ORCID Profile
0000-0002-3227-2620
Current Organisation
King's College London
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Research Topics
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ANZSRC Field of Research (FoR)
Biomedical and clinical sciences | Biological sciences | Genetics | Ophthalmology and optometry | Biological psychology | Psychology | Microbiology | Atomic, molecular and optical physics | Clinical sciences | Health services and systems | Bioinformatics and computational biology | Physical sciences | Engineering | Health sciences | Nursing | Immunology | Resources engineering and extractive metallurgy
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Publications
Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci
Publisher: Public Library of Science (PLoS)
Date: 06-05-2010
Early life factors for myopia in the British Twins Early Development Study
Publisher: BMJ
Date: 06-11-2018
DOI: 10.1136/BJOPHTHALMOL-2018-312439
Abstract: Myopia is an increasingly prevalent condition globally. A greater understanding of contemporaneous, early life factors associated with myopia risk is urgently required, particularly in younger onset myopia as this correlates with higher severity and increased complications in adult life. Analysis of a subset of the longitudinal, UK-based Twins Early Development Study (n=1991) recruited at birth between 1994 and 1996. Subjective refraction was obtained from the twin’s optometrists mean age 16.3 years (SD 1.7). Myopia was defined as mean spherical equivalent ≤−0.75 dioptres. A life course epidemiology approach was used to appropriately weight candidate myopia risk factors during critical periods of eye growth. Adjusted ORs for myopia were estimated using multivariable logistic regression models at each life stage, together with variance explained (r 2 ) and area under the receiver operator characteristic curve (AUROC) statistic of predictive models. Factors significantly associated with myopia included level of maternal education (OR 1.33, 95% CI 1.11 to 1.59), fertility treatment (OR 0.63, 95% CI 0.43 to 0.92), summer birth (OR 1.93, 95% CI 1.28 to 2.90) and hours spent playing computer games (OR 1.03, 95% CI 1.01 to 1.06). The total variance explained by this model was 4.4 % (p .001) and the AUROC was 0.68 (95% CI 0.64 to 0.72). Consistent associations were observed with socioeconomic status, educational attainment, reading enjoyment and cognitive variables, particularly verbal cognition, at multiple points over the life course. This study identifies known and novel associations with myopia during childhood development associated factors identified in early life reflect sociological and lifestyle trends such as rates of maternal education, fertility treatment, early schooling and computer games.
The Relationship between Retinal Arteriolar and Venular Calibers Is Genetically Mediated, and Each Is Associated with Risk of Cardiovascular Disease
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 23-02-2011
DOI: 10.1167/IOVS.10-5927
Ascorbic acid metabolites are involved in intraocular pressure control in the general population
Publisher: Elsevier BV
Date: 2019
A twin study of cilioretinal arteries, tilted discs and situs inversus
Publisher: Springer Science and Business Media LLC
Date: 14-12-2017
Genetic epidemiology
Publisher: IMPERIAL COLLEGE PRESS
Date: 03-2012
Genetic and Dietary Factors Influencing the Progression of Nuclear Cataract
Publisher: Elsevier BV
Date: 06-2016
Cohort Profile: TwinsUK and Healthy Ageing Twin Study
Publisher: Oxford University Press (OUP)
Date: 09-01-2012
DOI: 10.1093/IJE/DYR207
The Heritability of Macular Response to Supplemental Lutein and Zeaxanthin: A Classic Twin Study
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 26-07-2012
DOI: 10.1167/IOVS.12-9618
Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
Associations with Intraocular Pressure in a Large Cohort
Publisher: Elsevier BV
Date: 04-2016
Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations
Publisher: Springer Science and Business Media LLC
Date: 10-2018
Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
Publisher: Public Library of Science (PLoS)
Date: 20-12-2012
Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma
Publisher: Springer Science and Business Media LLC
Date: 21-05-2018
Low‐concentration atropine eyedrops for myopia control in a multi‐racial cohort of Australian children: A randomised clinical trial
Publisher: Wiley
Date: 09-09-2022
DOI: 10.1111/CEO.14148
Abstract: To test the hypothesis that 0.01% atropine eyedrops are a safe and effective myopia‐control approach in Australian children. Children (6–16 years 49% Europeans, 18% East Asian, 22% South Asian, and 12% other/mixed ancestry) with documented myopia progression were enrolled into this single‐centre randomised, parallel, double‐masked, placebo‐controlled trial and randomised to receive 0.01% atropine ( n = 104) or placebo ( n = 49) eyedrops (2:1 ratio) instilled nightly over 24 months (mean index age = 12.2 ± 2.5 and 11.2 ± 2.8 years, respectively). Outcome measures were the changes in spherical equivalent (SE) and axial length (AL) from baseline. At 12 months, the mean SE and AL change from baseline were −0.31D (95% confidence interval [CI] = −0.39 to −0.22) and 0.16 mm (95%CI = 0.13–0.20) in the atropine group and −0.53D (95%CI = −0.66 to −0.40) and 0.25 mm (95%CI = 0.20–0.30) in the placebo group (group difference p ≤ 0.01). At 24 months, the mean SE and AL change from baseline was −0.64D (95%CI = −0.73 to −0.56) and 0.34 mm (95%CI = 0.30–0.37) in the atropine group, and −0.78D (95%CI = −0.91 to −0.65) and 0.38 mm (95%CI = 0.33–0.43) in the placebo group. Group difference at 24 months was not statistically significant ( p = 0.10). At 24 months, the atropine group had reduced accommodative litude and pupillary light response compared to the placebo group. In Australian children, 0.01% atropine eyedrops were safe, well‐tolerated, and had a modest myopia‐control effect, although there was an apparent decrease in efficacy between 18 and 24 months, which is likely driven by a higher dropout rate in the placebo group.
The Heritability of Ocular Traits
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.SURVOPHTHAL.2010.07.003
Abstract: Heritability is the proportion of phenotypic variation in a population that is attributable to genetic variation among in iduals. Many ophthalmic disorders and biometric traits are known to have a genetic basis and consequently much work has been published in the literature estimating the heritability of various ocular parameters. We collated and summarized the findings of heritability studies conducted in the field of ophthalmology. We grouped the various studies broadly by phenotype as follows: refraction, primary open-angle glaucoma, age-related macular degeneration (AMD), cataract, diabetic retinopathy, and others. A total of 82 articles were retrieved from the literature relating to estimation of heritability for an ocular disease or biometric trait of these, 37 papers were concerned with glaucoma, 28 with refraction, 4 with AMD, 5 with diabetic retinopathy, and 4 with cataract. The highest reported heritability for an ophthalmic trait is 0.99 for the phenotype ≥ 20 small hard drusen, indicating that observed variation in this parameter is largely governed by genetic factors. Over 60% of the studies employed a twin study design and a similar percentage utilized variance components methods and structural equation modeling (SEM) to derive their heritability values. Using modern SEM techniques, heritability estimates derived from twin subjects were generally higher than those from family data. Many of the estimates are in the moderate to high range, but to date the majority of genetic variants accounting for these findings have not been uncovered, hence much work remains to be undertaken to elucidate fully their molecular etiology.
Association analyses of rare variants identify two genes associated with refractive error
Publisher: Public Library of Science (PLoS)
Date: 22-09-2022
DOI: 10.1371/JOURNAL.PONE.0272379
Abstract: 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 s le sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort. 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. 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. 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.
Electrical responses from human retinal cone pathways associate with a common genetic polymorphism implicated in myopia
Publisher: Proceedings of the National Academy of Sciences
Date: 20-05-2022
Abstract: Myopia prevalence has increased dramatically over recent decades. Genome-wide association studies have identified numerous loci, but mechanisms by which genotypic identity confers myopia susceptibility are unknown. The common variant most strongly associated with myopia is near a gene encoding retinal gap junctions. We analyzed retinal electrophysiological responses from 186 twins genotyped at this locus, finding association between cone-driven, but not rod-driven, electroretinogram signals and allelic genotype. Examination of responses to further, nonstandard testing protocols, together with recordings from patients with selective loss of bipolar cell signals, points to an effect on cone-driven hyperpolarizing (“OFF”) signals. The pattern of retinal expression of this gene appears consistent with these findings, which support a potential role for altered cone-driven signaling in myopia development.
Effects of age on genetic influence on bone loss over 17 years in women: The Healthy Ageing Twin Study (HATS)
Publisher: Wiley
Date: 18-09-2012
DOI: 10.1002/JBMR.1659
Abstract: The rate of bone loss varies across the aging period via multiple complex mechanisms. Therefore, the role of genetic factors on bone loss may also change similarly. In this study, we investigated the effect of age on the genetic component of bone loss in a large twin-based longitudinal study. During 17 years of follow-up in TwinsUK and Healthy Ageing Twin Study (HATS), 15,491 hip and lumbar spine dual-energy X-ray absorptiometry (DXA) scans were performed in 7056 twins. Out of these subjects, 2716 female twins aged >35 years with at least two scans separated for >4 years (mean follow-up 9.7 years) were included in this analysis. We used a mixed-effects random-coefficients regression model to predict hip and spine bone mineral density (BMD) values for exact ages of 40, 45, 50, 55, 60, 65, 70, 75, and 80 years, with adjustment for baseline age, weight, height, and duration of hormone replacement therapy. We then estimated heritability of the changes in BMD measures between these age ranges. Heritability estimates for cross-sectional hip and spine BMD were high (ranging between 69% and 88%) at different ages. Heritability of change of BMD was lower and more variable, generally ranging from 0% to 40% for hip and 0% to 70% for spine between age 40 and 45 years genetic factors explained 39.9% (95% confidence interval [CI], 25%-53%) of variance of BMD loss for total hip, 46.4% (95% CI, 32%-58%) for femoral neck, and 69.5% (95% CI, 59%-77%) for lumbar spine. These estimates decreased with increasing age, and there appeared to be no heritability of BMD changes after the age of 65 years. There was some evidence at the spine for shared genetic effects between cross-sectional and longitudinal BMD. Whereas genetic factors appear to have an important role in bone loss in early postmenopausal women, nongenetic mechanisms become more important determinants of bone loss with advanced age.
Association Between Myopia, Ultraviolet B Radiation Exposure, Serum Vitamin D Concentrations, and Genetic Polymorphisms in Vitamin D Metabolic Pathways in a Multicountry European Study
Publisher: American Medical Association (AMA)
Date: 2017
DOI: 10.1001/JAMAOPHTHALMOL.2016.4752
Abstract: Myopia is becoming increasingly common globally and is associated with potentially sight-threatening complications. Spending time outdoors is protective, but the mechanism underlying this association is poorly understood. To examine the association of myopia with ultraviolet B radiation (UVB directly associated with time outdoors and sunlight exposure), serum vitamin D concentrations, and vitamin D pathway genetic variants, adjusting for years in education. A cross-sectional, population-based random s le of participants 65 years and older was chosen from 6 study centers from the European Eye Study between November 6, 2000, to November 15, 2002. Of 4187 participants, 4166 attended an eye examination including refraction, gave a blood s le, and were interviewed by trained fieldworkers using a structured questionnaire. Myopia was defined as a mean spherical equivalent of -0.75 diopters or less. Exclusion criteria included aphakia, pseudophakia, late age-related macular degeneration, and vision impairment due to cataract, resulting in 371 participants with myopia and 2797 without. Exposure to UVB estimated by combining meteorological and questionnaire data at different ages, single-nucleotide polymorphisms in vitamin D metabolic pathway genes, serum vitamin D3 concentrations, and years of education. Odds ratios (ORs) of UVB, serum vitamin D3 concentrations, vitamin D single-nucleotide polymorphisms, and myopia estimated from logistic regression. Of the included 3168 participants, the mean (SD) age was 72.4 (5) years, and 1456 (46.0%) were male. An SD increase in UVB exposure at age 14 to 19 years (OR, 0.81 95% CI, 0.71-0.92) and 20 to 39 years (OR, 0.7 95% CI, 0.62-0.93) was associated with a reduced adjusted OR of myopia those in the highest tertile of years of education had twice the OR of myopia (OR, 2.08 95% CI, 1.41-3.06). No independent associations between myopia and serum vitamin D3 concentrations nor variants in genes associated with vitamin D metabolism were found. An unexpected finding was that the highest quintile of plasma lutein concentrations was associated with a reduced OR of myopia (OR, 0.57 95% CI, 0.46-0.72). Increased UVB exposure was associated with reduced myopia, particularly in adolescence and young adulthood. The association was not altered by adjusting for education. We found no convincing evidence for a direct role of vitamin D in myopia risk. The relationship between high plasma lutein concentrations and a lower risk of myopia requires replication.
