Features Associated with Visible Lamina Cribrosa Pores in Individuals of African Ancestry with Glaucoma: Primary Open-Angle African Ancestry Glaucoma Genetics (POAAGG) Study.

There are scarce data regarding the rate of the occurrence of primary open-angle glaucoma (POAG) and visible lamina cribrosa pores (LCPs) in the eyes of individuals with African ancestry; the potential impact of these features on disease burden remains unknown. We recruited subjects with POAG to the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Through regression models, we evaluated the association between the presence of LCPs and various phenotypic features. In a multivariable analysis of 1187 glaucomatous eyes, LCPs were found to be more likely to be present in eyes with cup-to-disc ratios (CDR) of ≥0.9 (adjusted risk ratio (aRR) 1.11, 95%CI: 1.04-1.19, p = 0.005), eyes with cylindrical-shaped (aRR 1.22, 95%CI: 1.11-1.33) and bean pot (aRR 1.24, 95%CI: 1.13-1.36) cups versus conical cups (p < 0.0001), moderate cup depth (aRR 1.24, 95%CI: 1.06-1.46) and deep cups (aRR 1.27, 95%CI: 1.07-1.50) compared to shallow cups (p = 0.01), and the nasalization of central retinal vessels (aRR 1.33, 95%CI: 1.23-1.44), p < 0.0001). Eyes with LCPs were more likely to have a higher degree of African ancestry (q0), determined by means of SNP analysis (aRR 0.96, 95%CI: 0.93-0.99, p = 0.005 for per 0.1 increase in q0). Our large cohort of POAG cases of people with African ancestry showed that LCPs may be an important risk factor in identifying severe disease, potentially warranting closer monitoring by physicians.

Stress, Allostatic Load, and Neuroinflammation: Implications for Racial and Socioeconomic Health Disparities in Glaucoma.

Glaucoma is the leading cause of irreversible blindness, and its pathophysiology includes neuroinflammatory changes. The present therapies for glaucoma target pressure-lowering mechanisms with limited success, making neuroinflammation a target for future interventions. This review summarizes the neuroinflammatory pathways seen in glaucoma and their interplay with stress. Glucocorticoids have been shown to activate proinflammatory glial cells, contributing to the neuroinflammation in glaucoma. Glucocorticoids have also been shown to increase the IOP directly. Stress-associated autonomic dysfunction can affect the vascular homeostasis in the retina and create oxidative stress. Diabetes, hyperglycemic-mediated endothelial damage, and vascular inflammation also play important roles in the neuroinflammation in glaucoma and diabetic retinopathy. Psychosocial stress has been implicated in an increased IOP and glaucoma outcomes. People who experience maladaptive chronic stress suffer from a condition known as allostatic load, which describes pathologic neuroendocrine dysregulation. The effects of allostatic load and chronic stress have been studied in patients affected by a lower socioeconomic status (SES) and marginalized racial identities. A lower SES is associated with higher rates of glaucoma and also affects the access to care and screening. Additionally, people of African ancestry are disproportionately affected by glaucoma for reasons that are multifactorial. In conclusion, this review explores neuroinflammation in glaucoma, highlighting opportunities for future investigation.

Advancing Glaucoma Care: Integrating Artificial Intelligence in Diagnosis, Management, and Progression Detection.

Glaucoma, the leading cause of irreversible blindness worldwide, comprises a group of progressive optic neuropathies requiring early detection and lifelong treatment to preserve vision. Artificial intelligence (AI) technologies are now demonstrating transformative potential across the spectrum of clinical glaucoma care. This review summarizes current capabilities, future outlooks, and practical translation considerations. For enhanced screening, algorithms analyzing retinal photographs and machine learning models synthesizing risk factors can identify high-risk patients needing diagnostic workup and close follow-up. To augment definitive diagnosis, deep learning techniques detect characteristic glaucomatous patterns by interpreting results from optical coherence tomography, visual field testing, fundus photography, and other ocular imaging. AI-powered platforms also enable continuous monitoring, with algorithms that analyze longitudinal data alerting physicians about rapid disease progression. By integrating predictive analytics with patient-specific parameters, AI can also guide precision medicine for individualized glaucoma treatment selections. Advances in robotic surgery and computer-based guidance demonstrate AI's potential to improve surgical outcomes and surgical training. Beyond the clinic, AI chatbots and reminder systems could provide patient education and counseling to promote medication adherence. However, thoughtful approaches to clinical integration, usability, diversity, and ethical implications remain critical to successfully implementing these emerging technologies. This review highlights AI's vast capabilities to transform glaucoma care while summarizing key achievements, future prospects, and practical considerations to progress from bench to bedside.

