How the Genetics of Eye Color Variation May be Even More Complex Than We Think

A new study published in the journal Science Advances has reported the identification of 50 previously unknown genes involved in the determination of human eye color variation. The study was led by a team of researchers at King’s College London and Erasmus University Medical Center Rotterdam.

The research team conducted a genome-wide association study (GWAS) for eye color, the largest of its kind to date, which involved the analysis of 195,000 individuals across Europe and Asia. The analysis uncovered 61 discrete genomic regions, with 50 of them being newly identified regions, associated with eye color variation.

Among the findings, researchers found that different shades of brown eye color found among Asians are genetically similar to eye color variations in Europeans that range from dark brown to light blue.

Previous GWASs have identified several different single-nucleotide polymorphisms (SNPs) located near a dozen or so genes that are significantly associated with eye color. Prior to this, scientists believed that eye color variation was controlled by only one or two genes, with brown eyes dominant over blue eyes.

With this latest study, it appears that eye color is governed by more than five times the number of genes than previously thought, making the trait even more genetically complex than previously thought.

The research findings further underscore the complexity of the genetic determination of human eye color. The researchers say they will also help to improve the understanding of eye diseases such as pigmentary glaucoma and ocular albinism in which eye pigment levels play a role.

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Eye color is mainly determined by melanin levels within the iris pigment epithelium of the eye, with greater amounts found in brown eyes than blue eyes. Iris color is a significantly heritable and polygenic trait, as it is determined by more than one gene.

The study looked at both European and Asian populations. People of European origin display the largest diversity in iris color, varying from the lightest blue to darkest brown. There is a correlation between the prevalence of blue eyes and geographic latitude across Europe and surrounding areas, likely owing to human migration and sexual and even natural selection.

Asian populations also show significant eye color variation with different degrees of brown iris pigmentation, but with a lesser range in variation than Europeans.

Previously, eye color variation could be predicted based on just six SNPs from six genes including HERC2 and OCA2, which are involved in skin, hair and eye pigmentation and melanin production, respectively. The OCA2 promoter has been found to act as a molecular switch between light and dark pigmentation.

These genes cannot predict non-blue and non-brown eyes with accuracy. In addition, phenotypic variances of 26 percent and 50 percent for blue and brown eyes, respectively, could not be explained by only the SNPs in the six genes, suggesting that there were more SNPs and genes at play.

In this study, 192,986 European participants from ten populations were analyzed. The researchers identified 124 independent associations stemming from 61 discrete genomic regions, including 50 that were previously unidentified. The newly identified genes include those involved in melanin pigmentation, and interestingly, genes involved in iris morphology and structure.

The newly identified genomic regions in the discovery analysis included 41 novel genetic loci. Significant eye color association was found for SNPs within TPCN2 and MITF and five others near the genes DTL, AP3M2, SOX5, DCT and SIK1, all of which are associated with hair and skin pigmentation. OCA genes involved in five of the seven known types of oculocutaneous albinism were also implicated: OCA1, OCA2, OCA3, OCA4 and OCA6.

Analyses conducted in 1,636 Asian participants from two populations indicate that iris pigmentation variation in Asians is genetically similar to Europeans, but with smaller variative effects.

The researchers say that collectively, 53.2 percent of eye color variation can be explained using SNPs in and around these genes.

In a news release from King’s College London, co-senior author Dr. Pirro Hysi, King’s College London, said, “The findings are exciting because they bring us to a step closer to understanding the genes that cause one of the most striking features of the human faces, which has mystified generations throughout our history. This will improve our understanding of many diseases that we know are associated with specific pigmentation levels.”

Co-senior author Dr. Manfred Kayser, Erasmus University Medical Center Rotterdam, commented that, “This study delivers the genetic knowledge needed to improve eye color prediction from DNA as already applied in anthropological and forensic studies, but with limited accuracy for the non-brown and non-blue eye colors.”

The results of the study highlight the fact that the genetic complexity of human eye color is far greater than previously thought, making it a very genetically complex human trait.