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 families with non-coding structural variants associated with a typical presentation of PITX2-associated ARS: one family with a 450 kb deletion removing a series of conserved enhancer elements distal to PITX2, and the second family with a 12.54 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. PITX2 enhancer-disrupting inversions are an emerging 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.

Objective:To identify risk loci for Fuchs endothelial corneal dystrophy (FECD) and improve a genetic risk prediction model. Design:Genome-wide association study (GWAS), polygenic risk score (PRS) construction, and TCF4 CTG18.1 short tandem repeat (STR) length inference. Participants:The study included 7,316 Europeans (EUR) with FECD or related corneal dystrophy phenotypes and 1,588,467 controls from the UK Biobank, All of Us, FinnGen, and the Million Veteran Program. Two independent EUR FECD cohorts were used for PRS validation (1,851/2,679 cases/controls and 124/257 cases/controls). African (AFR) ancestry analyses included 455 cases and 121,154 controls to build PRS. A subset of All of Us participants was used for joint PRS and STR modelling. Methods:GWAS meta-analyses were performed using FECD diagnoses or corneal dystrophy proxies where necessary, with validity assessed via genetic correlation. Risk loci were identified, and ancestry-specific PRSs were constructed using SBayesRC. PRS performance was evaluated across ancestries with and without TCF4 STR data. Main Outcome:We identified novel loci for corneal dystrophy and constructed PRS-based and STR-based prediction models. Results:The GWAS meta-analysis identified 24 risk loci associated with corneal dystrophy, including 12 novel loci, doubling previous FECD studies. The optimised PRS outperformed existing models in two independent FECD validation cohorts (AUC = 0.83, 95% CI: 0.82-0.84; DeLong's P = 7.04 × 10-19), with individuals in the top PRS decile showing 14-fold and 19-fold increased risk in the two validation sets, respectivelyIn All of Us, STR expansion (>40 repeats) was the key predictor of FECD risk, yielding excellent discrimination (AUC = 0.89; OR = 54) with minimal improvement from PRS. Consistent with this, STR expansion remained the primary driver of risk across ancestries, while PRS provided modest independent value for broader corneal dystrophy phenotypes in EUR and admixed American populations.Among participants without large STR expansion, overall predictive performance was modest; PRS was the only significant genetic contributor (OR = 1.37) for broader corneal dystrophy in Europeans, whereas analyses in FECD non-expansion carriers were underpowered. Conclusions:These findings refine the genetic architecture of FECD, enhance risk prediction, and support a tiered strategy integrating STR expansion testing with PRS.

Importance:While FOXC1 single-nucleotide variants and deletions are well-established causes of Axenfeld-Rieger syndrome, few FOXC1 duplications have been reported. This study investigated families with duplications encompassing the FOXC1 gene to refine the associated phenotypic spectrum and contribution to glaucoma. Objective:To investigate the prevalence and phenotype of FOXC1 duplications in 2 large glaucoma registries. Design, Setting, and Participants:This retrospective observational genetic cohort study included participants recruited from the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) and the Massachusetts Eye and Ear (MEE) cohort from 2008 through 2025. Participants with glaucoma, and available relatives, underwent genomic testing to identify duplications encompassing FOXC1 using exome sequencing and genotyping arrays (ANZRAG) or whole-genome sequencing (MEE). Data analyses were conducted from 2022 through 2025. Main Outcomes and Measures:Prevalence of FOXC1 duplications, age at glaucoma onset, and phenotype, including ocular and systemic features. Results:Twenty individuals from 10 families (50% female and 50% male; 70% self-described as broadly European [Australian/British, British, English/German, English/Polish, European, or Scottish], 25% as Asian [Chinese or Filipino], and 5% as Latin American [Salvadoran]) were identified with FOXC1 duplications. All genetically tested individuals were diagnosed with glaucoma, demonstrating high penetrance. Seventeen individuals were referred with juvenile open-angle glaucoma (JOAG), 1 with primary open-angle glaucoma, 1 with primary congenital glaucoma, and 1 with anterior segment dysgenesis. The diagnosis of 4 individuals from 1 family with ectropion uveae was revised to anterior segment dysgenesis. Systemic features were reported for 2 participants (10.5%), including subtle dental findings and mild facial dysmorphism. Duplications encompassing FOXC1 were among the most common monogenic contributors to JOAG. In the ANZRAG group, they accounted for 13.5% (95% CI, 6.7%-25.3%) of JOAG probands with a genetic diagnosis, second to MYOC (53.8%; 95% CI, 40.5%-66.7%). In the MEE group, FOXC1 duplications accounted for 9.5% (95% CI, 2.7%-28.9%) of JOAG probands with a genetic diagnosis. Conclusions and Relevance:These findings suggest FOXC1 duplications are an underrecognized, highly penetrant, but variably expressive, genetic variation associated with JOAG. Findings for the relatively modest number of individuals in the retrospective study were associated with wide confidence intervals. This limitation is often inherent to studies of JOAG, a rare condition for which individual genetic variants account for only a subset of cases. Despite this, the findings highlight the genetic heterogeneity of JOAG and support the potential importance of considering routine genetic copy-number variant analysis for individuals with JOAG.

