Dataset Information

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

ABSTRACT: Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

SUBMITTER: Springelkamp H

PROVIDER: S-EPMC5968632 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Springelkamp Henriët H Iglesias Adriana I AI Mishra Aniket A Höhn René R Wojciechowski Robert R Khawaja Anthony P AP Nag Abhishek A Wang Ya Xing YX Wang Jie Jin JJ Cuellar-Partida Gabriel G Gibson Jane J Bailey Jessica N Cooke JN Vithana Eranga N EN Gharahkhani Puya P Boutin Thibaud T Ramdas Wishal D WD Zeller Tanja T Luben Robert N RN Yonova-Doing Ekaterina E Viswanathan Ananth C AC Yazar Seyhan S Cree Angela J AJ Haines Jonathan L JL Koh Jia Yu JY Souzeau Emmanuelle E Wilson James F JF Amin Najaf N Müller Christian C Venturini Cristina C Kearns Lisa S LS Kang Jae Hee JH Tham Yih Chung YC Zhou Tiger T van Leeuwen Elisabeth M EM Nickels Stefan S Sanfilippo Paul P Liao Jiemin J van der Linde Herma H Zhao Wanting W van Koolwijk Leonieke M E LM Zheng Li L Rivadeneira Fernando F Baskaran Mani M van der Lee Sven J SJ Perera Shamira S de Jong Paulus T V M PT Oostra Ben A BA Uitterlinden André G AG Fan Qiao Q Hofman Albert A Tai E-Shyong ES Vingerling Johannes R JR Sim Xueling X Wolfs Roger C W RC Teo Yik Ying YY Lemij Hans G HG Khor Chiea Chuen CC Willemsen Rob R Lackner Karl J KJ Aung Tin T Jansonius Nomdo M NM Montgomery Grant G Wild Philipp S PS Young Terri L TL Burdon Kathryn P KP Hysi Pirro G PG Pasquale Louis R LR Wong Tien Yin TY Klaver Caroline C W CC Hewitt Alex W AW Jonas Jost B JB Mitchell Paul P Lotery Andrew J AJ Foster Paul J PJ Vitart Veronique V Pfeiffer Norbert N Craig Jamie E JE Mackey David A DA Hammond Christopher J CJ Wiggs Janey L JL Cheng Ching-Yu CY van Duijn Cornelia M CM MacGregor Stuart S

Human molecular genetics 20170101 2

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, w ...[more]

PMID: 28073927

Similar Datasets

Project description:ObjectiveTo characterize the 24-h habitual-position intraocular pressure (IOP) patterns of optic disc phenotypes (ODPs) in untreated normal-tension glaucoma (NTG) and the relationships between nocturnal IOP elevation and various clinical factors.DesignProspective, cross-sectional, observational study.MethodsEighty-two NTG patients with focal ischemic (FI) ODP and 82 age- and disease severity-matched NTG patients with myopic glaucomatous (MG) ODP were recruited prospectively over 3 years. The IOP was recorded 11 times over a 24-hour (h) period by a single ophthalmologist using a hand-held tonometer (TonoPen®XL). A cosinor model was used to describe the 24-h IOP rhythm. Associations between nocturnal IOP elevation and both ocular and demographic variables were evaluated using the generalized estimating equation (GEE).ResultsMean habitual-position IOP was significantly higher during nighttime than daytime in the FI group (16.44 vs. 14.23 mmHg, P < 0.001), but not in the MG group (15.91 vs. 15.70 mmHg, P = 0.82). The FI group also exhibited a significantly higher peak IOP during sleeping hours (P = 0.01) and lower trough IOP during the 24-h period than the MG group (P < 0.01). The MG group showed a significantly higher peak IOP during waking hours than the FI group (P < 0.01). Therefore, 24-h IOP fluctuation range was significantly higher in the FI group than the MG group (P = 0.013). In the FI group, peak habitual-position IOP and the highest frequency of IOP peaks occurred during sleeping hours (12 AM-6 AM). By contrast, IOP peaks in the MG group occurred during morning hours (8 AM-12 PM). The FI group showed an overall nocturnal acrophase in habitual-position IOP, with 45 patients (54.9%) having a nocturnal acrophase; 10 (12.2%), a diurnal acrophase; and 27 (32.9%), no evident acrophase. By contrast, the MG group showed no evident peak in habitual-position IOP, with 9 patients (10.9%) having a nocturnal acrophase; 43 (52.4%), a diurnal acrophase; and 30 (36.6%), no evident acrophase. In multivariate modeling using the GEE, ODP (P < 0.001) and spherical equivalent (SE, P = 0.001) were independently associated with nocturnal IOP elevation.ConclusionsBased on 24-h habitual-position IOP data, FI is associated with significant nocturnal IOP elevation, while no such nocturnal IOP elevation is observed in MG ODP. In untreated NTG, there are also significant differences in the 24-h IOP pattern between FI and MG ODPs.

