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- Title
Deep Ocular Phenotyping Across Primary Open-Angle Glaucoma Genetic Burden.
- Authors
Sekimitsu, Sayuri; Xiang, David; Smith, Sophie Lloyd; Curran, Katie; Elze, Tobias; Friedman, David S.; Foster, Paul J.; Luo, Yuyang; Pasquale, Louis R.; Peto, Tunde; Segrè, Ayellet V.; Shweikh, Yusrah; Warwick, Alasdair; Zhao, Yan; Wiggs, Janey L.; Zebardast, Nazlee
- Abstract
This cross-sectional study investigates how the phenotypic features of patients vary across genetic burden for primary open-angle glaucoma. Key Points: Question: How do phenotypic features of patients vary across genetic burden for primary open-angle glaucoma (POAG)? Findings: In a population-based cross-sectional study including 407 667 participants and 14 171 POAG cases, individuals at higher risk of glaucoma were identified using a genome-wide polygenic risk score. Higher polygenic risk was associated with more advanced disease (higher cup-disc ratio, intraocular pressure, thinner retinal nerve fiber layers/ganglion cell complex layers, or greater medication requirements, laser, or surgery treatment). Meaning: Polygenic risk for POAG identified individuals at higher risk for POAG, supporting polygenic risk score stratification to identify individuals at higher risk of severe disease, potentially informing health care resource allocation and clinical decisions. Importance: Better understanding of primary open-angle glaucoma (POAG) genetics could enable timely screening and promote individualized disease risk prognostication. Objective: To evaluate phenotypic features across genetic burden for POAG. Design, Setting, and Participants: This was a cross-sectional, population-based study conducted from 2006 to 2010. Included participants were individuals from the UK Biobank aged 40 to 69 years. Individuals with non-POAG forms of glaucoma were excluded from the analysis. Data were statistically analyzed from October 2022 to January 2023. Main Outcomes and Measures: POAG prevalence based on structural coding, self-reports, and glaucoma-related traits. Results: Among 407 667 participants (mean [SD] age, 56.3 [8.1] years; 219 183 majority sex [53.8%]) were 14 171 POAG cases. Area under receiver operating characteristic curve for POAG detection was 0.748 in a model including polygenic risk score (PRS), age, sex, and ancestry. POAG prevalence in the highest decile of PRS was 7.4% (3005 of 40 644) vs 1.3% (544 of 40 795) in lowest decile (P <.001). A 1-SD increase in PRS was associated with 1.74 times higher odds of POAG (95% CI, 1.71-1.77), a 0.61-mm Hg increase in corneal-compensated intraocular pressure (IOP; 95% CI, 0.59-0.64), a −0.09-mm Hg decrease in corneal hysteresis (95% CI, −0.10 to −0.08), a 0.08-mm Hg increase in corneal resistance factor (95% CI, 0.06-0.09), and a −0.08-diopter decrease in spherical equivalent (95% CI, −0.11 to −0.07; P <.001 for all). A 1-SD increase in PRS was associated with a thinning of the macula-region retinal nerve fiber layer (mRNFL) of 0.14 μm and macular ganglion cell complex (GCC) of 0.26 μm (P <.001 for both). In the subset of individuals with fundus photographs, a 1-SD increase in PRS was associated with 1.42 times higher odds of suspicious optic disc features (95% CI, 1.19-1.69) and a 0.013 increase in cup-disc ratio (CDR; 95% CI, 0.012-0.014; P <.001 for both). A total of 22 of 5193 fundus photographs (0.4%) in decile 10 had disc hemorrhages, and 27 of 5257 (0.5%) had suspicious optic disc features compared with 9 of 5158 (0.2%) and 10 of 5219 (0.2%), respectively, in decile 1 (P <.001 for both). CDR in decile 10 was 0.46 compared with 0.41 in decile 1 (P <.001). Conclusion and Relevance: Results suggest that PRS identified a group of individuals at substantially higher risk for POAG. Higher genetic risk was associated with more advanced disease, namely higher CDR and corneal-compensated IOP, thinner mRNFL, and thinner GCC. Associations with POAG PRS and corneal hysteresis and greater prevalence of disc hemorrhages were identified. These results suggest that genetic risk is an increasingly important parameter for risk stratification to consider in clinical practice.
- Publication
JAMA Ophthalmology, 2023, Vol 141, Issue 9, p891
- ISSN
2168-6165
- Publication type
Article
- DOI
10.1001/jamaophthalmol.2023.3645