Estimating Heritability and Shared Environmental Effects for Refractive Error in Twin and Family Studies
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 2009
DOI: 10.1167/IOVS.08-2385
Abstract: Twin studies have demonstrated a high heritability for refractive error of up to 90%, but some family studies have suggested up to one-third of population variance is attributable to the effects of shared family environment. This large twin study aimed to explore the role of shared environment in refractive error. Refractive error was measured using autorefraction in 4602 subjects (1152 monozygotic and 1149 dizygotic twin pairs), aged between 16 and 82 years, recruited from the TwinsUK Adult Twin Registry. Maximum-likelihood methods were used to estimate the variance of genetic, environmental, and age variance components. Maximum likelihood model fitting estimate of the heritability from the best-fit model was 77% (95% confidence interval [CI], 68%-84%). Shared environmental effects explained 7% (95% CI, 0%-15%) and in idual environmental effects explained 16% (95% CI, 15%-18%) of the spherical equivalent variance, respectively. Inclusion of age effects into the modeling reduced shared environmental effects to an estimated 2% of variation. Analysis of 2301 twin pairs confirms that the twin study design results in a very low estimate of shared family environmental effects in refractive error. Several factors may explain these differences we believe the most likely is that twins are perfectly age matched and do not include cross-generation or cohort effects. This means twin study designs have more power to detect heritable effects in variance component models of myopia, whereas family studies have more power to detect shared environment effects.
Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians
Publisher: Springer Science and Business Media LLC
Date: 11-12-2011
DOI: 10.1038/NG.1019
Meta‐analysis of Genome‐Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology
Publisher: Wiley
Date: 28-01-2015
DOI: 10.1002/GEPI.21886
Family-Based Genome-Wide Association Study of South Indian Pedigrees SupportsWNT7Bas a Central Corneal Thickness Locus
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 18-05-2018
A Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens as Biomarkers
Publisher: Elsevier BV
Date: 04-2017
Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium
Publisher: Springer Science and Business Media LLC
Date: 05-06-2012
Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus
Publisher: Springer Science and Business Media LLC
Date: 06-01-2013
DOI: 10.1038/NG.2506
Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2013
Abstract: Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type–restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type–specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type–restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.
Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhäuser Syndrome and Central Corneal Thickness
Publisher: Public Library of Science (PLoS)
Date: 05-08-2014
Genome-Wide Association Study Identifies Two Novel Regions at 11p15.5-p13 and 1p31 with Major Impact on Acute-Phase Serum Amyloid A
Publisher: Public Library of Science (PLoS)
Date: 18-11-2010
Genome-Wide Association Studies of Refractive Error and Myopia, Lessons Learned, and Implications for the Future
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 29-05-2014
Prevalence of electronegative electroretinograms in a healthy adult cohort
Publisher: BMJ
Date: 07-2021
DOI: 10.1136/BMJOPHTH-2021-000751
Abstract: An electronegative electroretinogram (ERG) can indicate important ocular or systemic disease. This study explored the prevalence of electronegative responses to dark-adapted stimuli in a largely healthy cohort. 211 participants recruited from the TwinsUK cohort underwent ERG testing incorporating international standard (International Society for Clinical Electrophysiology of Vision (ISCEV)) protocols and additional stimuli. Responses were recorded using conductive fibre electrodes, following pupil dilation and 20 min dark adaptation. Responses analysed were to the ISCEV standard and strong flashes (3.0 and 10 cd/m 2 s), and to additional white flashes (0.67–67 cd/m 2 s). A-wave and b-wave litudes were extracted b:a ratios were calculated and proportions of eyes with ratios were noted. Mean (SD) age was 62.4 (11.4) years (median, 64.3 range 23–86 years). 93% were female. Mean (SD) b:a ratios for right and left eyes, respectively, were 1.86 (0.33) and 1.81 (0.29) for the standard flash, and 1.62 (0.25) and 1.58 (0.23) for the stronger flash average b:a ratio was lower for the stronger flash (p .0001). No waveforms were electronegative. For additional flashes, b:a ratio decreased with increasing flash strength. No electronegative waveforms were seen except in three eyes (0.7%) for the strongest flash in some cases, drift in the waveform may have artefactually reduced the b:a ratio. For standard dark-adapted stimuli, no participants had electronegative waveforms. The findings support the notion that electronegative waveforms (in response to standard flash strengths) are unusual, and should prompt further investigation.
Clarifying the role ofATOH7in glaucoma endophenotypes
Publisher: BMJ
Date: 23-01-2014
DOI: 10.1136/BJOPHTHALMOL-2013-304080
Abstract: The ATOH7 gene has been previously associated with glaucoma and glaucoma-related traits, such as disc size and cup/disc ratio (CDR). CDR is an important part of the glaucoma phenotype, whereas the relationship between the disc size and the disease is not well understood. The aim of this study was to investigate whether ATOH7 is associated independently with CDR or merely with the size of the optic disc. We carried out an association analysis for a candidate region, including ATOH7 for two populations: the Blue Mountains Eye Study and the TwinsUK cohort. We performed three linear regression models for (1) disc size adjusted on age, sex and intraocular pressure (IOP), (2) CDR adjusted on age, sex and IOP and (3) CDR adjusted on age, sex, IOP and disc size. A strong signal was found at rs7916697 for disc size. This single nucleotide polymorphism (SNP) was also associated with CDR adjusted on age, sex and IOP. However, this SNP was not associated with CDR when adjusted on age, sex, IOP and also disc size. This study finds that ATOH7 is associated with optic disc size but not independently with CDR.
Choice of Analytic Approach for Eye-Specific Outcomes: One Eye or Two?
Publisher: Elsevier BV
Date: 04-2012
Leading Wound Care Technology: The ARANZ Medical Silhouette
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2011
Common Polymorphisms in theSERPINI2Gene Are Associated with Refractive Error in the 1958 British Birth Cohort
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 25-01-2012
DOI: 10.1167/IOVS.10-5640
Abstract: To identify heritable genetic factors altering susceptibility to refractive error in the general population. This was a genetic association study of refractive error investigating genetic polymorphisms in regions previously reported through linkage. Two study panels were drawn from the British 1958 Birth Cohort, composed of 2211 persons 44 years of age at the time of visit. Two main outcomes were considered: refractive error as a continuous outcome (spherical equivalent) and myopia as a diagnosis (defined as spherical equivalent equal to or worse than-1.00 diopter). Genotyping was initially performed in 1188 subjects from the outer tertiles of the population distribution, using customized arrays of single nucleotide polymorphisms (SNPs) saturating regions of previously reported highly significant linkage. In a second stage, SNPs most significantly associated were validated in 1023 more persons. Findings were investigated further through human fetal expression studies. Polymorphisms within the SERPINI2 gene were associated with refractive error in two different European subgroups from the 1958 British Birth Cohort (meta-analysis P = 7.4E-05 for rs9810473). Association was also significant for myopia (best association: OR = 0.80 95% CI, 0.69-0.93 P = 0.003 for rs10936538). Expression profiling of SERPINI2 revealed that the gene is expressed in the retina and in other eye and CNS tissues. The novel association of SERPINI2 with refractive error and myopia is suggestive of a possible link between physiological pathways controlling eye growth and development and those controlling glucose metabolism. The findings indicate that SERPINI2 is a promising candidate for further investigations of the genetic susceptibility to myopia.
A System Pharmacology Study for Deciphering Anti Depression Activity of Nardostachys jatamansi.
Publisher: Bentham Science Publishers Ltd.
Date: 16-05-2018
DOI: 10.2174/1389200219666180305151011
Abstract: The plant Nardostachys jatamansi from Valerianaceae family is a well known antidepressant plant and has historically been used in traditional medicine. As N. jatamansi contains many different compounds, to identify its mechanisms of action, we need a network-based study. Network-based studies are becoming an increasingly important tool in understanding the mechanisms of actions of drugs. Systems pharmacology (SP) and bioinformatics are two emerging tools that use computation to develop an understanding of drug actions in molecular and cellular levels. SP can provide mechanistic understanding of protein-protein (drug-target) interaction involved in a common biological pathway. The present study was undertaken to identify unknown targets and mechanisms of antidepressant activity of N. jatamansi according to a systems pharmacology approach. First of all a list of all the targets (receptors and metabolites) involved in depression process were provided based on KEGG database. The 3D structures of protein targets were collected as PDB files and their active sites coordinates were found. In the next step the structures of known compounds of N. jatamansi were collected. For identifying the protein-lagand interactions, a docking process was run in AutoDock and an output was received. To complete our study, the similarity between antidepressant conventional drugs and N. jatamansi compounds was analyzed. A SP map figured by Cytoscape Software, shows the relations between herbal compounds, molecular targets and depression. According to the docking results, we can suggest several important targets that we have no drugs for, or several natural compounds that play an important role in depression process. According to the similarity results we can suggest several molecules for extraction or synthesis that need more researches for their therapeutic effects. This study shows that how N. jatamansi can effect on depression by multiple molecular targeting with multiple compounds.
Investigation of Genetic Variation in Scavenger Receptor Class B, Member 1 (SCARB1) and Association with Serum Carotenoids
Publisher: Elsevier BV
Date: 08-2013
Genome-wide multi-ethnic meta-analysis identifies 22 independent risk loci for normal tension glaucoma and predominantly overlaps with high tension glaucoma.
