bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.07.20.665796

A comparative GWAS of eye colour in light and dark eye genetic backgrounds defined by HERC2 rs12913832 polymorphism

Abbatangelo, C.·Lona Durazo, F.·Edwards, M.·Parra, E. J.
View original source ↗Export metadata ↓

Abstract

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? Building upon our prior investigation of iris pigmentation genetics in individuals with an expected "blue eye" background (rs12913832:GG genotype) in a sample of the Canadian Partnership for Tomorrows Health (CanPath) cohort, this study extends the analysis to include individuals with an expected "brown eye" background (rs12913832:AA+AG). 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 importance of gene-gene interactions and the polygenic nature of pigmentation traits, emphasizing modifying effects that can sometimes counteract the dominant influence of rs12913832, contributing to advancements in pigmentation genetics and forensic applications.

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Abbatangelo, C., Lona Durazo, F., Edwards, M., Parra, E. J.. 2025-07-24. A comparative GWAS of eye colour in light and dark eye genetic backgrounds defined by HERC2 rs12913832 polymorphism. https://doi.org/10.1101/2025.07.20.665796

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Large language model-based bibliometric evaluation of population descriptors in human genetics

As the use of population descriptors such as race, ethnicity, and ancestry have become increasingly common in modern genetics research, there have been growing calls to critically examine their use. Most notably, in 2023, the National Academies of Science, Engineering, and Medicine (NASEM) published a report titled Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field, which included eight specific and actionable recommendations for researchers to implement the ethical and accurate use of population descriptors in genetic research. Here, we use the 2023 NASEM report as a benchmark to analyze the use of population descriptors in genome-wide association studies (GWAS). We develop a general toolkit for large language model-based bibliometrics, operationalize the report's recommendations into an evaluation framework, and apply this framework to evaluate all 4,007 papers from the GWAS Catalog published between 2007 and 2025 with full text available on PubMedCentral. We find significant improvements in adherence to NASEM report recommendations over time. However, most improvements predate the publication of the NASEM report itself, suggesting the report functioned primarily as a synthesis of existing best practices rather than a catalyst for change. We conclude by highlighting opportunities for growth in the field of human genetics.

genetics↗
bioRxiv2026

Mitigating biases of rescaling in forward-in-time population genetic simulations

Forward-in-time population genetic simulations are widely used in evolutionary analyses, but simulating large populations and long genomic regions remains computationally demanding. To reduce this cost, parameter rescaling is widely employed, in which the original evolutionary process is approximated by one with a smaller population size and fewer generations. Recently, several studies using the SLiM simulator have raised concerns about the accuracy of this rescaling approach. In this study, we show that many of the biases reported in these studies can be mitigated by using a different simulation algorithm. These results reveal that the accuracy of parameter rescaling depends on how well the simulation algorithm preserves diffusion-limit properties under rescaling.

genetics↗
bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