A Primary Open-Angle Glaucoma Locus Near Transcription Factor PRRX1 Identified in the Million Veteran Program

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.

A case-control genome-wide association study (GWAS) with integrative functional follow-up.

A total of 234 153 United States Veterans of European ancestry enrolled in the Million Veteran Program, including 10 738 POAG cases and 223 415 controls.

We conducted a POAG GWAS using electronic health record-based phenotyping and logistic regression adjusted for age, sex, and genetic ancestry. Genome-wide significant loci were evaluated using statistical fine-mapping and colocalization with expression and splicing quantitative trait loci across ocular and nonocular 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 (CMS) with and without transforming growth factor beta 2 (TGFβ2) in primary human trabecular meshwork (HTM) cells. Ortholog expression was assessed in zebrafish.

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.

Genome-wide association study 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 trabecular meshwork and optic nerve head fibroblasts, pericytes, and astrocytes. In primary HTM cells, PRRX1 was significantly downregulated under combined CMS and TGFβ2 exposure. Zebrafish ortholog analyses support neuro-ocular relevance.

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. Identification and integrative evaluation of this POAG-associated locus advances understanding of disease biology and may inform future risk stratification and therapeutic investigation.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.