Genomic structural equation Modeling analysis of glaucoma Endophenotypes: investigating genetic architecture and non-intraocular pressure mechanisms.

To explore the genetic underpinnings of glaucoma endophenotypes influenced by mechanisms other than intraocular pressure (IOP), this study employs genomic structural equation modelling (GenomicSEM) and utilises summary statistics from Genome-Wide Association Studies (GWAS) to examine endophenotypes associated with non-IOP mechanisms. We investigated the genetic relationships among primary open-angle glaucoma (POAG) and key endophenotypes: IOP, normal tension glaucoma (NTG), vertical cup disc ratio (VCDR), total macular thickness, ganglion cell-inner plexiform layer (GCIPL), and retinal nerve fiber layer (RNFL), through exploratory factorial analysis (EFA) and confirmatory factorial analyses (CFA). GWAS-by-subtraction approach was employed to explore the genetic architecture of non-IOP components. Post-GWAS analyses implemented in Functional Mapping and Annotation (FUMA) and Multi-marker Analysis of Genomic Annotation (MAGMA) were conducted to identify non-IOP genes and pathways. The EFA revealed that 60% of the cumulative variance was explained by two latent factors (F1, F2). F1 included VCDR, POAG, NTG, and IOP, while F2 comprised RNFL, GCIPL, macular thickness, and VCDR. Significant associations between F2 and macular thickness and RNFL persisted after subtracting IOP. MAGMA analysis identified IOP-independent pathways for macular thickness and VCDR, primarily involving nerve and vascular pathways. Despite lower IOP levels in NTG patients, GWAS-by-subtraction revealed both significant IOP and non-IOP components for NTG. This research highlights the significance of non-IOP mechanisms in the development of glaucoma. Targeting these mechanisms could pave the way for developing novel treatments that extend beyond conventional IOP-based therapies. Further research is needed to explore non-IOP pathways in NTG and validate these findings across diverse populations.