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Polygenic Risk Score-Based Phenome-Wide Association for Glaucoma and its Impact on Disease Susceptibility in Two Large Biobanks
30 Pages Posted: 12 Jan 2024
More...Abstract
Background: Glaucoma is a leading cause of worldwide irreversible blindness. Considerable uncertainty remains regarding the association between a variety of phenotypes and the genetic risk of glaucoma, as well as the impact they exert on the glaucoma development.
Methods: We investigated the associations of genetic liability for POAG with a wide range of potential risk factors for and to assess its impact on the risk of incident glaucoma.
Participants: The phenome-wide association study (PheWAS) approach was applied to determine the association of POAG polygenic risk score (PRS) with a wide range of phenotypes in 377,909 participants from the UK Biobank study and 43,623 participants from the Penn Medicine Biobank study. Participants were stratified into four risk tiers: low, intermediate, high, and very high-risk. Cox proportional hazard models assessed the relationship of POAG PRS and ocular factors with new glaucoma events.
Findings: In both discovery and replication set in the PheWAS, a higher genetic predisposition to POAG was specifically correlated with ocular disease phenotypes. The genetic risk score exhibited correlations with low corneal hysteresis, refractive error, and ocular hypertension, demonstrating a strong association with the onset of glaucoma. Individuals carrying a high genetic burden exhibited a 9.2-fold, 11.88-fold, and 28.85-fold increase in glaucoma incidence when associated with low corneal hysteresis, high myopia, and elevated intraocular pressure (IOP), respectively.
Interpretation: Genetic susceptibility to POAG primarily influences ocular conditions, with limited systemic associations. Notably, the baseline polygenic risk for POAG robustly associates with new glaucoma events, revealing a large combined effect of genetic and ocular risk factors on glaucoma incidents.
Funding: The National Research Foundation of Korea Grant funded by the Korean government (MSIP) (No. NRF- 2022R1A2C1012677).
Declaration of Interest: The authors declare no conflicts of interest.
Ethical Approval: This UK Biobank study was ethically approved by the Northwest Multi-center Research Ethics Committee (June 17, 2011 [reference 11/NW/0382]; this was extended on May 13, 2016 [reference 16/NW/0274] and on June 29, 2021 [reference 21/NW/0157]). The present research was conducted using the UK Biobank Resource under application number 90981. All research adhered to the tenets of the Declaration of Helsinki.
Keywords: Primary Open-Angle Glaucoma, Polygenic Risk Score, Phenome-Wide Associations
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