Multi-ancestry genome-wide association study in all of Us for primary open-angle glaucoma

This study aims to identify new genetic loci associated with primary open-angle glaucoma (POAG) and explore shared genetic risk factors across African, European, and Admixed American/Latino populations. Genome-wide Association Study (GWAS) utilizing data from the All of Us Research Program. The study included 374,254 participants, with 4,305 individuals diagnosed with POAG and 369,949 controls. Participants were categorized by ancestry: European, African, and Admixed American/Latino. We used short-read sequencing data and applied strict quality control measures (MAF > 0.01, INFO > 0.8). GWAS were conducted for each ancestry group using a logistic mixed model, adjusting for age, sex, and the top 11 principal components. A fixed-effect meta-analysis combined the results across ancestries. Genome-wide significance was set at p < 5 × 10− 8. The primary outcome measures were the identification of genetic loci associated with POAG, and the analysis of transcription factors linked to these loci in relevant tissues. In the European cohort, we identified four novel loci associated with POAG, linked to the TUT4, RYK, MOXD1, and UBAP2 genes, as well as the previously known TMCO1 locus. In the African cohort, we found five new loci, including TSPAN17, SLC16A7, LOC100506869, LINC02388, and LOC107984606. For the Admixed American/Latino cohort, we identified GATA5, FAM135B, and LINC00871 genes as novel loci. Our analysis identified three novel loci in individuals of European ancestry, mapped to the genes TUT4, RYK, and MOXD1. We identified 56 genome-wide significant variants, including six putative novel loci, and found that most ancestry-specific signals replicated in the cross-ancestry meta-analysis, with the exception of several attenuated associations in the smaller Admixed American/Latino cohort. These findings indicate that the genetic determinants contributing to POAG may differ across populations, underscoring the importance of accounting for population-specific genetic architectures in the study of complex traits. Given the substantial variation in POAG prevalence among ancestries, it is plausible that certain genetic variants exert ancestry-specific effects. Consequently, conducting ancestry-stratified GWAS is essential for elucidating these unique genetic contributions.