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Comparative Study
. 2008 Feb;82(2):411-23.
doi: 10.1016/j.ajhg.2007.10.003. Epub 2008 Jan 25.

Three Genome-Wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene

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Free PMC article
Comparative Study

Three Genome-Wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene

Manfred Kayser et al. Am J Hum Genet. .
Free PMC article

Erratum in

  • Am J Hum Genet. 2008 Mar;82(3):801

Abstract

Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of 1406 persons and a genome-wide linkage study of 1292 relatives, all from the Netherlands, we found that the 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genome-wide evidence for association and linkage to iris color. Single nucleotide polymorphisms (SNPs) in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene were independently associated to iris color variation. OCA2 has been implicated in iris color previously. A replication study within two populations confirmed that the HERC2 gene is a new and significant determinant of human iris color variation, in addition to OCA2. Furthermore, HERC2 rs916977 showed a clinal allele distribution across 23 European populations, which was significantly correlated to iris color variation. We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.

Figures

Figure 1
Figure 1
Design of the Study
Figure 2
Figure 2
Genome-wide Association for Human Iris Color in Three Independent Population Samples from The Netherlands (A) GWA-ERF250K: the ERF study (n = 192, distant relatives) with Affymetrix 250K SNPs. (B) GWA-ERF318K: the ERF study (n = 733, related) with Illumina 318K SNPs. (C) GWA-Rdam500K: the Rotterdam study (n = 481, unrelated) with Affymetrix 500K SNPs. The x axis represents the chromosome, and the y axis shows −log10P in respect of iris color association.
Figure 3
Figure 3
Single SNP and Haplotype Association Analysis for Human Iris Color in Three Independent Population Samples from The Netherlands in Region 25.0–26.8 Mb of Chromosome 15 (A) GWA-ERF250K. (B) GWA-Rdam500K. (C) GWA-ERF318K (no haplotypes were estimated in this family-based study). The x axis represents the regional position on chromosome 15, and the y axis shows −log10P in respect of iris color association. The OCA2 and the HERC2 genes are highlighted with green and blue boxes, respectively. The −log10 P-values for haplotype analysis were truncated at 20. (D) Number of regionally genotyped SNPs in HapMap Europeans and their locations. (E) Regional genes and hypothetical proteins as well as their locations.
Figure 4
Figure 4
Patterns of Linkage Disequilibrium in Region 25.86–26.19 Mb of Chromosome 15 Data from (A) HapMap Europeans, (B) GWA-ERF250K, and (C) GWA-Rdam500K. Locations of the OCA2 and the HERC2 genes are depicted on top. LD plots are arranged to each other according to the physical positions of the SNPs involved. The same SNP and block numbers were used for (B) and (C).
Figure 5
Figure 5
Step-wise Prediction Probabilities for Brown Iris Color Analysis is based on three SNPs: rs916977 (HERC2), rs11855019 (OCA2), and rs7495174 (OCA2).
Figure 6
Figure 6
Allele Frequency Distribution of rs916977 across 23 European Populations and Spatial Autocorrelation Analysis (A) HERC2 rs916977 allele frequencies superimposed on a map of Europe with indication of classes of human iris color phenotypes. Sizes of the pie charts indicate sample size. Map (without data on rs916977) published previously by Allyn and Bacon, Boston, MA. Copyright 1965 by Pearson Education. Reprinted by permission of the publisher. (B) Spatial autocorrelation analysis of rs916977 allele frequencies across Europe.

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