3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity.

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18 and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.

Factors Associated with Large Cup-to-Disc Ratio and Blindness in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study.

BACKGROUND/AIMS: Primary open-angle glaucoma (POAG) disproportionately affects individuals of African ancestry. In these patients' eyes, a large cup-to-disc ratio (LCDR > 0.90) suggests greater retinal ganglion cell loss, though these patients often display varied visual ability. This study investigated the prevalence and risk factors associated with LCDR in African ancestry individuals with POAG and explored the differences between blind (>20/200) and not blind (≤20/200) LCDR eyes. METHODS: A case-control methodology was used to investigate the demographic, optic disc, and genetic risk factors of subjects in the Primary Open-Angle African American Glaucoma Genetics Study. Risk factors were analyzed using univariable and multivariable logistic regression models with inter-eye correlation adjusted using generalized estimating equations. RESULTS: Out of 5605 eyes with POAG, 1440 eyes (25.7%) had LCDR. In the multivariable analysis, LCDR was associated with previous glaucoma surgery (OR = 1.72), increased intraocular pressure (OR = 1.04), decreased mean deviation (OR = 1.08), increased pattern standard deviation (OR = 1.06), thinner retinal nerve fiber layer (OR = 1.05), nasalization of vessels (OR = 2.67), bayonetting of vessels (OR = 1.98), visible pores in the lamina cribrosa (OR = 1.68), and a bean-shaped cup (OR = 2.11). Of LCDR eyes, 30.1% were classified as blind (≤20/200). In the multivariable analysis, the statistically significant risk factors of blindness in LCDR eyes were previous glaucoma surgery (OR = 1.72), increased intraocular pressure (OR = 1.05), decreased mean deviation (OR = 1.04), and decreased pattern standard deviation (OR = 0.90). CONCLUSIONS: These findings underscore the importance of close monitoring of intraocular pressure and visual function in African ancestry POAG patients, particularly those with LCDR, to preserve visual function.

The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review.

Glaucoma, an age-related neurodegenerative disease, is characterized by the death of retinal ganglion cells (RGCs) and the corresponding loss of visual fields. This disease is the leading cause of irreversible blindness worldwide, making early diagnosis and effective treatment paramount. The pathophysiology of primary open-angle glaucoma (POAG), the most common form of the disease, remains poorly understood. Current available treatments, which target elevated intraocular pressure (IOP), are not effective at slowing disease progression in approximately 30% of patients. There is a great need to identify and study treatment options that target other disease mechanisms and aid in neuroprotection for POAG. Increasingly, the role of mitochondrial injury in the development of POAG has become an emphasized area of research interest. Disruption in the function of mitochondria has been linked to problems with neurodevelopment and systemic diseases. Recent studies have shown an association between RGC death and damage to the cells' mitochondria. In particular, oxidative stress and disrupted oxidative phosphorylation dynamics have been linked to increased susceptibility of RGC mitochondria to secondary mechanical injury. Several mitochondria-targeted treatments for POAG have been suggested, including physical exercise, diet and nutrition, antioxidant supplementation, stem cell therapy, hypoxia exposure, gene therapy, mitochondrial transplantation, and light therapy. Studies have shown that mitochondrial therapeutics may have the potential to slow the progression of POAG by protecting against mitochondrial decline associated with age, genetic susceptibility, and other pathology. Further, these therapeutics may potentially target already present neuronal damage and symptom manifestations. In this review, the authors outline potential mitochondria-targeted treatment strategies and discuss their utility for use in POAG.

Risk factors for structural and functional progression of primary open-angle glaucoma in an African ancestry cohort.

