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1. SOME COMBUSTION NOISE PROBLEMS AND COUNTERMEASURES

Author: FOSTER, PJ, primary
Published: 2024
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2. The Association of Urinary Sodium Excretion with Glaucoma and Related Traits in a Large United Kingdom Population.

Author: Stuart, KV, Biradar, MI, Luben, RN, Dhaun, N, Wagner, SK, Warwick, AN, Sun, Z, Madjedi, KM, Pasquale, LR, Wiggs, JL, Kang, JH, Lentjes, MAH, Aschard, H, Kim, J, Foster, PJ, Khawaja, AP, Modifiable Risk Factors for Glaucoma Collaboration, UK Biobank Eye and Vision Consortium, International Glaucoma Genetics Consortium, Stuart, KV, Biradar, MI, Luben, RN, Dhaun, N, Wagner, SK, Warwick, AN, Sun, Z, Madjedi, KM, Pasquale, LR, Wiggs, JL, Kang, JH, Lentjes, MAH, Aschard, H, Kim, J, Foster, PJ, Khawaja, AP, Modifiable Risk Factors for Glaucoma Collaboration, UK Biobank Eye and Vision Consortium, and International Glaucoma Genetics Consortium
Abstract: PURPOSE: Excessive dietary sodium intake has known adverse effects on intravascular fluid volume and systemic blood pressure, which may influence intraocular pressure (IOP) and glaucoma risk. This study aimed to assess the association of urinary sodium excretion, a biomarker of dietary intake, with glaucoma and related traits, and determine whether this relationship is modified by genetic susceptibility to disease. DESIGN: Cross-sectional observational and gene-environment interaction analyses in the population-based UK Biobank study. PARTICIPANTS: Up to 103 634 individuals (mean age: 57 years; 51% women) with complete urinary, ocular, and covariable data. METHODS: Urine sodium:creatinine ratio (UNa:Cr; mmol:mmol) was calculated from a midstream urine sample. Ocular parameters were measured as part of a comprehensive eye examination, and glaucoma case ascertainment was through a combination of self-report and linked national hospital records. Genetic susceptibility to glaucoma was calculated based on a glaucoma polygenic risk score comprising 2673 common genetic variants. Multivariable linear and logistic regression, adjusted for key sociodemographic, medical, anthropometric, and lifestyle factors, were used to model associations and gene-environment interactions. MAIN OUTCOME MEASURES: Corneal-compensated IOP, OCT derived macular retinal nerve fiber layer and ganglion cell-inner plexiform layer (GCIPL) thickness, and prevalent glaucoma. RESULTS: In maximally adjusted regression models, a 1 standard deviation increase in UNa:Cr was associated with higher IOP (0.14 mmHg; 95% confidence interval [CI], 0.12-0.17; P < 0.001) and greater prevalence of glaucoma (odds ratio, 1.11; 95% CI, 1.07-1.14; P < 0.001) but not macular retinal nerve fiber layer or ganglion cell-inner plexiform layer thickness. Compared with those with UNa:Cr in the lowest quintile, those in the highest quintile had significantly higher IOP (0.45 mmHg; 95% CI, 0.36-0.53, P < 0.001) and prevalence of
Published: 2024

3. Experiences with developing and implementing a virtual clinic for glaucoma care in an NHS setting

Author: Kotecha A, Baldwin A, Brookes J, and Foster PJ
Subjects: Ophthalmology, RE1-994
Abstract: Aachal Kotecha,1,2 Alex Baldwin,1 John Brookes,1 Paul J Foster1,2 1Glaucoma Service, Moorfields Eye Hospital National Health Service Foundation Trust, 2NIHR BRC, Moorfields Eye Hospital, NHS Foundation Trust and UCL Institute of Ophthalmology, University College London, London, UK Background: This article describes the development of a virtual glaucoma clinic, whereby technicians collect information for remote review by a consultant specialist.Design and Methods: This was a hospital-based service evaluation study. Patients suitable for the stable monitoring service (SMS) were low-risk patients with “suspect”, “early”-to-“moderate” glaucoma who were deemed stable by their consultant care team. Three technicians and one health care assistant ran the service. Patients underwent tests in a streamlined manner in a dedicated clinical facility, with virtual review of data by a consultant specialist through an electronic patient record.Main outcome measure: Feasibility of developing a novel service within a UK National Health Service setting and improvement of patient journey time within the service were studied.Results: Challenges to implementation of virtual clinic include staffing issues and use of information technology. Patient journey time within the SMS averaged 51 minutes, compared with 92 minutes in the glaucoma outpatient department. Patient satisfaction with the new service was high.Conclusion: Implementing innovation into existing services of the National Health Service is challenging. However, the virtual clinic showed an improved patient journey time compared with that experienced within the general glaucoma outpatient department. There exists a discrepancy between patient management decisions of reviewers, suggesting that some may be more risk averse than others when managing patients seen within this model. Future work will assess the ability to detect progression of disease in this model compared with the general outpatient model of care. Keywords: glaucoma, virtual clinic, implementation, service delivery
Published: 2015

4. Retinal microvascular associations with cardiometabolic risk factors differ by diabetes status: results from the UK Biobank

Author: Tapp, RJ, Owen, CG, Barman, SA, Strachan, DP, Welikala, RA, Foster, PJ, Whincup, PH, Rudnicka, AR, and UK Biobank Eyes and Vision Consortium
Abstract: AIMS/HYPOTHESIS: The aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status. METHODS: The UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering). RESULTS: A total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction
Published: 2022

5. In vivo MR detection of fluorine-labeled human MSC using the bSSFP sequence

Author: Ribot EJ, Gaudet JM, Chen Y, Gilbert KM, and Foster PJ
Subjects: Medicine (General), R5-920
Abstract: Emeline J Ribot,1 Jeffrey M Gaudet,1,2 Yuhua Chen,1 Kyle M Gilbert,1 Paula J Foster1,2 1Imaging Research Laboratories, Robarts Research Institute, London, ON, Canada; 2Department of Medical Biophysics, University of Western Ontario, London, ON, Canada Abstract: Mesenchymal stem cells (MSC) are used to restore deteriorated cell environments. There is a need to specifically track these cells following transplantation in order to evaluate different methods of implantation, to follow their migration within the body, and to quantify their accumulation at the target. Cellular magnetic resonance imaging (MRI) using fluorine-based nanoemulsions is a great means to detect these transplanted cells in vivo because of the high specificity for fluorine detection and the capability for precise quantification. This technique, however, has low sensitivity, necessitating improvement in MR sequences. To counteract this issue, the balanced steady-state free precession (bSSFP) imaging sequence can be of great interest due to the high signal-to-noise ratio (SNR). Furthermore, it can be applied to obtain 3D images within short acquisition times. In this paper, bSSFP provided accurate quantification of samples of the perfluorocarbon Cell Sense-labeled cells in vitro. Cell Sense was internalized by human MSC (hMSC) without adverse alterations in cell viability or differentiation into adipocytes/osteocytes. The bSSFP sequence was applied in vivo to track and quantify the signals from both Cell Sense-labeled and iron-labeled hMSC after intramuscular implantation. The fluorine signal was observed to decrease faster and more significantly than the volume of iron-associated voids, which points to the advantage of quantifying the fluorine signal and the complexity of quantifying signal loss due to iron. Keywords: bSSFP, fluorine MRI, mesenchymal stem cell, mouse, cell tracking
Published: 2014

6. Association of ambient air pollution with age-related macular degeneration and retinal thickness in UK Biobank

Author: Chua, SYL, Warwick, A, Peto, T, Balaskas, K, Moore, AT, Reisman, C, Desai, P, Lotery, AJ, Dhillon, B, Khaw, PT, Owen, CG, Khawaja, AP, Foster, PJ, Patel, PJ, and UK Biobank Eye and Vision Consortium
Subjects: genetic structures, sense organs, eye diseases
Abstract: AIM: To examine the associations of air pollution with both self-reported age-related macular degeneration (AMD), and in vivo measures of retinal sublayer thicknesses. METHODS: We included 115 954 UK Biobank participants aged 40-69 years old in this cross-sectional study. Ambient air pollution measures included particulate matter, nitrogen dioxide (NO2) and nitrogen oxides (NOx). Participants with self-reported ocular conditions, high refractive error (< -6 or > +6 diopters) and poor spectral-domain optical coherence tomography (SD-OCT) image were excluded. Self-reported AMD was used to identify overt disease. SD-OCT imaging derived photoreceptor sublayer thickness and retinal pigment epithelium (RPE) layer thickness were used as structural biomarkers of AMD for 52 602 participants. We examined the associations of ambient air pollution with self-reported AMD and both photoreceptor sublayers and RPE layer thicknesses. RESULTS: After adjusting for covariates, people who were exposed to higher fine ambient particulate matter with an aerodynamic diameter
Published: 2022

7. High Blood Pressure and Intraocular Pressure: A Mendelian Randomization Study

Author: Plotnikov, D, Huang, Y, Khawaja, AP, Foster, PJ, Zhu, Z, Guggenheim, JA, He, M, Plotnikov, D, Huang, Y, Khawaja, AP, Foster, PJ, Zhu, Z, Guggenheim, JA, and He, M
Abstract: PURPOSE: To test for causality with regard to the association between blood pressure (BP) and intraocular pressure (IOP) and glaucoma. METHODS: Single nucleotide polymorphisms (SNPs) associated with BP were identified in a genome-wide association study (GWAS) meta-analysis of 526,001 participants of European ancestry. These SNPs were used to assess the BP versus IOP relationship in a distinct sample (n = 70,832) whose corneal-compensated IOP (IOPcc) was measured. To evaluate the BP versus primary open-angle glaucoma (POAG) relationship, additional Mendelian randomization (MR) analyses were conducted using published GWAS summary statistics. RESULTS: Observational analysis revealed a linear relationship between BP traits and IOPcc, with a +0.28 mm Hg increase in IOPcc per 10-mm Hg increase in systolic BP (95% confidence interval [CI], 0.26-0.29); for diastolic blood pressure (DBP) and pulse pressure (PP), these estimates were +0.41 mm Hg and +0.36 mm Hg, respectively. An inverse-variance weighted MR analysis did not support a causal relationship, as the estimated causal effect was +0.01 mm Hg IOPcc per 10-mm Hg increase in systolic blood pressure (SBP); +0.13 mm Hg IOPcc per 10-mm Hg increase in DBP; and +0.02 mm Hg IOPcc per 10-mm Hg increase in PP (all P > 0.05). With regard to the risk of POAG, MR analyse yielded causal effect estimate of odds ratio = 0.98 (95% CI, 0.92-1.04) per 10-mm Hg increase in SBP. Neither DBP nor PP demonstrated evidence of a causal effect on POAG. CONCLUSIONS: A range of different MR analysis methods provided evidence, in general, that the causal effect of BP on IOP (and POAG) was modest, or even zero. However, interpretation was complicated by SNPs associated with BP potentially having pleiotropic effects on IOP.
Published: 2022

