Genetic prioritisation of candidate drug targets for glaucoma through multi-trait and multi-omics integration.

Background: Glaucoma causes permanent blindness. Current treatments have limited effectiveness, necessitating novel therapeutic strategies. We aimed to identify potential drug targets for glaucoma by integrating multi-trait and multi-omic analyses.

Methods: We sourced druggable gene expression and protein abundance summary-level data from quantitative trait loci studies, and genetic associations with glaucoma from a large-scale multi-trait analysis. We employed proteome and transcriptome Mendelian randomization (MR) and colocalisation to identify potential therapeutic targets, glaucoma endophenotype MR to explore the potential mechanisms of identified associations, and phenome-wide MR to investigate possible adverse effects of candidate targets.

Results: We identified CPXM1 and FLT4 as tier 1; INSR as tier 2; and CPZ and PXDN as tier 3 druggable genes. Genetically predicted higher levels of CPXM1 [odds ratio (OR): 0.86, 95% confidence interval (CI): 0.81-0.91, P < 0.001], FLT4 (OR: 0.74, 95% CI: 0.64 - 0.87, P = 0.033), INSR (OR: 0.58, 95% CI: 0.43 - 0.78, P = 0.042), and CPZ (OR: 0.55, 95% CI: 0.40 - 0.74, P = 0.033) were associated with decreased glaucoma risk while those of PXDN (OR: 1.33, 95% CI: 1.15 - 1.54, P = 0.033) with increased risk. The associations for CPXM1 (OR: 0.53, 95% CI: 0.39 - 0.73, P < 0.001) and FLT4 (OR: 0.86, 95% CI: 0.78 - 0.95, P = 0.005) were confirmed transcriptome-wide and colocalisation was confirmed for CPXM1 [posterior probability H4 (PPH) = 0.940], FLT4 (PPH = 0.701), and INSR (PPH = 0.706). The protective effects of CPXM1 and CPZ may be attributed to intraocular pressure-lowering activities. The risk associated with PXDN is due to its involvement in glaucomatous neuropathy. No significant adverse effects were identified.

Conclusions: This study provides novel insights into glaucoma pathophysiology and promotes pharmaceutical target innovation.