Common genetic determinants of intraocular pressure and primary open-angle glaucoma.

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P=6.2x10(-10), near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P=3.4x10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P=1.3x10(-10) to 4.3x10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P=1.5x10(-7), in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P=0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls.

Identification and replication of three novel myopia common susceptibility gene loci on chromosome 3q26 using linkage and linkage disequilibrium mapping.

Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1). Map 1 was divided into 51 LDU windows and additional SNPs were genotyped for six regions (Map 2) that showed preliminary evidence of multi-marker association using composite likelihood. A total of 575 cases and controls selected from the tails of the trait distribution were genotyped for the discovery sample. Malecot model estimates indicate three loci with putative common functional variants centred on MFN1 (180,566 kb; 95% confidence interval 180,505-180, 655 kb), approximately 156 kb upstream from alternate-splicing SOX2OT (182,595 kb; 95% CI 182,533-182,688 kb) and PSARL (184,386 kb; 95% CI 184,356-184,411 kb), with the loci showing modest to strong evidence of association for the Map 2 discovery samples (p<10(-7), p<10(-10), and p = 0.01, respectively). Using an unselected independent sample of 1,430 individuals, results replicated for the MFN1 (p = 0.006), SOX2OT (p = 0.0002), and PSARL (p = 0.0005) gene regions. MFN1 and PSARL both interact with OPA1 to regulate mitochondrial fusion and the inhibition of mitochondrial-led apoptosis, respectively. That two mitochondrial regulatory processes in the retina are implicated in the aetiology of myopia is surprising and is likely to provide novel insight into the molecular genetic basis of common myopia.

Factors Predicting Treatment Response in Anti-Vascular Endothelial Growth Factor Naïve Diabetic Macular Edema Patients Treated with Intravitreal Bevacizumab.

Purpose: To identify factors that affect the therapeutic response of intravitreal bevacizumab in diabetic macular edema (DMO) and explore the correlation between the functional and anatomical outcomes observed. Methods: A retrospective, noncomparative, consecutive case series design was used. Baseline imaging data and clinical records of 65 eyes with DMO, secondary to type II diabetes mellitus, which received intravitreal bevacizumab for the first time in 2016, were analyzed. The central macular thickness (CMT), macular volume, and best-corrected visual acuity (BCVA), following the initial 3 injection loading phase were recorded. Outcomes were compared to multiple variables including glycemic control, diabetic retinopathy grade, DMO subtype on optical coherence tomography, and use of past macular laser therapy. Results: The participants' age ranged from 46 to 84 of which 63% were men and 37% were women. The mean baseline CMT was 443.21 µm. A mean reduction of 11.23% (P < 0.0005) in CMT was observed following the loading phase. Women exhibited a greater reduction in CMT (P = 0.032). Participants with diffuse retinal thickening (DRT) and with cystoid macular edema (CMO) showed a net reduction in CMT of 17.39% (P = 0.047) and 8.24% (P = 0.04) respectively. Eyes with proliferative diabetic retinopathy demonstrated a mean gain in CMT of 16.86% (P = 0.001). Conclusions: Female patients and DRT demonstrated a positive anatomical response. Patients with CMO and proliferative diabetic retinopathy displayed a negative therapeutic response. Such observations may be considered in clinical decision-making when opting for anti-vascular endothelial growth factor (VEGF) therapy for DMO.

Evaluation of an AI system for the automated detection of glaucoma from stereoscopic optic disc photographs: the European Optic Disc Assessment Study.

OBJECTIVES: To evaluate the performance of a deep learning based Artificial Intelligence (AI) software for detection of glaucoma from stereoscopic optic disc photographs, and to compare this performance to the performance of a large cohort of ophthalmologists and optometrists. METHODS: A retrospective study evaluating the diagnostic performance of an AI software (Pegasus v1.0, Visulytix Ltd., London UK) and comparing it with that of 243 European ophthalmologists and 208 British optometrists, as determined in previous studies, for the detection of glaucomatous optic neuropathy from 94 scanned stereoscopic photographic slides scanned into digital format. RESULTS: Pegasus was able to detect glaucomatous optic neuropathy with an accuracy of 83.4% (95% CI: 77.5-89.2). This is comparable to an average ophthalmologist accuracy of 80.5% (95% CI: 67.2-93.8) and average optometrist accuracy of 80% (95% CI: 67-88) on the same images. In addition, the AI system had an intra-observer agreement (Cohen's Kappa, κ) of 0.74 (95% CI: 0.63-0.85), compared with 0.70 (range: -0.13-1.00; 95% CI: 0.67-0.73) and 0.71 (range: 0.08-1.00) for ophthalmologists and optometrists, respectively. There was no statistically significant difference between the performance of the deep learning system and ophthalmologists or optometrists. CONCLUSION: The AI system obtained a diagnostic performance and repeatability comparable to that of the ophthalmologists and optometrists. We conclude that deep learning based AI systems, such as Pegasus, demonstrate significant promise in the assisted detection of glaucomatous optic neuropathy.

The heritability of optic disc parameters: a classic twin study.

PURPOSE: To examine the roles of genetic and environmental factors in the optic disc in a classic twin study. METHODS: Five hundred six pairs of twins were recruited to participate from the Twins U.K. Adult Twin Registry at St. Thomas' Hospital, London. Photographs of the optic disc were obtained, and the covariance of optic disc, cup, and rim areas within monozygotic (MZ) and dizygotic (DZ) pairs was compared, and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in optic disc parameters in this population. RESULTS: Mean optic disc, cup, and rim areas were 2.62 (range, 1.06-4.87), 0.98 (range, 0.25-4.72), and 1.64 (range, 1.43-6.16) mm(2), respectively. The MZ correlations were higher than those of DZ pairs for disc and cup areas (correlation coefficient, 0.73/0.81 and 0.41/0.50 for MZ and DZ twins, respectively). The correlation for optic rim was also higher in MZ (0.62) than in DZ (0.43) pairs. Modeling suggested heritability for the optic disc area of 0.73 and for the optic cup area of 0.66. The heritability of the rim area was lower at 0.34, with a significant shared environmental component of 0.27 and individual factors (including measurement error) explaining 39% of the variance of the rim area. CONCLUSIONS: This study has demonstrated that genetic effects were important in the determination of optic disc parameters in this twin population, with genetic factors explaining 73%, 66%, and 34% of the variation of optic disc, cup, and rim areas, respectively. Environmental factors also seemed to be important.

The heritability of corneal hysteresis and ocular pulse amplitude: a twin study.

PURPOSE: To examine the roles of genetic and environmental factors in corneal hysteresis and ocular pulse amplitude by performing a classic twin study. DESIGN: Cross-sectional twin study. PARTICIPANTS AND/OR CONTROLS: Two hundred sixty-four twin pairs: 135 monozygotic (MZ) and 129 dizygotic (DZ). METHODS: Corneal hysteresis was measured using the Reichert Ocular Response Analyzer (ORA; Reichert, Buffalo, NY), and ocular pulse amplitude was measured using the Pascal Dynamic Contour Tonometer (DCT; Swiss Microtechnology AG, Port, Switzerland). MAIN OUTCOME MEASURES: Contribution of genetic and environmental effects on corneal hysteresis and OPA among MZ and DZ twins. RESULTS: The mean corneal hysteresis was 10.24+/-1.54 mmHg and the mean ocular pulse amplitude was 2.88+/-0.97 mmHg. The MZ correlations were higher than DZ for both corneal hysteresis and ocular pulse amplitude (correlation coefficients, 0.75:0.42 and 0.59:0.32 for MZ:DZ twins, respectively). Modeling suggested heritability of corneal hysteresis of 0.77 (95% confidence interval [CI], 0.70-0.82), with the remaining proportion of variance because of individual environmental effects of 0.23 (95% CI, 0.18-0.30). For ocular pulse amplitude, the heritability was 0.62 (95% CI, 0.51-0.70), with the remaining proportion of variance the result of individual environmental effects of 0.38 (95% CI, 0.30-0.49). CONCLUSIONS: This study demonstrated that additive genetic influences explained most of the individual differences in corneal hysteresis and ocular pulse amplitude among these twins.

A Case of Advanced Glaucoma with Increased Episcleral Venous Pressure in a 17-Year-Old with Eisenmenger Syndrome.

Eisenmenger syndrome refers to reversal of shunt and central cyanosis due to pulmonary hypertension induced by congenital heart disease with a large systemic-to-pulmonary shunt. We report a case of a 17-year-old man with Eisenmenger syndrome who presented with gradual deterioration in visual acuity and was diagnosed with advanced secondary open angle glaucoma. There have been reports of patients suffering from thrombosis due to hyperviscosity associated with this syndrome; however, to our knowledge, the association of secondary open angle glaucoma with Eisenmenger syndrome has not yet been documented.

Optic disc planimetry, corneal hysteresis, central corneal thickness, and intraocular pressure as risk factors for glaucoma.

PURPOSE: To determine whether corneal hysteresis and central corneal thickness are independent risk factors for glaucoma. DESIGN: A cross-sectional population-based cohort study. METHODS: Associations were tested between corneal hysteresis, measured in 1754 population-based subjects from the TwinsUK cohort, and glaucoma-related endophenotypes, including intraocular pressure (IOP), vertical cup-to-disc ratio, optic disc area, and optic disc cup area. Corneal hysteresis, IOP, and central corneal thickness (CCT) were measured; optic disc photographs were analyzed; and multivariable linear regression analysis was performed. RESULTS: Data were available on 1645 individuals. Multiple regression analysis showed corneal hysteresis to be significantly negatively associated with age (beta coefficient = -0.03, P < .00005) and IOP (beta coefficient = -0.06, P < .00005). Corneal hysteresis was also found to be associated with CCT (beta coefficient = 0.02, P < .0005). There was no significant association between corneal hysteresis and optic disc area (P = .6), cup area (P = .77), vertical cup-to-disc ratio (P = .51), or spherical equivalent (P = .08). CCT was also found to be significantly associated with IOP (beta coefficient = 3.3, P < .0005) and corneal hysteresis (beta coefficient = 9.4, P < .0005), but not with age (P = .59) or spherical equivalent (P = .16). CONCLUSION: In this large cohort of healthy British twins, we found no relationship between corneal hysteresis or CCT and quantitative measures of optic disc cupping, suggesting that corneal hysteresis and CCT are not independent risk factors for glaucoma.

A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25.

Myopia and hyperopia are at opposite ends of the continuum of refraction, the measure of the eye's ability to focus light, which is an important cause of visual impairment (when aberrant) and is a highly heritable trait. We conducted a genome-wide association study for refractive error in 4,270 individuals from the TwinsUK cohort. We identified SNPs on 15q25 associated with refractive error (rs8027411, P = 7.91 × 10⁻8). We replicated this association in six adult cohorts of European ancestry with a combined 13,414 individuals (combined P = 2.07 × 10⁻9). This locus overlaps the transcription initiation site of RASGRF1, which is highly expressed in neurons and retina and has previously been implicated in retinal function and memory consolidation. Rasgrf1(-/-) mice show a heavier average crystalline lens (P = 0.001). The identification of a susceptibility locus for refractive error on 15q25 will be important in characterizing the molecular mechanism responsible for the most common cause of visual impairment.

Estimating heritability and shared environmental effects for refractive error in twin and family studies.

PURPOSE: Twin studies have demonstrated a high heritability for refractive error of up to 90%, but some family studies have suggested up to one-third of population variance is attributable to the effects of shared family environment. This large twin study aimed to explore the role of shared environment in refractive error. METHODS: Refractive error was measured using autorefraction in 4602 subjects (1152 monozygotic and 1149 dizygotic twin pairs), aged between 16 and 82 years, recruited from the TwinsUK Adult Twin Registry. Maximum-likelihood methods were used to estimate the variance of genetic, environmental, and age variance components. RESULTS: Maximum likelihood model fitting estimate of the heritability from the best-fit model was 77% (95% confidence interval [CI], 68%-84%). Shared environmental effects explained 7% (95% CI, 0%-15%) and individual environmental effects explained 16% (95% CI, 15%-18%) of the spherical equivalent variance, respectively. Inclusion of age effects into the modeling reduced shared environmental effects to an estimated 2% of variation. CONCLUSIONS: Analysis of 2301 twin pairs confirms that the twin study design results in a very low estimate of shared family environmental effects in refractive error. Several factors may explain these differences; we believe the most likely is that twins are perfectly age matched and do not include cross-generation or cohort effects. This means twin study designs have more power to detect heritable effects in variance component models of myopia, whereas family studies have more power to detect shared environment effects.

Repeated measures of intraocular pressure result in higher heritability and greater power in genetic linkage studies.

PURPOSE: To analyze the effect of using one reading, the mean of two readings (from the same eye), or the mean of four readings (two from each eye) on the heritability estimates of intraocular pressure (IOP). This was a cohort study in which 344 pairs of twins, 163 monozygotic (MZ) and 181 dizygotic (DZ), were enrolled. METHODS: IOP was measured using three tonometers: the gold standard Goldmann applanation tonometer (GAT), the Ocular Response Analyzer (ORA; Reichert Buffalo, NY), and the Dynamic Contour Tonometer (DCT, Pascal; Swiss Microtechnology AG, Port, Switzerland). The main outcome measure was the heritability of IOP correlated with the number of measurements. RESULTS: The mean IOPs of all four readings with the three tonometers were: 14.1 +/- 2.9 mm Hg for GAT, 15.9 +/- 3.2 mm Hg for ORA, and 16.9 +/- 2.7 mm Hg for DCT. As the number of readings increased, the calculated heritability (h(2)) of IOP measured using the GAT readings increased from 0.56 for one reading (95% confidence interval [CI], 0.44-0.65) to 0.58 for the mean of two readings (95% CI, 0.46-0.67) to 0.64 for the mean of all four readings (two right and two left; 95% CI, 0.55-0.72). Similar results were seen with the other two instruments. CONCLUSIONS: The results demonstrated that the use of the mean of several readings from both eyes reduced measurement error, yielding a higher heritability estimate. The higher heritability would increase the power to detect linkage in a genome-wide analysis.