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

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.

Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci

“…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 null 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 C HS2 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).…”

Clinal distribution of human genomic diversity across the Netherlands despite archaeological evidence for genetic discontinuities in Dutch population history

“…Notably, we did not observe a strong SPA signal in the LCT gene region on chromosome 2, which is known to be involved in lactase persistency and positive selection in Europeans, or the OCA2-HERC2 region on chromosome 15, which is known to be involved in blue-brown eye color determination and positive selection in Europeans. Both phenotypes, and also the genotypes at various SNPs in these genomic regions, have been previously reported to show a north to south gradient across Europe [4,42]. One explanation for why we did not pick-up these signals in our data might be that the genotype frequency gradients in these genomic regions are too small for detection on a micro-geographic level such as within the Netherlands using the methods we applied.…”

Genome-wide Association Study Identifies a Genetic Variant Associated with Risk for More Aggressive Prostate Cancer

“…SNP rs6497287 is located in HERC2 , a large 93 exon gene on 15q11–13. This gene functions as a determinant of human iris color (44, 45) and has recently been shown to have a role in the DNA damage response. HERC2 protein both mediates the specificity of E3 ubiquitin ligase binding (46) and acts as an E3 ligase itself, regulating XPA (47) and BRCA1 protein levels (48).…”