Druggable Genome Mendelian Randomization and GWAS-sceQTLs MR Analysis Reveal Genetic Associations Between Open-Angle Glaucoma and Immune Cells, and Identify Potential Drugs.

PURPOSE

The purpose of this study was to identify therapeutic targets and repurposable drugs for primary open-angle glaucoma (POAG) by investigating its immunometabolic mechanisms using druggable genomic and single-cell transcriptomic approaches.

METHODS

We integrated druggable genome-wide and single-cell Mendelian randomization (MR) using POAG genome-wide association study (GWAS) data, blood and single-cell expression quantitative trait loci (eQTL) datasets. Causal genes were identified via colocalization and MR inference (inverse-variance weighted [IVW]). Drug-gene interactions were predicted using molecular docking (DSigDB/CB-Dock2), and safety was assessed via phenome-wide association studies (PheWAS).

RESULTS

(1) Identified two POAG causal genes: risk genes YWHAG (odds ratio [OR] = 1.207, 95% confidence interval [CI] = 1.131-1.288) and protective genes GFPT1 (OR = 0.874, 95% CI = 0.840-0.910). (2) Cell-type-specific paradoxical effect: In CD4+KLRB1-T cells, high GFPT1 expression increased POAG risk (OR = 1.448, 95% CI = 1.241-1.690, P = 2.545 × 10-6), suggesting its role in driving immunometabolic reprogramming via the hexosamine biosynthesis pathway (HBP). (3) Drug screening: Molecular docking confirmed strong binding of trimipramine, desipramine, and cyclosporin to GFPT1 (Vina score < -5), with PheWAS indicating no significant off-target effects.

CONCLUSIONS

GFPT1 in CD4+ memory T cells contributes to POAG pathogenesis through immunometabolic dysregulation. Three existing drugs identify potential for therapeutic repurposing.

TRANSLATIONAL RELEVANCE

This study identifies GFPT1-driven immunometabolic dysfunction as a novel target in POAG and nominates three US Food and Drug Administration (FDA)-approved drugs for immediate clinical translation, accelerating the path to trials.