Search

International audience; PurposeTo examine the association of physical activity (PA) with glaucoma and related traits; to assess whether genetic predisposition to glaucoma modified these associations; and to probe causal relationships using Mendelian randomization (MR).ParticipantsUK Biobank participants with data on self-reported or accelerometer-derived PA and intraocular pressure (IOP) (N=94 206 and N=27 777, respectively); macular inner retinal optical coherence tomography (OCT) measures (N = 36 274; N=9 991); and glaucoma status (N= 86 803; N=23 556).DesignCross-sectional observational and gene–environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia.MethodsWe evaluated multivariable-adjusted associations of self-reported (International Physical Activity Questionnaire, IPAQ) and accelerometer-derived PA with IOP and macular inner retinal OCT parameters using linear regression, and with glaucoma status using logistic regression. For all outcomes, we examined gene-PA interactions using a polygenic risk score (PRS) that combined the effects of 2 673 genetic variants associated with glaucoma.Main outcome measuresIOP; macular retinal nerve fiber layer (mRNFL) thickness; macular ganglion cell inner plexiform layer (mGCIPL) thickness, and glaucoma status.ResultsIn multivariable-adjusted regression models, we found no association of PA level or time spent in PA with glaucoma status. Higher overall levels and greater time spent in higher levels of both self-reported and accelerometer-derived PA were positively associated with thicker mGCIPL (P trend

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

Purpose Genetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort. Methods Genetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses. Results We found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10−10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10−08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error. Conclusion The results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the origins of the genetic signals seen in GWAS but also report for the first time a completely novel association with the CRX gene.

Purpose: To examine whether sociodemographic, and ocular factors relate to optical coherence tomography (OCT)-derived foveal curvature (FC) in healthy individuals. Methods: We developed a deep learning model to quantify OCT-derived FC from 63,939 participants (age range, 39-70 years). Associations of FC with sociodemographic, and ocular factors were obtained using multilevel regression analysis (to allow for right and left eyes) adjusting for age, sex, ethnicity, height (model 1), visual acuity, spherical equivalent, corneal astigmatism, center point retinal thickness (CPRT), intraocular pressure (model 2), deprivation (Townsend index), higher education, annual income, and birth order (model 3). Fovea curvature was modeled as a z-score. Results: Males had on average steeper FC (0.077; 95% confidence interval [CI] 0.077-0.078) than females (0.068; 95% CI 0.068-0.069). Compared with whites, non-white individuals showed flatter FC, particularly those of black ethnicity. In black males, -0.80 standard deviation (SD) change when compared with whites (95% CI -0.89, -0.71; P 5.2e10-68). In black females, -0.70 SD change when compared with whites (95% CI -0.77, -0.63; p 2.3e10-93). Ocular factors (visual acuity, refractive status, and CPRT) showed a graded inverse association with FC that persisted after adjustment. Macular curvature showed a positive association with FC. Income showed a linear trend increase in males (P for linear trend = 0.005). Conclusions: We demonstrate marked differences in FC with ethnicity on the largest cohort studied for this purpose to date. Ocular factors showed a graded association with FC. Implementation of FC quantification in research and on the clinical setting can enhance the understanding of clinical macular phenotypes in health and disease.

Importance: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. Objective: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. Design, Setting, and Participants: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502682 participants, 117279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. Exposures: Four refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. Main Outcomes and Measures: Odds ratios (ORs) of polygenic risk scores in replication samples. Results: A total of 51841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16). Conclusions and Relevance: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM..

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

Purpose: Hyperopia (farsightedness) has been associated with a deficit in children's educational attainment in some studies. We aimed to investigate the causality of the relationship between refractive error and educational attainment.Methods: Mendelian randomization (MR) analysis in 74,463 UK Biobank participants was used to estimate the causal effect of refractive error on years spent in full-time education, which was taken as a measure of educational attainment. A polygenic score for refractive error derived from 129 genetic variants was used as the instrumental variable. Both linear and nonlinear (allowing for a nonlinear relationship between refractive error and educational attainment) MR analyses were performed.Results: Assuming a linear relationship between refractive error and educational attainment, the causal effect of refractive error on years spent in full-time education was estimated as -0.01 yr/D (95% confidence interval, -0.04 to +0.02; P = 0.52), suggesting minimal evidence for a non-zero causal effect. Nonlinear MR supported the hypothesis of the nonlinearity of the relationship (I2 = 80.3%; Cochran's Q = 28.2; P = 8.8e-05) but did not suggest that hyperopia was associated with a major deficit in years spent in education.Conclusions: This work suggested that the causal relationship between refractive error and educational attainment was nonlinear but found no evidence that moderate hyperopia caused a major deficit in educational attainment. Importantly, however, because statistical power was limited and some participants with moderate hyperopia would have worn spectacles as children, modest adverse effects may have gone undetected.Translational Relevance: These findings suggest that moderate hyperopia does not cause a major deficit in educational attainment.

