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New genetic loci for eye colour identified

An international team of researchers led by King’s College London and Erasmus University Medical Center Rotterdam have discovered 50 new genes for eye colour in the largest genetic study of its kind to date.

Eye colour

Human eye colour is primarily determined by melanin abundance within the iris pigment epithelium. Both the density and distribution of stromal melanocyte cells also affect this trait. Additional factors include the ratio of the two forms of melanin (eumelanin and pheomelanin) as well as light absorption and scattering by extracellular components. In brown eyes, the abundance of melanin and the eumelanin:pheomelanin ratio is higher. Whereas blue or green irises have very little of both pigments and relatively more pheomelanin.

European populations display the largest diversity of iris colour. Researchers have found that the prevalence of blue eyes correlates with geographic latitude across Europe. This is likely the result of human migration, and sexual and natural selection.

Iris colour is highly heritable. Previous genome-wide association studies have identified several SNPs in and around 10 genes that significantly associate with eye colour, highlighting its polygenic nature. Neighbouring HERC2 and OCA2 genes exert the strongest genetic influence on eye colour. A DNA test system based on six SNPs from six genes, including HERC2 and OCA2, allows for accurate prediction of blue and brown eye colour.

Nonetheless, the accuracy in non-blue and non-brown eye colour is considerably lower. In addition, there remains phenotypic variance that has not yet been explained by GWASs. This illustrates the likely presence of unknown genes responsible for the missing genetic predicting accuracy and missing heritability.

Largest GWAS

In this study, published in Science Advances, researchers carried out the largest eye colour GWAS to date. Their study involved 157,485 individuals of European ancestry in the discovery stage and an additional 35,501 ancestral European individuals in the replication stage. The study also involved 1,636 Asians (of Han Chinese and Indian ancestry) for replication purposes.

The team identified 124 independent associations from 61 discrete genomics regions. Of these regions, 50 were previously unidentified. They found evidence for genes involved in melanin pigmentation, but also genes involved in iris morphology and structure.

Analyses in the Asian cohort suggested that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes.

These findings collectively explain 53.2% of eye colour variations using common SNPs. Overall, the study demonstrates the genetic complexity of human eye colour, which has considerably exceeded previous expectations and knowledge.

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.”

Image credit: By freepik – freepik

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Eye / Genetic Variants