Publisher: Research Square Platform LLC
Date: 16-08-2023
DOI: 10.21203/RS.3.RS-3176408/V1
Abstract: Background Primary open-angle glaucoma (POAG) is often ided into two subtypes. High-tension glaucoma (HTG) is characterized by elevated intraocular pressure (IOP), while normal-tension glaucoma (NTG) is characterized by IOP consistently in the normal range. However, this notion is still controversial as some studies argue that different tension subtypes is part of the same pathogenic process while other studies claim that NTG represents a different etiological process where primary neurodegeneration has a higher impact. This study aimed to elucidate the shared and distinct genetic architecture for NTG and HTG. Method To identify risk loci specific to NTG, we conducted a large international multi-ethnic multi-trait meta-analysis of 7,942 NTG cases and 384,431 controls without any form of glaucoma, and a structural measurement of the integrity of the optic nerve, vertical cup-to-disc ratio (VCDR, N = 282,100), adjusted for IOP using the mtCOJO method. We also performed an assessment of the genetic overlap between NTG and HTG (N HTG cases = 5144, N controls = 47,997) using the GWAS pairwise method (GWAS-PW). Findings: This study identified 22 risk loci associated with NTG. Of these, 17 loci are novel for NTG, and two loci, BMP4 and TBKBP1 , have not previously been associated at the genome-wide significant level with glaucoma. The contribution of BMP4 in the development of NTG was further supported by integrating single-cell transcriptomic data from neuron-like cells, along with methylomic data from peripheral blood. Examination of each locus across the genome using the GWAS-PW method indicated that risk loci are shared across NTG and HTG. The magnitude of the effect of the genome-wide significant loci tends to be lower in NTG compared to their effects on HTG, particularly for IOP-related loci. Additionally, we identified 42 drug-gene interactions with four genes ( ABCA1, CDKN2A, CDKN2B and ITGB3 ) that were prioritized through our gene-based analysis. Interpretation: This work expands our understanding of the genetics of NTG and highlights a strong genetic overlap between HTG and NTG. Despite the genetic overlap, we have shown that IOP-related loci tend to have a smaller effect size in NTG when compared with HTG whereas neurodegenerative loci independent of IOP have similar effect sizes on NTG and HTG. These results indicate that while there is a significant overlap in risk loci between NTG and HTG, a precise estimation of their effect sizes on NTG using larger studies could help develop genetic risk prediction models to identify in iduals at a higher risk of developing NTG. We have also identified some potential targets for neuroprotective treatment through the interaction of four genes and multiple drugs. By harnessing multi-omics data, we substantiated the involvement of gene expression and DNA methylation of BMP4 in the etiology of NTG.
Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-03-2021
Abstract: A GWAS including 192,986 European and 1636 Asian participants identifies 50 novel discrete associations with eye color.
Outcomes of ptosis surgery assessed using a patient-reported outcome measure: an exploration of time effects
Publisher: BMJ
Date: 16-12-2013
DOI: 10.1136/BJOPHTHALMOL-2013-303946
Abstract: To explore effects of time following ptosis surgery on patient-reported quality-of-life outcomes. The Glasgow Benefit Inventory (GBI), a validated, postinterventional questionnaire was administered to consecutive adults undergoing ptosis surgery on the operating list of one surgeon over a 30-month period. Patients who were not contactable or unable to provide answers were excluded. Mean scores of patients grouped by time since surgery were compared (unpaired t test and Westlake intervals to test equivalence). Of 63 consecutive patients, 50 (79%) were included. Mean age was 63 years. Mean time since surgery was 561 days (range 21-973). There was no significant difference in mean total scores of patients assessed less than 18 months since surgery compared with those assessed later (p=0.544). Distributions of total scores were similar. No significant differences were found for subscores or when patients were ided into three groups according to time after surgery. Multivariate logistic regression revealed no significant effect of time since surgery. Trends were seen with regard to age and type of operation, but did not reach significance. Patient-perceived benefit following ptosis surgery shows stability with time, as assessed using the GBI. Future studies could explore correlations with age and type of surgery.
Executive and Attention Functioning Among Children in the PANDAS Subgroup
Publisher: Informa UK Limited
Date: 10-03-2009
Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci
Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
DOI: 10.1038/S41588-023-01428-5
Abstract: Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total s le size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total s le size over 2.8 million 296 loci replicated at P 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus.
Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium
Publisher: Springer Science and Business Media LLC
Date: 13-05-2016
DOI: 10.1038/SREP25853
Abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry s les (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4 P = 6.3E–04).
Naïve and memory B cells exhibit distinct biochemical responses following BCR engagement.
Publisher: Wiley
Date: 17-05-2016
DOI: 10.1038/ICB.2016.41
Abstract: Immunological memory is characterized by the rapid reactivation of memory B cells that produce large quantities of high-affinity antigen-specific antibodies. This contrasts the response of naïve B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines. Although we have known about the phenomenon of long-lived memory for centuries, the biochemical differences underlying these erse responses of naïve and memory B cells is incompletely resolved. Here we investigated the nature of B-cell receptor (BCR) signaling in human splenic naïve, IgM(+) memory and isotype-switched memory B cells following multivalent BCR crosslinking. We observed comparable rapid and transient phosphorylation kinetics for proximal (phosphotyrosine and spleen tyrosine kinase) and propagation (B-cell linker, phospholipase Cγ2) signaling components in these different B-cell subsets. However, the magnitude of activation of downstream components of the BCR signaling pathway were greater in memory compared with naïve cells. Although no differences were observed in the magnitude of Ca(2+) mobilization between subsets, IgM(+) memory B cells exhibited a more rapid Ca(2+) mobilization and a greater depletion of the Ca(2+) endoplasmic reticulum stores, while IgG(+) memory B cells had a prolonged Ca(2+) uptake. Collectively, our findings show that intrinsic signaling features of B-cell subsets contribute to the robust response of human memory B cells over naïve B cells. This has implications for our understanding of memory B-cell responses and provides a framework to modulate these responses in the setting of vaccination and immunopathologies, such as immunodeficiency and autoimmunity.
Copy Number Variation at Chromosome 5q21.2 Is Associated With Intraocular Pressure
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 24-05-2013
Ophthalmic Phenotypes and the Representativeness of Twin Data for the General Population
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 24-04-0007
DOI: 10.1167/IOVS.11-7258
Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract
Publisher: Springer Science and Business Media LLC
Date: 11-12-2020
DOI: 10.1038/S42003-020-01421-2
Abstract: Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable ( h 2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10 −16 ) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10 −19 ), TMPRSS5 (rs4936279, P = 2.5 × 10 −10 ), LINC01412 (rs16823886, P = 1.3 × 10 −9 ), GLTSCR1 (rs1005911, P = 9.8 × 10 −9 ), and COMMD1 (rs62149908, P = 1.2 × 10 −8 ). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.
Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma
Publisher: Public Library of Science (PLoS)
Date: 03-05-2012
Role of Educational Exposure in the Association Between Myopia and Birth Order
Publisher: American Medical Association (AMA)
Date: 12-2015
The physical and mental burden of dry eye disease: A large population-based study investigating the relationship with health-related quality of life and its determinants
Publisher: Elsevier BV
Date: 07-2021
Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error
Publisher: Elsevier BV
Date: 08-2013
Increasing Prevalence of Myopia in Europe and the Impact of Education
Publisher: Elsevier BV
Date: 07-2015
The Heritability of Dry Eye Disease in a Female Twin Cohort
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 13-11-2014
Repeatability of the macular pigment spatial profile: A comparison of objective versus subjective classification
Publisher: Wiley
Date: 29-08-2018
DOI: 10.1111/AOS.13725
Candidate gene study of macular response to supplemental lutein and zeaxanthin
Publisher: Elsevier BV
Date: 10-2013
High Heritability of Posterior Corneal Tomography, as Measured by Scheimpflug Imaging, in a Twin Study
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 25-11-2014
Abstract: Anterior corneal curvature shows significant heritability. Scheimpflug imaging also permits assessment of posterior tomography. We estimated heritability of posterior and anterior tomographic parameters. Oculus Pentacam images were obtained in twins from the TwinsUK cohort. Mean anterior and posterior radii of curvature (right cornea) were compared within twin pairs, and heritability calculated (maximum likelihood structural equation modeling, using OpenMx package). Heritability estimates also were calculated for other parameters (anterior and posterior elevation at apex and thinnest point pachymetry at apex and thinnest point average pachymetry progression index). Images from 138 twins were included (32 monozygotic [MZ] and 37 dizygotic [DZ] twin pairs). Mean (SD) age was 61 (11) years 91% were female. Coefficients for intrapair correlation for MZ and DZ twins were, respectively, 0.89 and 0.42 for anterior curvature, and 0.93 and 0.46 for posterior curvature (P ≤ 0.0001 for differences between MZ and DZ correlations Fisher r-to-z transformation). Heritability estimates (95% confidence interval [CI]) for anterior and posterior curvature were 89% (79%-93%) and 90% (83%-94%), respectively. Estimates for all other parameters were 75% or higher, except anterior apical elevation (61%). Point estimates for posterior parameters were consistently higher than anterior parameters, although CIs overlapped. Age-matching yielded similar estimates. Intereye correlations were high correlations with age were weak (r < 0.30). This is the first study to explore heritability of a number of different parameters of corneal tomography, including posterior curvature. Almost all parameters appeared highly heritable, with a trend toward higher heritability estimates for posterior (versus anterior) parameters.
Risk factors for myopia in a discordant monozygotic twin study
Publisher: Wiley
Date: 17-09-2015
DOI: 10.1111/OPO.12246
Genome-wide association identifies ATOH7 as a major gene determining human optic disc size
Publisher: Oxford University Press (OUP)
Date: 15-04-2010
DOI: 10.1093/HMG/DDQ144
Lumican and muscarinic acetylcholine receptor 1 gene polymorphisms associated with high myopia
Publisher: Springer Science and Business Media LLC
Date: 23-04-2010
DOI: 10.1038/EYE.2010.55
Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images
Publisher: Public Library of Science (PLoS)
Date: 12-05-2021
DOI: 10.1371/JOURNAL.PGEN.1009497
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.
Relationship Between Dry Eye Symptoms and Pain Sensitivity
Publisher: American Medical Association (AMA)
Date: 10-2013
DOI: 10.1001/JAMAOPHTHALMOL.2013.4399
Abstract: Dry eye disease (DED) is common, but little is known about factors contributing to symptoms of dry eye, given the poor correlation between these symptoms and objective signs at the ocular surface. To explore whether pain sensitivity plays a role in patients' experience of DED symptoms. A population-based cross-sectional study of 1635 female twin volunteers, aged 20 to 83 years, from the TwinsUK adult registry. Dry eye disease was diagnosed if participants had at least 1 of the following: (1) a diagnosis of DED by a clinician, (2) the prescription of artificial tears, and/or (3) symptoms of dry eyes for at least 3 months. A subset of 689 women completed the Ocular Surface Disease Index (OSDI) questionnaire. Quantitative sensory testing using heat stimulus on the forearm was used to assess pain sensitivity (heat pain threshold [HPT]) and pain tolerance (heat pain suprathreshold [HPST]). Of the 1622 participants included, 438 (27.0%) were categorized as having DED. Women with DED showed a significantly lower HPT (P = .03) and HPST (P = .003)--and hence had higher pain sensitivity--than those without DED. A strong significant association between the presence of pain symptoms on the OSDI and the HPT and HPST was found (P = .008 for the HPT and P = .003 for the HPST). In addition, participants with an HPT below the median had DED pain symptoms almost twice as often as those with an HPT above the median (31.2% vs 20.5% odds ratio, 1.76 95% CI, 1.15-2.71 P = .01). High pain sensitivity and low pain tolerance are associated with symptoms of DED, adding to previous associations of the severity of tear insufficiency, cell damage, and psychological factors. Management of DED symptoms is complex, and physicians need to consider the holistic picture, rather than simply treating ocular signs.
‘Dilatation’ and ‘dilation’: trends in use on both sides of the Atlantic
Publisher: BMJ
Date: 25-02-2014
Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Publisher: Springer Science and Business Media LLC
Date: 14-05-2018
DOI: 10.1038/S41467-018-03646-6
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, % 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.