BACKGROUND/AIMS: To investigate the rates of structural and functional progression of primary open-angle glaucoma in an African ancestry cohort and identify risk factors for progression. METHODS: This retrospective study included 1424 eyes from glaucoma cases in the Primary Open-Angle African American Glaucoma Genetics cohort, with ≥2 visits for retinal nerve fibre layer (RNFL) thickness and mean deviation (MD) measurements over ≥6-month follow-up. The rates of structural progression (change in RNFL thickness/year) and functional progression (change in MD/year) were calculated from linear mixed effects models, accounting for intereye correlation and longitudinal correlation. Eyes were categorised as slow, moderate or fast progressors. Risk factors for progression rates were assessed using univariable and multivariable regression models. RESULTS: The median (interquartile) rates of progression were -1.60 (-2.05 to -1.15) µm/year for RNFL thickness and -0.40 (-0.44 to -0.34) decibels/year for MD. Eyes were categorised as slow (structural: 19%, functional: 88%), moderate (structural: 54%, functional: 11%) and fast (structural: 27%, functional: 1%) progressors. In multivariable analysis, faster RNFL progression was independently associated with thicker baseline RNFL (p<0.0001), lower baseline MD (p=0.003) and beta peripapillary atrophy (p=0.03). Faster MD progression was independently associated with higher baseline MD (p<0.0001), larger cup-to-disc ratios (p=0.02) and lower body mass index (p=0.0004). CONCLUSION: The median rates of structural and functional progression in this African ancestry cohort were faster than the rates reported from previously published studies in other ethnic groups. Higher baseline RNFL thickness and MD values were associated with faster progression rates. Results highlight the importance of monitoring structural and functional glaucoma progression to provide timely treatment in early disease.

Eye-brain connections revealed by multimodal retinal and brain imaging genetics in the UK Biobank.

As an anatomical extension of the brain, the retina of the eye is synaptically connected to the visual cortex, establishing physiological connections between the eye and the brain. Despite the unique opportunity retinal structures offer for assessing brain disorders, less is known about their relationship to brain structure and function. Here we present a systematic cross-organ genetic architecture analysis of eye-brain connections using retina and brain imaging endophenotypes. Novel phenotypic and genetic links were identified between retinal imaging biomarkers and brain structure and function measures derived from multimodal magnetic resonance imaging (MRI), many of which were involved in the visual pathways, including the primary visual cortex. In 65 genomic regions, retinal imaging biomarkers shared genetic influences with brain diseases and complex traits, 18 showing more genetic overlaps with brain MRI traits. Mendelian randomization suggests that retinal structures have bidirectional genetic causal links with neurological and neuropsychiatric disorders, such as Alzheimer's disease. Overall, cross-organ imaging genetics reveals a genetic basis for eye-brain connections, suggesting that the retinal images can elucidate genetic risk factors for brain disorders and disease-related changes in intracranial structure and function.

ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma.

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.

Approach of an Academic Ophthalmology Department to Recovery During the Coronavirus Pandemic.

Introduction: A methodology for safe recovery of an ophthalmology department during a pandemic does not currently exist. This study describes successful recovery strategies for an urban, multi-specialty ophthalmology department serving a high-risk patient population. Methods: The study took place at a large multi-specialty tertiary care academic ophthalmology department in a metropolitan city during a seven-month period (March-October 2020). Five recovery ad hoc committees were charged with formulating metrics and initiatives to manage clinical volumes while maintaining safe practices, providing patient access, and minimizing financial damage. A six-tier system was created to resume non-urgent appointments in May 2020. Educational and research activities were maintained through the development of virtual curricula and research platforms. Results: The number of clinical and surgical visits per month in 2020 compared to 2019 and the time to reach ≥95% of pre-COVID patient volumes were monitored. In October 2020, ≥95% of pre-COVID volumes were attained (11,975 vs 12,337 patient visits in October 2019; 266 vs 272 surgical cases in October 2019). Despite significant financial losses, the department surpassed December 2019 collections in December 2020. No faculty, staff, or trainees received furloughs or pay cuts. There was no COVID-19 transmission between faculty, staff, and patients. Discussion: With strategic implementation of recovery strategies following CDC safety measures, it was possible to safely deliver care to patients with urgent and non-urgent eye conditions. Patient volumes were fully recovered in an ambulatory urban healthcare setting within a high-risk COVID-19 population within seven months while educational and research missions were successfully sustained.

Prevalence and Factors Associated with Optic Disc Tilt in the Primary Open-Angle African American Glaucoma Genetics Study.

