From Gene Discovery to Understanding the Molecular Pathways in Primary Open-Angle Glaucoma

Primary open-angle glaucoma (POAG) is a complex and heterogeneous disease in which the primary site of injury is the optic nerve. Damage to the optic nerve alters the transmission of visual information from the retina to the brain, leading to vision loss. The pathogenesis of POAG includes several interacting pathological mechanisms, influenced by genetic and environmental factors.

This thesis aimed to identify and understand which and how genetic factors and pathways contribute to the pathophysiology of POAG. We investigated five quantitative traits related to POAG, including intraocular pressure (IOP), optic disc parameters (i.e., cup, disc and vertical-cup disc ratio), and central corneal thickness (CCT). In total, we identified 2 new genetic factors influencing IOP, 20 for optic disc parameters and 19 for CCT. To understand the pathogenic mechanisms, we performed fine-mapping and functional analyses in zebrafish and found that depletion of SIX6, a well-known POAG gene, leads to small eye phenotype and modifies the expression of other POAG genes such as CDKN1A and CDKN2B which play a role in cell-cycle. In addition, we explored the role of rare genetic variation in POAG quantitative traits and examined the implications of new imputation reference panels in future genetic studies. The studies described in this thesis integrated human and experimental research and provide new insights into the risk of POAG