Genetic evidence and cross-species functional characterization implicate <i>CNN2</i> in age-related macular degeneration susceptibility.

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in the aging population globally. Although genome-wide association studies (GWAS) have identified many AMD susceptibility loci, the genes and mechanisms underlying many of these associations remain unresolved. Here, we integrated expression quantitative trait locus (eQTL) data with AMD GWAS to prioritize nine putative genes. Through in vivo screening in zebrafish, we demonstrated that the downregulation of <i>cnn2</i> and <i>sarm1</i> expression led to ocular structural abnormalities and visual functional impairment. Subsequent mouse model studies confirmed that <i>Cnn2</i> deficiency affected photoreceptor structure and function, impaired contrast sensitivity, and caused abnormalities in cone cell immunostaining. Given that <i>CNN2</i> is predominantly expressed in endothelial cells, we propose that endothelial dysfunction may cascade to impair photoreceptor function. Collectively, through in silico prioritization and cross-species functional characterization, we identify <i>CNN2</i> as a candidate susceptibility gene in AMD pathogenesis, providing vital underlying mechanistic insights.