Genetic Architecture of Trans-Laminar Cribrosa Pressure Difference and Primary Open-Angle Glaucoma.
Hong In-Shik, Cho Chamlee, Kim Beomsu, Shim Injeong, Lee Yeong Chan, Jung Sang-Hyuk, Song Minku, Park Sanghyeon, Hong Sanghoon, Jo Hyeonbin
AI Summary
This study identified genetic factors influencing translaminar cribrosa pressure difference (TLCPD). A high TLCPD genetic risk score significantly predicts primary open-angle glaucoma, highlighting TLCPD's crucial role in glaucoma development beyond IOP.
Abstract
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.
MeSH Terms
Key Concepts6
A genome-wide association study (GWAS) of trans-laminar cribrosa pressure difference (TLCPD) in 82,147 individuals of European ancestry identified 77 independent loci, including 12 previously unreported loci.
Functional enrichment and colocalization analyses in individuals of European ancestry identified candidate genes related to retinal cell death, including SDCCAG8, PILRB, FBXO46, NUPR1, and JUND, which were not previously associated with elevated intraocular pressure (IOP).
Individuals in the top 1% of the polygenic risk score (PRS) for trans-laminar cribrosa pressure difference (TLCPD) had a 4.48-fold higher risk of developing primary open-angle glaucoma (POAG) than those in the bottom 20% (95% confidence interval = 3.70-5.43) in an independent set of 268,734 unrelated European-ancestry individuals.
A phenome-wide association study (PheWAS) of the polygenic risk score (PRS) for trans-laminar cribrosa pressure difference (TLCPD) identified associations with traits including hypertension, glaucoma, obesity, arthropathies, and sleep apnea.
The study utilized a genome-wide association study (GWAS) of trans-laminar cribrosa pressure difference (TLCPD) in 82,147 individuals of European ancestry from the UK Biobank.
A survival analysis was utilized to examine the association between the polygenic risk score (PRS) for trans-laminar cribrosa pressure difference (TLCPD) and the incidence of primary open-angle glaucoma (POAG) in an independent set of 268,734 unrelated European-ancestry individuals.
Related Articles5
Predictive Power of Polygenic Risk Scores for Intraocular Pressure or Vertical Cup-Disc Ratio.
Observational StudyIndependent Effects of Blood Pressure on Intraocular Pressure and Retinal Ganglion Cell Degeneration: A Mendelian Randomization Study.
Observational StudyProfiling IOP-Responsive Genes in the Trabecular Meshwork and Optic Nerve Head in a Rat Model of Controlled Elevation of Intraocular Pressure.
Basic ScienceOptic Nerve Head Gene Transcription Sequelae to a Single Elevated IOP Exposure Provides Insights Into Known Responses to Chronically Elevated IOP.
Basic ScienceAngiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma.
Basic ScienceIs this article assigned to the wrong chapter(s)? Let us know.