Genetic Architecture and Clinical Phenotypes of Primary Open-Angle Glaucoma: An Updated Review of Mendelian Genes, GWAS Loci, and Polygenic Risk
TL;DR
POAG comprises genetically and clinically distinct subtypes defined by dominant molecular axes, and the framework supports genotype-guided decisions on screening intensity, IOP targets, and neuroprotective adjuncts.
Abstract
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.