A Genome-Wide Association Study of Optic Disc Parameters

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72 x 10(-19)) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67 x 10(-33)) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15610 211) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93 x 10(-10)) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origi

Nutrient intake and risk of open-angle glaucoma: the Rotterdam Study

Open-angle glaucoma (OAG) is the commonest cause of irreversible blindness worldwide. Apart from an increased intraocular pressure (IOP), oxidative stress and an impaired ocular blood flow are supposed to contribute to OAG. The aim of this study was to determine whether the dietary intake of nutrients that either have anti-oxidative properties (carotenoids, vitamins, and flavonoids) or influence the blood flow (omega fatty acids and magnesium) is associated with incident OAG. We investigated this in a prospective population-based cohort, the Rotterdam Study. A total of 3502 participants aged 55 years and older for whom dietary data at baseline and ophthalmic data at baseline and follow-up were available and who did not have OAG at baseline were included. The ophthalmic examinations comprised measurements of the IOP and perimetry; dietary intake of nutrients was assessed by validated questionnaires and adjusted for energy intake. Cox proportional hazard regression analysis was applied to calculate hazard ratios of associations between the baseline intake of nutrients and incident OAG, adjusted for age, gender, IOP, IOP-lowering treatment, and body mass index. During an average follow-up of 9.7 years, 91 participants (2.6%) developed OAG. The hazard ratio for retinol equivalents (highest versus lowest tertile) was 0.45 (95% confidence interval 0.23-0.90), for vitamin B1 0.50 (0.25-0.98), and for magnesium 2.25 (1.16-4.38). The effects were stronger after the exclusion of participants taking supplements. Hence, a low intake of retinol equivalents and vitamin B1 (in line with hypothesis) and a high intake of magnesium (less unambiguous to interpret) appear to be associated with an increased risk of OAG

Defining Glaucomatous Optic Neuropathy from a Continuous Measure of Optic Nerve Damage - The Optimal Cut-off Point for Risk-factor Analysis in Population-based Epidemiology

Purpose: Diseases characterized by a continuous trait can be defined by setting a cut-off point for the disease measure in question, accepting some misclassification. The 97.5th percentile is commonly used as a cut-off point. However, it is unclear whether this percentile is the optimal cut-off point from the point of view of risk-factor analysis. The optimal cut-off point for risk-factor analysis can be found with a statistical method that minimizes the effect of misclassification. We applied this method to glaucomatous optic neuropathy. Here, the continuous trait is the cup-disc ratio. The aim of this study was to determine the optimal cup-disc ratio cut-off point for risk-factor analysis in population-based epidemiology. Methods: All participants in the population-based Rotterdam Study underwent intraocular pressure (IOP) measurements, assessment of the cup-disc ratio with the Heidelberg Retina Tomograph (HRT) and visual field testing. In the statistical method, the cup-disc ratio (the continuous trait) and the IOP (a major risk factor) were independent variables and glaucomatous visual field loss (the true glaucoma endpoint) the dependent variable in a logistic regression model. The optimal cup-disc ratio cut-off point was found by minimizing the influence of IOP in this model. Variability of the approach was assessed by using a bootstrap resampling technique. Results: Of 2444 included participants, 93 had glaucomatous visual field loss. The median optimal cup-disc ratio cut-off point was the 97.0th percentile with a 95% central range from 95.5 to 98.5. Conclusion: The optimal cup-disc ratio cut-off point for risk-factor analysis is close to the commonly used 97.5th percentile

Optimizing the Information Yield of 3-D OCT in Glaucoma

PURPOSE. To determine, first, which regions of 3-D optical coherence tomography (OCT) volumes can be segmented completely in the majority of subjects and, second, the relationship between analyzed area and thickness measurement test-retest variability. METHODS. Three-dimensional OCT volumes (6X6 mm) centered around the fovea and optic nerve head (ONH) of 925 Rotterdam Study participants were analyzed; 44 participants were scanned twice. Volumes were segmented into 10 layers, and we determined the area where all layers could be identified in at least 95% (macula) or 90% (ONH) of subjects. Macular volumes were divided in 2 x 2, 4 x 4, 6 x 6, 8 x 8, or 68 blocks. We placed two circles around the ONH; the ONH had to fit into the smaller circle, an RESULTS. Eighty-two percent of the macular volume could be segmented in at least 95% of subjects; for the ONH, this was 65% in at least 90%. The radii of the circles were 1.03 and 1.84 mm. Depending on the analyzed area, median test-retest variability ranged from 8% to 15% for macular RNFL, 11% to 22% for macular RGCL, 5% to 11% for the two together, and 18% to 22% for ONH RNFL. CONCLUSIONS. Test-retest variability hampers a detailed analysis of 3-D OCT data. Combined macular RNFL and RGCL thickness averaged over larger areas had the best test-retest variability. (Invest Ophthalmol Vis Sci. 2012; 53: 8162-8171) DOI:10.1167/iovs.12-1055

Population-Based Evaluation of Retinal Nerve Fiber Layer, Retinal Ganglion Cell Layer, and Inner Plexiform Layer as a Diagnostic Tool For Glaucoma

PURPOSE. We determined the glaucoma screening performance of regional optical coherence tomography (OCT) layer thickness measurements in the peripapillary and macular region, in a population-based setting. METHODS. Subjects (n = 1224) in the Rotterdam Study underwent visual field testing (Humphrey Field Analyzer) and OCT of the macula and optic nerve head (Topcon 3-D OCT-1000). We determined the mean thicknesses of the retinal nerve fiber layer (RNFL), retinal ganglion cell layer (RGCL), and inner plexiform layer for regions-of-interest; thus, defining a series of OCT parameters, using the Iowa Reference Algorithms. Reference standard was the presence of glaucomatous visual field loss (GVFL); controls were subjects without GVFL, an intraocular pressure (IOP) of 21 mm Hg or less, and no positive family history for glaucoma. We calculated the area under the receiver operating characteristics curve (AUCs) and the sensitivity at 97.5% specificity for each parameter. RESULTS. After excluding 23 subjects with an IOP > 21 mm Hg and 73 subjects with a positive family history for glaucoma, there were 1087 controls and 41 glaucoma cases. Mean RGCL thickness in the inferior half of the macular region showed the highest AUC (0.85; 95% confidence interval [CI] 0.77-0.92) and sensitivity (53.7%; 95% CI, 38.7-68.0%). The mean thickness of the peripapillary RNFL had an AUC of 0.77 (95% CI, 0.69-0.85) and a sensitivity of 24.4% (95% CI, 13.7-39.5%). CONCLUSIONS. Macular RGCL loss is at least as common as peripapillary RNFL abnormalities in population-based glaucoma cases. Screening for glaucoma using OCT-derived regional thickness identifies approximately half of those cases of glaucoma as diagnosed by perimetry