Genetic Architecture and Clinical Phenotypes of Primary Open-Angle Glaucoma: An Updated Review of Mendelian Genes, GWAS Loci, and Polygenic Risk.

PURPOSE: To synthesize the genetic architecture of primary open-angle glaucoma (POAG) across the full variant spectrum and map each genetic subtype to its clinical phenotype, IOP profile, optic nerve morphology, systemic associations, and treatment response. METHODS: PubMed/MEDLINE was searched from inception through April 2025 for POAG genetics, susceptibility genes, GWAS loci, polygenic risk scores, and gene-specific clinical correlations. Eligible designs included peer-reviewed original research, GWAS meta-analyses, candidate-gene studies, family-based linkage analyses, cohort and case-control studies, and PRS development in human subjects. Genetic association studies were appraised using Q-Genie; observational clinical studies were appraised using the Newcastle-Ottawa Scale. RESULTS: Seven high-penetrance Mendelian genes (MYOC, OPTN, TBK1, WDR36, NTF4, FOXC1, CYP1B1) account for fewer than 10% of cases, each defining a clinically distinct subtype: juvenile high-tension glaucoma (MYOC), normal-tension neurodegeneration (OPTN, TBK1), and syndromic developmental glaucoma (FOXC1, CYP1B1). GWAS meta-analyses have identified 100 to 127 susceptibility loci converging on five biological axes: trabecular meshwork dysfunction, retinal ganglion cell survival, autophagy and protein homeostasis, neuroinflammation, and extracellular matrix integrity. Polygenic risk scores combined with clinical variables achieve an AUC of 0.89. CONCLUSION: POAG comprises genetically and clinically distinct subtypes defined by dominant molecular axes. Gene-specific data reveal actionable pharmacogenomic signals: ROCK inhibitors for ARHGEF12 and AFAP1 carriers, nicotinamide for OPTN and TXNRD2 subtypes, and goniotomy for CYP1B1-associated congenital glaucoma. IOP-centric management is insufficient for normal-tension subtypes driven by autophagy failure and neuroinflammation. The framework supports genotype-guided decisions on screening intensity, IOP targets, and neuroprotective adjuncts.