8. The Association between Serum Lipids and Intraocular Pressure in 2 Large United Kingdom Cohorts.

Author: Madjedi, KM, Stuart, KV, Chua, SYL, Luben, RN, Warwick, A, Pasquale, LR, Kang, JH, Wiggs, JL, Lentjes, MAH, Aschard, H, Sattar, N, Foster, PJ, Khawaja, AP, Modifiable Risk Factors for Glaucoma Collaboration and the UK Biobank Eye and Vision Consortium, Madjedi, KM, Stuart, KV, Chua, SYL, Luben, RN, Warwick, A, Pasquale, LR, Kang, JH, Wiggs, JL, Lentjes, MAH, Aschard, H, Sattar, N, Foster, PJ, Khawaja, AP, and Modifiable Risk Factors for Glaucoma Collaboration and the UK Biobank Eye and Vision Consortium
Abstract: PURPOSE: Serum lipids are modifiable, routinely collected blood test features associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) with intraocular pressure (IOP). DESIGN: Cross-sectional study in the UK Biobank and European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohorts. PARTICIPANTS: We included 94 323 participants from the UK Biobank (mean age, 57 years) and 6230 participants from the EPIC-Norfolk (mean age, 68 years) cohorts with data on TC, HDL-C, LDL-C, and triglycerides collected between 2006 and 2009. METHODS: Multivariate linear regression adjusting for demographic, lifestyle, anthropometric, medical, and ophthalmic covariables was used to examine the associations of serum lipids with corneal-compensated IOP (IOPcc). MAIN OUTCOME MEASURES: Corneal-compensated IOP. RESULTS: Higher levels of TC, HDL-C, and LDL-C were associated independently with higher IOPcc in both cohorts after adjustment for key demographic, medical, and lifestyle factors. For each 1-standard deviation increase in TC, HDL-C, and LDL-C, IOPcc was higher by 0.09 mmHg (95% confidence interval [CI], 0.06-0.11 mmHg; P < 0.001), 0.11 mmHg (95% CI, 0.08-0.13 mmHg; P < 0.001), and 0.07 mmHg (95% CI, 0.05-0.09 mmHg; P < 0.001), respectively, in the UK Biobank cohort. In the EPIC-Norfolk cohort, each 1-standard deviation increase in TC, HDL-C, and LDL-C was associated with a higher IOPcc by 0.19 mmHg (95% CI, 0.07-0.31 mmHg; P = 0.001), 0.14 mmHg (95% CI, 0.03-0.25 mmHg; P = 0.016), and 0.17 mmHg (95% CI, 0.06-0.29 mmHg; P = 0.003). An inverse association between triglyceride levels and IOP in the UK Biobank (-0.05 mmHg; 95% CI, -0.08 to -0.03; P < 0.001) was not replicated in the EPIC-Norfolk cohort (P = 0.30). CONCLUSIONS: Our findings suggest that serum TC, HDL-C, and LDL-C are a
Published: 2022

9. Visual impairment and risk of dementia in two population-based prospective cohorts: UK Biobank and EPIC-Norfolk

Author: Littlejohns, T, Hayat, S, Luben, R, Brayne, C, Conroy, M, Foster, PJ, Khawaja, AP, and Kuźma, E
Abstract: Visual impairment has emerged as a potential modifiable risk factor for dementia. However, there are a lack of large studies with objective measures of vison and with more than ten years of follow-up. We investigated whether visual impairment is associated with an increased risk of incident dementia in UK Biobank and EPIC-Norfolk. In both cohorts, visual acuity was measured using a “logarithm of the minimum angle of resolution” (LogMAR) chart and categorised as no (≤0.30 LogMAR), mild (>0.3 - ≤0.50 LogMAR), and moderate to severe (>0.50 LogMAR) impairment. Dementia was ascertained through linkage to electronic medical records. After restricting to those aged ≥60 years, without prevalent dementia and with eye measures available, the analytic samples consisted of 62,206 UK Biobank and 7,337 EPIC-Norfolk participants, respectively. In UK Biobank and EPIC-Norfolk. respectively, 1,113 and 517 participants developed dementia over 11 and 15 years of follow-up. Using multivariable cox proportional-hazards models, the hazard ratios for mild and moderate to severe visual impairment were 1.26 (95% Confidence Interval [CI] 0.92-1.72) and 2.16 (95% CI 1.37-3.40), in UK Biobank, and 1.05 (95% CI 0.72-1.53) and 1.93 (95% CI 1.05-3.56) in EPIC-Norfolk, compared to no visual impairment. When excluding participants censored within 5 years of follow-up or with prevalent poor or fair self-reported health, the direction of the associations remained similar for moderate impairment but were not statistically significant. Our findings suggest visual impairment might be a promising target for dementia prevention, however the possibility of reverse causation cannot be excluded.
Published: 2021

10. Associations with Corneal Hysteresis in a Population Cohort: Results from 96 010 UK Biobank Participants

Author: Zhang, B, Shweikh, Y, Khawaja, AP, Gallacher, J, Bauermeister, S, Foster, PJ, and Consortium, Ukbiobank Eye And Vision
Subjects: Adult, Male, Corneal Pachymetry, genetic structures, Age Factors, Middle Aged, Health Surveys, Elasticity, United Kingdom, eye diseases, Biomechanical Phenomena, Cohort Studies, Cornea, Cross-Sectional Studies, Sex Factors, Ethnicity, Humans, Regression Analysis, Female, sense organs, Intraocular Pressure, Aged, Biological Specimen Banks
Abstract: Purpose To describe the distribution of corneal hysteresis (CH) in a large cohort and explore its associated factors and possible clinical applications. Design Cross-sectional study within the UK Biobank, a large cohort study in the United Kingdom. Participants We analyzed CH data from 93 345 eligible participants in the UK Biobank cohort, aged 40 to 69 years. Methods All analyses were performed using left eye data. Linear regression models were used to evaluate associations between CH and demographic, lifestyle, ocular, and systemic variables. Piecewise logistic regression models were used to explore the relationship between self-reported glaucoma and CH. Main Outcome Measures Corneal hysteresis (mmHg). Results The mean CH was 10.6 mmHg (10.4 mmHg in male and 10.8 mmHg in female participants). After adjusting for covariables, CH was significantly negatively associated with male sex, age, black ethnicity, self-reported glaucoma, diastolic blood pressure, and height. Corneal hysteresis was significantly positively associated with smoking, hyperopia, diabetes, systemic lupus erythematosus (SLE), greater deprivation (Townsend index), and Goldmann-correlated intraocular pressure (IOPg). Self-reported glaucoma and CH were significantly associated when CH was less than 10.1 mmHg (odds ratio, 0.86; 95% confidence interval, 0.79–0.94 per mmHg CH increase) after adjusting for covariables. When CH exceeded 10.1 mmHg, there was no significant association between CH and self-reported glaucoma. Conclusions In our analyses, CH was significantly associated with factors including age, sex, and ethnicity, which should be taken into account when interpreting CH values. In our cohort, lower CH was significantly associated with a higher prevalence of self-reported glaucoma when CH was less than 10.1 mmHg. Corneal hysteresis may serve as a biomarker aiding glaucoma case detection.
Published: 2019

11. Relationships between retinal layer thickness and brain volumes in the UK Biobank cohort

Author: Chua, SYL, Lascaratos, G, Atan, D, Zhang, B, Reisman, C, Khaw, PT, Smith, SM, Matthews, PM, Petzold, A, Strouthidis, NG, Foster, PJ, Khawaja, AP, Patel, PJ, UK Biobank Eye, Vision Consortium, Neurology, Ophthalmology, APH - Mental Health, APH - Methodology, and Amsterdam Neuroscience - Neuroinfection & -inflammation
Subjects: Adult, Male, Retinal Ganglion Cells, medicine.medical_specialty, retinal neurodegeneration, Grey matter, brain MRI markers, Retina, White matter, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Optical coherence tomography, Neuroimaging, Ophthalmology, medicine, Humans, 030212 general & internal medicine, Dementia and Cognitive Disorder, cognitive impairment, Aged, Biological Specimen Banks, optical coherence tomography, medicine.diagnostic_test, business.industry, Brain, Retinal, Magnetic resonance imaging, retinal layers, Middle Aged, United Kingdom, Cross-Sectional Studies, medicine.anatomical_structure, Neurology, chemistry, Biomarker (medicine), Original Article, Female, Neurology (clinical), sense organs, business, Tomography, Optical Coherence, 030217 neurology & neurosurgery, Neuroanatomy
Abstract: Background and purpose Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image‐derived phenotypes (IDPs) in a large cohort of healthy older people. Methods UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell‐inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors. Results A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p, Thinner inner retinal layers and total macular thickness were associated with smaller brain volumes in a cohort of healthy UK Biobank adults. Our findings suggest that retinal structure may be a biomarker for processes affecting brain structure.
Published: 2021

12. Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

Author: Hauser, MA, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, Khawaja, AP, Hauser, MA, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, and Khawaja, AP
Abstract: Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.
Published: 2021

13. Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images (vol 17, e1009497, 2021)

Author: Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, Khawaja, AP, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, and Khawaja, AP
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1009497.].
Published: 2021

14. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author: Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segre, A, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Bailey, JNC, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, S-S, Aung, T, Vithana, EN, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, C, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S, Wiggs, JL, Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segre, A, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Bailey, JNC, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, S-S, Aung, T, Vithana, EN, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, C, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S, and Wiggs, JL
Abstract: Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
Published: 2021

15. Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma

Author: Nair, S, Waseem, NH, Low, S, Shah, AZ, Avisetti, D, Ostergaard, P, Simpson, M, Niemiec, KA, Martin-Martin, B, Aldehlawi, H, Usman, S, Lee, PS, Khawaja, AP, Ruddle, JB, Shah, A, Sackey, E, Day, A, Jiang, Y, Swinfield, G, Viswanathan, A, Alfano, G, Chakarova, C, Cordell, HJ, Garway-Heath, DF, Khaw, PT, Bhattacharya, SS, Waseem, A, Foster, PJ, Nair, S, Waseem, NH, Low, S, Shah, AZ, Avisetti, D, Ostergaard, P, Simpson, M, Niemiec, KA, Martin-Martin, B, Aldehlawi, H, Usman, S, Lee, PS, Khawaja, AP, Ruddle, JB, Shah, A, Sackey, E, Day, A, Jiang, Y, Swinfield, G, Viswanathan, A, Alfano, G, Chakarova, C, Cordell, HJ, Garway-Heath, DF, Khaw, PT, Bhattacharya, SS, Waseem, A, and Foster, PJ
Abstract: Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c.1432_1440del; p.478_480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis.
Published: 2020

16. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author: Fan, Q, Pozarickij, A, Tan, NYQ, Guo, X, Verhoeven, VJM, Vitart, V, Guggenheim, JA, Miyake, M, Tideman, JWL, Khawaja, AP, Zhang, L, MacGregor, S, Hoehn, R, Chen, P, Biino, G, Wedenoja, J, Saffari, SE, Tedja, MS, Xie, J, Lanca, C, Wang, YX, Sahebjada, S, Mazur, J, Mirshahi, A, Martin, NG, Yazar, S, Pennell, CE, Yap, M, Haarman, AEG, Enthoven, CA, Polling, J, Hewitt, AW, Jaddoe, VWV, van Duijn, CM, Hayward, C, Polasek, O, Tai, E-S, Yoshikatsu, H, Hysi, PG, Young, TL, Tsujikawa, A, Wang, JJ, Mitchell, P, Pfeiffer, N, Parssinen, O, Foster, PJ, Fossarello, M, Yip, SP, Williams, C, Hammond, CJ, Jonas, JB, He, M, Mackey, DA, Wong, T-Y, Klaver, CCW, Saw, S-M, Baird, PN, Cheng, C-Y, Fan, Q, Pozarickij, A, Tan, NYQ, Guo, X, Verhoeven, VJM, Vitart, V, Guggenheim, JA, Miyake, M, Tideman, JWL, Khawaja, AP, Zhang, L, MacGregor, S, Hoehn, R, Chen, P, Biino, G, Wedenoja, J, Saffari, SE, Tedja, MS, Xie, J, Lanca, C, Wang, YX, Sahebjada, S, Mazur, J, Mirshahi, A, Martin, NG, Yazar, S, Pennell, CE, Yap, M, Haarman, AEG, Enthoven, CA, Polling, J, Hewitt, AW, Jaddoe, VWV, van Duijn, CM, Hayward, C, Polasek, O, Tai, E-S, Yoshikatsu, H, Hysi, PG, Young, TL, Tsujikawa, A, Wang, JJ, Mitchell, P, Pfeiffer, N, Parssinen, O, Foster, PJ, Fossarello, M, Yip, SP, Williams, C, Hammond, CJ, Jonas, JB, He, M, Mackey, DA, Wong, T-Y, Klaver, CCW, Saw, S-M, Baird, PN, and Cheng, C-Y
Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.
Published: 2020

17. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Author: Craig, JE, Han, X, Qassim, A, Hassall, M, Bailey, JNC, Kinzy, TG, Khawaja, AP, An, J, Marshall, H, Gharahkhani, P, Igo, RP, Graham, SL, Healey, PR, Ong, J-S, Zhou, T, Siggs, O, Law, MH, Souzeau, E, Ridge, B, Hysi, PG, Burdon, KP, Mills, RA, Landers, J, Ruddle, JB, Agar, A, Galanopoulos, A, White, AJR, Willoughby, CE, Andrew, NH, Best, S, Vincent, AL, Goldberg, I, Radford-Smith, G, Martin, NG, Montgomery, GW, Vitart, V, Hoehn, R, Wojciechowski, R, Jonas, JB, Aung, T, Pasquale, LR, Cree, AJ, Sivaprasad, S, Vallabh, NA, Viswanathan, AC, Pasutto, F, Haines, JL, Klaver, CCW, van Duijn, CM, Casson, RJ, Foster, PJ, Khaw, PT, Hammond, CJ, Mackey, DA, Mitchell, P, Lotery, AJ, Wiggs, JL, Hewitt, AW, MacGregor, S, Craig, JE, Han, X, Qassim, A, Hassall, M, Bailey, JNC, Kinzy, TG, Khawaja, AP, An, J, Marshall, H, Gharahkhani, P, Igo, RP, Graham, SL, Healey, PR, Ong, J-S, Zhou, T, Siggs, O, Law, MH, Souzeau, E, Ridge, B, Hysi, PG, Burdon, KP, Mills, RA, Landers, J, Ruddle, JB, Agar, A, Galanopoulos, A, White, AJR, Willoughby, CE, Andrew, NH, Best, S, Vincent, AL, Goldberg, I, Radford-Smith, G, Martin, NG, Montgomery, GW, Vitart, V, Hoehn, R, Wojciechowski, R, Jonas, JB, Aung, T, Pasquale, LR, Cree, AJ, Sivaprasad, S, Vallabh, NA, Viswanathan, AC, Pasutto, F, Haines, JL, Klaver, CCW, van Duijn, CM, Casson, RJ, Foster, PJ, Khaw, PT, Hammond, CJ, Mackey, DA, Mitchell, P, Lotery, AJ, Wiggs, JL, Hewitt, AW, and MacGregor, S
Abstract: Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10-6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
Published: 2020

18. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author: Hysi, PG, Choquet, H, Khawaja, AP, Wojciechowski, R, Tedja, MS, Yin, J, Simcoe, MJ, Patasova, K, Mahroo, OA, Thai, KK, Cumberland, PM, Melles, RB, Verhoeven, VJM, Vitart, V, Segre, A, Stone, RA, Wareham, N, Hewitt, AW, Mackey, DA, Klaver, CCW, MacGregor, S, Khaw, PT, Foster, PJ, Guggenheim, JA, Rahi, JS, Jorgenson, E, Hammond, CJ, Hysi, PG, Choquet, H, Khawaja, AP, Wojciechowski, R, Tedja, MS, Yin, J, Simcoe, MJ, Patasova, K, Mahroo, OA, Thai, KK, Cumberland, PM, Melles, RB, Verhoeven, VJM, Vitart, V, Segre, A, Stone, RA, Wareham, N, Hewitt, AW, Mackey, DA, Klaver, CCW, MacGregor, S, Khaw, PT, Foster, PJ, Guggenheim, JA, Rahi, JS, Jorgenson, E, and Hammond, CJ
Abstract: Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.
Published: 2020

19. Associations of Retinal Microvascular Diameters and Tortuosity With Blood Pressure and Arterial Stiffness: United Kingdom Biobank

Author: Tapp, RJ, Owen, CG, Barman, SA, Welikala, RA, Foster, PJ, Whincup, PH, Strachan, DP, Rudnicka, AR, and UK Biobank Eye and Vision Consortium
Abstract: To examine the baseline associations of retinal vessel morphometry with blood pressure (BP) and arterial stiffness in United Kingdom Biobank. The United Kingdom Biobank included 68 550 participants aged 40 to 69 years who underwent nonmydriatic retinal imaging, BP, and arterial stiffness index assessment. A fully automated image analysis program (QUARTZ [Quantitative Analysis of Retinal Vessel Topology and Size]) provided measures of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiovascular disease risk factors/outcomes were examined using multilevel linear regression to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing within person clustering), adjusted for age, sex, ethnicity, clinic, body mass index, smoking, and deprivation index. Greater arteriolar tortuosity was associated with higher systolic BP (relative increase, 1.2%; 95% CI, 0.9; 1.4% per 10 mmHg), higher mean arterial pressure, 1.3%; 0.9, 1.7% per 10 mmHg, and higher pulse pressure (PP, 1.8%; 1.4; 2.2% per 10 mmHg). Narrower arterioles were associated with higher systolic BP (-0.9 µm; -0.94, -0.87 µm per 10 mmHg), mean arterial pressure (-1.5 µm; -1.5, -1.5 µm per 10 mmHg), PP (-0.7 µm; -0.8, -0.7 µm per 10 mmHg), and arterial stiffness index (-0.12 µm; -0.14, -0.09 µm per ms/m2). Associations were in the same direction but marginally weaker for venular tortuosity and diameter. This study assessing the retinal microvasculature at scale has shown clear associations between retinal vessel morphometry, BP, and arterial stiffness index. These observations further our understanding of the preclinical disease processes and interplay between microvascular and macrovascular disease.
Published: 2019

