An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity

Abstract

Objective: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. Design: Cross-sectional study. Participants: For the primary analysis, we examined the glaucoma phenotype of 2,154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) including cases recruited from the UK. For replication, we examined an independent cohort of 624 early POAG patients. Methods: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP associated variants and stratified POAG patients into three risk tiers. The lowest and highest quintiles of the score were set as the low and high risk groups respectively and the other quintiles as the intermediate risk group. Main Outcome Measures: Clinical glaucoma phenotype including maximum recorded IOP, age of diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. Results: There was a dose-response relationship between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 (SD 0.62) mmHg than the low genetic risk group (P = 0.006). Compared to the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 (1.0) years (P < 0.001), more family members affected by 0.46 (0.11) members (P < 0.001), and higher rates of incisional surgery (odds ratio 1.5; 95% confidence interval 1.1-2.0; P = 0.007). There was no statistically significant difference in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). Conclusions: The IOP polygenic risk score was positively correlated with maximum IOP, disease severity, need for surgery and number of family members. Genes acting via IOP mediated pathways, when considered in aggregate have clinically important and reproducible implications for glaucoma patients and their close family members.

Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology

“…We recently reported a PRS derived from 146 IOPassociated SNPs to be associated with higher maximal IOP, younger age of glaucoma diagnosis, more family members affected, and higher treatment intensity in an independent Australian cohort. 23 These findings were also validated in an independent cohort of early glaucoma cases, further supporting the utility of IOPderived variants in glaucoma risk stratification. 23 Another PRS constructed from 68 VCDRassociated SNPs applied to a Latino population showed a relatively modest risk of POAG (OR, 1.75 [95% CI, 1.09-2.81] for the top quintile relative to the bottom quintile).…”

“…23 These findings were also validated in an independent cohort of early glaucoma cases, further supporting the utility of IOPderived variants in glaucoma risk stratification. 23 Another PRS constructed from 68 VCDRassociated SNPs applied to a Latino population showed a relatively modest risk of POAG (OR, 1.75 [95% CI, 1.09-2.81] for the top quintile relative to the bottom quintile). 45 This is likely owing to input SNPs being derived from GWAS of primarily European and Asian ancestries, which are unlikely to capture all risk variants relevant to the Latino population.…”

“…38 The latest glaucoma PRS risk stratification is promising in identifying individuals not carrying single high-impact variants to be at a higher risk of developing advanced glaucoma and disease progression. 23,38 A PRS-based risk stratification will be more effective in combination with demographic risk factors and may be best applied to older individuals (50 years or older), those with a family history of glaucoma, or those who may have optic disc features suspicious of developing glaucoma. 54 In addition, PRS may aid in triaging referrals of "glaucoma suspects" to specialists by identifying high-risk individuals prior to clinical review, resource allocations in light of increasing glaucoma prevalence, and potentially a targeted screening program.…”

“…POAG represents an ideal case scenario for the clinical utility of PRS: it is one of the most heritable common human diseases without any strong environmental or lifestyle risk factors 35 ; has a prolonged asymptomatic disease phase with irreversible vision loss 54 ; has good outcomes with early cost-effective and low-risk treatment that can effectively halt vision loss 86,87 ; there are highly sensitive and noninvasive screening methods available using optical coherence tomography 88 ; and the availability of highly predictive PRS of disease risk and phenotype. 23,38 In health care systems with finite resources, targeting high-risk individuals with low-risk interventions, and minimizing screening and interventions in lowrisk individuals, will improve the cost-benefit ratio of these strategies and optimize resource allocation. There will be a significant clinical and economic advantage to target screening strategies to individuals at high risk of developing a disease, while saving resources spent on screening low-risk individuals, as has been shown in the cancer screening setting.…”

“…A commonly used PRS stratification method is quintiles, in which the bottom 20% is considered low risk, the top 20% as high risk, and the rest as intermediate risk. 9 , 13 , 22 , 23 Similarly, tertile or decile groups may be used. Importantly, a PRS allows disease risk stratification but is never a diagnostic tool: its clinical utility is best achieved when combined with demographic and/or clinical factors usually evaluated in routine clinical risk assessment.…”