# Iris Pigmented Lesions: Unraveling the Genetic Basis of Iris Freckles and Nevi

## TL;DR

This study explores the genetic and demographic factors behind iris freckles and nevi in a Spanish population, linking them to pigmentation genes and traits like eye color and age.

## Contribution

The study identifies specific genetic associations with iris freckles and nevi, particularly highlighting IRF4 and sex-specific effects.

## Key findings

- Iris freckles and nevi are linked to IRF4, HERC2, OCA2, and SLC45A2 genes, especially in females.
- Iris nevi are associated with IRF4, HERC2, and TYR in brown-eyed individuals.
- MC1R, a key gene for skin freckles, is not associated with iris freckles or nevi.

## Abstract

To investigate the diversity of pigmented benign lesions in the human iris, aiming to provide insights for forensic, biomedical, and ophthalmological research.

A cohort of 1014 individuals of Spanish descent was analyzed. Digital slit-lamp photographs were used to evaluate iris pigmentation traits, including iris freckles, iris nevi, iris color, and the presence of a pigmented collarette. A candidate gene association study was performed on these pigmentation traits.

Both iris freckles and nevi were associated with increased age, female sex, pigmented collarette, and eye color (mainly green). Additionally, higher freckle and nevus counts were observed in participants with more facial freckles and cutaneous nevi and were positively associated with each other. After adjustment, a positive significant association was identified between the presence of iris freckles and genetic variants in the IRF4, HERC2, and OCA2 genes, as well as SLC45A2, although only in females. The prevalence of iris nevi was significantly lower compared to freckles. The presence of iris nevi also showed positive associations with genetic variants in IRF4 and HERC2, plus TYR in brown-eyed individuals only. No association was identified between MC1R, the major cutaneous freckle gene, and the presence of iris freckles or nevi.

The genetic basis of iris freckles and nevi reveals associations with well-known pigmentation genes (particularly IRF4), as well as eye color, sex, and age. These findings contribute to our understanding of iris pigmented benign lesions and their potential implications in conditions such as uveal melanoma, age-related macular degeneration, or solar damage.