Shared Genetic Architecture Between Myopia and Primary Open-Angle Glaucoma: A Multidimensional Genome-Wide Analysis

Purpose: Observational studies have suggested a positive association between myopia and primary open-angle glaucoma (POAG), yet the genetic mechanisms underlying their comorbidity remain incompletely understood. This study aimed to systematically characterize the shared genetic architecture between myopia and POAG using a multidimensional analytical framework. Methods: We conducted an integrative genetic analysis using large-scale European ancestry genome-wide association study (GWAS) summary statistics for myopia (65,574 cases; 333,242 controls) and POAG (16,677 cases; 199,580 controls). Global and local genetic correlations were estimated using linkage disequilibrium score regression (LDSC), Genetic Covariance Analyzer, and SUPERGNOVA. Polygenic overlap was quantified using a bivariate causal mixture model (MiXeR). Shared loci were identified through conjunctional false discovery rate (conjFDR) analyses. Transcriptome-wide association studies, Multi-marker Analysis of GenoMic Annotation, and Polygenic Priority Score were applied for shared gene prioritization. Spatial enrichment was evaluated using genetically informed spatial mapping of cells for complex traits (gsMap). Results: Myopia and POAG showed a significant positive genetic correlation (LDSC rg = 0.16, P = 1.09 × 10-5). MiXeR revealed substantial polygenic overlap, with 403 shared trait-influencing variants (Dice coefficient = 0.47), of which 71.9% showed concordant effects. ConjFDR identified 31 shared loci, including a strong signal at the BICC1 locus. Gene-level analyses highlighted BICC1, TFAP2B, AFAP1, and LOXL1 as key shared candidate genes. Spatial mapping localized shared genetic enrichment to mesenchymal-derived embryonic tissues. Conclusions: Myopia and POAG exhibit a significant genetic correlation, substantial polygenic overlap, and multiple shared susceptibility loci and genes. Their comorbidity is likely driven by convergent developmental and biomechanical pathways. These findings provide novel insights into the genetic basis of myopia-POAG comorbidity and may facilitate future mechanistic studies and risk stratification.