A POAG Locus Near Transcription Factor PRRX1 Identified in the Million Veteran Program

Abstract Objective To identify genetic risk variants for primary open-angle glaucoma (POAG) and prioritize biologically relevant genes through integration of genetic association, regulatory annotation, ocular transcriptomics, and functional modeling. Design Case-control genome-wide association study (GWAS) with integrative functional follow-up. Participants 234,153 United States Veterans of European ancestry enrolled in the Million Veteran Program, including 10,738 POAG cases and 223,415 controls. Methods We conducted a POAG GWAS using electronic health record–based phenotyping and logistic regression adjusted for age, sex, and genetic ancestry. Genome-wide significant (GWS) loci were evaluated using statistical fine-mapping and colocalization with expression and splicing quantitative trait loci across ocular and non-ocular tissues. Bulk and single-cell transcriptomic datasets were interrogated to assess gene expression in glaucoma-relevant tissues and cell types. Functional relevance was evaluated by examining gene expression responses to cyclic mechanical stretch with and without transforming growth factor beta 2 (TGFβ2) in primary human trabecular meshwork (HTM) cells. Ortholog expression was assessed in zebrafish. Main Outcome Measures Genome-wide significant variant associations with POAG, colocalized regulatory signals, ocular tissue and cell-type expression patterns, and differential gene expression under biomechanical and profibrotic stress conditions. Results GWAS identified a significant association near PRRX1 (lead variant rs10919469:G; odds ratio ≈ 0.92; p-value = 1.9×10⁻⁸) that replicated in FinnGen and UK Biobank. Fine-mapping yielded a 95% credible set of 25 variants without a single high probability causal variant. Although regulatory annotation implicated multiple genes, PRRX1 showed broad expression across glaucoma-relevant ocular tissues and cell types, including TM and optic nerve head fibroblasts, pericytes, and astrocytes. In primary HTM cells, PRRX1 was significantly downregulated under combined cyclic mechanical stretch and TGFβ2 exposure. Zebrafish ortholog analyses support neuro-ocular relevance. Conclusions Integration of GWAS, regulatory annotation, ocular transcriptomics, and functional modeling prioritizes PRRX1 as a plausible gene of interest warranting further investigation for potential involvement in POAG. Translational relevance Identification and integrative evaluation of a POAG-associated locus near PRRX1 advances understanding of disease biology and may inform future risk stratification and therapeutic investigation.