Investigating the genetic architecture of eye colour in a Canadian cohort
Bibliographic record
Abstract
Abstract The main factors that determine eye colour are the amount of melanin concentrated in iris melanocytes, as well as the shape and distribution of melanosomes. Eye colour is highly variable in populations with European ancestry, in which eye colour categories cover a continuum of low to high quantities of melanin accumulated in the iris. A few polymorphisms in the HERC2/OCA2 locus in chromosome 15 have the largest effect on eye colour in these populations, although there is evidence of other variants in the locus and across the genome also influencing eye colour. To improve our understanding of the genetic loci determining eye colour, we performed a meta-analysis of genome-wide association studies in a Canadian cohort of European ancestry (N= 5,641) and investigated putative causal variants. Our fine-mapping results indicate that there are several candidate causal signals in the HERC2/OCA2 region, whereas other significant loci in the genome likely harbour a single causal signal (TYR, TYRP1, IRF4, SLC24A4). Furthermore, a short subset of the associated eye colour regions was colocalized with the gene expression or methylation profiles of cultured melanocytes (HERC2, OCA2), and transcriptome-wide association studies highlighted the expression of two genes associated with eye colour: SLC24A4 and OCA2. Finally, genetic correlations of eye and hair colour from the same cohort suggest high pleiotropy at the genome level, but locus-level evidence hints at several differences in the genetic architecture of both traits. Overall, we provide a better picture of how polymorphisms modulate eye colour variation, particularly in the HERC2/OCA2 locus, which may be a consequence of specific molecular processes in the iris melanocytes. Author Summary Eye colour differences among humans are the result of different amounts of melanin produced, as well as due to differences in the shape and distribution of the organelles in charge of producing melanin. Eye colour is a highly heritable trait, where several genes across the genome are involved in the process, but we currently do not fully understand which are the causal variants and how they modulate eye colour variation. By performing genome-wide association studies of eye colour across Canadian individuals of European ancestry, we identify several candidate causal signals in and near the gene OCA2, and one candidate signal in other genes, such as TYR, TYRP1, IRF4 and SLC24A4. Furthermore, we provide insights about how significant loci may modulate eye colour variation by testing for shared signals with polymorphisms associated with the expression of genes and DNA methylation. Overall, we provide a better picture of the genetic architecture of eye colour and the molecular mechanisms contributing to its variation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.004 |
| Science and technology studies | 0.003 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".