20. Prevalence of glaucoma in Thailand: a population based survey in Rom Klao District, Bangkok

Author: Bourne, RRA, Sukudom, P, Foster, PJ, Tantisevi, V, Jitapunkul, S, Lee, PS, Johnson, GJ, and Rojanapongpun, P
Subjects: Glaucoma -- Research -- Statistics, Health, Statistics, Research
Abstract: Aim: To determine prevalence, demography, mechanism, and visual morbidity of glaucoma in urban Thai people. Methods: 790 subjects aged 50 years or older from Rom Klao district, Bangkok, Thailand, were [...]
Published: 2003

21. Risk factors for nuclear, cortical and posterior subcapsular cataracts in the Chinese population of Singapore: the Tanjong Pagar survey

Author: Foster, PJ, Wong, TY, Machin, D, Johnson, GJ, and Seah, SKL
Subjects: Cataract -- Prevention -- Research, Health, Prevention, Research
Abstract: Aim: To describe risk factors for nuclear, cortical, and posterior subcapsular (PSC) cataracts in Chinese Singaporeans. Methods: A population based cross sectional study was carried out on ethnic Chinese men [...]
Published: 2003

22. The Relationship Between Ambient Atmospheric Fine Particulate Matter (PM2.5) and Glaucoma in a Large Community Cohort

Author: Chua, SYL, Khawaja, AP, Morgan, J, Strouthidis, N, Reisman, C, Dick, AD, Khaw, PT, Patel, PJ, Foster, PJ, and for the UK Biobank Eye and Vision Consortium
Subjects: genetic structures, sense organs, eye diseases
Abstract: Purpose: Glaucoma is more common in urban populations than in others. Ninety percent of the world's population are exposed to air pollution above World Health Organization (WHO) recommended limits. Few studies have examined the association between air pollution and glaucoma. Methods: Questionnaire data, ophthalmic measures, and ambient residential area air quality data for 111,370 UK Biobank participants were analyzed. Particulate matter with an aerodynamic diameter < 2.5 μm (PM2.5) was selected as the air quality exposure of interest. Eye measures included self-reported glaucoma, intraocular pressure (IOP), and average thickness of macular ganglion cell-inner plexiform layer (GCIPL) across nine Early Treatment Diabetic Retinopathy Study (ETDRS) retinal subfields as obtained from spectral-domain optical coherence tomography. We examined the associations of PM2.5 concentration with self-reported glaucoma, IOP, and GCIPL. Results: Participants resident in areas with higher PM2.5 concentration were more likely to report a diagnosis of glaucoma (odds ratio = 1.06, 95% confidence interval [CI] = 1.01-1.12, per interquartile range [IQR] increase P = 0.02). Higher PM2.5 concentration was also associated with thinner GCIPL (β = -0.56 μm, 95% CI = -0.63 to -0.49, per IQR increase, P = 1.2 × 10-53). A dose-response relationship was observed between higher levels of PM2.5 and thinner GCIPL (P < 0.001). There was no clinically relevant relationship between PM2.5 concentration and IOP. Conclusions: Greater exposure to PM2.5 is associated with both self-reported glaucoma and adverse structural characteristics of the disease. The absence of an association between PM2.5 and IOP suggests the relationship may occur through a non-pressure-dependent mechanism, possibly neurotoxic and/or vascular effects.
Published: 2019

23. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Grp, BMES-G, Consortium, N, and Control, WTC
Subjects: Lumican, genetic structures, Fibrillin-1, General Physics and Astronomy, Gene Expression, Q1, Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, Myopia, Link (knot theory), lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Corneal Dystrophies, Hereditary, Multidisciplinary, Eye Diseases, Hereditary, symbols, NEIGHBORHOOD consortium, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Proteoglycans, Decorin, Glaucoma, Open-Angle, Science, Quantitative Trait Loci, Computational biology, Biology, Keratoconus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, White People, Article, symbols.namesake, Transforming Growth Factor beta2, Quantitative Trait, Heritable, Asian People, Genome-Wide Association Analysis, Humans, Author Correction, Eye Disease and Disorders of Vision, Loeys-Dietz Syndrome, Genome, Human, Wellcome Trust Case Control Consortium 2, Blue Mountains Eye Study - GWAS group, General Chemistry, Mendelian Randomization Analysis, R1, eye diseases, Mendelian inheritance, Ehlers-Danlos Syndrome, lcsh:Q, sense organs, Genome-Wide Association Study
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation., Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
Published: 2019

24. Associations with photoreceptor thickness measures in the UK Biobank

Author: Chua, SYL, Dhillon, B, Aslam, T, Balaskas, K, Yang, Q, Keane, PA, Tufail, A, Reisman, C, Foster, PJ, Patel, PJ, Bishop, P, Barman, SA, Barrett, JH, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Sudlow, C, Dick, AD, Egan, C, Ennis, S, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Guggenheim, JA, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Khaw, SPT, Khawaja, AP, Lascaratos, G, Lotery, AJ, Macgillivray, T, Mackie, S, Martin, K, Mcgaughey, M, Mcguinness, B, Mckay, GJ, Mckibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnicka, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Thaung, C, Thomas, D, Trucco, E, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, C, Williams, K, Woodside, J, Yates, MM, Yip, J, Zheng, Y, Tapp, R, Chua, SYL, Dhillon, B, Aslam, T, Balaskas, K, Yang, Q, Keane, PA, Tufail, A, Reisman, C, Foster, PJ, Patel, PJ, Bishop, P, Barman, SA, Barrett, JH, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Sudlow, C, Dick, AD, Egan, C, Ennis, S, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Guggenheim, JA, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Khaw, SPT, Khawaja, AP, Lascaratos, G, Lotery, AJ, Macgillivray, T, Mackie, S, Martin, K, Mcgaughey, M, Mcguinness, B, Mckay, GJ, Mckibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnicka, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Thaung, C, Thomas, D, Trucco, E, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, C, Williams, K, Woodside, J, Yates, MM, Yip, J, Zheng, Y, and Tapp, R
Abstract: Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness.
Published: 2019

25. IMI - Myopia Genetics Report

Author: Tedja, MS, Haarman, AEG, Meester-Smoor, MA, Kaprio, J, Mackey, DA, Guggenheim, JA, Hammond, CJ, Verhoeven, VJM, Klaver, CCW, Bailey-Wilson, JE, Baird, PN, Veluchamy, AB, Biino, G, Burdon, KP, Campbell, H, Chen, LJ, Cheng, C-Y, Chew, EY, Craig, JE, Cumberland, PM, Deangelis, MM, Delcourt, C, Ding, X, van Duijn, CM, Evans, DM, Fan, Q, Fossarello, M, Foster, PJ, Gharahkhani, P, Iglesias, AI, Guol, X, Haller, T, Han, X, Hayward, C, He, M, Hewitt, AW, Hoang, Q, Hysi, PG, Igo, RP, Iyengar, SK, Jonas, JB, Kahonen, M, Khawaja, AP, Klein, BE, Klein, R, Lass, JH, Lee, K, Lehtimaki, T, Lewis, D, Li, Q, Li, S-M, Lyytikainen, L-P, MacGregor, S, Martin, NG, Meguro, A, Metspalu, A, Middlebrooks, C, Miyake, M, Mizuki, N, Musolf, A, Nickels, S, Oexle, K, Pang, CP, Parssinen, O, Paterson, AD, Pfeiffer, N, Polasek, O, Rahi, JS, Raitakari, O, Rudan, I, Sahebjada, S, Saw, S-M, Stambolian, D, Simpson, CL, Tai, E-S, Tideman, JWL, Tsujikawa, A, Vitart, V, Wang, N, Wedenoja, J, Wei, WB, Williams, C, Williams, KM, Wilson, JF, Wojciechowski, R, Wang, YX, Yamashiro, K, Yam, JCS, Yap, MKH, Yazar, S, Yip, SP, Young, TL, Zhou, X, Tedja, MS, Haarman, AEG, Meester-Smoor, MA, Kaprio, J, Mackey, DA, Guggenheim, JA, Hammond, CJ, Verhoeven, VJM, Klaver, CCW, Bailey-Wilson, JE, Baird, PN, Veluchamy, AB, Biino, G, Burdon, KP, Campbell, H, Chen, LJ, Cheng, C-Y, Chew, EY, Craig, JE, Cumberland, PM, Deangelis, MM, Delcourt, C, Ding, X, van Duijn, CM, Evans, DM, Fan, Q, Fossarello, M, Foster, PJ, Gharahkhani, P, Iglesias, AI, Guol, X, Haller, T, Han, X, Hayward, C, He, M, Hewitt, AW, Hoang, Q, Hysi, PG, Igo, RP, Iyengar, SK, Jonas, JB, Kahonen, M, Khawaja, AP, Klein, BE, Klein, R, Lass, JH, Lee, K, Lehtimaki, T, Lewis, D, Li, Q, Li, S-M, Lyytikainen, L-P, MacGregor, S, Martin, NG, Meguro, A, Metspalu, A, Middlebrooks, C, Miyake, M, Mizuki, N, Musolf, A, Nickels, S, Oexle, K, Pang, CP, Parssinen, O, Paterson, AD, Pfeiffer, N, Polasek, O, Rahi, JS, Raitakari, O, Rudan, I, Sahebjada, S, Saw, S-M, Stambolian, D, Simpson, CL, Tai, E-S, Tideman, JWL, Tsujikawa, A, Vitart, V, Wang, N, Wedenoja, J, Wei, WB, Williams, C, Williams, KM, Wilson, JF, Wojciechowski, R, Wang, YX, Yamashiro, K, Yam, JCS, Yap, MKH, Yazar, S, Yip, SP, Young, TL, and Zhou, X
Abstract: The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.
Published: 2019

