RARE CODING VARIANT ASSOCIATIONS WITH PRIMARY OPEN-ANGLE GLAUCOMA IN AFRICAN ANCESTRY:A MULTI-COHORT EXOME-WIDE META ANALYSIS

ABSTRACT Primary open-angle glaucoma (POAG) disproportionately affects individuals of African ancestry, yet rare coding variation in this population remains understudied. To address this gap, we performed a multi-cohort exome-wide meta-analysis across POAAGG, PMBB, All of Us, and UK Biobank, including 4,815 POAG cases and 22,922 controls of genetically inferred African ancestry. Although no gene reached exome-wide significance, we identified several suggestive gene-level associations driven by rare variants (minor allele frequency ≤0.1% or singletons),including signals in SRF, BLTP3A, METTL2A , and KRT10 . Among these, SRF demonstrated the strongest association and was driven by rare missense variants with moderate effect sizes. Given its role in cytoskeletal organization and actin dynamics; processes central to trabecular meshwork function and intraocular pressure regulation SRF represents a biologically plausible candidate gene. Notably, these genes have not been previously highlighted in predominantly European ancestry POAG association studies, suggesting potential ancestry-specific rare variant contributions. Overall, our findings highlight the critical importance of investigating rare coding variation in POAG, in disproportionately affected populations to deepen understanding of POAG etiology and genetic risk.