Definitive Zygosity Scores in the Peas in the Pod Questionnaire is a Sensitive and Accurate Assessment of the Zygosity of Adult Twins
Publisher: Cambridge University Press (CUP)
Date: 27-03-2018
DOI: 10.1017/THG.2018.9
Abstract: Twin researchers face the challenge of accurately determining the zygosity of twins for research. As part of the annual questionnaire between 1999 and 2006, 8,307 twins from the TwinsUK registry were asked to complete five questions (independently from their co-twin) to ascertain their self-perceived zygosity during childhood on up to five separate occasions. This questionnaire is known as the ‘peas in the pod’ questionnaire (PPQ), but there is little evidence of its validation. Answers were scored and classified as monozygotic (MZ), dizygotic (DZ), or unknown zygosity (UZ) and were compared with 4,484 twins with genotyping data who had not been selected for zygosity. Of these, 3,859 in iduals (46.5% of those who had a zygosity from PPQ) had zygosity classified by both the PPQ and genotyping. Of the 708 in idual twins whose answers meant that they were consistently classed as MZ in the PPQ, 683 (96.5%) were MZ within the genotype data. Of the 945 in idual twins consistently classed as DZ within questionnaire, 936 (99.0%) were DZ in the genotype data. Where both twins scored MZ consistently across multiple questionnaires, 99.6% were MZ on genotyping, 99.7% were DZ on genotyping if both twins consistently scored DZ. However, for the initial questionnaire, 88.6% of those scoring as MZ were genotypically MZ and 98.7% DZ. For twin pairs where both scored UZ, 94.7% were DZ. Using the PPQ on a single occasion provided a definitive classification of whether the twin was MZ or DZ with an overall accuracy of 86.9%, increasing to 97.9% when there was a consistent classification of zygosity across multiple questionnaires. This study has shown that the PPQ questionnaire is an excellent proxy indicator of zygosity in the absence of genotyping information.
Identification of a Candidate Gene for Astigmatism
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 13-02-2013
Common Genetic Variants near the Brittle Cornea Syndrome Locus ZNF469 Influence the Blinding Disease Risk Factor Central Corneal Thickness
Publisher: Public Library of Science (PLoS)
Date: 13-05-2010
Deep Intronic Sequence Variants inCOL2A1Affect the Alternative Splicing Efficiency of Exon 2, and May Confer a Risk for Rhegmatogenous Retinal Detachment
Publisher: Hindawi Limited
Date: 21-08-2016
DOI: 10.1002/HUMU.23050
Abstract: COL2A1 mutations causing haploinsufficiency of type II collagen cause type 1 Stickler syndrome that has a high risk of retinal detachment and failure of the vitreous to develop normally. Exon 2 of COL2A1 is alternatively spliced, expressed in the eye but not in mature cartilage and encodes a region that binds growth factors TGFβ1 and BMP-2. We investigated how both an apparently de novo variant and a polymorphism in intron 2 altered the efficiency of COL2A1 exon 2 splicing and how the latter may act as a predisposing risk factor for the occurrence of posterior vitreous detachment (PVD)-associated rhegmatogenous retinal detachment (RRD) in the general population. Using lification of illegitimate transcripts and allele-specific minigenes expressed in cultured cells, we demonstrate variability in exon 2 inclusion not only between different control in iduals, but also between different COL2A1 alleles. We identify transacting factors that bind to allele-specific RNA sequences, and investigate the effect of knockdown and overexpression of these factors on exon 2 splicing efficiency. Finally, using a specific cohort of patients with PVD-associated RRD and a control population, we demonstrate a significant difference in the frequency of the COL2A1 intronic variant rs1635532 between the two groups.
Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM
Publisher: Springer Science and Business Media LLC
Date: 30-08-2011
DOI: 10.1038/MP.2011.101
Comparison of Associations with Different Macular Inner Retinal Thickness Parameters in a Large Cohort
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.OPHTHA.2019.08.015
Abstract: To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell-inner plexiform layer (GCIPL) thicknesses in a large cohort. Cross-sectional study. We included 42 044 participants in the UK Biobank. The mean age was 56 years. Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. Thicknesses of mRNFL, GCC, and GCIPL. We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: -0.46 μm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61-0.30] P = 1.1×10 The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma.
Improving outcomes in congenital cataract
Publisher: Springer Science and Business Media LLC
Date: 04-2018
DOI: 10.1038/NATURE26148
Optic Disc Planimetry, Corneal Hysteresis, Central Corneal Thickness, and Intraocular Pressure as Risk Factors for Glaucoma
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.AJO.2013.10.017
Abstract: To determine whether corneal hysteresis and central corneal thickness are independent risk factors for glaucoma. A cross-sectional population-based cohort study. Associations were tested between corneal hysteresis, measured in 1754 population-based subjects from the TwinsUK cohort, and glaucoma-related endophenotypes, including intraocular pressure (IOP), vertical cup-to-disc ratio, optic disc area, and optic disc cup area. Corneal hysteresis, IOP, and central corneal thickness (CCT) were measured optic disc photographs were analyzed and multivariable linear regression analysis was performed. Data were available on 1645 in iduals. Multiple regression analysis showed corneal hysteresis to be significantly negatively associated with age (beta coefficient = -0.03, P < .00005) and IOP (beta coefficient = -0.06, P < .00005). Corneal hysteresis was also found to be associated with CCT (beta coefficient = 0.02, P < .0005). There was no significant association between corneal hysteresis and optic disc area (P = .6), cup area (P = .77), vertical cup-to-disc ratio (P = .51), or spherical equivalent (P = .08). CCT was also found to be significantly associated with IOP (beta coefficient = 3.3, P < .0005) and corneal hysteresis (beta coefficient = 9.4, P < .0005), but not with age (P = .59) or spherical equivalent (P = .16). In this large cohort of healthy British twins, we found no relationship between corneal hysteresis or CCT and quantitative measures of optic disc cupping, suggesting that corneal hysteresis and CCT are not independent risk factors for glaucoma.
Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process
Publisher: Springer Science and Business Media LLC
Date: 22-09-2014
DOI: 10.1038/NCOMMS5883
Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 in iduals of European ancestry and 6,784 in iduals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Genome-Wide Association Study Identifies Two Common Loci Associated with Pigment Dispersion Syndrome/Pigmentary Glaucoma and Implicates Myopia in its Development
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.OPHTHA.2022.01.005
Abstract: To identify genetic variants associated with pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) in unrelated patients and to further understand the genetic and potentially causal relationships between PDS and associated risk factors. A 2-stage genome-wide association meta-analysis with replication and subsequent in silico analyses including Mendelian randomization. A total of 574 cases with PG or PDS and 52 627 controls of European descent. Genome-wide association analyses were performed in 4 cohorts and meta-analyzed in 3 stages: (1) a discovery meta-analysis was performed in 3 cohorts, (2) replication was performed in the fourth cohort, and (3) all 4 cohorts were meta-analyzed to increase statistical power. Two-s le Mendelian randomization was used to determine whether refractive error and intraocular pressure exert causal effects over PDS. The association of genetic variants with PDS and whether myopia exerts causal effects over PDS. Significant association was present at 2 novel loci for PDS/PG. These loci and follow-up analyses implicate the genes gamma secretase activator protein (GSAP) (lead single nucleotide polymorphism [SNP]: rs9641220, P = 6.0×10 Common SNPs relating to the GSAP and GRM5/TYR genes are associated risk factors for the development of PDS and PG. Although myopia is a known risk factor, this study uses genetic data to demonstrate that myopia is, in part, a cause of PDS and PG.
Prevalence and risk factors of dry eye disease in a British female cohort
Publisher: BMJ
Date: 03-09-2014
DOI: 10.1136/BJOPHTHALMOL-2014-305201
Abstract: To estimate the prevalence and risk factors of dry eye disease (DED) in a female cohort in the UK. Population-based cross-sectional association study of 3824 women from the TwinsUK cohort aged 20-87 years. A questionnaire was used to evaluate DED and several risk factors. Binary logistic regression, corrected for age, was used to examine the association between DED and risk factors. 9.6% of women had a DED diagnosis and concomitant use of artificial tears, and 20.8% experienced DED symptoms in the past 3 months. Risk factors that were significantly associated with DED were age, asthma, eczema, the presence of any allergy, cataract surgery, rheumatoid arthritis, osteoarthritis, migraine and stroke. The highest effect sizes were found with depression, pelvic pain, irritable bowel syndrome and chronic widespread pain syndrome (all p<0.0005). Subjects with DED symptoms scored significantly lower on self-perceived health, compared with controls (p=0.001). DED is common and increases with age within this cohort of female twins. We confirmed established risk factors for the first time in a British population, and found important risk factors that might relate to an underlying aetiology involving chronic pain predisposition or somatisation.
Prevalence of Age-Related Macular Degeneration in Europe
Publisher: Elsevier BV
Date: 12-2017
Clinical Characteristics of Dry Eye Patients With Chronic Pain Syndromes
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.AJO.2015.11.017
Abstract: To investigate clinical characteristics of dry eye disease (DED) patients with a chronic pain syndrome. Cross-sectional study. Four hundred twenty-five patients of a tertiary care DED patient cohort in the Netherlands were included. Chronic pain syndromes irritable bowel syndrome, chronic pelvic pain, and fibromyalgia were assessed by questionnaires. Outcome variables were the Ocular Surface Disease Index (OSDI) symptom questionnaire, tear osmolarity, Schirmer test, tear breakup time, conjunctival hyperemia, staining of the cornea and conjunctiva, and amount of mucus. Outcomes were cross-sectionally compared between DED patients with a chronic pain syndrome and those without. A total of 74 out of 425 DED patients (17%) had at least 1 chronic pain syndrome. The total symptom score was significantly higher in DED patients with a chronic pain syndrome than in those without (45.8 vs 33.8, P < .0005). Moreover, patients with a chronic pain syndrome scored higher on every single subscale of the 12-item OSDI symptom questionnaire. However, ocular signs were similar or even less severe in these patients. Similarly, in 64 DED patients from the population-based cohort TwinsUK, patients with a chronic pain syndrome (n = 24, 38%) had higher subscale and total (34.1 vs 14.4, P = .001) symptom scores. In DED patients, chronic pain syndromes are common and are associated with increased severity of DED symptoms across all domains of the OSDI, even though objective ocular surface signs are no worse. In clinical practice, more awareness of chronic pain syndromes might help in understanding the discrepancy between signs and symptoms in DED.
Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients
Publisher: BMJ
Date: 14-08-2015
DOI: 10.1136/JMEDGENET-2015-103290
Abstract: Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype-phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown. We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan-Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2. The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6-15 had lower mortality than patients with splice-site mutations in exons 1-5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier. Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.
A Genome-Wide Association Study of Optic Disc Parameters
Publisher: Public Library of Science (PLoS)
Date: 10-06-2010
Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study
Publisher: Oxford University Press (OUP)
Date: 06-06-2017
DOI: 10.1093/IJE/DYX068
Low-dose (0.01%) atropine eye-drops to reduce progression of myopia in children: A multicentre placebo-controlled randomised trial in the UK (CHAMP-UK) - Study protocol
Publisher: BMJ
Date: 25-10-2019
DOI: 10.1136/BJOPHTHALMOL-2019-314819
Abstract: To report the protocol of a trial designed to evaluate the efficacy, safety and mechanism of action of low-dose atropine (0.01%) eye-drops for reducing progression of myopia in UK children. Multicentre, double-masked, superiority, placebo-controlled, randomised trial. We will enrol children aged 6–12 years with myopia of −0.50 dioptres or worse in both eyes. We will recruit 289 participants with an allocation ratio of 2:1 (193 atropine 96 placebo) from five centres. Participants will instil one drop in each eye every day for 2 years and attend a research centre every 6 months. The vehicle and preservative will be the same in both study arms. The primary outcome is SER of both eyes measured by autorefractor under cycloplegia at 2 years (adjusted for baseline). Secondary outcomes include axial length, best corrected distance visual acuity, near visual acuity, reading speed, pupil diameter, accommodation, adverse event rates and allergic reactions, quality of life (EQ-5D-Y) and tolerability at 2 years. Mechanistic evaluations will include: peripheral axial length, peripheral retinal defocus, anterior chamber depth, iris colour, height and weight, activities questionnaire, ciliary body biometry and chorioretinal thickness. Endpoints from both eyes will be pooled in combined analysis using generalised estimating equations to allow for the correlation between eyes within participant. Three years after cessation of treatment, we will also evaluate refractive error and adverse events. The Childhood Atropine for Myopia Progression in the UK study will be the first randomised trial reporting outcomes of low-dose atropine eye-drops for children with myopia in a UK population. ISRCTN99883695 , NCT03690089 .
