Integrative Multi-Omics Analysis Prioritizes Candidate Therapeutic Targets for Primary Open-Angle Glaucoma.

Area of Science:

• Ophthalmology
• Genetics
• Proteomics

Background:

• Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness.
• Elevated intraocular pressure due to compromised aqueous humor outflow underlies POAG.
• Existing genome-wide association studies (GWAS) have identified risk loci but lack specific protein candidates and mechanisms.

Purpose of the Study:

• To identify specific causal proteins and their cellular mechanisms implicated in POAG.
• To integrate multi-omics data for a comprehensive understanding of POAG pathogenesis.
• To discover novel therapeutic targets for POAG.

Main Methods:

• Utilized a multi-omics framework combining UK Biobank plasma proteomics (N=53,022) with large-scale POAG GWAS summary statistics.
• Performed Proteome-Wide Association Study, Mendelian Randomization, and Bayesian colocalization to infer causality.
• Mapped candidate proteins to ocular single-cell RNA sequencing (scRNA-seq) atlases for cell-type specificity and assessed druggability.

Main Results:

• Prioritized five putative causal proteins for POAG, with SEL1L and TFPI showing the strongest evidence.
• SEL1L and SERPINF1 are highly expressed in the trabecular meshwork (TM), particularly juxtacanalicular tissue, suggesting a role in outflow resistance.
• TFPI and SLC9A3R2 localize to Schlemm's canal endothelium, indicating involvement in barrier function modulation.
• Pathway analyses implicated endoplasmic reticulum protein processing and coagulation cascades.

Conclusions:

• Identified specific causal proteins linked to POAG pathogenesis within the conventional aqueous outflow pathway.
• SEL1L emerges as a novel therapeutic target for maintaining TM homeostasis.
• TFPI presents an opportunity for drug repurposing in glaucoma treatment.
• Provides data-driven hypotheses for developing precision glaucoma therapeutics.