Large-scale GWAS integrated with fine-mapping and single-cell analyses prioritizes effector genes, cell-contexts of glaucoma risk

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide, and the genetic architecture of POAG at cellular level remains incompletely understood. In this study, we conducted a large-scale genome-wide association study of POAG involving approximately 3 million individuals (97,229 cases) and identified 495 loci (198 novel). External evaluation in 23andMe Research Institute (114,468 cases and 3,525,660 controls) showed that 412 (84.6%) had P < 0.0001 after Bonferroni correction. Integrating multi-omics datasets with advanced fine-mapping approaches, we developed a glaucoma gene prioritization framework and identified 285 effector genes. Single-cell RNA-seq analysis revealed retinal cell types including astrocytes, Müller glia, retinal pigment epithelial cells, and retinal ganglion cells. Using our new scRNA-seq in primary trabecular meshwork cells (TMCs), we further prioritized TMC-context putative genes, including ADAM15 and GAS7. Finally, drug-repurposing analyses identified therapeutic target hypotheses for POAG. Together, these findings provide a comprehensive genetic architecture for POAG, highlighting novel effector genes and cellular contexts, and offering potential drug repurposing opportunities.