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Genetic determinants of hair, eye and skin pigmentation in Europeans

Abstract

Hair, skin and eye colors are highly heritable and visible traits in humans. We carried out a genome-wide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun and freckling among 2,986 Icelanders. We then tested the most closely associated SNPs from six regions—four not previously implicated in the normal variation of human pigmentation—and replicated their association in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. The SNPs from all six regions met the criteria for genome-wide significance. A variant in SLC24A4 is associated with eye and hair color, a variant near KITLG is associated with hair color, two coding variants in TYR are associated with eye color and freckles, and a variant on 6p25.3 is associated with freckles. The fifth region provided refinements to a previously reported association in OCA2, and the sixth encompasses previously described variants in MC1R.

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Figure 1: A schematic representation of how different genetic variants are associated with pigmentation.
Figure 2: Overview of the accuracy of pigmentation prediction based on genotype status.

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References

  1. Relethford, J.H. Hemispheric difference in human skin color. Am. J. Phys. Anthropol. 104, 449–457 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Sturm, R.A. A golden age of human pigmentation genetics. Trends Genet. 22, 464–468 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Jablonski, N.G. & Chaplin, G. The evolution of human skin coloration. J. Hum. Evol. 39, 57–106 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Sturm, R.A., Box, N.F. & Ramsay, M. Human pigmentation genetics: the difference is only skin deep. Bioessays 20, 712–721 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Galton, F. Family-likeness in eye-colour. Nature 34, 137 (1886).

    Article  Google Scholar 

  6. Posthuma, D. et al. Replicated linkage for eye color on 15q using comparative ratings of sibling pairs. Behav. Genet. 36, 12–17 (2006).

    Article  PubMed  Google Scholar 

  7. Barsh, G.S. What controls variation in human skin color? PLoS Biol. 1, E27 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Brauer, G. & Chopra, V.P. [Estimation of the heritability of hair and eye color.] Anthropol. Anz. 36, 109–120 (1978).

    CAS  PubMed  Google Scholar 

  9. Bataille, V., Snieder, H., MacGregor, A.J., Sasieni, P. & Spector, T.D. Genetics of risk factors for melanoma: an adult twin study of nevi and freckles. J. Natl. Cancer Inst. 92, 457–463 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Eiberg, H. & Mohr, J. Major locus for red hair color linked to MNS blood groups on chromosome 4. Clin. Genet. 32, 125–128 (1987).

    Article  CAS  PubMed  Google Scholar 

  11. Hoekstra, H.E. Genetics, development and evolution of adaptive pigmentation in vertebrates. Heredity 97, 222–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Valverde, P., Healy, E., Jackson, I., Rees, J.L. & Thody, A.J. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat. Genet. 11, 328–330 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Rees, J.L. The genetics of sun sensitivity in humans. Am. J. Hum. Genet. 75, 739–751 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Makova, K. & Norton, H. Worldwide polymorphism at the MC1R locus and normal pigmentation variation in humans. Peptides 26, 1901–1908 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Eiberg, H. & Mohr, J. Assignment of genes coding for brown eye colour (BEY2) and brown hair colour (HCL3) on chromosome 15q. Eur. J. Hum. Genet. 4, 237–241 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Sturm, R.A. & Frudakis, T.N. Eye colour: portals into pigmentation genes and ancestry. Trends Genet. 20, 327–332 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Frudakis, T. et al. Sequences associated with human iris pigmentation. Genetics 165, 2071–2083 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Duffy, D.L. et al. A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. Am. J. Hum. Genet. 80, 241–252 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Lamason, R.L. et al. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 310, 1782–1786 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Norton, H.L. et al. Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Mol. Biol. Evol. 24, 710–722 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Bonilla, C. et al. The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans. Hum. Genet. 116, 402–406 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Shriver, M.D. et al. Skin pigmentation, biogeographical ancestry and admixture mapping. Hum. Genet. 112, 387–399 (2003).

