Genes associated with human pigmentation traits in Genome-Wide Association Studies (GWAS)

Although there are many issues, Genome-Wide association study (GWAS) has been a powerful method to identify genetic variants associated with phenotypic traits.  GWAS is generally used to find genetic variants associated with disease, but it also found variants associated with anthropometric traits, such as height and BMI.  Also, there are several GWAS mainly among people of European descents aiming to find genetic variants associated with pigmentation characteristics (hair, eye, and skin color, freckles, and skin sensitivity to sun or tanning ability) (e.g., Eriksson, 2010; Han, 2008; Kayser, 2008; Liu, 2010; Nan, 2009; Sulem, 2008; Sulem, 2007)   These GWAS identified variants associated with pigmentation characteristics on SLC45A2 (Chr5), IRF4 (Chr6), TYRP1 (Chr9), TYR (Chr11), KITLG (Chr12), SLC24A4 (Chr14), OCA2/HERC2 (Chr15), MC1R (Chr16), and ASIP (Chr20).  These studies showed very strong association of variants in these genes with hair color, eye color, freckles, sensitivity to the sun, and tanning ability.

However, because the skin color does not vary much in European populations, these GWAS were not very successful showing the association between genetic variants and skin pigmentation, and only one of these studies, in which people of non-European descents were included, successfully showed the association between skin color and an IRF4 variant (Han et al. 2008).

Another GWAS among South Asians demonstrated the association of skin color with variants in two genes (SLC45A2 and TYR), but the study also found that another gene, SLC24A5 (Chr15) is associated with skin color (Stokowski et al. 2007).  The association of SLC24A5 variants with skin color in African Americans has been reported previously (Lamason et al. 2005).  More recently, Kenny et al. report that an amino acid change in TYRP1 associated with blond hair among Solomon Islanders (Kenny, 2012).

Identifying these genetic variants is important not only to understand major human phenotypic variation and the mechanism of evolution of pigmentation traits, but also to find variants that may be associated with skin cancer and to understand the risk factors for vitamin D deficiency.  Because of admixture, African Americans exhibit a great range of skin color, so they are desirable for genetic study of skin pigmentation.

Eriksson, N., J. M. Macpherson, et al. (2010). “Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits.” PLoS Genet 6(6): e1000993.

Han, J., P. Kraft, et al. (2008). “A Genome-Wide Association Study Identifies Novel Alleles Associated with Hair Color and Skin Pigmentation.” PLoS Genet 4(5): e1000074.

Kayser, M., F. Liu, et al. (2008). “Three Genome-wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene.” American Journal of Human Genetics 82(2): 411-423

Kenny, E. E., N. J. Timpson, et al. (2012). “Melanesian Blond Hair Is Caused by an Amino Acid Change in TYRP1.” Science (New York, N.Y.) 336(6081): 554.

Lamason, R. L., M. A. Mohideen, et al. (2005). “SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans.” Science (New York, N.Y.) 310(5755): 1782-1786.

Liu, F., A. Wollstein, et al. (2010). “Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci.” PLoS Genet 6(5): e1000934.

Nan, H., P. Kraft, et al. (2009). “Genome-Wide Association Study of Tanning Phenotype in a Population of European Ancestry.” J Invest Dermatol 129(9): 2250-2257.

Stokowski, R. P., P. V. K. Pant, et al. (2007). “A Genomewide Association Study of Skin Pigmentation in a South Asian Population.” American Journal of Human Genetics 81(6): 1119-1132.

Sulem, P., D. F. Gudbjartsson, et al. (2008). “Two newly identified genetic determinants of pigmentation in Europeans.” Nat Genet 40(7): 835-837.

Sulem, P., D. F. Gudbjartsson, et al. (2007). “Genetic determinants of hair, eye and skin pigmentation in Europeans.” Nat Genet 39(12): 1443-1452.

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