Novel insights into the relationship between glaucoma and brain diseases from the genetic to diseases levels: A cross-sectional study

Abstract

Glaucoma is a heterogeneous group of diseases which is one of the leading causes of irreversible blindness worldwide. Although the eye-brain axis has been proposed, its functional connectivity remains poorly defined. This study aimed to explore the mechanisms and causal relationship between glaucoma and brain cortical structure, focusing on the eye-brain axis. A Mendelian randomization (MR) study was conducted using inverse variance weighting as the primary estimator, alongside MR-PRESSO, MR-Egger, and weighted median methods to assess sensitivity, heterogeneity, and pleiotropy. Pathway analysis, transcriptomic analysis, and weighted gene co-expression network analysis (WGCNA) were applied to investigate brain-eye interactions in Alzheimer's disease (AD) and primary open-angle glaucoma (POAG), revealing shared pathogenic mechanisms. Significant associations between glaucoma and brain cortex regions, including the superior temporal sulcus, anterior cingulate, cuneus, entorhinal, inferior temporal, and insula, were identified. About 18 overlapping genes between AD and POAG were found, including MYH14, EFNA1, FZD1, and CACNG3. Using WGCNA, 11 overlapping genes were identified as most related to both AD and POAG, including TSC2, MAGED4, LSS, and DNM1. These results contributed to understanding the association between glaucoma and the brain, indicating the eye-brain axis and may provide clues for early screening of high-risk populations.

Keywords: Alzheimer’s disease; IOP; Mendelian randomization; brain cortical structure; glaucoma; visual field defects.

Figure 1.

The conception atlas of eye-brain axis. Description of the concept construction of eye-brain axis. IOP = intraocular pressure, RNFL = retinal nerve fiber layer.

Figure 2.

Overview of Mendelian randomization study design. A flow diagram of our MR study design to study the causal relationship of glaucoma on the SA and TH of total and 34 regional brain cortexes. The MR analysis was primarily estimated using inverse variance weighted (IVW). CDR = cup-disc ratio, MR‑Egger and weighted median. GWAS = genome-wide association study, IOP = intraocular pressure, IVW = inverse variance weighted, MR = Mendelian randomization, RNFL = retinal nerve fiber layer, SA = surface area, SNPs = single nucleotide polymorphisms, TH = thickness.

Figure 3.

Heatmap for the IVW estimates of glaucoma and brain cortical structure. IVW estimates from glaucoma, right intraocular pressure, left intraocular pressure, CDR, visual field defects and retinal nerve fiber layer on brain cortical structure as defined using magnetic resonance imaging-measured brain cortical surficial area and thickness. The color of each block represents the IVW-derived P-values in which P-values of <.05 were shown in red and P-values of >.05 were shown in white or blue. P-value < .05 is set as nominally significant, whereas <6.127 × 10⁻⁵ is set as significant. CDR = cup-disc ratio, IVW = inverse variance weighted, LIOP = left intraocular pressure, RIOP = right intraocular pressure, RNFL = retinal nerve fiber layer, SA = surface area, TH = thickness.

Figure 4.

Integration of transactional analysis of AD and POAG. (A) Volcano plot for DEGs in POAG. (B) Volcano plot for DEGs in AD. (C) Venn diagram summarizing the differential and overlapping DEGs for POAG and AD. (D) KEGG enrichment analysis for overlapping DEGs. (E) GO analysis for overlapping DEGs. AD = Alzheimer’s disease, DEGs = differentially expressed genes, KEGG = Kyoto Encyclopedia of Genes and Genomes, GO = Gene Ontology, POAG = primary open-angle glaucoma.

Figure 5.

WGCNA analysis for GSE27276, and GSE260873. (A) Dynamic tree plot for glaucoma. (B) Dynamic tree plot for AD. (C) Specific and concrete gene module division and correlation index respectively for glaucoma and AD. (D) Significance and correlation index for genes in the most related gene modules in POAG and AD. (E) Venn diagram summarizing the differential and overlapping genes between the most related gene module for POAG and AD. (F) KEGG analysis for overlapping genes in the most related gene modules. POAG = primary open-angle glaucoma, AD = Alzheimer’s disease, KEGG = Kyoto Encyclopedia of Genes and Genomes, WGCNA = weighted gene co-expression network analysis.