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. 2007 Feb;80(2):241-52.
doi: 10.1086/510885. Epub 2006 Dec 20.

A Three-Single-Nucleotide Polymorphism Haplotype in Intron 1 of OCA2 Explains Most Human Eye-Color Variation

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A Three-Single-Nucleotide Polymorphism Haplotype in Intron 1 of OCA2 Explains Most Human Eye-Color Variation

David L Duffy et al. Am J Hum Genet. .
Free PMC article


We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations. Fifty-eight synonymous and nonsynonymous exonic single-nucleotide polymorphisms (SNPs) and tagging SNPs were typed in a collection of 3,839 adolescent twins, their siblings, and their parents. The highest association for blue/nonblue eye color was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T, and rs11855019 T/C (P values of 1.02x10(-61), 1.57x10(-96), and 4.45x10(-54), respectively) in intron 1. These three SNPs are in one major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color. This genotype was also at highest frequency in subjects with light brown hair and was more frequent in fair and medium skin types, consistent with the TGT haplotype acting as a recessive modifier of lighter pigmentary phenotypes. Homozygotes for rs11855019 C/C were predominantly without freckles and had lower mole counts. The minor population impact of the nonsynonymous coding-region polymorphisms Arg305Trp and Arg419Gln associated with nonblue eyes and the tight linkage of the major TGT haplotype within the intron 1 of OCA2 with blue eye color and lighter hair and skin tones suggest that differences within the 5' proximal regulatory control region of the OCA2 gene alter expression or messenger RNA-transcript levels and may be responsible for these associations.


Figure  1.
Figure 1.
A, Positions of the OCA2 haplotyping SNPs, shown on the bar in alignment with those indicated in panel B. These are connected by lines to the linkage disequilibrium (r2) heat plot for the 58 tagging SNPs covering the region from OCA2 exon 1 to exon 24. Haplotype blocks showing mean values of the correlation coefficient r2 >0.8 are highlighted by triangles, with the intron 1 block in blue. B, Likelihood test statistic (Y-axis), plotted against the physical map distance from chromosome 15pter (X-axis) aligned with the exon positions as shown directly below (panel C). The score of the −log10 P values for each SNP association with blue/nonblue eye color (table 3) is shown here as a continuous line plot, with the intron 1 SNPs shown in blue. The positions of a selected subset of OCA2 SNPs used for haplotype analysis are shown above the plot. C, Schematic representation of the physical structure of OCA2 genomic locus, with the transcription unit blocked. Exons are indicated by black vertical lines and are numbered below, from exon 1 (E1) to exon 24 (E24), with intron 1 highlighted in blue.
Figure  2.
Figure 2.
OCA2 SNP prediction of eye color. A regression tree of 37 nodes based on 18 OCA2 tagging SNPs is shown with nodal P values and genotypes. A histogram of percentage eye color as blue (Bl), green (Gr), and brown (Br) for the 19 branching haplotype combinations is plotted, with the number of twin samples (n) indicated above each panel. Nodes shown branching to the left are higher for brown, and those to the right are higher for blue. Most striking are the nodes with high sample numbers, which approach 80% of individuals who have brown (node 4, n=301; node 8, n=116) or blue (node 34, n=413; node 37, n=193) eyes, with the major node 31 (n=1,113) comprising 80% of individuals with blue or green eyes. Minor nodes are predominantly higher for brown or green eyes.
Figure  3.
Figure 3.
A, Histogram of percentage facial ephelidae score (Y-axis) in the twin collection divided on a four-point scale (none, mild, moderate, or severe), as indicated by the color shading. The left three bars are plotted by eye color as blue (Bl), green (Gr), and brown (Br), and the right three bars are plotted by genotype at OCA2 SNP rs11855019. B, Mean total-nevus count (Y-axis), plotted against eye color in the left panel and by genotype at OCA2 SNP rs11855019 in the right panel.

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