Asia Pac J Ophthalmol (Phila). 2026 Jan 8:100277. doi: 10.1016/j.apjo.2026.100277. Online ahead of print.
ABSTRACT
PURPOSE: Myopia, particularly pathological myopia (PM), poses a significant global health burden due to its increasing prevalence and associated vision-threatening complications. Despite extensive genetic research, the molecular mechanisms underlying myopia progression remain unclear. This study aims to identify key causal proteins and metabolic pathways in myopia and PM and explore potential therapeutic targets.
METHODS: We employed a multi-omics framework integrating Mendelian Randomization (MR), colocalization analysis, protein-protein interaction (PPI) networks, metabolic pathway enrichment, and molecular docking to investigate the molecular mechanisms of myopia and PM. We analyzed five proteome-wide pQTL datasets, two whole-blood eQTL datasets, and a metabolic GWAS to identify causal proteins, genes, and metabolites. Small-molecule docking and molecular dynamics (MD) simulations were performed to assess potential drug-target interactions.
RESULTS: We identified PDGFRA, LRRTM2, and PCOLCE as key regulators of myopia and PM. PDGFRA was associated with extracellular matrix (ECM) remodeling and fibroblast activation, LRRTM2 with retinal neurotransmission and dopamine signaling, and PCOLCE with collagen stability and scleral biomechanics. Functional enrichment analysis highlighted immune signaling, lipid metabolism, and oxidative stress pathways as contributors to myopia pathogenesis. Molecular docking and MD simulations identified 1,3-Propanediol, Cis-9-Octadecenoic Acid, and 17-Beta-Estradiol as potential therapeutic compounds that may stabilize ECM, enhance neurotransmission, and reinforce scleral integrity.
CONCLUSIONS: Our multi-omics framework prioritizes PDGFRA, LRRTM2, and PCOLCE as candidates linked to ECM remodeling, neurotransmission, and scleral biomechanics in myopia and PM. Integrating MR with colocalization, PPI, and pathway analyses yields mechanistic hypotheses and testable targets. Docking/MD findings are exploratory and will require experimental validation before any therapeutic inference.
PMID:41519384 | DOI:10.1016/j.apjo.2026.100277