Glaucoma is the leading cause of irreversible blindness globally
. Despite its gravity, the disease is frequently undiagnosed in the community
. Raised intraocular pressure (IOP) is the most ...important risk factor for primary open-angle glaucoma (POAG)
. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.
Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary ...open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total sample size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total sample size over 2.8 million; 296 loci replicated at P < 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The purpose of this study was to explore differences in genotype, ocular surface microbiome, tear inflammatory markers, and environmental and behavioral exposures in soft contact lens (SCL) wearers ...with and without a history of corneal infiltrative events (CIEs).
Nine SCL wearers with a recent CIE and nine age-, sex-, and SCL material- and modality-matched controls were enrolled. The Contact Lens Risk Survey, slit-lamp examination data, basal tears, conjunctival microbial cultures, and peripheral blood samples were collected. Tear inflammatory mediator concentrations, genomic DNA from swabs, and whole exome sequencing of blood samples were quantified.
There were no marked differences in SCL wear behaviors or exposures between case and control subjects. Predominant organisms detected among case and control subjects were Staphylococcus, Propionibacterium, Streptococcus, and Corynebacterium. Marginally higher levels of Neisseria were found in three of nine cases but zero of nine control samples (P = 0.056). A potentially deleterious missense single nucleotide polymorphism (SNP) variant in IL-6 Signal Transducer (IL6ST) was found in seven of eight cases and zero of nine controls (rs2228046; P = 0.03). The concentration of tear IL-6 was significantly higher in cases (4.5 range, 2.1 to 6.2 pg/mL) versus controls (3.5 range, 2.5 to 6.6 Pg/mL; = 0.02).
Tear IL-6 concentration was higher, and SNP variants were detected in subjects with a history of CIEs compared with healthy controls. The synthesis, signaling, and ocular surface cytokine concentration of IL-6 may be related to susceptibility to CIE. A larger study population is required to further explore relationships between genetic variations, the ocular surface microbiome, inflammatory mediators, and environmental exposures.
Although glaucoma is a disease modulated by eye pressure, the mechanisms of pressure sensing in the eye are not well understood. Here, we investigated associations between mechanosensitive ion ...channel gene variants and primary open-angle glaucoma (POAG). Common (minor allele frequency > 5%) single nucleotide polymorphisms located within the genomic regions of 20 mechanosensitive ion channel genes in the K2P, TMEM63, PIEZO and TRP channel families were assessed using genotype data from the NEIGHBORHOOD consortium of 3853 cases and 33,480 controls. Rare (minor allele frequency < 1%) coding variants were assessed using exome array genotyping data for 2606 cases and 2606 controls. Association with POAG was analyzed using logistic regression adjusting for age and sex. Two rare PIEZO1 coding variants with protective effects were identified in the NEIGHBOR dataset: R1527H, (OR 0.17, P = 0.0018) and a variant that alters a canonical splice donor site, g.16-88737727-C-G Hg38 (OR 0.38, P = 0.02). Both variants showed similar effects in the UK Biobank and the R1527H also in the FinnGen database. Several common variants also reached study-specific thresholds for association in the NEIGHBORHOOD dataset. These results identify novel variants in several mechanosensitive channel genes that show associations with POAG, suggesting that these channels may be potential therapeutic targets.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Prior studies have demonstrated that microglial activation is involved in the pathogenesis of primary open-angle glaucoma (POAG). Here we sought to identify genetic associations between POAG and ...variants in APOE and TREM2, genes associated with Alzheimer disease (AD) that critically regulate microglial neurodegeneration-associated molecular signature.
APOE genotypes were called using imputed data from the NEIGHBOR consortium (2120 POAG cases, 2262 controls) and a second cohort from the Massachusetts Eye and Ear Infirmary (MEEI; 486 cases, 344 controls). TREM2 coding variants were genotyped by means of the Illumina HumanExome BeadArray. The data set was analyzed for association with POAG overall, as well as the high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) subgroups, using logistic regression adjusting for age and sex.
In the combined NEIGHBOR-MEEI data set, significant association was observed for APOE ε4 in POAG overall (odds ratio OR, 0.83; 95% confidence interval CI, 0.74-0.94; P = 0.0022) and in both the HTG subgroup (OR, 0.81; 95% CI, 0.70-0.94; P = 0.0052) and NTG subgroup (OR, 0.71; 95% CI, 0.58-0.87; P = 0.0014). A rare TREM2 variant (A105V) was found only in HTG cases (3 of 2863 cases) and in none of the controls (P = 0.03). Three TREM2 rare variants associated with AD were not significantly associated with POAG (P > 0.05).