26. Cohort profile: design and methods in the eye and vision consortium of UK Biobank

Author: Chua, SYL, Thomas, D, Allen, N, Lotery, A, Desai, P, Patel, P, Muthy, Z, Sudlow, C, Peto, T, Khaw, PT, Foster, PJ, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Crabb, DP, Cumberland, PM, Day, A, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Guggenheim, JA, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Keane, PA, Khawaja, AP, Lascaratos, G, Lotery, AJ, Gillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, McKay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Paterson, E, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Trucco, E, Tufail, A, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Chua, SYL, Thomas, D, Allen, N, Lotery, A, Desai, P, Patel, P, Muthy, Z, Sudlow, C, Peto, T, Khaw, PT, Foster, PJ, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Crabb, DP, Cumberland, PM, Day, A, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway-Heath, DF, Gibson, J, Gore, D, Guggenheim, JA, Hammond, CJ, Hardcastle, A, Harding, SP, Hogg, RE, Hysi, P, Keane, PA, Khawaja, AP, Lascaratos, G, Lotery, AJ, Gillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, McKay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Paterson, E, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Trucco, E, Tufail, A, Vitart, V, Vernon, SA, Viswanathan, AC, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, and Zheng, Y
Abstract: PURPOSE: To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank. PARTICIPANTS: UK Biobank is a large, multisite, prospective cohort study. Extensive lifestyle and health questionnaires, a range of physical measures and collection of biological specimens are collected. The scope of UK Biobank was extended midway through data collection to include assessments of other measures of health, including eyes and vision. The eye assessment at baseline included questionnaires detailing past ophthalmic and family history, measurement of visual acuity, refractive error and keratometry, intraocular pressure (IOP), corneal biomechanics, spectral domain optical coherence tomography (OCT) of the macula and a disc-macula fundus photograph. Since recruitment, UK Biobank has collected accelerometer data and begun multimodal imaging data (including brain, heart and abdominal MRI) in 100 000 participants. Dense genotypic data and a panel of 20 biochemistry measures are available, and linkage to medical health records for the full cohort has begun. FINDINGS TO DATE: A total of 502 665 people aged between 40 and 69 were recruited to participate in UK Biobank. Of these, 117 175 took part in baseline assessment of vision, IOP, refraction and keratometry. A subgroup of 67 321 underwent OCT and retinal photography. The introduction of eye and vision measures in UK Biobank was accompanied by intensive training, support and a data monitoring quality control process. FUTURE PLANS: UK Biobank is one of the largest prospective cohorts worldwide with extensive data on ophthalmic diseases and conditions. Data collection is an ongoing process and a repeat of the baseline assessment including the questionnaires, measurements and sample collection will be performed in subsets of 25 000 participants every 2-3 years. The depth and breadth of this dataset, coupled with its open-access policy, will create a powerful resource for all researchers to inves
Published: 2019

27. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, and Whittaker, P
Abstract: Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019

28. The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data

Author: Delcourt, C, Le Goff, M, von Hanno, T, Mirshahi, A, Khawaja, AP, Verhoeven, Virginie, Hogg, RE, Anastosopoulos, E, Cachulo, ML, Hohn, R, Wolfram, H, Bron, A, Miotto, S, Carriere, I, Colijn, Annemarie, Buitendijk, Gabriëlle, Evans, J, Nitsch, D, Founti, P, Yip, JLY, Pfeiffer, N, Creuzot-Garcher, C, de Silva, R, Piermarocchi, S, Topouzis, F, Bertelsen, G, Foster, PJ, Fletcher, A, Klaver, Caroline, Korobelnik, JF, Epidemiology, and Ophthalmology
Subjects: VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Oftalmologi: 754, Prevalence, Visual Acuity, Humans, Visually Impaired Persons/statistics & numerical data, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Ophthalmology: 754, Vision, Low/epidemiology, 610 Medicine & health, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Aged, Europe/epidemiology
Abstract: Accepted manuscript version, licensed CC BY-NC-ND 4.0. Published version available at https://doi.org/10.1016/j.ophtha.2018.02.005. Topic: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older. Clinical Relevance: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates. Methods: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991–2006 and 2007–2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010. Results: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34–3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42–1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 million affected individuals in 2000 to 1.2 million in 2010. Of those, 584 000 were blind in 2000, in comparison with 170 000 who were blind in 2010. Conclusions: Despite the increase in the European older population, our study indicated that the number of visually impaired people has decreased in European high-income countries in the last 20 years. This may be the result of major improvements in eye care and prevention, the decreasing prevalence of eye diseases, or both.
Published: 2018

29. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author: Tedja, MS, Wojciechowski, R, Hysi, PG, Eriksson, N, Furlotte, NA, Verhoeven, VJM, Iglesias, AI, Meester-Smoor, MA, Tompson, SW, Fan, Q, Khawaja, AP, Cheng, C-Y, Höhn, R, Yamashiro, K, Wenocur, A, Grazal, C, Haller, T, Metspalu, A, Wedenoja, J, Jonas, JB, Wang, YX, Xie, J, Mitchell, P, Foster, PJ, Klein, BEK, Klein, R, Paterson, AD, Hosseini, SM, Shah, RL, Williams, C, Teo, YY, Tham, YC, Gupta, P, Zhao, W, Shi, Y, Saw, W-Y, Tai, E-S, Sim, XL, Huffman, JE, Polašek, O, Hayward, C, Bencic, G, Rudan, I, Wilson, JF, Consortium, Cream, Team, 23Andme Research, Consortium, Uk Biobank Eye And Vision, Joshi, PK, Tsujikawa, A, Matsuda, F, Whisenhunt, KN, Zeller, T, Van Der Spek, PJ, Haak, R, Meijers-Heijboer, H, Van Leeuwen, EM, Iyengar, SK, Lass, JH, Hofman, A, Rivadeneira, F, Uitterlinden, AG, Vingerling, JR, Lehtimäki, T, Raitakari, OT, Biino, G, Concas, MP, Schwantes-An, T-H, Igo, RP, Cuellar-Partida, G, Martin, NG, Craig, JE, Gharahkhani, P, Williams, KM, Nag, A, Rahi, JS, Cumberland, PM, Delcourt, C, Bellenguez, C, Ried, JS, Bergen, AA, Meitinger, T, Gieger, C, Wong, TY, Hewitt, AW, Mackey, DA, Simpson, CL, Pfeiffer, N, Pärssinen, O, Baird, PN, Vitart, V, Amin, N, Van Duijn, CM, Bailey-Wilson, JE, Young, TL, Saw, S-M, Stambolian, D, Macgregor, S, Guggenheim, JA, Tung, JY, Hammond, CJ, Klaver, CCW, Netherlands Institute for Neuroscience (NIN), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Pediatric surgery, Tedja, Milly S [0000-0003-0356-9684], Hysi, Pirro G [0000-0001-5752-2510], Verhoeven, Virginie JM [0000-0001-7359-7862], Iglesias, Adriana I [0000-0001-5532-764X], Tompson, Stuart W [0000-0001-9788-6730], Khawaja, Anthony P [0000-0001-6802-8585], Yamashiro, Kenji [0000-0001-9354-8558], Wedenoja, Juho [0000-0002-6155-0378], Jonas, Jost B [0000-0003-2972-5227], Wang, Ya Xing [0000-0003-2749-7793], Foster, Paul J [0000-0002-4755-177X], Klein, Ronald [0000-0002-4428-6237], Shah, Rupal L [0000-0001-8789-8869], Hayward, Caroline [0000-0002-9405-9550], Rudan, Igor [0000-0001-6993-6884], Wilson, James F [0000-0001-5751-9178], Joshi, Peter K [0000-0002-6361-5059], Whisenhunt, Kristina N [0000-0003-2412-7666], Rivadeneira, Fernando [0000-0001-9435-9441], Biino, Ginevra [0000-0002-9936-946X], Gharahkhani, Puya [0000-0002-4203-5952], Williams, Katie M [0000-0003-4596-3938], Delcourt, Cécile [0000-0002-2099-0481], Bellenguez, Céline [0000-0002-1240-7874], Hewitt, Alex W [0000-0002-5123-5999], Baird, Paul N [0000-0002-1305-3502], Bailey-Wilson, Joan E [0000-0002-9153-2920], Young, Terri L [0000-0001-6994-9941], Guggenheim, Jeremy A [0000-0001-5164-340X], Hammond, Christopher J [0000-0002-3227-2620], Klaver, Caroline CW [0000-0002-2355-5258], Apollo - University of Cambridge Repository, Epidemiology, Ophthalmology, Clinical Genetics, Pathology, Internal Medicine, Graduate School, Human Genetics, Experimental Immunology, ANS - Complex Trait Genetics, and ARD - Amsterdam Reproduction and Development
Subjects: 0301 basic medicine, Adult, Male, Cell type, ResearchInstitutes_Networks_Beacons/MICRA, In silico, taittovirheet, Genome-wide association study, Retinal Pigment Epithelium, Biology, Blindness, Polymorphism, Single Nucleotide, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, Retina, White People, 03 medical and health sciences, HIGH-GRADE MYOPIA, RETINAL-PIGMENT EPITHELIUM, SEROTONIN PATHWAY GENES, FORM-DEPRIVATION MYOPIA, COMMON VARIANTS, OCULAR GROWTH, RETINITIS-PIGMENTOSA, GENOTYPE IMPUTATION, MISSENSE MUTATIONS, DOPAMINE-RECEPTORS, Asian People, refractive errors, Retinitis pigmentosa, Genetics, medicine, Myopia, Journal Article, Humans, Genetic Predisposition to Disease, 610 Medicine & health, Regulation of gene expression, Retinal pigment epithelium, medicine.disease, Refractive Errors, 030104 developmental biology, medicine.anatomical_structure, Manchester Institute for Collaborative Research on Ageing, Gene Expression Regulation, genetic factors, Eye disorder, Female, sense organs, geneettiset tekijät, Neuroscience, Genome-Wide Association Study, Signal Transduction
Abstract: Skin affections after sulfur mustard (SM) exposure include erythema, blister formation and severe inflammation. An antidote or specific therapy does not exist. Anti-inflammatory compounds as well as substances counteracting SM-induced cell death are under investigation. In this study, we investigated the benzylisoquinoline alkaloide berberine (BER), a metabolite in plants like berberis vulgaris, which is used as herbal pharmaceutical in Asian countries, against SM toxicity using a well-established in vitro approach. Keratinocyte (HaCaT) mono-cultures (MoC) or HaCaT/THP-1 co-cultures (CoC) were challenged with 100, 200 or 300 mM SM for 1 h. Post-exposure, both MoC and CoC were treated with 10, 30 or 50 mu M BER for 24 h. At that time, supernatants were collected and analyzed both for interleukine (IL) 6 and 8 levels and for content of adenylate-kinase (AK) as surrogate marker for cell necrosis. Cells were lysed and nucleosome formation as marker for late apoptosis was assessed. In parallel, AK in cells was determined for normalization purposes. BER treatment did not influence necrosis, but significantly decreased apoptosis. Anti-inflammatory effects were moderate, but also significant, primarily in CoC. Overall, BER has protective effects against SM toxicity in vitro. Whether this holds true should be evaluated in future in vivo studies.
Published: 2018

30. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, and MacGregor, S
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018

31. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, Macgregor, S, Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, and Macgregor, S
Published: 2018

32. Prevalence of Age-Related Macular Degeneration in Europe

Author: Colijn, Annemarie, Buitendijk, Gabriëlle, Prokofyeva, E, Alves, D, Cachulo, ML, Khawaja, AP, Cougnard-Gregoire, A, Merle, BMJ, Korb, C, Erke, MG, Bron, A, Anastasopoulos, E, Meester - Smoor, Magda, Segato, T, Piermarocchi, S, de Jong, P, Vingerling, Hans, Topouzis, F, Creuzot-Garcher, C, Bertelsen, G, Pfeiffer, N, Fletcher, AE, Foster, PJ, de Silva, R, Korobelnik, JF, Delcourt, C, Klaver, Caroline, Colijn, Annemarie, Buitendijk, Gabriëlle, Prokofyeva, E, Alves, D, Cachulo, ML, Khawaja, AP, Cougnard-Gregoire, A, Merle, BMJ, Korb, C, Erke, MG, Bron, A, Anastasopoulos, E, Meester - Smoor, Magda, Segato, T, Piermarocchi, S, de Jong, P, Vingerling, Hans, Topouzis, F, Creuzot-Garcher, C, Bertelsen, G, Pfeiffer, N, Fletcher, AE, Foster, PJ, de Silva, R, Korobelnik, JF, Delcourt, C, and Klaver, Caroline
Published: 2017

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

Author: Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, Macgregor, S, Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, and Macgregor, S
Published: 2017

34. Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Author: Iglesias Gonzalez, Adriana, van der Lee, Sven, Bonnemaijer, Pieter, Hohn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, Linda, Foster, PJ, Hammond, CJ, Hysi, PG, Leeuwen, Elisa, Macgregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, André, Klaver, Caroline, Amin, Najaf, Duijn, Cornelia, Iggc, Iglesias Gonzalez, Adriana, van der Lee, Sven, Bonnemaijer, Pieter, Hohn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, Linda, Foster, PJ, Hammond, CJ, Hysi, PG, Leeuwen, Elisa, Macgregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, André, Klaver, Caroline, Amin, Najaf, Duijn, Cornelia, and Iggc
Published: 2017

35. Genome wide linkage scan of primary angle-closure glaucoma and its endophenotypes

Author: Low, S, Ostergaard, P, Waseem, N, Ruddle, J, He, M, Cordell, H, Bhattacharya, S, Garway-Heath, DF, Khaw, PT, and Foster, PJ
Published: 2016

36. Automated retinal image quality assessment on the UK Biobank dataset for epidemiological studies

Author: Welikala, RA, Fraz, MM, Foster, PJ, Whincup, PH, Rudnicka, AR, Owen, CG, Strachan, DP, Barman, SA, and UK Biobank Eye and Vision Consortium, UKBEVC
Abstract: Morphological changes in the retinal vascular network are associated with future risk of many systemic and vascular diseases. However, uncertainty over the presence and nature of some of these associations exists. Analysis of data from large population based studies will help to resolve these uncertainties. The QUARTZ (QUantitative Analysis of Retinal vessel Topology and siZe) retinal image analysis system allows automated processing of large numbers of retinal images. However, an image quality assessment module is needed to achieve full automation. In this paper, we propose such an algorithm, which uses the segmented vessel map to determine the suitability of retinal images for use in the creation of vessel morphometric data suitable for epidemiological studies. This includes an effective 3-dimensional feature set and support vector machine classification. A random subset of 800 retinal images from UK Biobank (a large prospective study of 500,000 middle aged adults; where 68,151 underwent retinal imaging) was used to examine the performance of the image quality algorithm. The algorithm achieved a sensitivity of 95.33% and a specificity of 91.13% for the detection of inadequate images. The strong performance of this image quality algorithm will make rapid automated analysis of vascular morphometry feasible on the entire UK Biobank dataset (and other large retinal datasets), with minimal operator involvement, and at low cost.
Published: 2016

37. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Author: Bailey, JNC, Loomis, SJ, Kang, JH, Allingham, RR, Gharahkhani, P, Khor, CC, Burdon, KP, Aschard, H, Chasman, DI, Igo, RP, Hysi, PG, Glastonbury, CA, Ashley-Koch, A, Brilliant, M, Brown, AA, Budenz, DL, Buil, A, Cheng, CY, Choi, H, Christen, WG, Curhan, G, De Vivo, I, Fingert, JH, Foster, PJ, Fuchs, C, Gaasterland, D, Gaasterland, T, Hewitt, AW, Hu, F, Hunter, DJ, Khawaja, AP, Lee, RK, Li, Z, Lichter, PR, Mackey, DA, McGuffin, P, Mitchell, P, Moroi, SE, Perera, SA, Pepper, KW, Qi, Q, Realini, T, Richards, JE, Ridker, PM, Rimm, E, Ritch, R, Ritchie, M, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Song, YE, Tamimi, RM, Topouzis, F, Viswanathan, AC, Verma, SS, Vollrath, D, Wang, JJ, Weisschuh, N, Wissinger, B, Wollstein, G, Wong, TY, Yaspan, BL, Zack, DJ, Zhang, K, Weinreb, RN, Pericak-Vance, MA, Small, K, Hammond, CJ, Aung, T, Liu, Y, Vithana, EN, MacGregor, S, Craig, JE, Kraft, P, Howell, G, Hauser, MA, and Pasquale, LR
Subjects: ANZRAG Consortium
Abstract: © 2016 Nature America, Inc. Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.
Published: 2016

38. Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis

Author: Kapetanakis, VV, Chan, MP, Foster, PJ, Cook, DG, Owen, CG, and Rudnicka, AR
Subjects: genetic structures, eye diseases
Abstract: Systematic review of published population based surveys to examine the relationship between primary open angle glaucoma (POAG) prevalence and demographic factors. A literature search identified population-based studies with quantitative estimates of POAG prevalence (to October 2014). Multilevel binomial logistic regression of log-odds of POAG was used to examine the effect of age and gender among populations of different geographical and ethnic origins, adjusting for study design factors. Eighty-one studies were included (37 countries, 216 214 participants, 5266 POAG cases). Black populations showed highest POAG prevalence, with 5.2% (95% credible interval (CrI) 3.7%, 7.2%) at 60 years, rising to 12.2% (95% CrI 8.9% to 16.6%) at 80 years. Increase in POAG prevalence per decade of age was greatest among Hispanics (2.31, 95% CrI 2.12, 2.52) and White populations (1.99, 95% CrI 1.86, 2.12), and lowest in East and South Asians (1.48, 95% CrI 1.39, 1.57; 1.56, 95% CrI 1.31, 1.88, respectively). Men were more likely to have POAG than women (1.30, 95% CrI 1.22, 1.41). Older studies had lower POAG prevalence, which was related to the inclusion of intraocular pressure in the glaucoma definition. Studies with visual field data on all participants had a higher POAG prevalence than those with visual field data on a subset. Globally 57.5 million people (95% CI 46.4 to 73.1 million) were affected by POAG in 2015, rising to 65.5 million (95% CrI 52.8, 83.2 million) by 2020. This systematic review provides the most precise estimates of POAG prevalence and shows omitting routine visual field assessment in population surveys may have affected case ascertainment. Our findings will be useful to future studies and healthcare planning.
Published: 2016

39. THU0413 Serum urate and its association with blood pressure and endothelial dysfunction in young adults

Author: Saddekni, MB, primary, Saag, KG, additional, Dudenbostel, T, additional, Calhoun, DA, additional, Oparil, S, additional, Feig, DI, additional, Muntner, P, additional, Foster, PJ, additional, Biggers, SR, additional, Rahn, EJ, additional, Li, P, additional, Redden, DT, additional, and Gaffo, AL, additional
Published: 2017
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40. AB0865 Serum urate and its association with race in young adults: baseline analysis from a randomized clinical trial

Author: Saddekni, MB, primary, Gaffo, AL, additional, Foster, PJ, additional, Biggers, SR, additional, Rahn, EJ, additional, Li, P, additional, and Saag, KG, additional
Published: 2017
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41. Measures of socioeconomic status and self-reported glaucoma in the U.K. Biobank cohort

Author: Shweikh, Y, Ko, F, Chan, MPY, Patel, PJ, Muthy, Z, Khaw, PT, Yip, J, Strouthidis, N, Foster, PJ, and UK Biobank Eye and Vision Consortium
Subjects: genetic structures, sense organs, eye diseases
Abstract: Purpose: To determine ocular, demographic, and socioeconomic associations with self-reported glaucoma in the UK Biobank.Methods: Biobank is a study of UK residents aged 40–69 years registered with the National Health Service. Data were collected on visual acuity, intraocular pressure (IOP), corneal biomechanics, and questionnaire from 112?690 participants. Relationships between ocular, demographic, and socioeconomic variables with reported diagnosis of glaucoma were examined.Results: In all, 1916 (1.7%) people in UK Biobank reported glaucoma diagnosis. Participants reporting glaucoma were more likely to be older (mean 61.4 vs 56.7 years, PConclusions: In a large UK cohort, individuals reporting glaucoma had more adverse socioeconomic characteristics. Study of the mechanisms explaining these effects may aid our understanding of health inequality and will help inform public health interventions.
Published: 2015

42. Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium.

