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Digital quantification of human eye color highlights genetic association of three new loci.

Liu F, Wollstein A, Hysi PG, Ankra-Badu GA, Spector TD, Park D, Zhu G, Larsson M, Duffy DL, Montgomery GW, Mackey DA, Walsh S, Lao O, Hofman A, Rivadeneira F, Vingerling JR, Uitterlinden AG, Martin NG, Hammond CJ, Kayser M - PLoS Genet. (2010)

Bottom Line: Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information.Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association.A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study.

View Article: PubMed Central - PubMed

Affiliation: Department of Forensic Molecular Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.

ABSTRACT
Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits.

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Related in: MedlinePlus

Observed and expected P values for eye color in the Rotterdam Study (RS123).Observed −log10 P values in a GWA of CHS1 are ranked on the y-axis and plotted against the expected distribution under the  on the x-axis. All P values smaller than 10−10 were truncated at 10 at the log scale. The red dots are the P values excluding the effects of sex, age, and population stratification. Blue dots are the P values excluding the effects of 7 genes previously known to be involved in eye color. Green dots are the P values after additionally excluding the effects of 3 newly identified loci, with no more SNPs showing significant association at the genome-wide level.
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pgen-1000934-g002: Observed and expected P values for eye color in the Rotterdam Study (RS123).Observed −log10 P values in a GWA of CHS1 are ranked on the y-axis and plotted against the expected distribution under the on the x-axis. All P values smaller than 10−10 were truncated at 10 at the log scale. The red dots are the P values excluding the effects of sex, age, and population stratification. Blue dots are the P values excluding the effects of 7 genes previously known to be involved in eye color. Green dots are the P values after additionally excluding the effects of 3 newly identified loci, with no more SNPs showing significant association at the genome-wide level.

Mentions: GWAS in three independent RS cohorts, as well as in the merged dataset (RS123), were carried out for 6 eye color traits i) H, ii) S, iii) CHS1, iv) CHS2, v) 3-category color classification (“blue”, “brown” and “intermediate”), and vi) 5-category color classification (“pure blue”, “light blue/grey”, “green/mixed with brown spots”, “light brown”, and “dark brown”). Genetic outliers of non-European ancestry were excluded (Figure S1A). No institutional heterogeneity between the three cohorts or residual population sub-stratification was noticed after merging the genotype data (Figure S1B). Inflation factors for all color traits were in the range from 1.02 to 1.03 after adjusting for population sub-stratification. The initial scan of the merged R123 samples for all color traits revealed a sharp deviation between the observed P values and the expected ones under the hypothesis (Figure 2), mainly due to a very strong effect of the HERC2 and OCA2 genes on chromosome 15q13.1 (Figure 3A and Table S1). SNPs in HERC2 showed the most significant effect on all color traits (rs12913832 P<10−300; except for CHS2 with P = 0.60) (Figure 3, Table S1), confirming previous findings on categorical eye color information [5]–[6], [11], [14]. In the subsequent scan adjusted for the effect of HERC2 rs12913832, five other genes known to be involved in eye color (OCA2, SLC2A4, TYR, TYRP1, and SLC45A2) [4], [7] revealed genome-wide significant eye color association (P<5×10−8), and the effect of IRF4 [7] was confirmed at a somewhat lower significance level (P = 1.4×10−6) (Figure 3B). We did not observe a significant effect of ASIP on eye color, which is in agreement with our earlier study on categorized eye color [8], and in line with previous findings suggesting that ASIP may be more involved in skin pigmentation [4], [15]. Noteworthy, SNPs in the previously known eye color genes TYRP1, TYR, and SLC24A4 showed more significant association with quantitative eye color compared with categorical ones (Figure 3B). In the subsequent GWAS adjusted for the effects of all 7 known genes, the P values derived for CHS1, H and S still significantly deviated from the expected ones (Figure 2). The tail of deviation was mainly explained by 10 SNPs at 3 new loci 1q42.3, 17q25.3, and 21q22.13 (Table 2, Figure 3C). The association of the three new loci met the genome-wide significance criterion of P<5×10−8. The allelic effects of the 10 SNPs were consistent through the 3 independent RS cohorts and were nominally significant (Table 2). No more SNPs were clearly associated with any eye color trait at the genome-wide significant level in an additional scan adjusted for all previously known genes as well as the 3 new loci.


