Post by Admin on Jun 29, 2017 19:28:45 GMT
Mapping loci associated with skin and eye color
We used information from 903,837 autosomal SNPs to carry out genotype- and ancestry-based association analyses for skin (n = 685) and eye (n = 625) color. For genotype-based association, four skin color loci (5p13.3, 11q14.3, 15q13.1, and 15q21.1) and two eye color loci (15q13.1 and 15q21.1) met genome-wide criteria for significance, P<5.7×10−8 (Table 1, Table S2). In analyses adjusted only for principal components and sex, the signals at 15q21.1 (for skin color, Figure 3a) and 15q13.1 (for eye color, Figure 3b), dominate the significance plots. As described below, these signals correspond to SLC24A5 for skin color and HERC2 (OCA2) for eye color; Figure 3c and 3d show P value distributions when genotypes at SLC24A5 and HERC2 (OCA2) are considered as covariates. No additional loci were found in conditional analyses that adjust for the most significant SNPs in the known loci (four for skin and two for eye color). After removing SNPs surrounding these six loci, the genomic control parameters were 1.02 and 1.00 for skin color and eye color, respectively. We also examined the six loci identified in the combined sample in each island separately (Table S1); the direction of effect is consistent across all groups, with the derived allele associated with lighter skin color or a lower T-index (Table 1). Taken together with similar results from EMMAX (Figure S1), these results suggest adequate correction for population structure.
![](http://journals.plos.org/plosgenetics/article/figure/image?size=inline&id=info:doi/10.1371/journal.pgen.1003372.g003)
Figure 3. GWAS results for skin and eye color in the total Cape Verdean cohort.
Results are shown as −log10(P value) for the genotyped SNPs. Plots are ordered by chromosomal position. (a,c) Genotype and admixture association scan results for skin color. (b,d) Genotype and admixture association scan results for eye color. (a,b) show the P values obtained in the initial scans and (c,d) the P values of the following scans adjusting for the strongest associated SNP (in SLC24A5 for skin color and in HERC2 for eye color). Dashed red lines correspond to the genome-wide significance threshold (P<5×10−8 in the genotype scan; P<7×10−6 in the ancestry scan [see Material and Methods]). The location and identity of candidate genes are colored to correspond with chromosomal location; individual SNPs are given in Table 1.
![](http://journals.plos.org/plosgenetics/article/figure/image?size=large&id=info:doi/10.1371/journal.pgen.1003372.t001)
Table 1. Major loci for skin and eye color.
For ancestry-based mapping, we used SABER+, an extension of a Markov-Hidden Markov Model method [24], to assign African vs. European ancestral segments along each chromosome, and then carried out a genome-wide evaluation of local ancestry association with skin and eye color, using the same covariates as for the genotype-based analysis. Ancestry-based association yields broader peaks than genotype-based association, but the distribution of significant regions is strikingly consistent for the two approaches, uncovering the identical set of six loci (Figure 3, Table 1).
We used information from 903,837 autosomal SNPs to carry out genotype- and ancestry-based association analyses for skin (n = 685) and eye (n = 625) color. For genotype-based association, four skin color loci (5p13.3, 11q14.3, 15q13.1, and 15q21.1) and two eye color loci (15q13.1 and 15q21.1) met genome-wide criteria for significance, P<5.7×10−8 (Table 1, Table S2). In analyses adjusted only for principal components and sex, the signals at 15q21.1 (for skin color, Figure 3a) and 15q13.1 (for eye color, Figure 3b), dominate the significance plots. As described below, these signals correspond to SLC24A5 for skin color and HERC2 (OCA2) for eye color; Figure 3c and 3d show P value distributions when genotypes at SLC24A5 and HERC2 (OCA2) are considered as covariates. No additional loci were found in conditional analyses that adjust for the most significant SNPs in the known loci (four for skin and two for eye color). After removing SNPs surrounding these six loci, the genomic control parameters were 1.02 and 1.00 for skin color and eye color, respectively. We also examined the six loci identified in the combined sample in each island separately (Table S1); the direction of effect is consistent across all groups, with the derived allele associated with lighter skin color or a lower T-index (Table 1). Taken together with similar results from EMMAX (Figure S1), these results suggest adequate correction for population structure.
Figure 3. GWAS results for skin and eye color in the total Cape Verdean cohort.
Results are shown as −log10(P value) for the genotyped SNPs. Plots are ordered by chromosomal position. (a,c) Genotype and admixture association scan results for skin color. (b,d) Genotype and admixture association scan results for eye color. (a,b) show the P values obtained in the initial scans and (c,d) the P values of the following scans adjusting for the strongest associated SNP (in SLC24A5 for skin color and in HERC2 for eye color). Dashed red lines correspond to the genome-wide significance threshold (P<5×10−8 in the genotype scan; P<7×10−6 in the ancestry scan [see Material and Methods]). The location and identity of candidate genes are colored to correspond with chromosomal location; individual SNPs are given in Table 1.
Table 1. Major loci for skin and eye color.
For ancestry-based mapping, we used SABER+, an extension of a Markov-Hidden Markov Model method [24], to assign African vs. European ancestral segments along each chromosome, and then carried out a genome-wide evaluation of local ancestry association with skin and eye color, using the same covariates as for the genotype-based analysis. Ancestry-based association yields broader peaks than genotype-based association, but the distribution of significant regions is strikingly consistent for the two approaches, uncovering the identical set of six loci (Figure 3, Table 1).