Whole-genome sequence genome-wide association study in

Objective: To assess how whole genome sequencing and varying phenotype definitions influence genetic discovery for primary open-angle glaucoma (POAG) in a diverse population. Design: Ancestry-stratified genome-wide association studies (GWASs) and cross-ancestry meta-analyses of POAG cases and controls using two phenotype definitions. Participants: Cases (age > 40) and controls (age > 65) were identified in the National Institutes of Health Methods: GWASs were conducted within European, African, and Latino/Admixed American ancestry groups individually using firth logistic regression with age, sex, and the top 10 genotype principal components included as covariates. The ancestry-stratified GWASs were then meta-analyzed using a fixed-effects, inverse variance-weighted approach. Main Outcome Measures: Identification of genome-wide significant loci ( Results: Known POAG risk loci (e.g., Conclusions: This study demonstrates the value of whole genome sequencing, diverse ancestry inclusion, and phenotypic refinement in uncovering novel POAG genetic risk loci. The findings underscore the need to prioritize both genetic diversity and refined case/control definitions to advance understanding of this complex ocular disease. Précis: This study identifies a novel primary open-angle glaucoma risk locus in individuals of African ancestry using whole genome sequencing and varying phenotype definitions in the diverse