Experimental Eye Research · Jun 25, 2025
Elucidating the genetic and metabolomic underpinnings of age-related macular degeneration through two-sample Mendelian randomization
By Shen W, Tan Y, Luo Z et al.
Age-related macular degeneration (AMD), a chronic and progressive retinal disorder, is a leading cause of severe and irreversible visual impairment. The pathogenesis of AMD is multifactorial and intricate. Mendelian randomization (MR) serves as a popular approach of instrumental variable analysis to decipher the causality of associations. We applied a two-sample MR to assess the causal effects of 1400 serum metabolites and two subtypes of AMD (dry AMD and wet AMD) using the genome-wide association study statistics. We performed the inverse variance weighted method, weighted median algorithm, and sensitivity analyses including Cochran Q test, MR-Egger intercept test, MR-PRESSO, radial MR, leave-one-out examination, and Steiger test. Meanwhile, we utilized the linkage disequilibrium score regression analysis to consolidate the genetic correlation analysis. 18 identified metabolites for dry AMD and 16 for wet AMD were confirmed to have significant associations with the risk of dry AMD and wet AMD, respectively. Among these metabolites, 13 and 12 genetically established metabolites had prominent correlations after strict sensitivity assessments. 4 and 3 metabolites were identified prominent heritability for two subtypes of AMD, respectively. After excluding one metabolite which displayed shared genetic interrelation with wet AMD, our results demonstrates 4 identified serum metabolites are related to a reduced risk of dry AMD (N-acetyl-2-aminooctanoate, N-acetyl-L-glutamine, N-acetylphenylalanine, and N2,N5-diacetylornithine); 2 chemically known serum metabolites are linked with a decreased risk of wet AMD (pregnenetriol disulfate and N2-acetyl,N6,N6-dimethyllysine), respectively. The results manifested their potential protective roles in the development of AMD, underlines the distinct genetic inferences between metabolomics and AMD, and provide a novel ponder angle for clinical screening, preventive measures, and therapeutic strategy exploration of distinct subtypes of AMD.