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PURPOSE: The purpose of this study was to investigate whether the genetic architecture of translaminar cribrosa pressure difference (TLCPD) provides genetic insights based on dual-pressure theory beyond intraocular pressure (IOP) and whether a TLCPD-based polygenic risk score (PRS) predicts primary open-angle glaucoma (POAG) risk and its pleiotropic effects.METHODS: The genome-wide association study (GWAS) of TLCPD was conducted in 82,147 individuals of European ancestry from the UK Biobank (UKBB). Functional enrichment analysis and colocalization analysis were performed to identify associated genes, tissues, and pathways. PRS was calculated in an independent set of 268,734 unrelated European-ancestry individuals not included in the TLCPD GWAS. A survival analysis was utilized to examine the association between the PRS for TLCPD and the incidence of POAG. The phenome-wide association study (PheWAS) of PRS was applied to identify associations between TLCPD and other diseases.RESULTS: We identified 77 independent loci, including 12 previously unreported loci. Enrichment and colocalization analyses identified candidate genes related to retinal cell death, including SDCCAG8, PILRB, FBXO46, NUPR1, and JUND, which were not previously associated with elevated IOP. Individuals in the top 1% of the PRS had a 4.48-fold higher risk of developing POAG than those in the bottom 20% (95% confidence interval = 3.70-5.43). PheWAS identified TLCPD PRS-associated traits including hypertension, glaucoma, obesity, arthropathies, and sleep apnea.CONCLUSIONS: This study identified TLCPD-associated variants, genes, cell types, tissues, and diseases in UKBB participants of European ancestry. These findings support the clinical relevance of TLCPD in glaucoma pathogenesis, implicating TLCPD-related genetic variants as contributor to POAG susceptibility.