    PubMed  Google Scholar 

  23. Lao, O., de Gruijter, J.M., van Duijn, K., Navarro, A. & Kayser, M. Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms. Ann. Hum. Genet. 71, 354–369 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. McEvoy, B., Beleza, S. & Shriver, M.D. The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model. Hum. Mol. Genet. 15, R176–R181 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Myles, S., Somel, M., Tang, K., Kelso, J. & Stoneking, M. Identifying genes underlying skin pigmentation differences among human populations. Hum. Genet. 120, 613–621 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Williamson, S.H. et al. Localizing recent adaptive evolution in the human genome. PLoS Genet. 3, e90 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lin, J.Y. & Fisher, D.E. Melanocyte biology and skin pigmentation. Nature 445, 843–850 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  29. 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).

  30. Wehrle-Haller, B. The role of Kit-ligand in melanocyte development and epidermal homeostasis. Pigment Cell Res. 16, 287–296 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Seitz, J.J., Schmutz, S.M., Thue, T.D. & Buchanan, F.C. A missense mutation in the bovine MGF gene is associated with the roan phenotype in Belgian Blue and Shorthorn cattle. Mamm. Genome 10, 710–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Izagirre, N., Garcia, I., Junquera, C., de la Rua, C. & Alonso, S. A scan for signatures of positive selection in candidate loci for skin pigmentation in humans. Mol. Biol. Evol. 23, 1697–1706 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Harding, R.M. et al. Evidence for variable selective pressures at MC1R. Am. J. Hum. Genet. 66, 1351–1361 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gulcher, J.R., Kristjansson, K., Gudbjartsson, H. & Stefansson, K. Protection of privacy by third-party encryption in genetic research in Iceland. Eur. J. Hum. Genet. 8, 739–742 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Fitzpatrick, T.B. The validity and practicality of sun-reactive skin types I through VI. Arch. Dermatol. 124, 869–871 (1988).

    Article  CAS  PubMed  Google Scholar 

  36. Gudmundsson, J. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39, 631–637 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Falk, C.T. & Rubinstein, P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann. Hum. Genet. 51, 227–233 (1987).

    Article  CAS  PubMed  Google Scholar 

  39. Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

    CAS  PubMed  Google Scholar 

  40. Grant, S.F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 38, 320–323 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Devlin, B., Bacanu, S.-A. & Roeder, K. Genomic control to the extreme. Nat. Genet. 36, 1129–1130 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Seldin, M.F. et al. European population substructure: clustering of northern and southern populations. PLoS Genet. 2, e143 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bersaglieri, T. et al. Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 74, 1111–1120 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Beaumont, M.A. & Nichols, R.A. Evaluating loci for use in the genetic analysis of population structure. Proc. R. Soc. Lond. B 263, 1619–1626 (1996).

    Article  Google Scholar 

  48. Sabeti, P.C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Helgason, A. et al. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat. Genet. 39, 218–225 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Voight, B.F., Kudaravalli, S., Wen, X. & Pritchard, J.K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the study participants from Iceland and Holland whose contributions made this work possible. We also thank the nurses at Noatun (deCODE's sample recruitment center) and the personnel at the deCODE core facilities for their hard work and enthusiasm. This work was funded in part by contract number 018827 (Polygene) from the 6th Framework Program of the European Union.

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Contributions

P.S., D.F.G., A.H. and K.S. wrote the first draft of the paper. S.N.S., T.R., K.P.M., A.K., F.J., B.S., K.T., R.R., K.R.B. and J.H.O. collected the Icelandic samples and phenotypes. K.K.A. and L.A.K. collected the Dutch samples and phenotypes. S.N.S., T.R., M.J. and U.T. carried out the genotyping. P.S., D.F.G., A.H., A.M., A.P., G.T., S.S., S.P. and A.K. analyzed the data. P.S., D.F.G., S.N.S., A.H., F.J., L.A.K., J.H.O., J.G., U.T. and K.S. planned, supervised and coordinated the work. All authors contributed to the final version of the paper.

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Correspondence to Daniel F Gudbjartsson or Kari Stefansson.

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The employees of deCODE Genetics own stocks and stock options in the company.

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Sulem, P., Gudbjartsson, D., Stacey, S. et al. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 39, 1443–1452 (2007). https://doi.org/10.1038/ng.2007.13

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