PURPOSE: To investigate the prevalence and factors associated with optic disc tilt in the eyes of Black Americans with glaucoma. DESIGN: Cross-sectional. PARTICIPANTS: Subjects with glaucoma participating in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. METHODS: Stereo pairs of optic disc images were assessed independently by POAAGG-certified nonphysician graders for quantitative features including maximum and minimum linear disc diameters, and qualitative features including gradeability of images, shape of the cup, rim plane position, ß-peripapillary atrophy, sloping region adjacent to the outer disc margin, and rim pallor. Discrepancies were adjudicated by an ophthalmologist. Descriptive statistics and P values were generated for associations of tilt with demographic and ocular characteristics. Stepwise multivariable analysis was performed with logistic regression using Generalized Estimating Equations (GEEs) to account for inter-eye correlation within subjects. MAIN OUTCOME MEASURES: Tilt Ovality Index (TOI) of >1.30 and Stereoscopically Identified optic disc Tilt (SIT). RESULTS: Among 1251 subjects with data on both eyes, 104 (8.3%) had TOI. Subjects with TOI were less likely to be male (adjusted odds ratio [aOR], 0.46, 95% confidence interval [CI], 0.29-0.74, P < 0.001). Eyes with TOI were less likely to have large cup disc ratios (aOR, 0.18, 95% CI, 0.06-0.53, P < 0.001) and less likely to have cylinder-shaped cups compared with conical-shaped cups (aOR, 0.31, 95% CI, 0.19-0.49, P < 0.001). Among 1007 subjects with data on both eyes, 254 (25.2%) had SIT. Subjects with SIT were younger (aOR, 0.95, 95% CI, 0.93-0.96, P < 0.001), and eyes with SIT were more likely to have oval-shaped discs compared with round discs (aOR, 1.82, 95% CI, 1.32-2.52, P < 0.001), more likely to have a sloping region adjacent to the outer disc margin instead of being flat (aOR, 3.26, 95% CI, 2.32-4.59, P < 0.001), and less likely to have cylinder-shaped cups compared with conical-shaped cups (aOR, 0.59, 95% CI, 0.41-0.85, P < 0.001). Both TOI and SIT were not associated with myopia. CONCLUSIONS: There are substantial numbers of tilted optic discs in glaucoma patients with African ancestry. They occur more frequently in female subjects and younger subjects and are associated with several ocular features but not with myopia.

Assessing the efficacy of 3D-printed ear protectors on mask adherence at an academic ophthalmology center.

PURPOSE: In the ophthalmology setting, given the close proximity required for the clinical exam, appropriate mask usage and fit is essential. This study aims to assess how a simple, cost-effective 3D-printed face mask ear protectors (EP) attachment may decrease discomfort, increase compliance, and improve fit in an academic institution's Ophthalmology department. METHODS: Face mask EPs were distributed to patients and providers in the Ophthalmology department. A validated questionnaire was administered before and 2 weeks after EP usage. The survey included questions on demographics and frequency of mask usage during a spectrum of activities. Descriptive statistics were performed with Fischer's t test. RESULTS: Post-EP responses demonstrated an increased likelihood of mask usage across all activities, although not statistically significant. The greatest change was during outdoor activities, with a 14.3% increase in highest utilization. Post-EP, all subjects were very likely to wear masks while shopping and 91.7% while in the workplace. EP usage decreased the number of noncompliant individuals while spending time with friends and family by 93.3%. Almost no subjects reported mask removal of >15 times per hour post-EP. The increase in mask compliance was greatest for low mask utilizers. 91.9% reported improved comfort, 91.9% reported improved fit, and 81.6% reported increased mask usage. CONCLUSION: Our results suggest that simple cost-effective 3D-printed ear protectors may improve fit, comfort, and overall mask compliance. The results of this study should drive broader public health efforts to further investigate whether mask attachments can improve overall mask compliance through better comfort and fit.

Recruitment strategies and lessons learned from a large genetic study of African Americans.

Genetic studies must enroll large numbers of participants to obtain adequate statistical power. Data are needed on how researchers can best use limited financial and practical resources to achieve these targets, especially in under-represented populations. This paper provides a retrospective analysis of the recruitment strategies for a large glaucoma genetics study in African Americans. The Primary Open-Angle African American Glaucoma Genetics study enrolled 10,192 African American subjects from the Philadelphia region. Major recruitment approaches included clinic enrollment from University of Pennsylvania (UPenn) sites, clinic enrollment from external sites, sampling of Penn Medicine Biobank (PMBB), and community outreach. We calculated the enrollment yield, cost per subject, and seasonal trends of these approaches. The majority (65%) of subject were enrolled from UPenn sites with an average cost of $133/subject. Over time, monthly case enrollment declined as the pool of eligible subjects was depleted. Expanding to external sites boosted case numbers ($129/subject) and the biobank provided additional controls at low cost ($5/subject), in large part due to the generosity of PMBB providing samples free of cost. Community outreach was costly with low return on enrollment ($978/subject for 220 subjects). Summer months (Jun-Aug) produced the highest recruitment yields (p<0.001). Genetic studies will benefit from a multi-pronged and culturally sensitive recruitment approach. In our experience, the biobank was most cost-effective for control enrollment, while recruitment from clinics (including expansion to new sites) was necessary to recruit fully phenotyped cases.

