotype score and cardiovascular risk in women with type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 30:327–332

    Article  PubMed  CAS  Google Scholar 

  • Heston W, Vlahakis G (1961) Influence of the Ay gene on mammary-gland tumors, hepatomas, and normal growth in mice. J Natl Cancer Inst 26:969

    PubMed  CAS  Google Scholar 

  • Heston W, Vlahakis G (1968) C3H-Auv—a high hepatoma and high mammary tumor strain of mice. J Natl Cancer Inst 40:1161–1166

    PubMed  CAS  Google Scholar 

  • Kilpeläinen TO, den Hoed M, Ong KK, Grøntved A, Brage S (2011) Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals. Am J Clin Nutr 93:851

    Article  PubMed  Google Scholar 

  • Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155–157

    Article  PubMed  CAS  Google Scholar 

  • Larder R, Cheung M, Tung Y, Yeo GSH, Coll AP (2010) Where to go with FTO? Trends Endocrinol Metab 22(2):53–59

    PubMed  Google Scholar 

  • Loos RJF, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40:768

    Article  PubMed  CAS  Google Scholar 

  • Nan H, Kraft P, Hunter DJ, Han J (2009a) Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians. Int J Cancer 125:909–917

    Article  PubMed  CAS  Google Scholar 

  • Nan H, Kraft P, Qureshi AA, Guo Q, Chen C, Hankinson SE, Hu FB, Thomas G, Hoover RN, Chanock S (2009b) Genome-wide association study of tanning phenotype in a population of European ancestry. J Investig Dermatol 129:2250–2257

    Article  PubMed  CAS  Google Scholar 

  • Rees JL (2003) Genetics of hair and skin color. Annu Rev Genet 37:67–90

    Article  PubMed  CAS  Google Scholar 

  • Rees JL (2004) The genetics of sun sensitivity in humans. Am J Hum Genet 75:739–751

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Pulido L, Andrade-Navarro M (2007) The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily. BMC Biochem 8:23

    Article  PubMed  Google Scholar 

  • Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341

    Article  PubMed  CAS  Google Scholar 

  • Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orrú M, Usala G (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3:e115

    Article  PubMed  Google Scholar 

  • Shoag J, Haq R, Zhang M, Liu L, Rowe GC, Jiang A, Koulisis N, Farrel C, Amos CI, Wei Q (2013) PGC-1 coactivators regulate MITF and the tanning response. Mol Cell 67(5):e207–e208

    Google Scholar 

  • Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J, Mägi R (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat genet 42(11):937–948

    Article  PubMed  CAS  Google Scholar 

  • Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I (2008) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41:18–24

    Article  PubMed  Google Scholar 

  • Trewick SC, McLaughlin PJ, Allshire RC (2005) Methylation: lost in hydroxylation? EMBO Rep 6:315–320

    Article  PubMed  CAS  Google Scholar 

  • Willer CJ, Speliotes EK, Loos RJF, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C (2008) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25–34

    Article  PubMed  Google Scholar 

  • Yen T, Gill A, Frigeri L, Barsh G, Wolff G (1994) Obesity, diabetes, and neoplasia in yellow A (vy)/-mice: ectopic expression of the agouti gene. FASEB J 8:479–488

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are indebted to the participants in the NHS, HPFS, and MD Anderson melanoma case–control study for their dedication to this research. We thank the following 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.

Author information

Authors and Affiliations

  1. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Xin Li, Liming Liang & Jiali Han

  2. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    Liming Liang

  3. Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Mingfeng Zhang, Abrar A. Qureshi & Jiali Han

  4. Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Fengju Song & Jiali Han

  5. Division of Cancer Epidemiology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA

    Hongmei Nan

  6. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Li-E Wang & Qingyi Wei

  7. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jeffrey E. Lee

  8. Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA

    Christopher I. Amos

  9. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Abrar A. Qureshi & Jiali Han

Authors
  1. Xin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liming Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingfeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fengju Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongmei Nan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li-E Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qingyi Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jeffrey E. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christopher I. Amos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Abrar A. Qureshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jiali Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiali Han.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 40 kb)

Supplementary material 2 (PDF 285 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, X., Liang, L., Zhang, M. et al. Obesity-related genetic variants, human pigmentation, and risk of melanoma. Hum Genet 132, 793–801 (2013). https://doi.org/10.1007/s00439-013-1293-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-013-1293-4

Keywords

Search

Navigation