We report a case of visual field deterioration in previously stable open-angle glaucoma which resolved upon ventriculoperitoneal shunting (VPS) for coexisting normal pressure hydrocephalus (NPH). A woman in her 80s with bilateral open-angle glaucoma developed apparent progression of existing glaucomatous field defects, despite stable disease and consistent intraocular pressure control following bilateral trabeculectomies over a decade prior. She was concurrently diagnosed with NPH and underwent VPS. Following VPS, visual fields returned to a previously stable baseline.Visual field fluctuations may occur concurrently with NPH, a condition affecting intracranial pressure (ICP). Here, we report visual field worsening temporally associated with NPH onset and a rare association between VPS and field improvement in the context of prior trabeculectomy. VPS may improve visual fields in post-trabeculectomy eyes by reducing ICP, thereby narrowing the translaminar pressure gradient. Unexplained visual field changes in well-controlled glaucoma should prompt consideration of pathologies affecting ICP.

Pathogenic variants in the myocilin ( MYOC ) gene are the most common cause of Mendelian open-angle glaucoma. In 2022, the Clinical Genome Resource (ClinGen) Glaucoma Variant Curation Expert Panel (VCEP) published rule specifications for MYOC variant interpretation, including a pilot study of 81 variants. Here, we present the results of curating 271 MYOC variants reported in people with open-angle glaucoma using updated specification rules. Of all the variants, 11 were classified as benign (B), 45 as likely benign (LB), 166 as variants of uncertain significance (VUS), 35 as likely pathogenic (LP), and 14 as pathogenic (P). All LP/P variants were located within the conserved olfactomedin domain encoded by exon 3. The updated variant curation guidelines from the Glaucoma VCEP increased the number of clinically definitive classifications from 28% (74/265) to 39% (105/271), with 95% (41/43) of reclassified variants moving to greater clinical relevance. Functional evidence was lacking for 93% (154/166) of VUS. Additional functional evidence could further enhance classification by halving (85/166) the proportion of those classified as VUS. These findings highlight the role of rule calibration and rigorous functional evidence assessment toward improving variant classification with clinical utility for patients.

BACKGROUND:Current evidence on incidence and progression rate of diabetic retinopathy reveals disparities across Australasia, and no pooled estimates are available to guide region-wide planning. This review and meta-analysis assesses the overall incidence, determinants and progression of diabetic retinopathy in Australasia. METHODS:This systematic review followed the Joanna Briggs Institute manual for incidence synthesis. Articles were sourced from Ovid MEDLINE, Scopus, Web of Science, CINAHL, ProQuest and PsycINFO until October 2024. Articles reporting incidence, progression, and determinants of type 2 diabetes in Australia and surrounding islands were included. RESULTS:Nine cohorts, including seven population-based and two institution-based cohort studies, predominantly from Australia, were analysed. The pooled annual incidence of diabetic retinopathy was 4.22% (95% CI 2.29-6.15), while individual studies reported annual progression from 3.08% to 18.22%. Incident diabetic retinopathy was associated with elevated fasting blood glucose, haemoglobin A1c, systolic blood pressure and increasing connecting peptide levels. Diabetic retinopathy progression was associated with increasing age, higher haemoglobin A1c levels, fasting blood glucose, longer duration of diabetes, an increased albumin-creatinine ratio and no fenofibrate treatment. CONCLUSION:Diabetic retinopathy incidence in Australasia is highly variable, highest in institution-based cohorts and among Indigenous Australians. HbA1c is the only determinant consistently and significantly associated with both onset and progression. Because most evidence predates modern diabetes care, future prospective cohorts should adopt standardised, multifactorial designs to generate contemporary, comparable data and reduce persistent inequities in eye-care access.

