Genetics of Iris Color

Genetics, Vol. 165, 2071-2083, December 2003.

Sequences Associated With Human Iris Pigmentation

Tony Frudakis et al.

Abstract

To determine whether and how common polymorphisms are associated with natural distributions of iris colors, we surveyed 851 individuals of mainly European descent at 335 SNP loci in 13 pigmentation genes and 419 other SNPs distributed throughout the genome and known or thought to be informative for certain elements of population structure. We identified numerous SNPs, haplotypes, and diplotypes (diploid pairs of haplotypes) within the OCA2, MYO5A, TYRP1, AIM, DCT, and TYR genes and the CYP1A2-15q22-ter, CYP1B1-2p21, CYP2C8-10q23, CYP2C9-10q24, and MAOA-Xp11.4 regions as significantly associated with iris colors. Half of the associated SNPs were located on chromosome 15, which corresponds with results that others have previously obtained from linkage analysis. We identified 5 additional genes (ASIP, MC1R, POMC, and SILV) and one additional region (GSTT2-22q11.23) with haplotype and/or diplotypes, but not individual SNP alleles associated with iris colors. For most of the genes, multilocus gene-wise genotype sequences were more strongly associated with iris colors than were haplotypes or SNP alleles. Diplotypes for these genes explain 15% of iris color variation. Apart from representing the first comprehensive candidate gene study for variable iris pigmentation and constituting a first step toward developing a classification model for the inference of iris color from DNA, our results suggest that cryptic population structure might serve as a leverage tool for complex trait gene mapping if genomes are screened with the appropriate ancestry informative markers.

...

Genotypes for these 754 candidate SNPs were scored for 851 European-derived individuals of self-reported iris colors (292 blue, 100 green, 186 hazel, and 273 brown). Before screening these genotypes for association with iris colors, we used the 73 nonxenobiotic metabolism AIMs to determine BGA admixture proportions for each sample and we tested for correlation between BGA admixture and iris colors. This test showed that each of our 851 Caucasian samples was of majority Indo-European BGA, and although 58% of the samples were of significant (>4%) non-Indo-European BGA admixture, there was no correlation among low levels (<33%) of East Asian, sub-Saharan African, or Native American admixture and iris colors. For more extensively admixed individuals, we observed no correlation between higher levels (>33% but <50%) of Native American admixture and iris colors, although there was a weak association between higher levels of East Asian and sub-Saharan African admixture and darker iris colors (data not shown).

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