Rs12913832, a polymorphism located in an enhancer within the HERC2 gene, which is known to regulate OCA2 transcription, is heavily relied upon as a predictor of light versus dark eyes. Individuals with the GG genotype are projected to have blue eyes, while individuals with the AA or AG genotypes are projected to have darker eye colours (primarily brown). However, eye colour is a polygenic trait, and previous studies have revealed that a significant proportion of individuals self-report an eye colour that is not concordant with their genotype at rs12913832. Herein, we address the question: What common markers are influencing eye colour in individuals whose self-reported phenotype does not correspond to the expected phenotype based on their rs12913832 genotype? We present a stratified analysis of iris pigmentation genetics in individuals with an expected “blue eye” background (rs12913832:GG genotype) and individuals with an expected “brown eye” background (rs12913832:AA + AG) in a sample of European ancestry from the Canadian Partnership for Tomorrow’s Health (CanPath) cohort. We identified variants in SLC45A2, TYRP1, TYR, SLC24A4 and TSPAN10, which may influence eye colour presentation in individuals with the rs12913832:GG genotype and variants in IRF4, TYRP1 and OCA2, which may influence eye colour presentation in individuals with the rs12913832:AA + AG genotype. These markers include well-known pigmentation-associated single nucleotide polymorphisms, such as rs16891982 (SLC45A2), rs1126809 (TYR), rs12203592 (IRF4), rs1800407 (OCA2) and rs6420484 (TSPAN10). Several of these loci were replicated using independent quantitative eye colour measures, including heterochromia and CIELAB colour dimensions. This research highlights the polygenic nature of pigmentation traits, identifying polymorphisms that modify the well-known effects of rs12913832 on eye colour, contributing to advancements in pigmentation genetics and forensic applications.
Abbatangelo et al. (Mon,) studied this question.