Purpose:Polygenic risk score for glaucoma is an emerging tool showing effective risk stratification. Previous studies have shown public acceptability for the test as a hypothetical scenario. However, the potential uptake of the test and associated predictors has not been reported. Methods:Individuals who had previously participated in a questionnaire-based study evaluating attitudes toward polygenic testing for glaucoma were invited to participate in a prospective research study for which they will undergo polygenic testing for glaucoma. Individuals had to be over the age of 50 years and living in South Australia to be eligible and invited to participate. Uptake was assessed by decision to consent to the research project and provide a sample for polygenic testing. Multivariable logistic regression was performed to identify predictor variables associated with uptake. Results:Of the 418 individuals who completed the initial questionnaire, 292 were eligible to participate, of which 143 enrolled, yielding an uptake rate of 49.0%. The mean age of the enrolled cohort was 67.5 years, 67.1% were female, 83.2% were from an urban residency, and 58.7% had a family history of glaucoma. Interest in testing was not associated with participation (P = 0.61). Predictors of uptake included a positive family history (P < 0.001) urban residency (P = 0.004), higher education (P = 0.036), and obtaining more information (P = 0.027). Conclusions:This is the first study to demonstrate the potential uptake of polygenic testing for glaucoma among an unaffected population. Translational Relevance:These findings provide useful insights into the predictors of glaucoma polygenic testing to support effective clinical implementation.

We conducted the first genome-wide association meta-analyses of global and sectoral peripapillary retinal nerve fibre layer (pRNFL) thickness and Bruch's membrane opening-minimum rim width (BMO-MRW), the major optic nerve head structural and neurodegeneration biomarkers, including up to 25,942 and 12,080 participants, respectively, from the International Glaucoma Genetics Consortium. We identified 9 global pRNFL thickness and 9 global BMO-MRW loci, along with 28 and 19 loci for pRNFL and BMO-MRW sectors, respectively, comprising both shared and sector-specific loci. To identify intraocular pressure (IOP)-independent drug targets, global pRNFL thickness and BMO-MRW were conditioned on IOP. IOP-independent loci were then prioritised to identify candidate causal genes using transcriptome-wide association study and colocalization analysis. Several genes, such as NMNAT2 and TRIOBP, had robust associations with both phenotypes, with potential IOP-independent therapeutic translation for glaucoma. Overall, we identified novel loci for pRNFL thickness and BMO-MRW, highlighting potential drug-target genes acting independently from IOP, and elucidating genetic differences among pRNFL sectors.

Purpose:Diabetic maculopathy (including diabetic macular edema [DME]) is the leading cause of vision loss in people with diabetes. We aimed to identify the genetic determinants of diabetic maculopathy. Methods:We conducted a genome-wide association study (GWAS) in two cohorts with a meta-analysis. The Australian cohort comprised 551 cases of DME and 599 controls recruited from the states of South Australia and Tasmania. The Scottish cohort comprised 1951 cases of diabetic maculopathy and 6541 controls from the Genetics of Diabetes Audit and Research in Tayside Scotland study (GoDARTS). Genotyping, imputation, and association analysis using logistic regression were conducted in each cohort, before combining summary statistics in a meta-analysis using the GWAMA package. Results:A locus on chromosome 7 reached genome-wide significance in GoDARTS but showed the opposite direction of effect in the Australian cohort. The meta-analysis identified two suggestive associations (P < 5 × 10-6) for diabetic maculopathy risk with similar effect direction; one at chromosome 1 close to the RNU5E-1 gene and one at chromosome 13 upstream of the ERICH6B gene. The two loci were evaluated in silico for potential functional links to diabetic maculopathy. Both are located in regulatory regions and have annotations indicating regulatory functions. They are also expression quantitative trait locus (eQTLs) for genes plausibly involved in diabetic maculopathy pathogenesis, with links to folate metabolism and the regulation of VEGF. Conclusions:The study suggests several promising SNPs and genes related to diabetic maculopathy risk. Despite being the largest genetic study of diabetic maculopathy to date, larger, homogeneous cohorts will be required to identify robust genetic risk loci for the disease.

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.

