Abstract
Purpose :
Primary open-angle glaucoma (POAG) is a complex ocular disease characterized by death of retinal ganglion cells and atrophy of the optic nerve head that, if untreated, leads to blindness. Previous studies have shown that POAG has a genetic etiology component, however, the identification of all the causative genetic factors has proven to be challenging. Investigation of the underlying genetics and cell types involved in POAG can contribute to a better understanding of the disease mechanisms. In our study, we conducted post-GWAS analyses oriented to the investigation of pathway, gene, tissue, and cell types prioritization in a multi-ancestry POAG cohort.
Methods :
We used results generated from a large-scale genome-wide association POAG meta-analysis, conducted in subjects sourced from 15 global biobanks participating in the Global Biobank Meta-Initiative (GBMI), a collaboration of global biobanks. A total of 26,848 cases and 1,460,599 controls from six ancestries were analyzed. We evaluated if the genomic loci were implicated in POAG map specific cell types using Linkage Disequilibrium Score Regression (LDSC), and compared results obtained from Data-driven Expression Prioritized Integration for Complex Traits (DEPICT) analyses. GeneMANIA was used to investigate gene interaction. In order to prevent spurious findings, false discovery rate method was used for multiple testing corrections.
Results :
The significant results from LDSC pointed to mesenchymal, vascular and adipocytes cell types, showing consistency with the results also obtained in tissue-enrichment analysis from DEPICT. Furthermore, gene-prioritization identified 54 genes that were used to construct interaction networks. Potential hub genes identified were BMP2, CPE, FERMT2, FOXC1, MYBPC3, PARVA, SEMA3C, SIX4, TGFB2, TGFBR3, and TPM1. Nine of these genes have a role in epithelial to mesenchyme-like transition cellular mechanism.
Conclusions :
Our findings promote the potential role of the epithelial to mesenchyme-like transition in POAG and contribute to improving the biological mechanisms underlying this condition. Further experimental studies are required to investigate this potential contribution with respect to POAG pathogenesis and to identify novel target genes.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.