Evolutionary Origin of Ocular Melanoma: Associations With rs12913832 G Allele Frequency and Latitude

Ocular melanoma (OM) incidence varies worldwide, but the relative impact of geographic latitude versus pigmentation genetics remains debated. We investigated whether the country-level frequency of the rs12913832 derived (G) blue-eye allele (G allele frequency), or latitude better explains international differences in OM incidence.

We performed an observational ecological study of 29 countries using age-standardized OM incidence data from the International Agency for Research on Cancer (IARC), G allele frequencies from publicly available databases, and population-weighted centroids derived from nighttime lights data. We conducted correlation, linear regression, and mediation analyses to assess the associations among latitude, G allele frequency, and OM incidence.

In univariate analyses, both latitude and the G allele frequency were positively associated with OM incidence. In multivariate regression, latitude was no longer significant, whereas the G allele frequency explained substantially more variance and uniquely accounted for 61 times more variance (partial r²) than latitude. Mediation analysis indicated that about 92% of latitude's effect on incidence was mediated through G allele frequency.

At the population level, the G allele frequency is a markedly stronger predictor of OM incidence than geographic latitude. As an ecological analysis, this study identifies a population-level association rather than individual-level genetic risk and suggests that pigmentation genetics underlie much of the international variation in OM incidence.