A Genome-Wide Association Study Identifies Novel Alleles Associated with Hair Color and Skin Pigmentation

Abstract

We conducted a multi-stage genome-wide association study of natural hair color in more than 10,000 men and women of European ancestry from the United States and Australia. An initial analysis of 528,173 single nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified IRF4 and SLC24A4 as loci highly associated with hair color, along with three other regions encompassing known pigmentation genes. We confirmed these associations in 7,028 individuals from three additional studies. Across these four studies, SLC24A4 rs12896399 and IRF4 rs12203592 showed strong associations with hair color, with p = 6.0×10−62 and p = 7.46×10−127, respectively. The IRF4 SNP was also associated with skin color (p = 6.2×10−14), eye color (p = 6.1×10−13), and skin tanning response to sunlight (p = 3.9×10−89). A multivariable analysis pooling data from the initial GWAS and an additional 1,440 individuals suggested that the association between rs12203592 and hair color was independent of rs1540771, a SNP between the IRF4 and EXOC2 genes previously found to be associated with hair color. After adjustment for rs12203592, the association between rs1540771 and hair color was not significant (p = 0.52). One variant in the MATP gene was associated with hair color. A variant in the HERC2 gene upstream of the OCA2 gene showed the strongest and independent association with hair color compared with other SNPs in this region, including three previously reported SNPs. The signals detected in a region around the MC1R gene were explained by MC1R red hair color alleles. Our results suggest that the IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation.

Gene–gene interactions contribute to eye colour variation in humans

“…13,14,16,18,19,25,28,31,32 As variables without a main effect can still be involved in significant interactions determining polygenic traits, we also considered (in our study) pigmentation-related polymorphisms that have not been associated with eye colour, but have been correlated with other pigmentation traits; that is, skin and hair colour. 18,19,21,54 Analysis conducted revealed three pairs of SNPs with significant interaction effects contributing to eye colour variation in the studied population. These loci are rs12913832 in HERC2 and rs1800407 in OCA2 (for hazel versus non-hazel and green versus non-green eye colour categorisation), rs12913832 in HERC2 and rs12896399 in SLC24A4 (for blue versus non-blue model), rs12913832 in HERC2 and rs1408799 in TYRP1 (for the green versus non-green model).…”

“…The 24 (SNPs) located in 11 genes, which have been shown to be significantly associated with human pigmentation 10,13,14,16,18,19,[21][22][23][24][25][27][28][29][30][31][32] were genotyped in two multiplex minisequencing assays. The list of the studied polymorphisms is given in Supplementary Table 1.…”

“…[10][11][12][13][14][15][16] However, it is important to note that-unlike in the case of testing for many complex diseases 17 genome-wide association study has been particularly effective in association testing for human pigmentation and has confirmed already known, and revealed multiple new polymorphisms and loci involved in determination of human pigmentation. [18][19][20][21] This has been particularly striking in the case of variation in eye colour, which is assessed to be 50% explained by known polymorphisms. 22 This has led to the first predictive tests of extreme eye colours (blue or brown) in forensic sciences with relatively high accuracies.…”

A genome-wide scan study identifies a single nucleotide substitution in ASIP associated with white versus non-white coat-colour variation in sheep (Ovis aries)

“…Hence, we implemented additional analyses among individuals without white coat colour and compared those with white coat coloured individuals to evaluate whether there were loci at one or both of the phenotypic axes. The ordinal coding for coat colour was regressed on counts of minor alleles after excluding whitecoated individuals and logistic regression was used to test the association between the ordinal genotype coding and binary white-coated phenotypes (white versus non-white coat colour; refer to the method in the study by Han et al (2008) for details). The analyses were conducted in a categorical way with white versus non-white.…”

“…The coat colours and patterns (or spotting) in the Finnsheep are comparable with those in the Icelandic sheep, where three loci (the basic colour gene B, the pattern gene A and the spotting locus S) are involved in the dominant and recessively coloured coat phenotypes (for example, Adalsteinsson, 1970;Reinieri et al, 2008), while little has been understood about the molecular genetic cause of coat colour variation in the Finnsheep. In the meantime, the list of candidate genes associated with coat colour and skin pigmentation in other domestic animals and humans has been supplemented with additional inputs such as FGF5, TP53BP1, SLC24A4, OCA2 and HERC2 by using the GWAS (for example, Sulem et al, 2007;Han et al, 2008;Cadieu et al, 2009). These findings have enabled not only an increasingly detailed genetic dissection of the pigmentation and colour phenotypes but also the realization that the phenotypes could be much more complex than previously imagined and controlled by a gene network rather than single genes.…”