David A. Mackey

Description:Age-related changes in glaucoma endophenotypes have been described thoroughly, yet, there are limited data on the normal age-related changes in young adults. This study profiles the 8-year longitudinal change in peripapillary retinal nerve fiber layer (pRNFL), intraocular pressure (IOP), and central corneal thickness (CCT) in young adults. A community-based cohort of young adults from the Raine Study underwent eye examinations that included optical coherence tomography of the optic disc, tonometry, and pachymetry when they were 20 and 28 years old. The main outcome measures were the changes in pRNFL thickness, IOP, and CCT over 8 years, adjusted for sex, ethnicity, and other potential confounders. A total of 693, 712, and 680 participants were included in the pRNFL, IOP, and CCT analyses, respectively. Over the 8 years, the global pRNFL reduced from a mean of 100.6 ± 9.3 to 97.9 ± 9.4 µm, at an average rate of 0.27 µm/year (95% confidence interval [CI], 0.24-0.30). Sectoral pRNFL similarly thinned by 0.06 to 0.38 µm/year, but this thinning was not statistically significant at the superotemporal and inferonasal sectors. IOP decreased and CCT increased between 20 and 28 years old, at an average rate of 0.18 mm Hg/year (95% CI, 0.15-0.20) and 0.18 µm/year (95% CI, 0.10-0.27), respectively. During the third decade of life, there is a decrease in pRNFL thickness and IOP in healthy adults. The current study findings will enable clinicians to differentiate potential pathological change from normal age-related variations in these measures.

Description:Leber hereditary optic neuropathy (LHON) predominantly manifests during adolescence or young adulthood, resulting in sudden and profound vision loss in individuals who previously had normal vision. This abrupt change significantly impacts daily life, necessitating emotional support, counseling and low-vision rehabilitative services to help affected individuals cope with the shock and adapt to their residual vision. The psychosocial burden of dealing with vision loss extends beyond the individuals directly affected by LHON, affecting matrilineal relatives who face the dual challenges of grieving for their loved one's vision loss and managing their own uncertainty about potential vision loss and its familial implications. We reviewed key information that needs to be obtained prior to genetic counseling for LHON. We reviewed key counseling issues within LHON-affected families and the issues pending several subgroups of family members with distinct and varying genetic counseling needs. Family subgroups requiring specific counseling issues include the individuals affected by LHON, their mother, siblings, father, partner, and children. Genetic counseling plays an integral part of clinical care in families affected by LHON, providing tailored support and information to each subgroup. To provide accurate information to families and guide them toward potential supports, treatments and preventive measures, health professionals need to be aware of the factors influencing visual recovery and individual risk of vision loss.

Description:Early 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. To construct IOP and VCDR PRSs with clinically relevant predictive power. This 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. IOP and VCDR PRSs and phenotypic variance (R2) explained by each PRS. Participants 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. VCDR 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.

Description:Objective: Rare variants in the MYOC gene are associated with glaucoma risk, with p.Gln368Ter the most common pathogenic variant in Europeans. Genetics-based risk stratification may aid with early diagnosis for glaucoma but it is unclear how best to combine the p.Gln368Ter status with polygenic risk scores (PRS). Our study aimed to examine approaches for identifying p. Gln368Ter carriers using genotyping array data and the utility of integrating p.Gln368Ter status into glaucoma PRS. Methods: Retrospective cohort study. Methods: We identified p.Gln368Ter carriers using directly genotyped and imputed data. Results were confirmed in a subset with sequencing data. We evaluated the combined effects of p.Gln368Ter status and PRS in stratified analyses by considering them as two separate factors and as an aggregate score. Methods: A total of 58,452 participants from the Genetics of Glaucoma, the QSkin Sun and Health Study (QSKIN), and CARTaGENE projects, including 6015 with sequencing data. Methods: The concordance of direct genotyping, compared with imputation and sequencing for p.Gln368Ter identification. Results: Without appropriate quality control, substantial mis-calling may occur. Nevertheless, the p.Gln368Ter variant could be accurately genotyped in most cases by filtering individuals for call rate and heterozygosity. In 6015 individuals with sequencing data, direct genotyping exhibited perfect concordance with sequencing results. Filtered direct genotyping results showed high agreement with imputed results, with only 16 discrepancies among 57,468 individuals. When quality control is not possible (eg, heterozygosity filtering for an individual), we recommend comparing genotyped and imputed results to ensure accuracy. Incorporating p.Gln368Ter into PRS had additional effects on stratifying high-risk individuals, but did not improve risk prediction for the general population given the variant's rarity. The MYOC-enhanced PRS increased the proportion of p.Gln368Ter carriers classified as high risk from 32.31% to 75.38% in QSKIN and from 38.24% to 79.41% in CARTaGENE. Conclusions: The p.Gln368Ter variant can be genotyped with high accuracy using array data, provided careful quality control measures are implemented. Incorporating p.Gln368Ter into glaucoma PRS improved risk stratification for carriers.

Description: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.