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.

Purpose: Emmetropization requires coordinated scaling of the major ocular components, corneal curvature and axial length. This coordination is achieved in part through a shared set of genetic variants that regulate eye size. Poorly coordinated scaling of corneal curvature and axial length results in refractive error. We tested the hypothesis that genetic variants regulating eye size in emmetropic eyes are distinct from those conferring susceptibility to refractive error. Methods: A genome-wide association study (GWAS) for corneal curvature in 22,180 adult emmetropic individuals was performed as a proxy for a GWAS for eye size. A polygenic score created using lead GWAS variants was tested for association with corneal curvature and axial length in an independent sample: 437 classified as emmetropic and 637 as ametropic. The genetic correlation between eye size and refractive error was calculated using linkage disequilibrium score regression for approximately 1 million genetic variants. Results: The GWAS for corneal curvature in emmetropes identified 32 independent genetic variants (P < 5.0e-08). A polygenic score created using these 32 genetic markers explained 3.5% (P < 0.001) and 2.0% (P = 0.001) of the variance in corneal curvature and axial length, respectively, in the independent sample of emmetropic individuals but was not predictive of these traits in ametropic individuals. The genetic correlation between eye size and refractive error was close to zero (rg = 0.00; SE = 0.06; P = 0.95). Conclusions: These results support the hypothesis that genetic variants regulating eye size in emmetropic eyes do not overlap with those conferring susceptibility to myopia. This suggests that distinct biological pathways regulate normal eye growth and myopia development. peerReviewed

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.

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.

Funder: DH | NIHR | Health Services Research Programme (NIHR Health Services Research Programme); doi: https://doi.org/10.13039/501100001923, 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.

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.

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH., The International Glaucoma Genetics Consortium reports a genome-wide association study meta-analysis of optic disc parameters relevant to primary open-angle glaucoma. They identify two novel variants in PPP1R36-PLEKHG3 and SERPINE3 by multi-trait analysis in European-ancestry cohorts that were replicated in independent Asian cohorts.

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.

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.

PurposeTo describe corneal astigmatism in the UK Biobank population, to look for associations with other biometric variables and socio-demographic factors, and to report the proportion with abnormal keratometry and irregular astigmatism suggestive of pathological corneal ectasias such as keratoconus.MethodsCross-sectional data were obtained from UK Biobank (www.ukbiobank.ac.uk/). A subsample of 107,452 participants from UK communities had undergone an enhanced ophthalmic examination including autorefractor keratometry (Tomey RC 5000, Tomey Corp., Nagoya, Japan). After quality control and applying relevant exclusions, data on corneal astigmatism on 83,751 participants was available for analysis. Potential associations were tested through univariable regression and significant parameters carried forward for multivariable analysis.ResultsIn a univariable analysis, the characteristics significantly protective against corneal astigmatism were gender (male), older age, darker skin colour and increased alcohol intake (all pConclusionsThis analysis of associations with astigmatism in a large cohort of volunteers confirms previous associations including adverse associations with younger age and female gender, and identified novel associations including darker skin colour and frequency of alcohol intake. The highest risk group for corneal astigmatism were younger females of lighter skin colour, having completed full time education later, with higher logMAR corrected visual acuity. We also confirmed that corneal astigmatism is a high risk factor for amblyopia and strabismus. Finally since no cases of keratoconus were identified, this would suggest that simple keratometry indices may not be sufficient for population screening of keratoconus.

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 investigate the eye diseases in later life.

