A Whole-Genome Sequence Genome-Wide Association Study in All of Us Identifies a Novel Glaucoma Risk Locus in African...

To assess how whole genome sequencing (WGS) and varying phenotype definitions influence genetic discovery for primary open-angle glaucoma (POAG) in a diverse population.

Ancestry-stratified genome-wide association studies (GWASs) and cross-ancestry meta-analyses of POAG cases and controls using 2 phenotype definitions.

Cases (age ≥40 years) and controls (age ≥65 years) were identified in the National Institutes of Health All of Us Research Program v8 data release and subdivided into genetically inferred ancestral groups. Using the relaxed phenotype (International Classification of Diseases [ICD] codes only), case/control counts were European (EUR; 1846/84 654), African (AFR; 1042/15 966), and Latino/Admixed American (AMR; 305/10 167). Using the stringent phenotype (ICD codes and evidence of glaucoma treatment in the electronic health record), case/control counts were EUR (1528/79 276), AFR (862/14 076), and AMR (250/9668). Cross-ancestry meta-analyses included 3193 cases/110 787 controls for the relaxed phenotype and 2640 cases/103 020 controls for the stringent phenotype.

Genome-wide association studies were conducted within EUR, AFR, and AMR 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.

Identification of genome-wide significant loci (P < 5 × 10^-8) for POAG using different phenotype definitions and ancestry groups.

Known POAG risk loci (e.g., TMCO1, CDKN2B-AS1, and GMDS) reached genome-wide significance in both the EUR GWASs and cross-ancestry meta-analyses (odds ratio range: 1.19-1.38). A novel risk locus near CYP2A7 (rs76935404[T], odds ratio = 1.35) was identified in the AFR ancestry GWAS using the stringent phenotype definition. Effect sizes for known POAG risk loci from prior large-scale meta-analyses strongly correlated with effect sizes in this study (Pearson r = 0.75-0.84, P < 1 × 10^-5 for all). The strength and consistency of these correlations support the robustness of the findings.

This study demonstrates the value of WGS, 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.

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