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

Background 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. Methods 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. Results 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 r 2 ) than latitude. Mediation analysis indicated that about 92% of latitude's effect on incidence was mediated through G allele frequency. Conclusion 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.