A genetic contribution to refractive error has been confirmed by the discovery of more than 150 associated variants in genome-wide association studies (GWAS). Environmental factors such as education and time outdoors also demonstrate strong associations. Currently however, the extent of gene-environment or gene-gene interactions in myopia is unknown. We tested the hypothesis that refractive error-associated variants exhibit effect size heterogeneity, a hallmark feature of genetic interactions. Of 146 variants tested, evidence of non-uniform, non-linear effects were observed for 66 (45%) at Bonferroni-corrected significance (P < 1.1 × 10−4) and 128 (88%) at nominal significance (P < 0.05). LAMA2 variant rs12193446, for example, had an effect size varying from −0.20 diopters (95% CI −0.18 to −0.23) to −0.89 diopters (95% CI −0.71 to −1.07) in different individuals. SNP effects were strongest at the phenotype extremes and weaker in emmetropes. A parsimonious explanation for these findings is that gene-environment or gene-gene interactions in myopia are pervasive.

PurposeTo describe corneal astigmatism in the UK Biobank population and to look for associations with other biometric variables and socio-demographic factors.MethodsThis analysis included a subsample of 107,452 participants of the UK Biobank study who underwent an enhanced ophthalmic examination including autorefractor keratometry (Tomey RC 5000, Tomey Corp., Nagoya, Japan). Participants were recruited from across the United Kingdom between 2006 and 2010, and all were between 40 to 69 years. After quality control and applying relevant exclusions, data on corneal astigmatism on 83,751 participants were included for analysis. Potential associations were tested through univariable regression and significant parameters carried forward for multivariable analysis.ResultsIn univariable analysis, the characteristics significantly associated with higher corneal astigmatism (PConclusionsThis analysis confirms previous associations with astigmatism such as younger age and female gender, and identified novel risk factors including lighter skin colour, lower alcohol intake, later age having completed full time education later, lower ccIOP and higher Townsend deprivation index. Further research is needed to investigate these novel associations.

PURPOSE: To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank. \ud \ud 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.\ud \ud 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.\ud \ud 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 investigate the eye diseases in later life.

Importance: Identifing potential screening tests for future cognitive decline is a priority for developing treatments for and the prevention of dementia. Objective: To examine the potential of retinal nerve fiber layer (RNFL) thickness measurement in identifying those at greater risk of cognitive decline in a large community cohort of healthy people. Design, Setting, and Participants: UK Biobank is a prospective, multicenter, community-based study of UK residents aged 40 to 69 years at enrollment who underwent baseline retinal optical coherence tomography imaging, a physical examination, and a questionnaire. The pilot study phase was conducted from March 2006 to June 2006, and the main cohort underwent examination for baseline measures from April 2007 to October 2010. Four basic cognitive tests were performed at baseline, which were then repeated in a subset of participants approximately 3 years later. We analyzed eyes with high-quality optical coherence tomography images, excluding those with eye disease or vision loss, a history of ocular or neurological disease, or diabetes. We explored associations between RNFL thickness and cognitive function using multivariable logistic regression modeling to control for demographic as well as physiologic and ocular variation. Main Outcomes and Measures: Odds ratios (ORs) for cognitive performance in the lowest fifth percentile in at least 2 of 4 cognitive tests at baseline, or worsening results on at least 1 cognitive test at follow-up. These analyses were adjusted for age, sex, race/ethnicity, height, refraction, intraocular pressure, education, and socioeconomic status. Results: A total of 32 038 people were included at baseline testing, for whom the mean age was 56.0 years and of whom 17 172 (53.6%) were women. A thinner RNFL was associated with worse cognitive performance on baseline assessment. A multivariable regression controlling for potential confounders showed that those in the thinnest quintile of RNFL were 11% more likely to fail at least 1 cognitive test (95% CI, 2.0%-2.1%; P = .01). Follow-up cognitive tests were performed for 1251 participants (3.9%). Participants with an RNFL thickness in the 2 thinnest quintiles were almost twice as likely to have at least 1 test score be worse at follow-up cognitive testing (quintile 1: OR, 1.92; 95% CI, 1.29-2.85; P Conclusions and Relevance: A thinner RNFL is associated with worse cognitive function in individuals without a neurodegenerative disease as well as greater likelihood of future cognitive decline. This preclinical observation has implications for future research, prevention, and treatment of dementia.