Effect of varying skin surface electrode position on electroretinogram responses recorded using a handheld stimulating and recording system
Publisher: Springer Science and Business Media LLC
Date: 25-07-2018
Can Visual Acuity Be Reliably Measured at Home? Validation of Telemedicine Remote Computerised Visual Acuity Measurements
Publisher: White Rose University Press
Date: 2021
DOI: 10.22599/BIOJ.179
Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia
Publisher: Springer Science and Business Media LLC
Date: 30-03-2020
Exploring correlations between change in visual acuity following routine cataract surgery and improvement in quality of life assessed with the Glasgow Benefit Inventory
Publisher: Springer Science and Business Media LLC
Date: 18-05-2018
Suitability of UK Biobank Retinal Images for Automatic Analysis of Morphometric Properties of the Vasculature
Publisher: Public Library of Science (PLoS)
Date: 22-05-2015
Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Publisher: Springer Science and Business Media LLC
Date: 08-01-2019
DOI: 10.1038/S41467-018-07819-1
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.
Metabolomic Pathways to Osteoporosis in Middle‐Aged Women: A Genome‐Metabolome‐Wide Mendelian Randomization Study
Publisher: Wiley
Date: 26-01-2018
DOI: 10.1002/JBMR.3358
Advances in the genomics of common eye diseases
Publisher: Oxford University Press (OUP)
Date: 19-08-2013
DOI: 10.1093/HMG/DDT396
The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study
Publisher: Public Library of Science (PLoS)
Date: 03-02-2011
Genome-wide association analysis identifies six new loci associated with forced vital capacity
Publisher: Springer Science and Business Media LLC
Date: 15-06-2014
DOI: 10.1038/NG.3011
EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans
Publisher: Public Library of Science (PLoS)
Date: 31-07-2009
Adjusted Sequence Kernel Association Test for Rare Variants Controlling for Cryptic and Family Relatedness
Publisher: Wiley
Date: 25-03-2013
DOI: 10.1002/GEPI.21725
Abstract: Recent progress in sequencing technologies makes it possible to identify rare and unique variants that may be associated with complex traits. However, the results of such efforts depend crucially on the use of efficient statistical methods and study designs. Although family-based designs might enrich a data set for familial rare disease variants, most existing rare variant association approaches assume independence of all in iduals. We introduce here a framework for association testing of rare variants in family-based designs. This framework is an adaptation of the sequence kernel association test (SKAT) which allows us to control for family structure. Our adjusted SKAT (ASKAT) combines the SKAT approach and the factored spectrally transformed linear mixed models (FaST-LMMs) algorithm to capture family effects based on a LMM incorporating the realized proportion of the genome that is identical by descent between pairs of in iduals, and using restricted maximum likelihood methods for estimation. In simulation studies, we evaluated type I error and power of this proposed method and we showed that regardless of the level of the trait heritability, our approach has good control of type I error and good power. Since our approach uses FaST-LMM to calculate variance components for the proposed mixed model, ASKAT is reasonably fast and can analyze hundreds of thousands of markers. Data from the UK twins consortium are presented to illustrate the ASKAT methodology.
IMI – Myopia Genetics Report
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 28-02-2019
Quantitative genetic analysis of the retinal vascular caliber: The australian twins eye study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
DOI: 10.1161/HYPERTENSIONAHA.109.132902
Abstract: Research into the genetic effects and specific genes associated with retinal vascular caliber, a risk marker of cardiovascular diseases, may provide new insights into the genetic contribution of early microvascular disease. A combined 374 monozygotic and 536 dizygotic twin pairs and 322 siblings from the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study underwent complete ophthalmic examinations, including retinal photography, and bilateral retinal vascular caliber was measured. Structural equation modeling was used to estimate the heritability. Genome-wide linkage analysis was conducted on 836 in iduals from 381 Brisbane Adolescent Twin Study families, with adjustments for age, sex, and other covariates. The heritabilities for the retinal arteriolar caliber were 59.4% (95% CI: 53.2% to 64.7%) and 56.5% (95% CI: 50.1% to 61.9%) in the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study, respectively, and for venular caliber they were 61.7% (95% CI: 55.6% to 67.0%) and 64.2% (95% CI: 58.7% to 68.8%), respectively, after adjusting for age, sex, and body mass index. Two multipoint peaks detected on chromosomes 3p12.3 and 8p23.1 for retinal arteriolar caliber had suggestive linkage, with the highest multipoint peak logarithm of odds score of 2.24 on chromosome 8p23.1 (genome-wide P =7.0×10 −4 ). Two suggestive logarithm of odds scores for venular caliber were identified on chromosomes 2p14 and 9q21.13. The largest multipoint logarithm of odds score was 2.69 on chromosome 2p14 (genome-wide P =2.0×10 −4 ). In this large twin population, genetic factors appear to play a significant role in the variation of retinal vascular caliber. Several putative loci were identified for the retinal vascular caliber.
Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis
Publisher: Springer Science and Business Media LLC
Date: 13-03-2011
DOI: 10.1038/NG.789
Interocular Asymmetries in Axial Length and Refractive Error in 4 Cohorts
Publisher: Elsevier BV
Date: 03-2015
Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders.
Publisher: Elsevier BV
Date: 06-2023
Book review
Publisher: Springer Science and Business Media LLC
Date: 11-1995
DOI: 10.1038/EYE.1995.211
Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NG.661
How strong is the relationship between glaucoma, the retinal nerve fibre layer, and neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis?
Publisher: Springer Science and Business Media LLC
Date: 04-09-2015
DOI: 10.1038/EYE.2015.158
Cascade screening for glaucoma in high-risk family members of African-Caribbean glaucoma patients in an urban population in London
Publisher: BMJ
Date: 10-12-2020
DOI: 10.1136/BJOPHTHALMOL-2020-317373
Abstract: Cascade screening has been used successfully in relatives of patients with inherited cancers and other genetic diseases to identify presymptomatic disease. This study was designed to examine if this approach would be successful in a high-risk group: first-degree relatives (FDR) of African-Caribbean glaucoma patients resident in London. African-Caribbean patients (probands) with glaucoma from an inner London hospital setting in a deprived area were asked to disseminate personalised information to their FDR over the age of 30 and to arrange a free hospital-based screening. Data collected, including optical coherence tomography imaging, were reviewed by a glaucoma specialist and if glaucoma was diagnosed or suspected, local specialist referral via family doctor was made. 203 probands were recruited from glaucoma clinics. 248 suitable FDR were identified as potentially eligible to attend screening. 57 (23%) FDR made contact with the research team of whom 18 (7%) attended a subsequent screening visit. No patients were diagnosed with glaucoma one participant was diagnosed as glaucoma suspect. Reasons for poor uptake included reluctance by probands to involve their family members, and retirees spending significant time abroad. Cascade screening of FDR of African-Caribbean glaucoma patients in inner city London was unsuccessful. Research confidentiality guidance prohibiting research teams directly contacting family members was a barrier. Greater community engagement, community-based screening and permission to contact FDR directly might have improved uptake.
Genetic variants near PDGFRA are associated with corneal curvature in Australians
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 11-10-2012
A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NG.664
Measures of socioeconomic status and self-reported glaucoma in the UK Biobank cohort
Publisher: Springer Science and Business Media LLC
Date: 28-08-2015
DOI: 10.1038/EYE.2015.157
A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NG.663
Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci
Publisher: Public Library of Science (PLoS)
Date: 18-09-2014
The Heritability of the Ring-Like Distribution of Macular Pigment Assessed in a Twin Study
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 07-04-2014
Leadership Enabling Effective Pedagogic Change in Higher Education
Publisher: Springer International Publishing
Date: 06-11-2014
The UK Adult Twin Registry (TwinsUK Resource)
Publisher: Cambridge University Press (CUP)
Date: 22-10-2012
DOI: 10.1017/THG.2012.89
Abstract: TwinsUK is a nation-wide registry of volunteer twins in the United Kingdom, with about 12,000 registered twins (83% female, equal number of monozygotic and dizygotic twins, predominantly middle-aged and older). Over the last 20 years, questionnaire and blood/urine/tissue s les have been collected on over 7,000 subjects, as well as three comprehensive phenotyping assessments in the clinical facilities of the Department of Twin Research and Genetic Epidemiology, King's College London. The primary focus of study has been the genetic basis of healthy aging process and complex diseases, including cardiovascular, metabolic, musculoskeletal, and ophthalmologic disorders. Alongside the detailed clinical, biochemical, behavioral, and socio-economic characterization of the study population, the major strength of TwinsUK is availability of several ‘omics’ technologies for the participants. These include genome-wide scans of single nucleotide variants, next-generation sequencing, exome sequencing, epigenetic markers (MeDIP sequencing), gene expression arrays and RNA sequencing, telomere length measures, metabolomic profiles, and gut flora microbiomics. The scientific community now can freely access parts of the phenotype data from the ‘TwinsUK’, and interested researchers are encouraged to contact us via our Web site ( www.twinsuk.ac.uk ) for future collaborations.
Relative Genetic and Environmental Contributions to Variations in Human Retinal Electrical Responses Quantified in a Twin Study
Publisher: Elsevier BV
Date: 08-2017
Audit of the use of IVC filters in the UK: experience from three centres over 12 years
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.CRAD.2009.01.009
Abstract: To audit the use of inferior vena cava (IVC) filter insertions at three UK centres over 12 years to assess whether trends in filter use in the UK mirrored those seen elsewhere. Radiology department databases were interrogated for IVC filter insertions and removals between 1994 and 2006. Reports for these interventions, along with prior and subsequent imaging reports, were analysed. Follow-up data were obtained when available. Five hundred and sixteen filters were placed with a significant year-on-year trend towards increasing use. Fifty-seven percent of filters placed were for absolute indications and 37% for relative indications. The filters were used for prophylaxis in 6% of patients in the absence of proven pulmonary embolism (PE) or deep vein thrombosis (DVT). A retrievable filter was used in 74% of cases with retrieval attempted in 40% of these and no evidence of an increasing rate of retrieval over time. A significant complication related to insertion or retrieval was encountered in 0.4 and 1% of procedures, respectively. Mean 24 h and 30 day mortalities were 1 and 8%, respectively. There was an absence of organized follow-up at all three centres. IVC filter use in the UK is increasing. The use of retrievable filters has not resulted in increased filter retrieval. Filter insertion and retrieval is associated with a low risk of significant complication, but lack of systematic follow-up limits conclusions regarding safety and efficacy.
Cohort profile: design and methods in the eye and vision consortium of UK Biobank
Publisher: BMJ
Date: 02-2019
DOI: 10.1136/BMJOPEN-2018-025077
Abstract: To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank. 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. 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. 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 s le 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.
New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.
