Bioinformatic Prioritization and Functional Annotation of GWAS-Based Candidate Genes for Primary Open-Angle Glaucoma

Abstract

Background: Primary open-angle glaucoma (POAG) is the most prevalent glaucoma subtype, but its exact etiology is still unknown. In this study, we aimed to prioritize the most likely ‘causal’ genes and identify functional characteristics and underlying biological pathways of POAG candidate genes. Methods: We used the results of a large POAG genome-wide association analysis study from GERA and UK Biobank cohorts. First, we performed systematic gene-prioritization analyses based on: (i) nearest genes; (ii) nonsynonymous single-nucleotide polymorphisms; (iii) co-regulation analysis; (iv) transcriptome-wide association studies; and (v) epigenomic data. Next, we performed functional enrichment analyses to find overrepresented functional pathways and tissues. Results: We identified 142 prioritized genes, of which 64 were novel for POAG. BICC1, AFAP1, and ABCA1 were the most highly prioritized genes based on four or more lines of evidence. The most significant pathways were related to extracellular matrix turnover, transforming growth factor-β, blood vessel development, and retinoic acid receptor signaling. Ocular tissues such as sclera and trabecular meshwork showed enrichment in prioritized gene expression (>1.5 fold). We found pleiotropy of POAG with intraocular pressure and optic-disc parameters, as well as genetic correlation with hypertension and diabetes-related eye disease. Conclusions: Our findings contribute to a better understanding of the molecular mechanisms underlying glaucoma pathogenesis and have prioritized many novel candidate genes for functional follow-up studies.

All-trans Retinoic Acids Synergistically and Beneficially Affect In Vitro Glaucomatous Trabecular Meshwork (TM) Models Using 2D and 3D Cell Cultures of Human TM Cells

“…That is, RAR alpha caused significant reductions in vascular leakage in the diabetic retina by antagonizing the loss of tight junction integrity that is induced by diabetes [ 38 ]. These observations corresponded well with our current results, which show that ATRA exerts synergistic and beneficial effects in TGF-β2-treated 2D- and 3D-cultured HTM cells; our results were found through in vitro models that replicate the single- and multiple-sheet barrier structures of the HTM [ 25 , 26 , 39 , 40 , 41 ].…”

“…Unexpectedly and interestingly, the addition of ATRA significantly suppressed the TGF-β2-induced enhancement in TEER values ( Figure 1 ). Since it was suggested that ATRA greatly affected mitochondrial functions [ 26 ] as well as glycolysis [ 27 ], we next investigated the issue of whether or not ATRA had any effects on TGF-β2-untreated and -treated 2D HTM cells. Interestingly, such discordant effects of ATRA between TGF-β2-untreated and -treated 2D HTM cells were also observed by a real-time cellular metabolic analysis using a Seahorse bioanalyzer ( Figure 2 ).…”

Regional Gene Expression in the Retina, Optic Nerve Head, and Optic Nerve of Mice with Experimental Glaucoma and Optic Nerve Crush

“…In MON, but not UON, further downstream partners of p53 that were upregulated included Serpine1 and Thbs1 , suggesting an effect of inhibiting angiogenesis. One genome wide association study found a relation between a p53 polymorphism and one human glaucoma phenotype[34], while another found KEGG pathways associated with human open angle glaucoma were focal adhesion, and Wnt and TGFβ signaling, strikingly similar to the naïve UON pathways active in our study [35].…”

Regional Gene Expression in the Retina, Optic Nerve Head, and Optic Nerve of Mice with Optic Nerve Crush and Experimental Glaucoma

“…In MON, but not UON, further downstream partners of p53 that were upregulated included Serpine1 and Thbs1, suggesting an effect of inhibiting angiogenesis. One genome-wide association study found a relation between a p53 polymorphism and one human glaucoma phenotype [34], while another found KEGG pathways associated with human open-angle glaucoma were focal adhesion, and Wnt and TGFβ signaling, which are strikingly similar to the naïve UON pathways active in our study [35].…”