Moreover, the phenotypic variance of eye color not previously explained by GWASs ranged between 26% for a blue versus a brown scale ( 10) and 50% for a scale using three categories ( 11) across studies. However, nonblue and nonbrown eye color can be genetically predicted with considerably lower accuracy ( 19, 21, 22), likely because of unknown predictive SNPs and responsible genes. Previously available genetic knowledge allows accurate prediction of blue and brown eye color, for instance, with a DNA test system based on six SNPs from six genes, including HERC2 and OCA2 ( 19 ), that has been used in anthropological ( 20) and forensic ( 21, 22) applications. The strongest genetic influence on eye color is exerted by the neighboring HERC2 and OCA2 genes ( 13, 14, 16, 17), where a long distance enhancer effect of an intronic SNP in HERC2 was demonstrated interacting with the OCA2 promoter functioning as a molecular switch between light and dark pigmentation ( 18). Previous genome-wide association studies (GWASs) have identified various single-nucleotide polymorphisms (SNPs) in and around 10 genes significantly associated with eye color ( 11– 14), highlighting the polygenic nature of a trait that, in the past, was assumed to be genetically simple ( 15). Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations.
Human eye color is highly heritable, but its genetic architecture is not yet fully understood. Martin, Ching-Yu Cheng, the 23andMe Research Team, the International Visible Trait Genetics Consortium, David A. van Duijn, Tamar Nijsten, Jiali Han, David A. Hammond, Yuan Shi, Yan Chen, Changqing Zeng, Caroline C. Medland, Dragana Vuckovic, Giorgia Girotto, Cinzia Sala, Eulalia Catamo, Maria Pina Concas, Marco Brumat, Paolo Gasparini, Daniela Toniolo, Massimiliano Cocca, Antonietta Robino, Seyhan Yazar, Alex Hewitt, Wenting Wu, Peter Kraft, Christopher J. Ring, … Show All …, George Davey Smith, David L.
Mark Simcoe, Ana Valdes, Fan Liu, Nicholas A.
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