Digital quantification of human eye color highlights genetic association of three new loci.

Liu F, Wollstein A, Hysi PG, Ankra-Badu GA, Spector TD, Park D, Zhu G, Larsson M, Duffy DL, Montgomery GW, Mackey DA, Walsh S, Lao O, Hofman A, Rivadeneira F, Vingerling JR, Uitterlinden AG, Martin NG, Hammond CJ, Kayser M - PLoS Genet. (2010)

Observed and expected P values for eye color in the Rotterdam Study (RS123).Observed −log10 P values in a GWA of CHS1 are ranked on the y-axis and plotted against the expected distribution under the  on the x-axis. All P values smaller than 10−10 were truncated at 10 at the log scale. The red dots are the P values excluding the effects of sex, age, and population stratification. Blue dots are the P values excluding the effects of 7 genes previously known to be involved in eye color. Green dots are the P values after additionally excluding the effects of 3 newly identified loci, with no more SNPs showing significant association at the genome-wide level.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865509&req=5

pgen-1000934-g002: Observed and expected P values for eye color in the Rotterdam Study (RS123).Observed −log10 P values in a GWA of CHS1 are ranked on the y-axis and plotted against the expected distribution under the on the x-axis. All P values smaller than 10−10 were truncated at 10 at the log scale. The red dots are the P values excluding the effects of sex, age, and population stratification. Blue dots are the P values excluding the effects of 7 genes previously known to be involved in eye color. Green dots are the P values after additionally excluding the effects of 3 newly identified loci, with no more SNPs showing significant association at the genome-wide level.
Mentions: GWAS in three independent RS cohorts, as well as in the merged dataset (RS123), were carried out for 6 eye color traits i) H, ii) S, iii) CHS1, iv) CHS2, v) 3-category color classification (“blue”, “brown” and “intermediate”), and vi) 5-category color classification (“pure blue”, “light blue/grey”, “green/mixed with brown spots”, “light brown”, and “dark brown”). Genetic outliers of non-European ancestry were excluded (Figure S1A). No institutional heterogeneity between the three cohorts or residual population sub-stratification was noticed after merging the genotype data (Figure S1B). Inflation factors for all color traits were in the range from 1.02 to 1.03 after adjusting for population sub-stratification. The initial scan of the merged R123 samples for all color traits revealed a sharp deviation between the observed P values and the expected ones under the hypothesis (Figure 2), mainly due to a very strong effect of the HERC2 and OCA2 genes on chromosome 15q13.1 (Figure 3A and Table S1). SNPs in HERC2 showed the most significant effect on all color traits (rs12913832 P<10−300; except for CHS2 with P = 0.60) (Figure 3, Table S1), confirming previous findings on categorical eye color information [5]–[6], [11], [14]. In the subsequent scan adjusted for the effect of HERC2 rs12913832, five other genes known to be involved in eye color (OCA2, SLC2A4, TYR, TYRP1, and SLC45A2) [4], [7] revealed genome-wide significant eye color association (P<5×10−8), and the effect of IRF4 [7] was confirmed at a somewhat lower significance level (P = 1.4×10−6) (Figure 3B). We did not observe a significant effect of ASIP on eye color, which is in agreement with our earlier study on categorized eye color [8], and in line with previous findings suggesting that ASIP may be more involved in skin pigmentation [4], [15]. Noteworthy, SNPs in the previously known eye color genes TYRP1, TYR, and SLC24A4 showed more significant association with quantitative eye color compared with categorical ones (Figure 3B). In the subsequent GWAS adjusted for the effects of all 7 known genes, the P values derived for CHS1, H and S still significantly deviated from the expected ones (Figure 2). The tail of deviation was mainly explained by 10 SNPs at 3 new loci 1q42.3, 17q25.3, and 21q22.13 (Table 2, Figure 3C). The association of the three new loci met the genome-wide significance criterion of P<5×10−8. The allelic effects of the 10 SNPs were consistent through the 3 independent RS cohorts and were nominally significant (Table 2). No more SNPs were clearly associated with any eye color trait at the genome-wide significant level in an additional scan adjusted for all previously known genes as well as the 3 new loci.

Bottom Line: Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information.Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association.A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study.

View Article: PubMed Central - PubMed

Affiliation: Department of Forensic Molecular Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.

ABSTRACT
Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits.

Show MeSH
Related in: MedlinePlus