Learning from Black/African American Participants: Applying the Integrated Behavioral Model to Assess Recruitment Strategies for a Glaucoma Genetic Study.

The underrepresentation of African American (AA) participants in medical research perpetuates racial health disparities in the United States. Open-ended phone interviews were conducted with 50 AA adults from Philadelphia who had previously participated in a genetic study of glaucoma that included complimentary ophthalmic screenings. Recruitment for the genetic study was done in partnership with a Black-owned radio station. Thematic analysis of interview transcripts, guided by the integrated behavior model (IBM), identified self-reported motivations for participating in this care-focused and community-promoted research program. Findings revealed that decisions to enroll were influenced by strong instrumental attitudes regarding learning more about personal health and contributing to future care options for others. Notable normative influences that factored into participants' decisions to enroll in the study included hearing about the study from a respected community media outlet, friends, and family. About one-third of respondents discussed past and current racial discrimination in medical research as an important sociocultural frame within which they thought about participation, suggesting that experiential attitudes play a continuing role in AA's decisions to enroll in medical research studies. Medical researchers seeking to recruit AA participants should collaborate with community partners, combine enrollment opportunities with access to health services, and emphasize the potential for new research to mitigate racial inequalities.

A Precise Method to Evaluate 360 Degree Measures of Optic Cup and Disc Morphology in an African American Cohort and Its Genetic Applications.

(1) Background: Vertical cup-to-disc ratio (CDR) is an important measure for evaluating damage to the optic nerve head (ONH) in glaucoma patients. However, this measure often does not fully capture the irregular cupping observed in glaucomatous nerves. We developed and evaluated a method to measure cup-to-disc ratio (CDR) at all 360 degrees of the ONH. (2) Methods: Non-physician graders from the Scheie Reading Center outlined the cup and disc on digital stereo color disc images from African American patients enrolled in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. After converting the resultant coordinates into polar representation, the CDR at each 360-degree location of the ONH was obtained. We compared grader VCDR values with clinical VCDR values, using Spearman correlation analysis, and validated significant genetic associations with clinical VCDR, using grader VCDR values. (3) Results: Graders delineated outlines of the cup contour and disc boundaries twice in each of 1815 stereo disc images. For both cases and controls, the mean CDR was highest at the horizontal bisector, particularly in the temporal region, as compared to other degree locations. There was a good correlation between grader CDR at the vertical bisector and clinical VCDR (Spearman Correlation OD: r = 0.78 [95% CI: 0.76-0.79]). An SNP in the MPDZ gene, associated with clinical VCDR in a prior genome-wide association study, showed a significant association with grader VCDR (p = 0.01) and grader CDR area ratio (p = 0.02). (4) Conclusions: The CDR of both glaucomatous and non-glaucomatous eyes varies by degree location, with the highest measurements in the temporal region of the eye. This method can be useful for capturing innate eccentric ONH morphology, tracking disease progression, and identifying genetic associations.

Single Cell Sequencing of Induced Pluripotent Stem Cell Derived Retinal Ganglion Cells (iPSC-RGC) Reveals Distinct Molecular Signatures and RGC Subtypes.

We intend to identify marker genes with differential gene expression (DEG) and RGC subtypes in cultures of human-induced pluripotent stem cell (iPSC)-derived retinal ganglion cells. Single-cell sequencing was performed on mature and functional iPSC-RGCs at day 40 using Chromium Single Cell 3' V3 protocols (10X Genomics). Sequencing libraries were run on Illumina Novaseq to generate 150 PE reads. Demultiplexed FASTQ files were mapped to the hg38 reference genome using the STAR package, and cluster analyses were performed using a cell ranger and BBrowser2 software. QC analysis was performed by removing the reads corresponding to ribosomal and mitochondrial genes, as well as cells that had less than 1X mean absolute deviation (MAD), resulting in 4705 cells that were used for further analyses. Cells were separated into clusters based on the gene expression normalization via PCA and TSNE analyses using the Seurat tool and/or Louvain clustering when using BBrowser2 software. DEG analysis identified subsets of RGCs with markers like MAP2, RBPMS, TUJ1, BRN3A, SOX4, TUBB3, SNCG, PAX6 and NRN1 in iPSC-RGCs. Differential expression analysis between separate clusters identified significant DEG transcripts associated with cell cycle, neuron regulatory networks, protein kinases, calcium signaling, growth factor hormones, and homeobox transcription factors. Further cluster refinement identified RGC diversity and subtype specification within iPSC-RGCs. DEGs can be used as biomarkers for RGC subtype classification, which will allow screening model systems that represent a spectrum of diseases with RGC pathology.

