Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

AimsTo compare the biomechanically corrected intraocular pressure (IOP) estimate (bIOP) provided by the Corvis-ST with Goldmann applanation tonometry (GAT-IOP) in patients with high-tension and normal-tension primary open-angle glaucoma (POAG; HTG and NTG), ocular hypertension (OHT) and controls. Moreover, we compared dynamic corneal response parameters (DCRs) of the Corvis-ST in POAG, OHT and controls, evaluated the correlation between global visual field parameters mean deviation and pattern SD (MD and PSD) and DCRs in the POAG group.Methods156 eyes of 156 patients were included in this prospective, single-centre, observational study, namely 41 HTG and 33 NTG, 45 OHT cases and 37 controls. Central corneal thickness (CCT), GAT-IOP and bIOP were measured, GAT-IOP was also adjusted for CCT (GATAdj). DCRs provided by Corvis-ST were evaluated, MD and PSD were recorded by 24–2 full-threshold visual field. To evaluate the difference in DCRs between OHT, HTG and NTG, a general linear model was used with sex, medications and group as fixed factors and bIOP and age as covariates.ResultsThere was a significant difference between GAT-IOP, GATAdj and bIOP in NTG and HTG, OHT and controls. NTG corneas were significantly softer and more deformable compared with controls, OHT and HTG as demonstrated by significantly lower values of stiffness parameters A1 and highest concavity and higher values of inverse concave radius (all p<0.05). There was a significant correlation (p<0.05) between MD, PSD and many DCRs with POAG patients with softer or more compliant corneas more likely to show visual field defects.ConclusionsCorneal biomechanics might be a significant confounding factor for IOP measurement that should be considered in clinical decision-making. The abnormality of corneal biomechanics in NTG and the significant correlation with visual field parameters might suggest a new risk factor for the development or progression of NTG.

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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.