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

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.