Publisher: Oxford University Press (OUP)
Date: 10-01-2017
DOI: 10.1093/HMG/DDW399
Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma
Publisher: Springer Science and Business Media LLC
Date: 31-08-2014
DOI: 10.1038/NG.3087
Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma
Publisher: Springer Science and Business Media LLC
Date: 11-01-2016
DOI: 10.1038/NG.3482
Spectral-Domain Optical Coherence Tomography Imaging in 67 321 Adults
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.OPHTHA.2015.11.009
Abstract: To derive macular thickness measures and their associations by performing rapid, automated segmentation of spectral-domain optical coherence tomography (SD OCT) images collected and stored as part of the UK Biobank (UKBB) study. Large, multisite cohort study in the United Kingdom. Analysis of cross-sectional data. Adults from the United Kingdom aged 40 to 69 years. Participants had nonmydriatic SD OCT (Topcon 3D OCT-1000 Mark II Topcon GB, Newberry, Berkshire, UK) performed as part of the ocular assessment module. Rapid, remote, automated segmentation of the images was performed using custom optical coherence tomography (OCT) image analysis software (Topcon Advanced Boundary Segmentation [TABS] Topcon GB) to generate macular thickness values. We excluded people with a history of ocular or systemic disease (diabetes or neurodegenerative diseases) and eyes with reduced vision (<0.1 logarithm of the minimum angle of resolution) or with low SD OCT signal-to-noise ratio and low segmentation success certainty. Macular thickness values across 9 Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields. The SD OCT scans of 67 321 subjects were available for analysis, with 32 062 people with at least 1 eye meeting the inclusion criteria. There were 17 274 women and 14 788 men, with a mean (standard deviation [SD]) age of 55.2 (8.2) years. The mean (SD) logarithm of the minimum angle of resolution visual acuity was -0.075 (0.087), and the refractive error was -0.071 (+1.91) diopters (D). The mean (SD) central macular thickness (CMT) in the central 1-mm ETDRS subfield was 264.5 (22.9) μm, with 95% confidence limits of 220.8 and 311.5 μm. After adjusting for covariates, CMT was positively correlated with older age, female gender, greater myopia, smoking, body mass index (BMI), and white ethnicity (all P < 0.001). Of note, macular thickness in other subfields was negatively correlated with older age and greater myopia. We report macular thickness data derived from SD OCT images collected as part of the UKBB study and found novel associations among older age, ethnicity, BMI, smoking, and macular thickness.
Low concentration atropine and myopia: a narrative review of the evidence for United Kingdom based practitioners
Publisher: Springer Science and Business Media LLC
Date: 16-09-2023
Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia
Publisher: Springer Science and Business Media LLC
Date: 10-02-2013
DOI: 10.1038/NG.2554
Modelling the initial phase of the human rod photoreceptor response to the onset of steady illumination
Publisher: Springer Science and Business Media LLC
Date: 19-02-2012
DOI: 10.1007/S10633-012-9316-3
Abstract: The initial time course of the change in photoreceptor outer segment membrane conductance in response to light flashes has been modelled using biochemical analysis of phototransduction, and the model has been successfully applied to a range of in vitro recordings and has also been shown to provide a good fit to the leading edge of the electroretinogram a-wave recorded in vivo. We investigated whether a simple modification of the model's equation would predict responses to the onset of steady illumination and tested this against electroretinogram recordings. Scotopic electroretinograms were recorded from three normal human subjects, using conductive fibre electrodes, in response to light flashes (0.30-740 scotopic cd m(-2) s) and to the onset of steady light (11-1,900 scotopic cd m(-2)). Subjects' pupils were dilated pharmacologically. The standard form of the model was applied to flash responses, as in previous studies, to obtain values for the three parameters: maximal response litude r (max), sensitivity S and effective delay time t (eff). A new "step response" equation was derived, and this equation provided a good fit to rod responses to steps of light using the same parameter values as for the flash responses. The results support the applicability of the model to the leading edge of electroretinogram responses: in each subject, the model could be used to fit responses both to flashes of light and to the onset of backgrounds with a single set of parameter values.
Surrogate Decision Making in the Case of a Pregnant Woman Newly Disabled With Brain Injury
Publisher: Wiley
Date: 2013
Association of FTO gene variants with body composition in UK twins
Publisher: Wiley
Date: 23-07-2012
Medication use and dry eye symptoms: A large, hypothesis-free, population-based study in the Netherlands
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.JTOS.2021.06.009
Abstract: To date, population-based studies reporting associations between dry eye disease and medications were hypothesis-driven, did not take into account underlying comorbidities, and did not investigate in idual drugs. The purpose of this study was to clarify the association of dry eye symptoms with medication classes and in idual drugs, using a hypothesis-free approach. 79,606 participants (age 20-97 years, 59.2% female) from the population-based Lifelines cohort in the Netherlands were cross-sectionally assessed for dry eye symptoms using the Womens' Health Study dry eye questionnaire. All medications used were coded with the ATC classification system. Logistic regression was used to assess the risk of the 59 most-used therapeutic harmacological subgroups and the 99 most-used in idual drugs (all n > 200) on dry eye symptoms, correcting for age, sex, body mass index, and 48 comorbidities associated with dry eye. Thirty-eight (64%) medication subgroups and fifty-two (53%) in idual drugs were associated with dry eye symptoms (P < 0.05), after correction for age and sex only. A multivariable model correcting for comorbidities revealed highly significant associations between dry eye symptoms and drugs for peptic ulcer (particularly proton pump inhibitors (PPIs)), antiglaucoma and anticholinergic medications. This study underlines that medication use is highly informative of risk of dry eye symptoms. Correction for underlying comorbidities is critical to avoid confounding effects. This study confirms suggested associations between medications and dry eye symptoms at a population level and shows several new associations. The novel link between PPIs and dry eye symptoms deserves particular attention given how commonly they are prescribed.
Self-reported symptoms of covid-19 including symptoms most predictive of SARS-CoV-2 infection, are heritable
Publisher: Cold Spring Harbor Laboratory
Date: 24-04-2020
DOI: 10.1101/2020.04.22.20072124
Abstract: Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n=2633) completing the C-19 Covid symptom tracker app allowed classical twin studies of covid-19 symptoms including predicted covid-19, a symptom-based algorithm predicting true infection derived in app users tested for SARS-CoV-2. We found heritability for fever = 41 (95% confidence intervals 12-70)% anosmia 47 (27-67)% delirium 49 (24-75)% and predicted covid-19 gave heritability = 50 (29-70)%.
Association Mapping of the High-Grade MyopiaMYP3Locus Reveals Novel CandidatesUHRF1BP1L,PTPRR, andPPFIA2
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 21-03-2013
Re: Datiles et al.: Longitudinal study of age-related cataract using dynamic light scattering: loss of α-crystallin leads to nuclear cataract development (Ophthalmology 2016;123:248-54)
Publisher: Elsevier BV
Date: 08-2016
Repeated Measures of Intraocular Pressure Result in Higher Heritability and Greater Power in Genetic Linkage Studies
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 11-2009
DOI: 10.1167/IOVS.09-3577
Low copy number of the salivary amylase gene predisposes to obesity
Publisher: Springer Science and Business Media LLC
Date: 30-03-2014
DOI: 10.1038/NG.2939
Age of myopia onset in a B ritish population‐based twin cohort
Publisher: Wiley
Date: 20-03-2013
DOI: 10.1111/OPO.12042
Abstract: School-age myopia is becoming more common in Asia and North America data from the United Kingdom has suggested a significant amount of myopia develops after the age of 17 years. Age of spectacle wear has been used as a proxy of myopia severity in a recent large genome-wide association study. The purpose of this study was to examine the age of onset of spectacle wear in a large British twin cohort, to examine the reliability and reproducibility of self-reported age of onset as a proxy measure of myopia severity, and to see if there is evidence in the UK of a rising prevalence of myopia. Non-cycloplegic autorefraction was performed on over 6000 subjects from the Twins UK cohort, a large, well-characterized volunteer cohort of British, predominantly Caucasian female twins, between 1998 and 2010. Questionnaires asking age of first spectacle wear were conducted in 2003 and 2008. Myopia was defined as worse than or equal to -1.00 Dioptres, and adult onset myopia as occurring on or after the age of 17 years. Autorefractive data was available on 6097 participants at a mean age of 53 years. The mean S.E. was -0.36 D (S.D. 2.67, range -25.13 to +9.38). 1705 subjects (28%) were myopic with a mean refractive error of -3.54 (S.D. 2.51, range -25.13 to -1.00) and the median age of first glasses wear was 15 years (mean 18.4 years, S.D. 12.24, range 0-74). Of those who provided an age at which they first wore glasses in both questionnaire sources (n = 628), there was median difference in response of 0 years (S.D. 7.18, mean 0.7, maximum 53). A statistically significant cohort effect for increased myopia prevalence across a range of age groups between 1998-1999 and 2008-2010 was identified, with myopia prevalence increasing from 27% to 34% in those aged 50-54 and from 16% to 32% in those aged 55-59. Almost half the myopes in this UK-based population wore glasses after the age of 17 further research into adult-onset myopia is required. Although self-reported age of glasses is reproducible and reflects severity, it only explains approximately 15% of the variance of spherical equivalent, so is a rough proxy of refractive error, but still may be useful in large-scale population studies without access to refraction. We have demonstrated a significant cohort effect for increased myopia prevalence in the UK population over a 10-year period.
Shared genetic factors underlie chronic pain syndromes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2014
DOI: 10.1016/J.PAIN.2014.05.002
Abstract: Chronic pain syndromes (CPS) are highly prevalent in the general population, and increasingly the evidence points to a common etiological pathway. Using a large cohort of twins (n=8564) characterized for chronic widespread musculoskeletal pain (CWP), chronic pelvic pain (PP), migraine (MIG), dry eye disease, and irritable bowel syndrome (IBS), we explored the underlying genetic and environmental factors contributing to CPS and the correlation between them. The s le was predominantly female (87.3%), with a mean age of 54.7 (±14.7) years. Prevalence of the different CPS ranged from 7.4% (PP) to 15.7% (MIG). For all CPS the within-twin correlation in monozygotic twin pairs was higher than in dizygotic pairs, suggesting a heritable component. Estimated heritability ranged from 19% (IBS) to 46% (PP). Except for MIG, we found significant pairwise phenotypic correlations between the CPS. The phenotypic correlation was highest between CWP and IBS (0.40 95% confidence interval: 0.27 to 0.46). Excluding MIG from further analyses, cross-twin cross-trait correlations were higher in monozygotic compared with dizygotic twin pairs, suggestive of shared genetic factors between CWP, PP, IBS, and dry eye disease. Twin modeling analysis revealed the common pathway model as the model best explaining the observed pattern of correlation between the traits, with an estimated heritability of 66% of the underlying latent variable. These results are evidence of shared genetic factors in conditions manifesting chronic pain and justify the search for underlying genetic variants.
Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
DOI: 10.1038/NCOMMS11008
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 in iduals, 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 .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.
