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A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation.

Han J, Kraft P, Nan H, Guo Q, Chen C, Qureshi A, Hankinson SE, Hu FB, Duffy DL, Zhao ZZ, Martin NG, Montgomery GW, Hayward NK, Thomas G, Hoover RN, Chanock S, Hunter DJ - PLoS Genet. (2008)

Bottom Line: 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.One variant in the MATP gene was associated with hair color.Our results suggest that the IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation.

View Article: PubMed Central - PubMed

Affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, United States of America.

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 = 6.0x10(-62) and p = 7.46x10(-127), respectively. The IRF4 SNP was also associated with skin color (p = 6.2x10(-14)), eye color (p = 6.1x10(-13)), and skin tanning response to sunlight (p = 3.9x10(-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.

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Related in: MedlinePlus

Association analysis of SNPs across IRF4 region.-log10 p-values from the primary test of association with hair color in the initial GWAS (top panel), from the test of association with hair color excluding individuals with red hair (middle), and from the test of association with red hair versus non-red hair (bottom). The region plotted spans Chr6:95272.789899 (NCBI build 35).
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pgen-1000074-g003: Association analysis of SNPs across IRF4 region.-log10 p-values from the primary test of association with hair color in the initial GWAS (top panel), from the test of association with hair color excluding individuals with red hair (middle), and from the test of association with red hair versus non-red hair (bottom). The region plotted spans Chr6:95272.789899 (NCBI build 35).

Mentions: The SNP rs12203592 in intron 4 of the IRF4 gene was strongly associated with hair color in the initial GWAS and validation study (black to red, pooled p value for trend = 8.5×10−28; black to blonde, pooled p value for trend = 7.1×10−49). The percentage of residual variation in hair color from black to blonde explained by this SNP after controlling for the top four principal components of genetic variation was 7.0%. This SNP is within 69.7 kb of two SNPs (rs4959270 and rs1540771) that were identified by a recent GWAS of natural hair color in women of European ancestry resident in Iceland [12]. However, neither of these variants, which lie between EXOC2 (SEC5L1) and IRF4, was as strongly associated with natural hair color in our initial GWAS as the IRF4 SNP rs12203592 (Figure 3). In our GWAS, the p values for association between hair color (black to blonde) and rs4959270 and rs1540771 were 2.9×10−4 and 0.007, respectively, and those for tanning ability were 0.002 and 0.001, respectively. In fact, the p-value for association between rs12203592 and natural hair color was more than 13 orders of magnitude smaller than the p-value for any other SNP on chromosome 6. This should not be taken as evidence that the loci that influence hair color in Iceland are different from those for the rest of Europe; rather, the previous GWAS may have failed to identify rs12203592 because this SNP is not on the Illumina HumanHap300 array used in that study, while it is on the Illumina HumanHap550 array used here.


A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation.

Han J, Kraft P, Nan H, Guo Q, Chen C, Qureshi A, Hankinson SE, Hu FB, Duffy DL, Zhao ZZ, Martin NG, Montgomery GW, Hayward NK, Thomas G, Hoover RN, Chanock S, Hunter DJ - PLoS Genet. (2008)

Association analysis of SNPs across IRF4 region.-log10 p-values from the primary test of association with hair color in the initial GWAS (top panel), from the test of association with hair color excluding individuals with red hair (middle), and from the test of association with red hair versus non-red hair (bottom). The region plotted spans Chr6:95272.789899 (NCBI build 35).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2367449&req=5

pgen-1000074-g003: Association analysis of SNPs across IRF4 region.-log10 p-values from the primary test of association with hair color in the initial GWAS (top panel), from the test of association with hair color excluding individuals with red hair (middle), and from the test of association with red hair versus non-red hair (bottom). The region plotted spans Chr6:95272.789899 (NCBI build 35).
Mentions: The SNP rs12203592 in intron 4 of the IRF4 gene was strongly associated with hair color in the initial GWAS and validation study (black to red, pooled p value for trend = 8.5×10−28; black to blonde, pooled p value for trend = 7.1×10−49). The percentage of residual variation in hair color from black to blonde explained by this SNP after controlling for the top four principal components of genetic variation was 7.0%. This SNP is within 69.7 kb of two SNPs (rs4959270 and rs1540771) that were identified by a recent GWAS of natural hair color in women of European ancestry resident in Iceland [12]. However, neither of these variants, which lie between EXOC2 (SEC5L1) and IRF4, was as strongly associated with natural hair color in our initial GWAS as the IRF4 SNP rs12203592 (Figure 3). In our GWAS, the p values for association between hair color (black to blonde) and rs4959270 and rs1540771 were 2.9×10−4 and 0.007, respectively, and those for tanning ability were 0.002 and 0.001, respectively. In fact, the p-value for association between rs12203592 and natural hair color was more than 13 orders of magnitude smaller than the p-value for any other SNP on chromosome 6. This should not be taken as evidence that the loci that influence hair color in Iceland are different from those for the rest of Europe; rather, the previous GWAS may have failed to identify rs12203592 because this SNP is not on the Illumina HumanHap300 array used in that study, while it is on the Illumina HumanHap550 array used here.

Bottom Line: 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.One variant in the MATP gene was associated with hair color.Our results suggest that the IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation.

View Article: PubMed Central - PubMed

Affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, United States of America.

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 = 6.0x10(-62) and p = 7.46x10(-127), respectively. The IRF4 SNP was also associated with skin color (p = 6.2x10(-14)), eye color (p = 6.1x10(-13)), and skin tanning response to sunlight (p = 3.9x10(-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.

Show MeSH
Related in: MedlinePlus