PURPOSE:Polygenic scores (PGS) for glaucoma is predictive of the disease in older adults. This study tested the hypothesis that multitrait PGS for primary open-angle glaucoma (POAG) and its associated traits are associated with glaucoma endophenotypes from a young age, but with larger effects in older adults. DESIGN:Cross-sectional and cohort analyses PARTICIPANTS: Young (<30 years; n = 1400) and older (45+ years; n∼ 3,500) community-based adults. METHODS:Participants underwent ocular tonometry, optical coherence tomography imaging, and genotyping. Their PGS for POAG, IOP, and vertical cup-to-disc ratio (VCDR) were generated. A subset of young participants (n∼614) had follow-up measurements 8 years later. Cross-sectional associations in both cohorts and the 8-year change in the young cohort were analysed against each PGS. MAIN OUTCOME MEASURES:Intraocular pressure (IOP), peripapillary retinal nerve fibre layer (pRNFL) thickness, and Bruch's membrane opening minimum rim width (BMO-MRW). RESULTS:IOP-PGS explained 4 and 8% of the variance in IOP in the young and older cohorts. Weak associations between pRNFL thickness and all 3 PGS were observed in the older group, but none were significant in the young participants. All 3 PGS were significantly associated with BMO-MRW, explaining 0.3-14.5% and 0.1-12.8% of the phenotypic variance in the older and younger cohorts, respectively. None of the PGS were associated with longitudinal IOP or pRNFL change in the young cohort. CONCLUSIONS:Associations between PGS and optic disc measures were present from young adulthood, but the effect sizes were greater in older adults. This, coupled with the lack of associations in the 8-year change in the young adults, suggests that glaucoma-related genetic effects on the optic nerve are not apparent until older age.

Polygenic risk scores (PRS), which provide an individual probabilistic estimate of genetic susceptibility to develop a disease, have shown effective risk stratification for glaucoma onset. However, there is limited best practice evidence for reporting PRS and patient-friendly reports for communicating PRS effectively are lacking. Here we developed patient-centred PRS reports for glaucoma screening based on the literature, and evaluated them with participants using a qualitative research approach. We first reviewed existing PRS reports and literature on probabilistic risk communication. This informed the development of a draft glaucoma screening PRS report for a hypothetical high risk individual from the general population. We designed three versions of the report to illustrate risk using a pictograph, a pie chart and a bell curve. We then conducted semi-structured interviews to assess preference of visual risk communication aids, understanding of risk, content, format and structure of the reports. Participants were invited from an existing study, which aims to evaluate the clinical validity of glaucoma PRS among individuals > 50 years from the general population. Numeracy and literacy levels were assessed. We interviewed 12 individuals. The cohort was highly educated (42

OBJECTIVE:Pigment dispersion syndrome (PDS) is a known risk factor for glaucoma, with at least 1 in 10 patients with PDS developing glaucoma. There are no standardized clinical tools to stratify the risk of glaucoma onset or progression in the context of PDS. This study investigated whether multitrait polygenic risk scores (PRSs) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup:disc ratio (VCDR) could stratify individuals with PDS for their risk of glaucoma development. DESIGN:Cross-sectional study of 2 independent PDS cohorts: the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG, n = 264), and the Glaucoma Services at the University of Iowa Carver College of Medicine (n = 203). PARTICIPANTS:Participants of European ancestry with PDS were classified as PDS-Glaucoma (n = 288), PDS-Glaucoma Suspect (n = 110), or PDS-No Glaucoma (n = 69). METHODS:Previously published and validated PRS for open-angle glaucoma, IOP, and VCDR were expressed as a percentile or quintile of an ancestrally matched normal population. Multivariable logistic and linear regressions and survival analyses were performed. MAIN OUTCOME MEASURES:Odds of pigmentary glaucoma and odds of clinically relevant outcomes. RESULTS:Participants from ANZRAG with PDS in the top quintile of an open-angle glaucoma-PRS had greater odds of glaucoma diagnosis compared with the bottom quintile (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 1.57-21.28; P = 0.011). This observation was replicated among participants with PDS from the University of Iowa (adjusted OR, 4.07; 95% CI, 1.24-13.85; P = 0.021). Among those with PDS-Glaucoma across both cohorts combined, participants in the top quintile of glaucoma-PRS compared with the bottom quintile were diagnosed 8 years earlier (95% CI, 5.17-10.41; P < 0.001), recorded a maximum IOP 8 mmHg higher (95% CI, 2.89-11.95; P = 0.001), were at greater risk of escalation to incisional surgery (adjusted OR, 1.37; 95% CI, 1.03-1.87; P = 0.038), and were at greater risk of additional incisional surgeries to the same eye (adjusted OR, 1.27; 95% CI, 1.08-1.52; P = 0.006). A PRS for IOP also differentiated pigmentary glaucoma status; a PRS for VCDR did not. CONCLUSIONS:A multitrait PRS for open-angle glaucoma stratifies risk of glaucoma onset and disease severity among individuals with PDS. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

