Causal Influence of Plasma Metabolites on Age-Related Macular Degeneration: A Mendelian Randomization Study.

Abstract

Background Age-related macular degeneration (AMD) is a prevalent eye condition in the elderly, profoundly affecting their quality of life. Despite its multifactorial nature, the precise mechanisms underlying AMD remain elusive. The potential role of metabolites as biomarkers has become a focal point of recent research. Utilizing Mendelian randomization analysis, this study aims to decipher the complex metabolic mechanisms associated with AMD, laying the groundwork for novel diagnostic and therapeutic approaches. Methods Employing Mendelian randomization (MR) analysis, this study leveraged single nucleotide polymorphisms (SNPs) significantly associated with plasma metabolites as instrumental variables (IVs). This approach established a causal link between metabolites and AMD. Analytical methods such as Inverse Variance Weighted (IVW), MR-Egger, and Weighted Median were applied to validate causality. MR-PRESSO was utilized for outlier detection and correction, and Cochran's Q test was conducted to assess heterogeneity. To delve deeper into the metabolic characteristics of AMD, metabolic enrichment analysis was performed using Metabo Analyst 5.0. These combined methods provided a robust framework for elucidating the metabolic underpinnings of AMD. Results The two-sample MR analysis, after meticulous screening, identified causal relationships between 88 metabolites and AMD. Of these, 16 metabolites showed a significant causal association. Following FDR correction, three metabolites remained significantly associated, with Androstenediol (3beta,17beta) disulfate (2) exhibiting the most potent protective effect against AMD. Further exploration using Metabo Analyst 5.0 highlighted four metabolic pathways potentially implicated in AMD pathogenesis. Conclusion This pioneering MR study has unravelled the causal connections between plasma metabolites and AMD. It identified several metabolites with a causal impact on AMD, with three maintaining significance after FDR correction. These insights offer robust causal evidence for future clinical applications and underscore the potential of these metabolites as clinical biomarkers in AMD screening, treatment, and prevention strategies.