Emmanuelle Souzeau

Precision medicine is paving the way for personalised risk assessment, and its translation into glaucoma clinics holds potential to change current management paradigms. Our understanding of glaucoma's genetic architecture has expanded in recent years, recognising both monogenic and polygenic contributions. Genetic testing within glaucoma populations can provide additional information for clinicians to support decision-making. Here, we review the evidence base for genetic variants strongly associated with glaucoma and outline a vision for translating these learnings into the clinic. Integrating clinical and genetic information will provide clinicians and patients with the strongest evidence to deliver personalised glaucoma management.

Axenfeld-Rieger Syndrome (ARS) is an autosomal dominant condition with both ocular and non-ocular manifestations. ARS is primarily caused by coding variants at the PITX2 or FOXC1 loci, yet many cases still remain undiagnosed. Here we used whole-genome sequencing to identify two non-coding structural variants associated with a typical presentation of PITX2 -associated ARS: one with a 450 kb deletion removing a series of conserved enhancer elements distal to PITX2 , and the second with a 12.5 Mb inversion displacing the PITX2 gene from these same enhancer elements. Neither variant disrupted the PITX2 gene itself, and therefore both were expected to reduce PITX2 expression by disrupting its proximity or access to enhancer elements. Enhancer-disrupting intergenic inversions therefore represent a unique genetic mechanism for the development of ARS, which should be carefully considered in the context of ARS and other conditions without a conclusive genetic diagnosis.

Glaucoma is the leading cause of irreversible blindness with early detection and intervention critical to slowing disease progression. However, half of those affected are undiagnosed. This is largely due to the early stages of disease being asymptomatic; current population-based screening measures being unsupported; and a lack of current efficient prediction models. Research investigating polygenic risk scores (PRS) for glaucoma have shown predictive ability to identify individuals at higher risk. Potential clinical applications include identification of high-risk individuals, resulting in earlier diagnosis and treatment to prevent glaucoma blindness, and adjusted monitoring for low-risk individuals. However, the psychological impact of receiving glaucoma PRS is unknown. There is a critical need to evaluate risk information communication and assess the impact of receiving results, to support clinical implementation of glaucoma PRS testing. In this prospective study, 300 individuals from the GRADE (Genetic Risk Assessment of Degenerative Eye disease) study will be recruited to investigate the psychosocial impact of disclosing polygenic risk results for glaucoma. GRADE aimed to apply PRS testing on 1,000 unexamined individuals aged 50 years or older from the general population and examine a subset of these individuals to assess the clinical validity of PRS to detect glaucoma. In this study, individuals each from the bottom decile (10%), top decile (10%), and middle (45-55%) of the PRS distributions will be invited to receive research glaucoma PRS results. Participants who choose to receive their results will complete up to four questionnaires (prior to receiving their results, and subsequently two-weeks, six- and 12-months after receiving their result). The questionnaires will include health belief model measures and assess glaucoma anxiety, general anxiety and depression, test-related distress, decisional regret, and recall and understanding of results. This research will provide guidance for the implementation of polygenic risk testing into clinical practice and inform delivery strategies.

Objective: Pseudoexfoliation syndrome (PEX) is a known risk factor for glaucoma, but its individual clinical course ranges from no glaucoma to total blindness. This study investigated whether polygenic risk scores (PRSs) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup-to-disc ratio (VCDR) can stratify individuals with pseudoexfoliation for the risk of glaucoma development. Methods: Retrospective multicohort study of 2 glaucoma registries and 1 population-based cohort. Methods: For the primary analysis, participants (n = 828) were classified as having PEX with glaucoma, PEX with suspected glaucoma, or PEX with no glaucoma. For the secondary analysis, a cohort of participants (n = 2460) were classified as having PEX with glaucoma, having PEX with no glaucoma, and being unaffected, and an independent cohort of participants (n = 3372) were classified as having primary open-angle glaucoma (POAG) or suspected POAG. Methods: Previously published and validated PRSs for open-angle glaucoma, IOP, and VCDR were expressed as a percentile, decile, or tertile of an ancestrally matched healthy population. Multivariable logistic and linear regressions and survival analyses were performed. Methods: The main outcome measures were odds of pseudoexfoliative glaucoma (PEX-G) and odds of clinically relevant outcomes. Results: Participants in the top tertile of the glaucoma PRS showed greater odds of receiving a PEX-G diagnosis (adjusted odds ratio [aOR], 4.22; 95% confidence interval [CI], 2.62-6.88; P < 0.001), greater odds of bilateral central vision loss (aOR, 3.43; 95% CI, 1.49-8.99; P = 0.007), and greater odds of bilateral incisional surgery (aOR, 3.35; 95% CI, 1.33-10.24; P = 0.018). Age at PEX-G diagnosis was 1 year younger with each increasing glaucoma PRS decile (1.06 years; 95% CI, 0.59-1.53 years; P < 0.001). Participants with manifest glaucoma and pseudoexfoliation showed a comparatively lower glaucoma PRS than counterparts with POAG. Conclusions: The PRSs for open-angle glaucoma, IOP, and VCDR stratify risk of glaucoma development and disease severity among individuals with PEX.

Objective: Pseudoexfoliation syndrome (PEX) is a known risk factor for glaucoma, but its individual clinical course ranges from no glaucoma to total blindness. This study investigated whether polygenic risk scores (PRS) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP) and vertical cup:disc ratio (VCDR) can stratify individuals with pseudoexfoliation for their risk of glaucoma development. Methods: Retrospective multicohort study of two glaucoma registries and one population-based cohort. Methods: For the primary analysis, participants (n=828) were classified as PEX-Glaucoma, PEX-Glaucoma Suspect, and PEX-No Glaucoma. For the secondary analysis, a cohort of participants (n=2459) were classified as PEX-Glaucoma, PEX-No Glaucoma, and Unaffected, and an independent cohort of participants (n=3360) were classified as primary open-angle glaucoma (POAG) and POAG-Suspect. Methods: Previously published and validated PRS for open-angle glaucoma, IOP and VCDR were expressed as a percentile, decile or tertile of an ancestrally-matched normal population. Multivariable logistic and linear regressions, and survival analyses were performed. Methods: Odds of pseudoexfoliative glaucoma, and odds of clinically-relevant outcomes. Results: Participants in the top tertile of the Glaucoma-PRS had greater odds of pseudoexfoliative glaucoma diagnosis (adjusted OR 4.22, 95% CI 2.62 - 6.88, p<0.001), greater odds of bilateral central vision loss (adjusted OR 3.43, 95% CI 1.49 - 8.99, p=0.007), and greater odds of bilateral incisional surgery (adjusted OR 3.35, 95% CI 1.33 - 10.24, p=0.018). Age of pseudoexfoliative glaucoma diagnosis was 1 year younger with each increasing Glaucoma-PRS decile (1.06 years, 95% CI 0.59-1.53, p<0.001). Manifest glaucoma participants with pseudoexfoliation had a comparatively lower Glaucoma-PRS than primary open-angle glaucoma counterparts. Conclusions: PRS for open-angle glaucoma, IOP and VCDR stratify risk of glaucoma development and disease severity amongst individuals with pseudoexfoliation syndrome.