To explore the genetic underpinnings of glaucoma endophenotypes influenced by mechanisms other than intraocular pressure (IOP), this study employs genomic structural equation modelling (GenomicSEM) and utilises summary statistics from Genome-Wide Association Studies (GWAS) to examine endophenotypes associated with non-IOP mechanisms. We investigated the genetic relationships among primary open-angle glaucoma (POAG) and key endophenotypes: IOP, normal tension glaucoma (NTG), vertical cup disc ratio (VCDR), total macular thickness, ganglion cell-inner plexiform layer (GCIPL), and retinal nerve fiber layer (RNFL), through exploratory factorial analysis (EFA) and confirmatory factorial analyses (CFA). GWAS-by-subtraction approach was employed to explore the genetic architecture of non-IOP components. Post-GWAS analyses implemented in Functional Mapping and Annotation (FUMA) and Multi-marker Analysis of Genomic Annotation (MAGMA) were conducted to identify non-IOP genes and pathways. The EFA revealed that 60% of the cumulative variance was explained by two latent factors (F1, F2). F1 included VCDR, POAG, NTG, and IOP, while F2 comprised RNFL, GCIPL, macular thickness, and VCDR. Significant associations between F2 and macular thickness and RNFL persisted after subtracting IOP. MAGMA analysis identified IOP-independent pathways for macular thickness and VCDR, primarily involving nerve and vascular pathways. Despite lower IOP levels in NTG patients, GWAS-by-subtraction revealed both significant IOP and non-IOP components for NTG. This research highlights the significance of non-IOP mechanisms in the development of glaucoma. Targeting these mechanisms could pave the way for developing novel treatments that extend beyond conventional IOP-based therapies. Further research is needed to explore non-IOP pathways in NTG and validate these findings across diverse populations.

PURPOSE: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. DESIGN:Retrospective multicohort study of 2 glaucoma registries and 1 population-based cohort. PARTICIPANTS: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. MAIN OUTCOME MEASURES: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. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

OBJECTIVE:To assess the early safety and effectiveness outcomes of the PreserFlo MicroShunt with and without an intraluminal suture stent. DESIGN:Multicenter observational retrospective study using data from the Fight Glaucoma Blindness registry. PARTICIPANTS:A total of 183 eyes in 172 patients, with a mean age of 73 ± 14 years, who underwent PreserFlo MicroShunt surgery with/without intraluminal stent suture placement, and with at least 6 months of follow-up. Eyes were divided into 2 groups: stent (68 eyes) and no-stent (115 eyes). METHODS:Baseline and postoperative measurements of intraocular pressure (IOP), visual acuity (VA), number of glaucoma medications, and adverse events were recorded at 1, 3, and 6 months. Outcomes were compared between stent and no-stent groups using t tests for continuous variables and Fisher exact tests for categorical variables. MAIN OUTCOME MEASURES:The primary outcome measures were the incidence of numerical hypotony (IOP ≤ 5 mmHg) and symptomatic hypotony (numerical hypotony plus ≥10 letters of VA loss) within 1 month, 1 to 3 months, and 3 to 6 months postoperatively. Secondary outcome measures included surgical success rates (defined as IOP ≤12, ≤15, ≤18, or ≤21 mmHg and ≥20% IOP reduction without hypotony and without additional glaucoma medications) and the need for secondary surgical interventions. RESULTS:In the first postoperative month, the stent group had significantly lower rates of numerical hypotony (24% vs. 44%; P = 0.007) and symptomatic hypotony (13% vs. 28%; P = 0.027) than the no-stent group. The rate of device revision, explant, or replacement with an alternative shunt was also significantly lower in the stent group (3 eyes; 4.4%) than in the no-stent group (17 eyes; 14.8%; P = 0.047). No significant differences in hypotony rates were observed in the later follow-up windows (1-3 and 3-6 months), nor were there significant differences in surgical success rates between the stent and no-stent groups at any time point. CONCLUSIONS:The use of an intraluminal suture stent in PreserFlo MicroShunt surgery reduces the incidence of early hypotony without compromising surgical success. These findings suggest that routine use of intraluminal sutures may improve early postoperative safety. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

