Exploring Therapeutic Targets for Age-Related Macular Degeneration From Circulating Proteins to Plasma Metabolites in the European Population.

PURPOSE

To explore the causal associations among circulating proteins, plasma metabolites, and age-related macular degeneration (AMD).

METHODS

We employed Mendelian randomization (MR) analysis and colocalization analysis to discern the causal relationship between proteomes and AMD. This investigation utilized data from protein quantitative trait loci (pQTL) studies in deCODE and the UK Biobank. Additionally, plasma metabolite-related genome-wide association studies (GWAS) data and AMD-related GWAS data were incorporated.

RESULTS

Our findings confirmed a potential causal relationship between cytoplasmic tryptophanyl-tRNA synthetase 1 (WARS1) and a higher risk of AMD. The observed causal impact of WARS1 on the two subtypes of AMD (dry and wet) align consistently with the aforementioned outcomes. Three plasma metabolites-N-acetyl-kynurenine, N-acetyltyrosine, and caproate (6:0)-were identified as mediators of the causal effect of WARS1 on AMD, and subgroup analysis revealed that N-acetyltyrosine is a specific negative metabolite associated with WARS1 and dry AMD, whereas X-16580 is a specific positive metabolite linked to WARS1 and wet AMD.

CONCLUSIONS

The outcomes of this study suggest a potential causal role of specific circulating proteins in AMD and identified the mediating role of plasma metabolites between WARS1 and AMD by integrating multiple genetic analyses. Nevertheless, further research is essential to validate and strengthen these conclusions.

TRANSLATIONAL RELEVANCE

This study establishes the causal role of specific circulating proteins in AMD and identified the mediating role of plasma metabolites between WARS1 and AMD.