Author: Khawaja, AP, Springelkamp, H, Creuzot-Garcher, C, Delcourt, C, Hofman, A, Höhn, R, Iglesias, AI, Wolfs, RCW, Korobelnik, J-F, Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, GHS, Cachulo, MDL, Cougnard-Grégoire, A, Dartigues, J-F, Hammond, CJ, Pfeiffer, N, Salonikiou, A, van Duijn, CM, Vingerling, JR, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, CCW, Jansonius, NM, Foster, PJ, European Eye Epidemiology (E³) Consortium, Khawaja, AP, Springelkamp, H, Creuzot-Garcher, C, Delcourt, C, Hofman, A, Höhn, R, Iglesias, AI, Wolfs, RCW, Korobelnik, J-F, Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, GHS, Cachulo, MDL, Cougnard-Grégoire, A, Dartigues, J-F, Hammond, CJ, Pfeiffer, N, Salonikiou, A, van Duijn, CM, Vingerling, JR, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, CCW, Jansonius, NM, Foster, PJ, and European Eye Epidemiology (E³) Consortium
Abstract: Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m2; 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.
Published: 2016

43. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error

Author: Fan, Q, Verhoeven, VJM, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hoehn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y, Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, X, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, T-H, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, van Leeuwen, EM, Amin, N, Uitterlinden, AG, Rivadeneira, F, Hofman, A, Vingerling, JR, Wang, YX, Wang, X, Boh, ET-H, Ikram, MK, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, E-S, Vithana, E, Mihailov, E, Khor, C-C, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, H-S, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, M, Paerssinen, O, van Duijn, CM, Wang, JJ, Williams, C, Jonas, JB, Teo, Y-Y, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, T-Y, Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, C-Y, Hammond, CJ, Klaver, CCW, Saw, S-M, Rahi, JS, Korobelnik, J-F, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, MacGregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, K-T, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, M-F, Li, X, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, JWL, Tedja, M, Deangelis, MM, Morrison, M, Farrer, L, Zhou, X, Chen, W, Mizuki, N, Meguro, A, Makela, KM, Fan, Q, Verhoeven, VJM, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hoehn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y, Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, X, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, T-H, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, van Leeuwen, EM, Amin, N, Uitterlinden, AG, Rivadeneira, F, Hofman, A, Vingerling, JR, Wang, YX, Wang, X, Boh, ET-H, Ikram, MK, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, E-S, Vithana, E, Mihailov, E, Khor, C-C, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, H-S, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, M, Paerssinen, O, van Duijn, CM, Wang, JJ, Williams, C, Jonas, JB, Teo, Y-Y, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, T-Y, Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, C-Y, Hammond, CJ, Klaver, CCW, Saw, S-M, Rahi, JS, Korobelnik, J-F, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, MacGregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, K-T, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, M-F, Li, X, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, JWL, Tedja, M, Deangelis, MM, Morrison, M, Farrer, L, Zhou, X, Chen, W, Mizuki, N, Meguro, A, and Makela, KM
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Published: 2016

44. Associations with intraocular pressure across Europe: The European Eye Epidemiology (E-3) Consortium

Author: Khawaja, AP, Springelkamp, Henriët, Creuzot-Garcher, C, Delcourt, C, Hofman, Bert, Hohn, R, Iglesias Gonzalez, Adriana, Wolfs, R.C.W., Korobelnik, JF, de Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, Gabriëlle, Cachulo, MD, Cougnard-Gregoire, A, Dartigues, JF, Hammond, CJ, Pfeiffer, N, Salonikiou, A, Duijn, Cornelia, Vingerling, Hans, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, Caroline, Jansonius, NM (Nomdo), Foster, PJ, Khawaja, AP, Springelkamp, Henriët, Creuzot-Garcher, C, Delcourt, C, Hofman, Bert, Hohn, R, Iglesias Gonzalez, Adriana, Wolfs, R.C.W., Korobelnik, JF, de Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, Gabriëlle, Cachulo, MD, Cougnard-Gregoire, A, Dartigues, JF, Hammond, CJ, Pfeiffer, N, Salonikiou, A, Duijn, Cornelia, Vingerling, Hans, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, Caroline, Jansonius, NM (Nomdo), and Foster, PJ
Abstract: Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E-3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m(2); 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.
Published: 2016

45. Increasing Prevalence of Myopia in Europe and the Impact of Education

Author: Williams, KM, Bertelsen, G, Cumberland, P, Wolfram, C, Verhoeven, Virginie, Anastasopoulos, E, Buitendijk, Gabriëlle, Cougnard-Gregoire, A, Creuzot-Garcher, C, Erke, MG, Hogg, R, Hohn, R, Hysi, P, Khawaja, AP, Korobelnik, JF, Ried, J, Vingerling, Hans, Bron, A, Dartigues, JF, Fletcher, A, Hofman, Bert, Kuijpers, Robert, Luben, RN, Oxele, K, Topouzis, F, von Hanno, T, Mirshahi, A, Foster, PJ, Duijn, Cornelia, Pfeiffer, N, Delcourt, C, Klaver, Caroline, Rahi, J, Hammond, CJ, Williams, KM, Bertelsen, G, Cumberland, P, Wolfram, C, Verhoeven, Virginie, Anastasopoulos, E, Buitendijk, Gabriëlle, Cougnard-Gregoire, A, Creuzot-Garcher, C, Erke, MG, Hogg, R, Hohn, R, Hysi, P, Khawaja, AP, Korobelnik, JF, Ried, J, Vingerling, Hans, Bron, A, Dartigues, JF, Fletcher, A, Hofman, Bert, Kuijpers, Robert, Luben, RN, Oxele, K, Topouzis, F, von Hanno, T, Mirshahi, A, Foster, PJ, Duijn, Cornelia, Pfeiffer, N, Delcourt, C, Klaver, Caroline, Rahi, J, and Hammond, CJ
Abstract: Purpose: To investigate whether myopia is becoming more common across Europe and explore whether increasing education levels, an important environmental risk factor for myopia, might explain any temporal trend. Design: Meta-analysis of population-based, cross-sectional studies from the European Eye Epidemiology (E-3) Consortium. Participants: The E-3 Consortium is a collaborative network of epidemiological studies of common eye diseases in adults across Europe. Refractive data were available for 61 946 participants from 15 population-based studies performed between 1990 and 2013; participants had a range of median ages from 44 to 78 years. Methods: Noncycloplegic refraction, year of birth, and highest educational level achieved were obtained for all participants. Myopia was defined as a mean spherical equivalent <=-0.75 diopters. A random-effects meta-analysis of age-specific myopia prevalence was performed, with sequential analyses stratified by year of birth and highest level of educational attainment. Main Outcome Measures: Variation in age-specific myopia prevalence for differing years of birth and educational level. Results: There was a significant cohort effect for increasing myopia prevalence across more recent birth decades; age-standardized myopia prevalence increased from 17.8% (95% confidence interval [CI], 17.6-18.1) to 23.5% (95% CI, 23.2-23.7) in those born between 1910 and 1939 compared with 1940 and 1979 (P = 0.03). Education was significantly associated with myopia; for those completing primary, secondary, and higher education, the age-standardized prevalences were 25.4% (CI, 25.0-25.8), 29.1% (CI, 28.8-29.5), and 36.6% (CI, 36.1-37.2), respectively. Although more recent birth cohorts were more educated, this did not fully explain the cohort effect. Compared with the reference risk of participants born in the 1920s with only primary education, higher education or being born in the 1960s doubled the myopia prevalence ratio-2.43 (CI, 1.26-4.17) and
Published: 2015

46. Prevalence of refractive error in Europe: the European Eye Epidemiology (E-3) Consortium

Author: Williams, KM, Verhoeven, Virginie, Cumberland, P, Bertelsen, G, Wolfram, C, Buitendijk, Gabriëlle, Hofman, Bert, Duijn, Cornelia, Vingerling, Hans, Kuijpers, Robert, Hohn, R, Mirshahi, A, Khawaja, AP, Luben, RN, Erke, MG, von Hanno, T, Mahroo, O, Hogg, R, Gieger, C, Cougnard-Gregoire, A, Anastasopoulos, E, Bron, A, Dartigues, JF, Korobelnik, JF, Creuzot-Garcher, C, Topouzis, F, Delcourt, C, Rahi, J, Meitinger, T, Fletcher, A, Foster, PJ, Pfeiffer, N, Klaver, Caroline, Hammond, CJ, Williams, KM, Verhoeven, Virginie, Cumberland, P, Bertelsen, G, Wolfram, C, Buitendijk, Gabriëlle, Hofman, Bert, Duijn, Cornelia, Vingerling, Hans, Kuijpers, Robert, Hohn, R, Mirshahi, A, Khawaja, AP, Luben, RN, Erke, MG, von Hanno, T, Mahroo, O, Hogg, R, Gieger, C, Cougnard-Gregoire, A, Anastasopoulos, E, Bron, A, Dartigues, JF, Korobelnik, JF, Creuzot-Garcher, C, Topouzis, F, Delcourt, C, Rahi, J, Meitinger, T, Fletcher, A, Foster, PJ, Pfeiffer, N, Klaver, Caroline, and Hammond, CJ
Abstract: To estimate the prevalence of refractive error in adults across Europe. Refractive data (mean spherical equivalent) collected between 1990 and 2013 from fifteen population-based cohort and cross-sectional studies of the European Eye Epidemiology (E-3) Consortium were combined in a random effects meta-analysis stratified by 5-year age intervals and gender. Participants were excluded if they were identified as having had cataract surgery, retinal detachment, refractive surgery or other factors that might influence refraction. Estimates of refractive error prevalence were obtained including the following classifications: myopia a parts per thousand currency signa'0.75 diopters (D), high myopia a parts per thousand currency signa'6D, hyperopia a parts per thousand yen1D and astigmatism a parts per thousand yen1D. Meta-analysis of refractive error was performed for 61,946 individuals from fifteen studies with median age ranging from 44 to 81 and minimal ethnic variation (98 % European ancestry). The age-standardised prevalences (using the 2010 European Standard Population, limited to those a parts per thousand yen25 and < 90 years old) were: myopia 30.6 % [95 % confidence interval (CI) 30.4-30.9], high myopia 2.7 % (95 % CI 2.69-2.73), hyperopia 25.2 % (95 % CI 25.0-25.4) and astigmatism 23.9 % (95 % CI 23.7-24.1). Age-specific estimates revealed a high prevalence of myopia in younger participants [47.2 % (CI 41.8-52.5) in 25-29 years-olds]. Refractive error affects just over a half of European adults. The greatest burden of refractive error is due to myopia, with high prevalence rates in young adults. Using the 2010 European population estimates, we estimate there are 227.2 million people with myopia across Europe.
Published: 2015

47. Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Author: Vithana, EN, Khor, CC, Qiao, C, Nongpiur, ME, George, R, Chen, LJ, Do, T, Abu-Amero, K, Huang, CK, Low, S, Tajudin, LSA, Perera, SA, Cheng, CY, Xu, L, Jia, H, Ho, CL, Sim, KS, Wu, RY, Tham, CCY, Chew, PTK, Su, DH, Oen, FT, Sarangapani, S, Soumittra, N, Osman, EA, Wong, HT, Tang, G, Fan, S, Meng, H, Huong, DTL, Wang, H, Feng, B, Baskaran, M, Shantha, B, Ramprasad, VL, Kumaramanickavel, G, Iyengar, SK, How, AC, Lee, KY, Sivakumaran, TA, Yong, VHK, Ting, SML, Li, Y, Wang, YX, Tay, WT, Sim, X, Lavanya, R, Cornes, BK, Zheng, YF, Wong, TT, Loon, SC, Yong, VKY, Waseem, N, Yaakub, A, Chia, KS, Rand Allingham, R, Hauser, MA, Lam, DSC, Hibberd, ML, Bhattacharya, SS, Zhang, M, Teo, YY, Tan, DT, Jonas, JB, Tai, ES, Saw, SM, Hon, DN, Al-Obeidan, SA, Liu, J, Chau, TNB, Simmons, CP, Bei, JX, Zeng, YX, Foster, PJ, Vijaya, L, and Wong, TY
Subjects: medicine.medical_specialty, Population, Glaucoma, Genome-wide association study, Biology, Collagen Type XI, Polymorphism, Single Nucleotide, Article, Polymorphism (computer science), Epidemiology, Protein D-Aspartate-L-Isoaspartate Methyltransferase, Genetics, medicine, Humans, Stickler syndrome, Genetic Predisposition to Disease, education, education.field_of_study, Principal Component Analysis, Case-control study, Odds ratio, medicine.disease, Repressor Proteins, Logistic Models, Genetic Loci, Case-Control Studies, Carrier Proteins, Glaucoma, Angle-Closure, Genome-Wide Association Study
Abstract: Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10-12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10-10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10-9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

48. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Author: Gharahkhani, P, Burdon, KP, Fogarty, R, Sharma, S, Hewitt, AW, Martin, S, Law, MH, Cremin, K, Bailey, JNC, Loomis, SJ, Pasquale, LR, Haines, JL, Hauser, MA, Viswanathan, AC, McGuffin, P, Topouzis, F, Foster, PJ, Graham, SL, Casson, RJ, Chehade, M, White, AJ, Zhou, T, Souzeau, E, Landers, J, Fitzgerald, JT, Klebe, S, Ruddle, JB, Goldberg, I, Healey, PR, Mills, RA, Wang, JJ, Montgomery, GW, Martin, NG, Radford-Smith, G, Whiteman, DC, Brown, MA, Wiggs, JL, Mackey, DA, Mitchell, P, MacGregor, S, Craig, JE, Gharahkhani, P, Burdon, KP, Fogarty, R, Sharma, S, Hewitt, AW, Martin, S, Law, MH, Cremin, K, Bailey, JNC, Loomis, SJ, Pasquale, LR, Haines, JL, Hauser, MA, Viswanathan, AC, McGuffin, P, Topouzis, F, Foster, PJ, Graham, SL, Casson, RJ, Chehade, M, White, AJ, Zhou, T, Souzeau, E, Landers, J, Fitzgerald, JT, Klebe, S, Ruddle, JB, Goldberg, I, Healey, PR, Mills, RA, Wang, JJ, Montgomery, GW, Martin, NG, Radford-Smith, G, Whiteman, DC, Brown, MA, Wiggs, JL, Mackey, DA, Mitchell, P, MacGregor, S, and Craig, JE
Abstract: Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
Published: 2014

49. ABCC5, a Gene That Influences the Anterior Chamber Depth, Is Associated with Primary Angle Closure Glaucoma

Author: Wiggs, JL, Nongpiur, ME, Khor, CC, Jia, H, Cornes, BK, Chen, L-J, Qiao, C, Nair, KS, Cheng, C-Y, Xu, L, George, R, Do, T, Abu-Amero, K, Perera, SA, Ozaki, M, Mizoguchi, T, Kurimoto, Y, Low, S, Tajudin, L-SA, Ho, C-L, Tham, CCY, Soto, I, Chew, PTK, Wong, H-T, Shantha, B, Kuroda, M, Osman, EA, Tang, G, Fan, S, Meng, H, Wang, H, Feng, B, Yong, VHK, Ting, SML, Li, Y, Wang, Y-X, Li, Z, Lavanya, R, Wu, R-Y, Zheng, Y-F, Su, DH, Loon, S-C, Allingham, RR, Hauser, MA, Soumittra, N, Ramprasad, VL, Waseem, N, Yaakub, A, Chia, K-S, Kumaramanickavel, G, Wong, TT, How, AC, Tran, NBC, Simmons, CP, Bei, J-X, Zeng, Y-X, Bhattacharya, SS, Zhang, M, Tan, DT, Teo, Y-Y, Al-Obeidan, SA, Do, NH, Tai, E-S, Saw, S-M, Foster, PJ, Vijaya, L, Jonas, JB, Wong, T-Y, John, SWM, Pang, C-P, Vithana, EN, Wang, N, Aung, T, Wiggs, JL, Nongpiur, ME, Khor, CC, Jia, H, Cornes, BK, Chen, L-J, Qiao, C, Nair, KS, Cheng, C-Y, Xu, L, George, R, Do, T, Abu-Amero, K, Perera, SA, Ozaki, M, Mizoguchi, T, Kurimoto, Y, Low, S, Tajudin, L-SA, Ho, C-L, Tham, CCY, Soto, I, Chew, PTK, Wong, H-T, Shantha, B, Kuroda, M, Osman, EA, Tang, G, Fan, S, Meng, H, Wang, H, Feng, B, Yong, VHK, Ting, SML, Li, Y, Wang, Y-X, Li, Z, Lavanya, R, Wu, R-Y, Zheng, Y-F, Su, DH, Loon, S-C, Allingham, RR, Hauser, MA, Soumittra, N, Ramprasad, VL, Waseem, N, Yaakub, A, Chia, K-S, Kumaramanickavel, G, Wong, TT, How, AC, Tran, NBC, Simmons, CP, Bei, J-X, Zeng, Y-X, Bhattacharya, SS, Zhang, M, Tan, DT, Teo, Y-Y, Al-Obeidan, SA, Do, NH, Tai, E-S, Saw, S-M, Foster, PJ, Vijaya, L, Jonas, JB, Wong, T-Y, John, SWM, Pang, C-P, Vithana, EN, Wang, N, and Aung, T
Abstract: Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.
Published: 2014

50. Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus

Author: Donnelly, P, Strange, A, Bellenguez, C, Sim, X, Luben, R, Hysi, PG, Ramdas, WD, van Koolwijk, LME, Freeman, C, Pirinen, M, Su, Z, Band, G, Pearson, R, Vukcevic, D, Langford, C, Deloukas, P, Hunt, S, Gray, E, Dronov, S, Potter, SC, Tashakkori-Ghanbaria, A, Edkins, S, Bumpstead, SJ, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, JAZ, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Wood, NW, Trembath, RC, Barroso, I, Peltonen, L, Healey, P, McGuffin, P, Topouzis, F, Klaver, CCW, van Duijn, CM, Mackey, DA, Young, TL, Hammond, CJ, Khaw, K-T, Wareham, N, Wang, JJ, Wong, TY, Foster, PJ, Mitchell, P, Spencer, CCA, Viswanathan, AC, Donnelly, P, Strange, A, Bellenguez, C, Sim, X, Luben, R, Hysi, PG, Ramdas, WD, van Koolwijk, LME, Freeman, C, Pirinen, M, Su, Z, Band, G, Pearson, R, Vukcevic, D, Langford, C, Deloukas, P, Hunt, S, Gray, E, Dronov, S, Potter, SC, Tashakkori-Ghanbaria, A, Edkins, S, Bumpstead, SJ, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, JAZ, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Wood, NW, Trembath, RC, Barroso, I, Peltonen, L, Healey, P, McGuffin, P, Topouzis, F, Klaver, CCW, van Duijn, CM, Mackey, DA, Young, TL, Hammond, CJ, Khaw, K-T, Wareham, N, Wang, JJ, Wong, TY, Foster, PJ, Mitchell, P, Spencer, CCA, and Viswanathan, AC
Abstract: To discover quantitative trait loci for intraocular pressure, a major risk factor for glaucoma and the only modifiable one, we performed a genome-wide association study on a discovery cohort of 2175 individuals from Sydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, P(combined) = 1.10 × 10(-8)). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30-0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.
Published: 2013

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