ImportanceEarly detection of glaucoma is essential to timely monitoring and treatment, and primary open-angle glaucoma risk can be assessed by measuring intraocular pressure (IOP) or optic nerve head vertical cup-disc ratio (VCDR). Polygenic risk scores (PRSs) could provide a link between genetic effects estimated from genome-wide association studies (GWASs) and clinical applications to provide estimates of an individual’s genetic risk by combining many identified variants into a score.ObjectiveTo construct IOP and VCDR PRSs with clinically relevant predictive power.Design, Setting, and ParticipantsThis genetic association study evaluated the PRSs for 6959 of 51 338 individuals in the Canadian Longitudinal Study on Aging (CLSA; 2010 to 2015 with data from 11 centers in Canada) and 4960 of 5107 individuals the community-based Busselton Healthy Aging Study (BHAS; 2010 to 2015 in Busselton, Western Australia) with an artificial intelligence grading approach used to obtain precise VCDR estimates for the CLSA dataset. Data for approximately 500 000 individuals in UK Biobank from 2006 to 2010 were used to validate the power of the PRS. Data were analyzed from June to November 2023.Main Outcomes and MeasuresIOP and VCDR PRSs and phenotypic variance (R2) explained by each PRS.ResultsParticipants in CLSA were aged 45 to 85 years; those in BHAS, 46 to 64 years; and those in UK Biobank, 40 to 69 years. The VCDR PRS explained 22.0% (95% CI, 20.1-23.9) and 19.7% (95% CI, 16.3-23.3) of the phenotypic variance in VCDR in CLSA and BHAS, respectively, while the IOP PRS explained 12.9% (95% CI, 11.3-14.6) and 9.6% (95% CI, 8.1-11.2) of phenotypic variance in CLSA and BHAS IOP measurements. The VCDR PRS variance explained 5.2% (95% CI, 3.6-7.1), 12.1% (95% CI, 7.5-17.5), and 14.3% (95% CI, 9.3-19.9), and the IOP PRS variance explained 2.3% (95% CI, 1.5-3.3), 3.2% (95% CI, 1.3-5.8), and 7.5% (95% CI, 6.2-8.9) (P < .001) across African, East Asian, and South Asian populations, respectively.Conclusions and RelevanceVCDR and IOP PRSs derived using a large recently published multitrait GWAS exhibited validity across independent cohorts. The findings suggest that an IOP PRS has the potential to identify individuals who may benefit from more intensive IOP-lowering treatments, which could be crucial in managing glaucoma risk more effectively. Individuals with a high VCDR PRS may be at risk of developing glaucoma even if their IOP measures fall within the normal range, suggesting that these PRSs could help in early detection and intervention, particularly among those who might otherwise be considered at low risk based on IOP alone.

Purpose:Deep learning architectures can automatically learn complex features and patterns associated with glaucomatous optic neuropathy (GON). However, developing robust algorithms requires a large number of data sets. We sought to train an adversarial model for generating high-quality optic disc images from a large, diverse data set and then assessed the performance of models on generated synthetic images for detecting GON. Methods:A total of 17,060 (6874 glaucomatous and 10,186 healthy) fundus images were used to train deep convolutional generative adversarial networks (DCGANs) for synthesizing disc images for both classes. We then trained two models to detect GON, one solely on these synthetic images and another on a mixed data set (synthetic and real clinical images). Both the models were externally validated on a data set not used for training. The multiple classification metrics were evaluated with 95% confidence intervals. Models' decision-making processes were assessed using gradient-weighted class activation mapping (Grad-CAM) techniques. Results:Following receiver operating characteristic curve analysis, an optimal cup-to-disc ratio threshold for detecting GON from the training data was found to be 0.619. DCGANs generated high-quality synthetic disc images for healthy and glaucomatous eyes. When trained on a mixed data set, the model's area under the receiver operating characteristic curve attained 99.85% on internal validation and 86.45% on external validation. Grad-CAM saliency maps were primarily centered on the optic nerve head, indicating a more precise and clinically relevant attention area of the fundus image. Conclusions:Although our model performed well on synthetic data, training on a mixed data set demonstrated better performance and generalization. Integrating synthetic and real clinical images can optimize the performance of a deep learning model in glaucoma detection. Translational Relevance:Optimizing deep learning models for glaucoma detection through integrating DCGAN-generated synthetic and real-world clinical data can be improved and generalized in clinical practice.