Project description:PurposePrimary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness in the United States and worldwide. Although deep learning methods have been proposed to diagnose POAG, these methods all used a single image as input. Contrastingly, glaucoma specialists typically compare the follow-up image with the baseline image to diagnose incident glaucoma. To simulate this process, we proposed a Siamese neural network, POAGNet, to detect POAG from optic disc photographs.DesignThe POAGNet, an algorithm for glaucoma diagnosis, is developed using optic disc photographs.ParticipantsThe POAGNet was trained and evaluated on 2 data sets: (1) 37 339 optic disc photographs from 1636 Ocular Hypertension Treatment Study (OHTS) participants and (2) 3684 optic disc photographs from the Sequential fundus Images for Glaucoma (SIG) data set. Gold standard labels were obtained using reading center grades.MethodsWe proposed a Siamese network model, POAGNet, to simulate the clinical process of identifying POAG from optic disc photographs. The POAGNet consists of 2 side outputs for deep supervision and uses convolution to measure the similarity between 2 networks.Main outcome measuresThe main outcome measures are the area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity.ResultsIn POAG diagnosis, extensive experiments show that POAGNet performed better than the best state-of-the-art model on the OHTS test set (area under the curve [AUC] 0.9587 versus 0.8750). It also outperformed the baseline models on the SIG test set (AUC 0.7518 versus 0.6434). To assess the transferability of POAGNet, we also validated the impact of cross-data set variability on our model. The model trained on OHTS achieved an AUC of 0.7490 on SIG, comparable to the previous model trained on the same data set. When using the combination of SIG and OHTS for training, our model achieved superior AUC to the single-data model (AUC 0.8165 versus 0.7518). These demonstrate the relative generalizability of POAGNet.ConclusionsBy simulating the clinical grading process, POAGNet demonstrated high accuracy in POAG diagnosis. These results highlight the potential of deep learning to assist and enhance clinical POAG diagnosis. The POAGNet is publicly available on https://github.com/bionlplab/poagnet.

Project description:PurposeTo investigate whether lamina cribrosa (LC) defects are associated with optic disc morphology in primary open angle glaucoma (POAG) eyes with high myopia.MethodsA total of 129 POAG patients and 55 age-matched control subjects with high myopia were evaluated. Three-dimensional scan images obtained by swept source optical coherence tomography were used to detect LC defects. Radial B-scans and infrared images obtained by spectral domain optical coherence tomography were used to measure ?-peripapillary atrophy (PPA) lengths with and without Bruch's membrane (BM) (temporal, nasal, superior, and inferior), tilt angle (vertical and horizontal), and disc diameter (transverse and longitudinal). Peripapillary intrachoroidal cavitations (PICCs), disc area, ovality index, and cyclotorsion of the optic disc were analyzed as well.ResultsLC defects were found in 70 of 129 (54.2%) POAG eyes and 1 of 55 (1.8%) control eyes (P < 0.001). Age, sex, spherical equivalent, axial length, intraocular pressure, and central corneal thickness were not significantly different among POAG eyes with LC defects, POAG eyes without LC defects, and control eyes. Temporal PPA lengths without BM in all three groups correlated significantly with vertical and horizontal tilt angles, although no PPA length with BM correlated significantly with any tilt angle. PICCs were detected more frequently in POAG eyes with LC defects than those without LC defects (P = 0.01) and control eyes (P = 0.02). POAG eyes with LC defects showed a smaller ovality index (P = 0.004), longer temporal PPA without BM (P < 0.001), and larger vertical/horizontal tilt angles (vertical, P < 0.001; horizontal, P = 0.01), and transverse diameter (P = 0.01). In multivariate analysis for the presence of LC defects, presence of POAG (P < 0.001) and vertical tilt angle (P < 0.001) were identified as significant.ConclusionsThe presence of LC defects was associated with myopic optic disc morphology in POAG eyes with high myopia.

Dataset Information

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Publications

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets