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 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 two phenotype definitions.

Cases (age > 40) and controls (age > 65) were identified in the National Institutes of Health All of Us Research Program v8 data release and sub-divided into genetically inferred ancestral groups. Using the relaxed phenotype (ICD codes only), case/control counts were: European (1,846/84,654), African (1,042/15,966), and Latino/Admixed American (305/10,167). Using the stringent phenotype (ICD codes and evidence of glaucoma treatment in the electronic health record), case/control counts were: European (1,528/79,276), African (862/14,076), and Latino/Admixed American (250/9,668). Cross-ancestry meta-analyses included 3,193 cases/110,787 controls for the relaxed phenotype and 2,640 cases/103,020 controls for the stringent phenotype.

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.

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 European GWASs and cross-ancestry meta-analyses (odds ratio (OR) range: 1.19-1.38). A novel risk locus near CYP2A7 (rs76935404[T], OR = 1.35) was identified in the African 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 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.

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 All of Us Research Program dataset.