The correlation between cognitive performance and retinal nerve fibre layer thickness is largely explained by genetic factors
Publisher: Springer Science and Business Media LLC
Date: 28-09-2016
DOI: 10.1038/SREP34116
Abstract: Retinal nerve fibre layer (RNFL) thickness has been associated with cognitive function but it is unclear whether RNFL thinning is secondary to cortical loss, or if the same disease process affects both. We explored whether there is phenotypic sharing between RNFL thickness and cognitive traits and whether such sharing is due to genetic factors. Detailed eye and cognitive examination were performed on 1602 twins (mean age: 56.4 years range: 18–89) from the TwinsUK cohort. Associations between RNFL thickness and ophthalmic, cognitive and other predictors were assessed using linear regression or analysis of variance models. Heritability analyses were performed using uni- and bivariate Cholesky decomposition models. RNFL was thinner with increase in myopia and with decrease in disc area (p 0.001). A thicker RNFL was associated with better performance on mini mental state examination (MMSE, F(5,883) = 5.8, p 0.001) and with faster reaction time (RT, β = −0.01 p = 0.01) independent of the effects of age, refractive error and disc area (p 0.05). RNFL thickness was highly heritable (82%) but there was low phenotypic sharing between RNFL thickness and MMSE (5%, 95% CI: 0–10%) or RT (7%, 95% CI: 1–12%). This sharing, however, was mostly due to additive genetic effects (67% and 92% of the shared variance respectively).
Potential effect of ‘cut-off intensity’ on correlation between light meter measurements and time outdoors
Publisher: Springer Science and Business Media LLC
Date: 24-05-2013
DOI: 10.1038/EYE.2013.88
Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility
Publisher: Springer Science and Business Media LLC
Date: 24-11-2017
DOI: 10.1038/S41467-017-00837-5
Abstract: Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1 , that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically erse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.
Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error
Publisher: Springer Science and Business Media LLC
Date: 28-05-2018
Do twins share the same dress code? Quantifying relative genetic and environmental contributions to subjective perceptions of “the dress” in a classical twin study
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 27-01-2017
DOI: 10.1167/17.1.29
Abstract: The phenomenon of contrasting color perceptions of "the dress" photograph has gained scientific interest. The mechanism underlying why in iduals differ is yet to be fully explained. We use the powerful twin model design to ascertain the relative contribution of genetic and environmental factors on perception variation. A s le of 466 twins from the British TwinsUK registry were invited to report what color they saw in a standard image of the dress in standard illumination. The mean age of the participants was 49.5 (SD = 17.8) years, and 85% were female. When asked to choose between white and gold (WG) or blue and black (BB), 328 reported WG (70.4%) and 135 (29.0%) reported BB. Subjects choosing WG were significantly older (p < 0.01), but there was no significant difference in gender. Monozygotic (MZ) twins were more concordant in their responses than dizygotic (DZ) twins (0.46 vs. 0.36). Twin modeling revealed that genetic factors accounted for 34% (95% confidence interval, 5%-59%) of variation in the reported color of the dress when adjusted for age, whereas environmental factors contributed 66% (95% CI, 41%-95%). This study suggests environmental factors play a significant role in how an in idual perceives the color of "the dress."
What is the appropriate age cut-off for cycloplegia in refraction?
Publisher: Wiley
Date: 19-03-2014
DOI: 10.1111/AOS.12388
Abstract: To investigate the age range for which cycloplegia provides additional information compared with non-cycloplegic refraction in teenagers and young adults. Data for 1295 subjects (704 female 591 male) from the Twins Eye Study in Tasmania (TEST) and the Brisbane Adolescent Twin Study (mean age: 19.65 ± 3.56, range: 13-26 years) were included. For all participants, cycloplegia was induced by instillation of either one drop of 1% cyclopentolate (13-14 years) or one drop of 1% tropicamide (15-26 years). Pre- and postcycloplegic refractive errors for both eyes were measured using a Humphrey-598 automated refractor and spherical equivalents of refractive error were calculated. Generalized Estimating Equations (GEE) were used to model the spherical equivalent refraction (SER) for each eye against age (by year) and axial length (in the given eye). The mean group difference between pre- and postcycloplegic SER (post minus pre) was 0.17 ± 0.52 D and 0.12 ± 0.51 D for the right and left eyes, respectively, indicating that postcycloplegic refraction was generally more hyperopic/less myopic. The mean difference between pre- and postcycloplegic SER decreased from 0.36 ± 0.41 D in the 13-year-olds to 0.06 ± 0.50 D in people aged 25 years. After adjusting for family-relatedness, the difference between pre- and postcycloplegia SER was significant in all age groups up until the age of 20 years. Non-cycloplegic autorefraction can result in group mean SER differences of greater myopia than cycloplegic autorefraction and occurs in teenagers (13-19 years of age), but not in adults 20-26 years. These data suggest that cycloplegia is not required in population estimates of refractive error for young adults once they reach approximately 20 years of age.
Comparison of three methods of intraocular pressure measurement and their relation to central corneal thickness
Publisher: Springer Science and Business Media LLC
Date: 12-02-2010
DOI: 10.1038/EYE.2010.11
Abstract: The purpose of this study was to compare the reliability of the 'gold standard' Goldmann applanation tonometer (GAT), with that of the ocular response analyser (ORA), and the dynamic contour tonometer (DCT). A total of 694 subjects were recruited to participate from the TwinsUK (UK Adult Twin Registry) at St Thomas' Hospital, London. Intraocular pressure (IOP) was measured using GAT, ORA, and the DCT. The agreement between the three methods was assessed using the Bland-Altman method. Repeatability coefficients and coefficient of variation between first and second readings of the same eye were used to assess reliability. Mean age was 57.5 years (SD, 13.1 range, 16.1-88.5). The mean IOPs, calculated using the mean of two readings from the right eye were as follows: Goldmann (GAT), 14.1+/-2.8 mm Hg IOPg (ORA), 15.9+/-3.2 mm Hg IOPcc (ORA), 16.6+/-3.2 mm Hg and DCT, 16.9+/-2.7 mm Hg. The 95% limits of agreement were for ORA (IOPcc): GAT, -2.07 to 7.18 mm Hg for DCT: GAT, -0.49 to 6.21 mm Hg and for DCT: ORA (IOPcc), -3.01 to 4.85 mm Hg. Coefficients of variation for the three tonometers were GAT, 8.3% ORA, 8.2% DCT, 6.3%. The repeatability coefficients were 3.4 mm Hg for GAT, 3.57 mm Hg for ORA and 3.09 mm Hg for DCT. GAT and ORA (IOPg) readings showed a positive correlation with central corneal thickness (P<0.005). This study found similar reliability in all three tonometers. Bland-Altman plots showed the three instruments to have 95% limits of agreement outside the generally accepted limits, which means they are not interchangeable. GAT measurements were found to be significantly lower than the two newer instruments.
Changes in quality of life shortly after routine cataract surgery
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.JCJO.2016.02.004
Abstract: To perform a pilot study to explore use of a generic patient-reported outcome measure to assess patient-perceived improvements in quality of life within 2-4 weeks of routine cataract surgery and to explore differences after first or second eye surgery. Secondary analysis explored effects of gender and ethnicity. Prospective observational study. Consecutive patients attending a weekly nurse-led postoperative clinic. The Glasgow Benefit Inventory (GBI), a validated, postinterventional questionnaire (not specific to one particular medical or surgical intervention), was administered. Mean scores were calculated. Scores were compared when patients were grouped by first or second eye, and by gender or ethnicity (unpaired t test). Scores potentially range from +100 (maximum benefit) to -100 (maximum detriment). The GBI was administered 113 times to 109 patients (4 patients were seen after both first and second eye surgery). Mean overall score was +22.8 (median +19.4 SD 19.7 95% CI +19.2 to +26.4). Mean (SD) subscores were +30.5 (25.3), +17.8 (26.7), and -3.1 (19.9) for general, social support, and physical health subdomains, respectively. Total benefit scores were not significantly different for first or second eye surgery, or across gender (p > 0.3). Scores for patients of African (including African Caribbean) ethnicity were significantly higher than those obtained from European patients (p = 0.002). Patients reported significant improvements in quality of life even a few weeks after cataract surgery, as assessed by the GBI. Second eye surgery appeared to confer similar benefit to first eye surgery. The significant difference in scores between ethnic groups invites further investigation.
Twins Eye Study in Tasmania (TEST): Rationale and Methodology to Recruit and Examine Twins
Publisher: Cambridge University Press (CUP)
Date: 10-2009
Abstract: Visual impairment is a leading cause of morbidity and poor quality of life in our community. Unravelling the mechanisms underpinning important blinding diseases could allow preventative or curative steps to be implemented. Twin siblings provide a unique opportunity in biology to discover genes associated with numerous eye diseases and ocular biometry. Twins are particularly useful for quantitative trait analysis through genome-wide association and linkage studies. Although many studies involving twins rely on twin registries, we present our approach to the Twins Eye Study in Tasmania to provide insight into possible recruitment strategies, expected participation rates and potential examination strategies that can be considered by other researchers for similar studies. Five separate avenues for cohort recruitment were adopted: (1) piggy-backing existing studies where twins had been recruited, (2) utilizing the national twin registry, (3) word-of-mouth and local media publicity, (4) directly approaching schools, and finally (5) collaborating with other research groups studying twins.
Genetic African Ancestry Is Associated With Central Corneal Thickness and Intraocular Pressure in Primary Open-Angle Glaucoma
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 23-06-2017
Abstract: To unravel the relationship between African ancestry, central corneal thickness (CCT), and intraocular pressure (IOP) by estimating the genetic African ancestry (GAA) proportion in primary open-angle glaucoma (POAG) patients and controls from an admixed South African Colored (SAC) and a South African Black (SAB) population. In this case-control study, 268 POAG patients and 137 controls were recruited from a university clinic in Cape Town, South Africa. All participants were genotyped on the Illumina HumanOmniExpress beadchip or HumanOmni2.5Exome beadchip. ADMIXTURE was used to infer participant's GAA among 86,632 SNPs. Linear and logistic regression models were used to assess the relation between GAA, POAG, CCT, and IOP. The median proportion of GAA was 60% in the study population. GAA was significantly associated with thinner CCT (P 60% GAA, CCT was not associated with POAG (P = 0.550). This study demonstrated that a higher proportion of GAA was associated with a thinner CCT and a higher IOP in POAG patients. Remarkably, at higher proportions of GAA, the difference in CCT between POAG and controls was reduced. This suggests that thinner CCT is not associated with POAG in Africans.
Phenotypic and genotypic correlation between myopia and intelligence
Publisher: Springer Science and Business Media LLC
Date: 06-04-2017
DOI: 10.1038/SREP45977
Abstract: Myopia, or near-sightedness, is our most common eye condition and the prevalence is increasing globally. Visual impairment will occur if uncorrected, whilst high myopia causes sight-threatening complications. Myopia is associated with higher intelligence. As both are heritable, we set out to examine whether there is a genetic correlation between myopia and intelligence in over 1,500 subjects (aged 14–18 years) from a twin birth cohort. The phenotypic correlation between refractive error and intelligence was −0.116 (p 0.01) - the inverse correlation due to the fact that myopia is a negative refractive error. Bivariate twin modeling confirmed both traits were heritable (refractive error 85%, intelligence 47%) and the genetic correlation was −0.143 (95% CI −0.013 to −0.273). Of the small phenotypic correlation the majority (78%) was explained by genetic factors. Polygenic risk scores were constructed based on common genetic variants identified in previous genome-wide association studies of refractive error and intelligence. Genetic variants for intelligence and refractive error explain some of the reciprocal variance, suggesting genetic pleiotropy in the best-fit model the polygenic score for intelligence explained 0.99% (p = 0.008) of refractive error variance. These novel findings indicate shared genetic factors contribute significantly to the covariance between myopia and intelligence.
Myopia: Why Study the Mechanisms of Myopia? Novel Approaches to Risk Factors Signaling Eye Growth- How Could Basic Biology Be Translated into Clinical Insights? Where Are Genetic and Proteomic Approac
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
Rare variant analyses across multiethnic cohorts identify novel genes for refractive error
Publisher: Research Square Platform LLC
Date: 03-09-2021
DOI: 10.21203/RS.3.RS-846265/V1
Abstract: Refractive error is a complex eye condition caused by both genetic and environmental factors. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests for rare variants on exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and East Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP , the circadian rhythm gene PER3 , and P4HTM , which affects eye morphology. Future work will include functional studies and validation.