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

The morphometric characteristics of the retinal vasculature are associated with future risk of many systemic and vascular diseases. However, analysis of data from large population based studies is needed to help resolve uncertainties in some of these associations. This requires automated systems that extract quantitative measures of vessel morphology from large numbers of retinal images. Associations between retinal vessel morphology and disease precursors/outcomes may be similar or opposing for arterioles and venules. Therefore, the accurate detection of the vessel type is an important element in such automated systems. This paper presents a deep learning approach for the automatic classification of arterioles and venules across the entire retinal image, including vessels located at the optic disc. This comprises of a convolutional neural network whose architecture contains six learned layers: three convolutional and three fully-connected. Complex patterns are automatically learnt from the data, which avoids the use of hand crafted features. The method is developed and evaluated using 835,914 centreline pixels derived from 100 retinal images selected from the 135,867 retinal images obtained at the UK Biobank (large population-based cohort study of middle aged and older adults) baseline examination. This is a challenging dataset in respect to image quality and hence arteriole/venule classification is required to be highly robust. The method achieves a significant increase in accuracy of 8.1% when compared to the baseline method, resulting in an arteriole/venule classification accuracy of 86.97% (per pixel basis) over the entire retinal image.

PURPOSE: To describe an approach to the use of optical coherence tomography (OCT) imaging in large, population-based studies, including methods for OCT image acquisition, storage, and the remote, rapid, automated analysis of retinal thickness.METHODS: In UK Biobank, OCT images were acquired between 2009 and 2010 using a commercially available "spectral domain" OCT device (3D OCT-1000, Topcon). Images were obtained using a raster scan protocol, 6 mm x 6 mm in area, and consisting of 128 B-scans. OCT image sets were stored on UK Biobank servers in a central repository, adjacent to high performance computers. Rapid, automated analysis of retinal thickness was performed using custom image segmentation software developed by the Topcon Advanced Biomedical Imaging Laboratory (TABIL). This software employs dual-scale gradient information to allow for automated segmentation of nine intraretinal boundaries in a rapid fashion.RESULTS: 67,321 participants (134,642 eyes) in UK Biobank underwent OCT imaging of both eyes as part of the ocular module. 134,611 images were successfully processed with 31 images failing segmentation analysis due to corrupted OCT files or withdrawal of subject consent for UKBB study participation. Average time taken to call up an image from the database and complete segmentation analysis was approximately 120 seconds per data set per login, and analysis of the entire dataset was completed in approximately 28 days.CONCLUSIONS: We report an approach to the rapid, automated measurement of retinal thickness from nearly 140,000 OCT image sets from the UK Biobank. In the near future, these measurements will be publically available for utilization by researchers around the world, and thus for correlation with the wealth of other data collected in UK Biobank. The automated analysis approaches we describe may be of utility for future large population-based epidemiological studies, clinical trials, and screening programs that employ OCT imaging.

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.

PURPOSE: To describe the associations of physical and demographic factors with Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated intraocular pressure (IOPcc) in a British cohort. DESIGN: Cross-sectional study within the UK Biobank, a large-scale multisite cohort study in the United Kingdom. PARTICIPANTS: We included 110 573 participants from the UK Biobank with intraocular pressure (IOP) measurements available. Their mean age was 57 years (range, 40-69 years); 54% were women, and 90% were white. METHODS: Participants had 1 IOP measurement made on each eye using the Ocular Response Analyzer noncontact tonometer. Linear regression models were used to assess the associations of IOP with physical and demographic factors. MAIN OUTCOME MEASURES: The IOPg and IOPcc. RESULTS: The mean IOPg was 15.72 mmHg (95% confidence interval [CI], 15.70-15.74 mmHg), and the mean IOPcc was 15.95 mmHg (15.92-15.97 mmHg). After adjusting for covariates, IOPg and IOPcc were both significantly associated with older age, male sex, higher systolic blood pressure (SBP), faster heart rate, greater myopia, self-reported glaucoma, and colder season (all P < 0.001). The strongest determinants of both IOPg and IOPcc were SBP (partial R(2): IOPg 2.30%, IOPcc 2.26%), followed by refractive error (IOPg 0.60%, IOPcc 1.04%). The following variables had different directions of association with IOPg and IOPcc: height (-0.77 mmHg/m IOPg; 1.03 mmHg/m IOPcc), smoking (0.19 mmHg IOPg, -0.35 mmHg IOPcc), self-reported diabetes (0.41 mmHg IOPg, -0.05 mmHg IOPcc), and black ethnicity (-0.80 mmHg IOPg, 0.77 mmHg IOPcc). This suggests that height, smoking, diabetes, and ethnicity are related to corneal biomechanical properties. The increase in both IOPg and IOPcc with age was greatest among those of mixed ethnicities, followed by blacks and whites. The same set of covariates explained 7.4% of the variability of IOPcc but only 5.3% of the variability of IOPg. CONCLUSIONS: This analysis of associations with IOP in a large cohort demonstrated that some variables clearly have different associations with IOPg and IOPcc, and that these 2 measurements may reflect different biological characteristics.