We have found that the APOE ε4 allele is associated with a reduced risk of POAG. Interestingly, the same allele is adversely associated with AD, suggesting a mechanistic difference between neurodegenerative diseases of the eye and the brain. TREM2 variants associated with AD did not significantly contribute to POAG risk.
IMPORTANCE: Mutations in the myocilin (MYOC) gene are the most common molecularly defined cause of primary open-angle glaucoma that typically occurs in patients with high intraocular pressures (IOP). ...One MYOC mutation, p.Gln368Ter, has been associated with as many as 1.6% of primary open-angle glaucoma cases that had a mean maximum recorded IOP of 30 mm Hg. However, to our knowledge, the role of the p.Gln368Ter mutation in patients with normal-tension glaucoma (NTG) with an IOP of 21 mm Hg or lower has not been investigated. OBJECTIVE: To evaluate the role of the p.Gln368Ter MYOC mutation in patients with NTG. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study of the prevalence of the p.Gln368Ter mutation in patients with NTG, cohort 1 was composed of 772 patients with NTG and 2152 controls from the United States (Iowa, Minnesota, and New York) and England and cohort 2 was composed of 561 patients with NTG and 2606 controls from the Massachusetts Eye and Ear Infirmary and the NEIGHBORHOOD consortium. Genotyping was conducted using real-time polymerase chain reaction that was confirmed with Sanger sequencing, the imputation of genome-wide association study data, or an analysis of whole-exome sequence data. Data analysis occurred between April 2007 and April 2018. MAIN OUTCOMES AND MEASURES: Comparison of the frequency of the p.Gln368Ter MYOC mutation between NTG cases and controls with the Fisher exact test. RESULTS: Of 6091 total participants, 3346 (54.9%) were women and 5799 (95.2%) were white. We detected the p.Gln368Ter mutation in 7 of 772 patients with NTG (0.91%) and 7 of 2152 controls (0.33%) in cohort 1 (P = .03). In cohort 2, we detected the p.Gln368Ter mutation in 4 of 561 patients with NTG (0.71%) and 10 of 2606 controls (0.38%; P = .15). When the cohorts were analyzed as a group, the p.Gln368Ter mutation was associated with NTG (odds ratio, 2.3; 95% CI, 0.98-5.3; P = .04). CONCLUSIONS AND RELEVANCE: In cohorts 1 and 2, the p.Gln368Ter mutation in MYOC was found in patients with IOPs that were 21 mm Hg or lower (NTG), although at a frequency that is lower than previously detected in patients with higher IOP. These data suggest that the p.Gln368Ter mutation may be associated with glaucoma in patients with normal IOPs as well as in patients with IOPs that are greater than 21 mm Hg.
Advances in the genomics of common eye diseases Cooke Bailey, Jessica N; Sobrin, Lucia; Pericak-Vance, Margaret A ...
Human molecular genetics,
10/2013, Volume:
22, Issue:
R1
Journal Article
Peer reviewed
Open access
Genome-wide association studies (GWAS) and other genomic technologies have accelerated the discovery of genes and genomic regions contributing to common human ocular disorders with complex ...inheritance. Age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and myopia account for the majority of visual impairment worldwide. Over 19 genes and/or genomic regions have been associated with AMD. Current investigations are assessing the clinical utility of risk score panels and therapies targeting disease-specific pathways. DR is the leading cause of blindness in the United States and globally is a major cause of vision loss. Genomic investigations have identified molecular pathways associated with DR in animal models which could suggest novel therapeutic targets. Three types of glaucoma, primary-open-angle glaucoma (POAG), angle-closure glaucoma and exfoliation syndrome (XFS) glaucoma, are common age-related conditions. Five genomic regions have been associated with POAG, three with angle-closure glaucoma and one with XFS. Myopia causes substantial ocular morbidity throughout the world. Recent large GWAS have identified >20 associated loci for this condition. In this report, we present a comprehensive overview of the genes and genomic regions contributing to disease susceptibility for these common blinding ocular disorders and discuss the next steps toward translation to effective gene-based screening tests and novel therapies targeting the molecular events contributing to disease.
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