Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is a significant cause of visual impairment in the aging population, with the pathophysiology driven by a complex interplay of genetics, environmental influences and immunometabolic factors. These immunometabolic mechanisms, in particular, those distinguishing between the dry and wet forms of AMD, remain incompletely understood. Utilizing an integrated multiomic approach, incorporating Mendelian Randomization (MR) and single-cell RNA sequencing (scRNA-seq), we have effectively delineated distinct immunometabolic pathways implicated in the development of AMD. Our comprehensive analysis indicates that the androgen-IL10RA-CD16+ monocyte axis could protect against wet AMD. We have also identified several immune and metabolic signatures unique to each AMD subtype, with TNF and Notch signaling pathways being central to disease progression. Furthermore, our analysis, leveraging expression Quantitative Trait Loci (eQTLs) from the Genotype-Tissue Expression (GTEx) project coupled with MR, have highlighted genes such as MTOR, PLA2G7, MAPKAPK3, ANGPTL1, and ARNT as prospective therapeutic targets. The therapeutic potential of these candidate genes was validated with observations from existing drug trial databases. Our robust genetic and transcriptomic approach has identified promising directions for novel AMD interventions, emphasizing the significance of an integrated multiomic approach in tackling this important cause of visual impairment.