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.

PURPOSE: To assess the suitability of retinal images held in the UK Biobank - the largest retinal data repository in a prospective population-based cohort - for computer assisted vascular morphometry, generating measures that are commonly investigated as candidate biomarkers of systemic disease.METHODS: Non-mydriatic fundus images from both eyes of 2,690 participants - people with a self-reported history of myocardial infarction (n=1,345) and a matched control group (n=1,345) - were analysed using VAMPIRE software. These images were drawn from those of 68,554 UK Biobank participants who underwent retinal imaging at recruitment. Four operators were trained in the use of the software to measure retinal vascular tortuosity and bifurcation geometry.RESULTS: Total operator time was approximately 360 hours (4 minutes per image). 2,252 (84%) of participants had at least one image of sufficient quality for the software to process, i.e. there was sufficient detection of retinal vessels in the image by the software to attempt the measurement of the target parameters. 1,604 (60%) of participants had an image of at least one eye that was adequately analysed by the software, i.e. the measurement protocol was successfully completed. Increasing age was associated with a reduced proportion of images that could be processed (p=0.0004) and analysed (pCONCLUSIONS: A proportion of the retinal images in UK Biobank are of insufficient quality for automated analysis. However, the large size of the UK Biobank means that tens of thousands of images are available and suitable for computational analysis. Parametric information measured from the retinas of participants with suspected cardiovascular disease was significantly different to that measured from a matched control group.

IMPORTANCE: Visual impairment due to myopia is an important public health issue. A prior analysis of population-based cohorts aged 15 to 22 years recruited from the United Kingdom and Israel suggested myopia and high myopia were approximately 10% more common in first-born compared with later-born children. OBJECTIVE: To examine whether myopia was associated with birth order in an earlier generation than studied previously and, if so, whether the association was attenuated after adjusting for education exposure, as predicted by the hypothesis that the education of children with later birth orders is less intense. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of UK Biobank participants recruited from 2006 to 2010. Analysis was restricted to participants aged 40 to 69 years who had a vision assessment, self-reported white ethnicity, and no history of eye disorders (N = 89,120). Myopia and high myopia were defined as autorefraction of -0.75 diopters (D) or less and -6.00 D or less, respectively. EXPOSURES: Birth order and information on potential confounders including highest educational qualification ascertained using a structured questionnaire. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) for myopia and high myopia by birth order, using logistic regression and adjusting for age and sex (model 1) or age, sex, and highest educational qualification (model 2). RESULTS: In model 1 (no adjustment for education), birth order was associated with both myopia and high myopia (eg, comparing first- vs second-born individuals; OR, 1.12; 95% CI, 1.08-1.16; P = 1.40E-11 and OR, 1.21; 95% CI, 1.11-1.30; P = 3.60E-06 for myopia and high myopia, respectively). The risk for myopia became progressively lower for later birth orders, suggesting a dose response. In model 2 (after adjusting for education), the effect sizes were attenuated by approximately 25% (OR, 1.09; 95% CI, 1.05-1.12; P = 1.30E-06 and OR, 1.15; 95% CI, 1.06-1.25; P = 4.60E-04 for myopia and high myopia, respectively) and the apparent dose response was abolished. CONCLUSIONS AND RELEVANCE: These data suggest that the association between birth order and myopia is not due to a new environmental pressure in the last 30 to 40 years. The attenuated effect size after adjusting for educational exposure supports a role for reduced parental investment in education of children with later birth orders in their relative protection from myopia.