Association of the SNP rs112369934 near TRIM66 Gene with POAG Endophenotypes in African Americans.

We investigated the association of the single nucleotide polymorphism (SNP) rs112369934 near the TRIM66 gene with qualitative and quantitative phenotypes of primary open-angle glaucoma (POAG) in African Americans (AA). AA subjects over 35 years old were recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study in Philadelphia, PA. Glaucoma cases were evaluated for phenotypes associated with POAG pathogenesis, and the associations between rs112369934 and phenotypes were investigated by logistic regression analysis and in gender-stratified case cohorts: The SNP rs112369934 was found to have a suggestive association with retinal nerve fiber layer (RNFL) thickness and cup-to-disc ratio (CDR) in 1087 male AA POAG cases, individuals with the TC genotype having thinner RNFL (95% CI 0.85 to 6.61, p = 0.01) and larger CDR (95% CI -0.07 to -0.01, p = 0.02) than those with wildtype TT. No other significant associations were found. In conclusion SNP rs112369934 may play a role in POAG pathogenesis in male AA individuals. However, this SNP has been implicated in higher POAG risk in both male and female AA POAG cases.

LMX1B Locus Associated with Low-Risk Baseline Glaucomatous Features in the POAAGG Study.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and has been associated with multiple genetic risk factors. The LMX1B gene is a genetic susceptibility factor for POAG, and several single-nucleotide polymorphisms (SNPs) were shown to be associated with POAG in our own prior Primary Open-Angle African American Glaucoma Genetics (POAAGG) study genome-wide association study (GWAS). This study evaluated the association of the LMX1B locus with baseline optic disc and clinical phenotypic characteristics of glaucoma patients from our African American cohort. Compared to the GG genotype in SNP rs187699205, the GC genotype in this SNP was found to be significantly associated with a smaller cup-to-disc ratio (CDR) and increased (better) visual field mean deviation (MD) in glaucoma cases. None of the glaucoma cases with the GC genotype had disc hemorrhages, disc notching, or beanpot disc appearance. In conclusion, glaucoma phenotypes differed significantly by LMX1B variant in African American patients with POAG, and a SNP variant was associated with certain disease features considered lower risk.

The Role of Genetic Ancestry as a Risk Factor for Primary Open-angle Glaucoma in African Americans.

Purpose: POAG is the leading cause of irreversible blindness in African Americans. In this study, we quantitatively assess the association of autosomal ancestry with POAG risk in a large cohort of self-identified African Americans. Methods: Subjects recruited to the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study were classified as glaucoma cases or controls by fellowship-trained glaucoma specialists. POAAGG subjects were genotyped using the MEGA Ex array (discovery cohort, n = 3830; replication cohort, n = 2135). Population structure was interrogated using principal component analysis in the context of the 1000 Genomes Project superpopulations. Results: The majority of POAAGG samples lie on an axis between African and European superpopulations, with great variation in admixture. Cases had a significantly lower mean value of the ancestral component q0 than controls for both cohorts (P = 6.14-4; P = 3-6), consistent with higher degree of African ancestry. Among POAG cases, higher African ancestry was also associated with thinner central corneal thickness (P = 2-4). Admixture mapping showed that local genetic ancestry was not a significant risk factor for POAG. A polygenic risk score, comprised of 23 glaucoma-associated single nucleotide polymorphisms from the NHGRI-EBI genome-wide association study catalog, was significant in both cohorts (P < 0.001), suggesting that both known POAG single nucleotide polymorphisms and an omnigenic ancestry effect influence POAG risk. Conclusions: In sum, the POAAGG study population is very admixed, with a higher degree of African ancestry associated with an increased POAG risk. Further analyses should consider social and environmental factors as possible confounding factors for disease predisposition.