Aging Trajectories in Different Body Systems Share Common Environmental Etiology: The Healthy Aging Twin Study (HATS)
Publisher: Cambridge University Press (CUP)
Date: 26-01-2016
DOI: 10.1017/THG.2015.100
Abstract: Little is known about the extent to which aging trajectories of different body systems share common sources of variance. We here present a large twin study investigating the trajectories of change in five systems: cardiovascular, respiratory, skeletal, morphometric, and metabolic. Longitudinal clinical data were collected on 3,508 female twins in the TwinsUK registry (complete pairs:740 monozygotic (MZ), 986 dizygotic (DZ), mean age at entry 48.9 ± 10.4, range 18–75 years mean follow-up 10.2 ± 2.8 years, range 4–17.8 years). Panel data on multiple age-related variables were used to estimate biological ages for each in idual at each time point, in linear mixed effects models. A weighted average approach was used to combine variables within predefined body system groups. Aging trajectories for each system in each in idual were then constructed using linear modeling. Multivariate structural equation modeling of these aging trajectories showed low genetic effects (heritability), ranging from 2% in metabolic aging to 22% in cardiovascular aging. However, we found a significant effect of shared environmental factors on the variations in aging trajectories in cardiovascular (54%), skeletal (34%), morphometric (53%), and metabolic systems (53%). The remainder was due to environmental factors unique to each in idual plus error. Multivariate Cholesky decomposition showed that among aging trajectories for various body systems there were significant and substantial correlations between the unique environmental latent factors as well as shared environmental factors. However, there was no evidence for a single common factor for aging. This study, the first of its kind in aging, suggests that erse organ systems share non-genetic sources of variance for aging trajectories. Confirmatory studies are needed using population-based twin cohorts and alternative methods of handling missing data.
Heritability of strabismus: Genetic influence is specific to eso-deviation and independent of refractive error
Publisher: Cambridge University Press (CUP)
Date: 13-06-2012
DOI: 10.1017/THG.2012.22
Abstract: Strabismus represents a complex oculomotor disorder characterized by the deviation of one or both eyes and poor vision. A more sophisticated understanding of the genetic liability of strabismus is required to guide searches for associated molecular variants. In this classical twin study of 1,462 twin pairs, we examined the relative influence of genes and environment in comitant strabismus, and the degree to which these influences can be explained by factors in common with refractive error. Participants were examined for the presence of latent (‘phoria’) and manifest (‘tropia’) strabismus using cover–uncover and alternate cover tests. Two phenotypes were distinguished: eso-deviation (esophoria and esotropia) and exo-deviation (exophoria and exotropia). Structural equation modeling was subsequently employed to partition the observed phenotypic variation in the twin data into specific variance components. The prevalence of eso-deviation and exo-deviation was 8.6% and 20.7%, respectively. For eso-deviation, the polychoric correlation was significantly greater in monozygotic (MZ) ( r = 0.65) compared to dizygotic (DZ) twin pairs ( r = 0.33), suggesting a genetic role ( p = .003). There was no significant difference in polychoric correlation between MZ ( r = 0.55) and DZ twin pairs ( r = 0.53) for exo-deviation ( p = .86), implying that genetic factors do not play a significant role in the etiology of exo-deviation. The heritability of an eso-deviation was 0.64 (95% CI 0.50–0.75). The additive genetic correlation for eso-deviation and refractive error was 0.13 and the bivariate heritability (i.e., shared variance) was less than 1%, suggesting negligible shared genetic effect. This study documents a substantial heritability of 64% for eso-deviation, yet no corresponding heritability for exo-deviation, suggesting that the genetic contribution to strabismus may be specific to eso-deviation. Future studies are now needed to identify the genes associated with eso-deviation and unravel their mechanisms of action.
Prevalence of refractive error in Europe: the European Eye Epidemiology (E3) Consortium
Publisher: Springer Science and Business Media LLC
Date: 18-03-2015
A punder in Catch-22
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-02-2009
Ophthalmic epidemiology in Europe: the “European Eye Epidemiology” (E3) consortium
Publisher: Springer Science and Business Media LLC
Date: 19-12-2015
DOI: 10.1007/S10654-015-0098-2
Abstract: The European Eye Epidemiology (E3) consortium is a recently formed consortium of 29 groups from 12 European countries. It already comprises 21 population-based studies and 20 other studies (case-control, cases only, randomized trials), providing ophthalmological data on approximately 170,000 European participants. The aim of the consortium is to promote and sustain collaboration and sharing of data and knowledge in the field of ophthalmic epidemiology in Europe, with particular focus on the harmonization of methods for future research, estimation and projection of frequency and impact of visual outcomes in European populations (including temporal trends and European subregions), identification of risk factors and pathways for eye diseases (lifestyle, vascular and metabolic factors, genetics, epigenetics and biomarkers) and development and validation of prediction models for eye diseases. Coordinating these existing data will allow a detailed study of the risk factors and consequences of eye diseases and visual impairment, including study of international geographical variation which is not possible in in idual studies. It is expected that collaborative work on these existing data will provide additional knowledge, despite the fact that the risk factors and the methods for collecting them differ somewhat among the participating studies. Most studies also include biobanks of various biological s les, which will enable identification of biomarkers to detect and predict occurrence and progression of eye diseases. This article outlines the rationale of the consortium, its design and presents a summary of the methodology.
Cilioretinal Artery Territory Infarction Associated With Papilledema in a Patient With Neurofibromatosis Type 2
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2016
Twin studies in inherited eye disease
Publisher: Wiley
Date: 04-12-2013
DOI: 10.1111/CEO.12233
Abstract: Eye diseases represent a significant source of health impairment in humans. Twin studies offer an excellent model to dissect the genetic basis of human diseases. In this review, we discuss the potential advantages of using twin-based studies in investigating the genetics of eye diseases--from heritability estimation to identifying underlying genetic and epigenetic changes. We also discuss some of the notable findings of twin studies exploring the genetics of eye diseases. Finally, we suggest other novel approaches that can be utilized to tap the potential of twin studies to provide a more complete understanding of genetic factors underlying ocular diseases.
Rare variant analyses across multiethnic cohorts identify novel genes for refractive error
Publisher: Springer Science and Business Media LLC
Date: 03-01-2023
DOI: 10.1038/S42003-022-04323-7
Abstract: Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. In iduals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP , the circadian rhythm gene PER3 , and P4HTM , which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.
Re: Lee et al.: Longitudinal changes in peripapillary retinal nerve fiber layer thickness in high myopia: a prospective, observational study (Ophthalmology. 2019;126:522-528)
Publisher: Elsevier BV
Date: 2020
Anterior Ischemic Optic Neuropathy After Strabismus Surgery
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2009
Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Genetic and Environmental Factors Associated With the Ganglion Cell Complex in a Healthy Aging British Cohort
Publisher: American Medical Association (AMA)
Date: 2017
DOI: 10.1001/JAMAOPHTHALMOL.2016.4486
Abstract: Measurement of ganglion cell complex (GCC) thickness may be more sensitive than current methods for glaucoma diagnosis and research. However, little is known about the factors influencing GCC thickness in the general population. To investigate the heritability of and factors associated with GCC thickness in a healthy aging population. A cross-sectional twin study was conducted from August 27, 2014, to March 31, 2016, among 1657 participants of white British ancestry from the TwinsUK study cohort without ocular pathologic conditions. Heritability analyses were conducted in 1432 twins (426 monozygous and 290 dizygous pairs). Association analyses were performed using univariable and multivariable stepwise linear regression models, taking family structure into account. Heritability analyses were conducted using maximum likelihood structural equation twin modeling. Parameters measured included GCC thickness, autorefraction, intraocular pressure, blood pressure, body mass index, and cholesterol, creatinine, glucose, insulin, triglycerides, and urea levels. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula. Among the 1657 participants (mean [SD] age, 56.0 [15.3] years 89.5% women and 10.5% men), the mean [SD] inner GCC thickness was 96.0 [7.6] μm (95% CI, 95.1-96.2). In multivariable modeling, the mean inner GCC thickness was associated with advancing age (β, -0.14 P < .001), increased body mass index (β, -0.15 P = .001), spherical equivalent (β, 0.70 P < .001), and higher estimated glomerular filtration rate (β, 0.03 P = .02). A 1-U increase in age or body mass index was associated with a 0.14-µm and 0.15-µm decrease in GCC thickness, respectively (P < .001), while a 1-U increase in spherical equivalent or estimated glomerular filtration rate was associated with a 0.70-µm (P < .001) and 0.03-µm (P = .02) increase in GCC thickness, respectively. Ganglion cell complex thickness was not associated with sex, intraocular pressure, or diabetes. Age-adjusted GCC thickness was highly heritable, with additive genetic effects explaining 81% (95% CI, 78%-84%) of phenotypic variance and in idual environmental factors explaining the remaining 19% (95% CI, 16%-22%). Ganglion cell complex thickness appears to be highly heritable and further genetic analysis may help identify new biological pathways for glaucoma. The results suggest it may be important to account for age, body mass index, refractive error, and sex when using GCC thickness as a diagnostic tool. Replication of their results is required, as is further research to explain the association between renal function and GCC thickness.
A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus
Publisher: Springer Science and Business Media LLC
Date: 03-2021
DOI: 10.1038/S42003-021-01784-0
Abstract: Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.
Frequency and Distribution of Refractive Error in Adult Life: Methodology and Findings of the UK Biobank Study
Publisher: Public Library of Science (PLoS)
Date: 02-10-2015
Common Mechanisms Underlying Refractive Error Identified in Functional Analysis of Gene Lists From Genome-Wide Association Study Results in 2 European British Cohorts
Publisher: American Medical Association (AMA)
Date: 2014
Response: Cycloplegia in refraction: age and cycloplegics
Publisher: Wiley
Date: 11-05-2016
DOI: 10.1111/AOS.13082
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Related Funding Activities
The Genetics Of Myopia And Refractive Error: Analysis Of Highly Significant Linkage Loci.
Start Date: 2006
End Date: 2009
Funder: Wellcome Trust
View Funded ActivityInternational Collaborative Twin Study Of Refractive Error And Glaucoma Endophenotypes
Start Date: 2008
End Date: 2010
Funder: National Eye Institute
View Funded ActivityThe Genetics Of Common Age-related Eye Disease: NIHR Senior Research Fellowship
Start Date: 2008
End Date: 2013
Funder: NIHR
View Funded ActivityLow Dose Atropine Eye Drops To Reduce Progression Of Myopia In Children
Start Date: 2017
End Date: 2025
Funder: National Institute for Health Research
View Funded ActivityRandomised Feasibility Trial Of Vtirectomy Plus Standard Care Versus Standard Care Alone In Patients With Diabetic Macular Edema
Start Date: 2017
End Date: 2019
Funder: Fight for Sight UK
View Funded ActivityA Genome-wide Association Study Of Keratoconus
Start Date: 2016
End Date: 2018
Funder: Moorfields Eye Charity
View Funded ActivityTwinsUK An Epidemiological And Genomic Resource
Start Date: 2015
End Date: 2017
Funder: Wellcome Trust
View Funded ActivityIdentification Of The Genetic Causes Of Pigmentary Glaucoma
Start Date: 2016
End Date: 2018
Funder: Fight for Sight UK
View Funded Activity