Refractive error has minimal influence on the risk of age-related macular degeneration: a Mendelian randomization study

Purpose To test the hypothesis that refractive errors such as myopia and hyperopia cause an increased risk of age-related macular degeneration (AMD), and to quantify the degree of risk. Design Two-sample Mendelian randomization analysis of data from a genome-wide association study Participants As instrumental variables for refractive error, 126 genome-wide significant genetic; variants identified by the CREAM consortium and 23andMe Inc. were chosen. The association with refractive error for the 126 variants was obtained from a published study for a sample of n=95,505 European ancestry participants from UK Biobank. Association with AMD for the 126; genetic variants was determined from a genome-wide association study (GWAS) published by; the International Age-related Macular Degeneration Genomics consortium of n=33,526 (16,144; cases and 17,832 controls) European ancestry participants. Methods Two-sample Mendelian randomization analysis was used to assess the causal role of refractive error on AMD risk, using the 126 genetic variants associated with refractive error as; instrumental variables, under the assumption that the relationship between refractive error and; AMD risk is linear. Main Outcome Measures The risk AMD caused by a 1 diopter (D) change in refractive error. Results Mendelian randomization analysis suggested that refractive error had very limited influence on the risk of AMD. Specifically, a 1 D more hyperopic refractive error was associated with an OR=1.080 (95% CI: 1.021 to 1.142, P=0.007) increased risk of AMD. MR-Egger, MR-PRESSO, weighted median, and Phenoscanner-based sensitivity analyses detected minimal evidence to suggest that this result was biased by horizontal pleiotropy. Conclusions Under the assumption of a linear relationship between refractive error and the risk of AMD, myopia and hyperopia only minimally influence the causal risk for AMD. Thus, inconsistently-reported strong associations between refractive error and AMD are likely to be; the result of non-causal factors, such as stochastic variation, confounding or selection bias

The chick as an animal model of eye disease

A diverse range of chicken lines harbouring highly-penetrant, spontaneously-occurring mutations with an ocular phenotype have been identified over the past 40 years. These lines serve as models for human monogenic disorders including ocular albinism, retinal dystrophies such as Leber's congenital amaurosis, and coloboma, as well as the common complex traits glaucoma and myopia. Recent technical advances in gene targeting, mapping quantitative trait loci, and phenotypic characterisation of eye phenotypes offer exciting prospects for exploiting chicken genomic resources in fundamental and translational eye research

Non-additive (dominance) effects of genetic variants associated with refractive error and myopia

Genome-wide association studies (GWAS) have revealed that the genetic contribution to certain complex diseases is well-described by Fisher’s infinitesimal model in which a vast number of polymorphisms each confer a small effect. Under Fisher’s model, variants have additive effects both across loci and within loci. However, the latter assumption is at odds with the common observation of dominant or recessive rare alleles responsible for monogenic disorders. Here, we searched for evidence of non-additive (dominant or recessive) effects for GWAS variants known to confer susceptibility to the highly heritable quantitative trait, refractive error. Of 146 GWAS variants examined in a discovery sample of 228,423 individuals whose refractive error phenotype was inferred from their age-of-onset of spectacle wear, only 8 had even nominal evidence (p < 0.05) of non-additive effects. In a replication sample of 73,577 individuals who underwent direct assessment of refractive error, 1 of these 8 variants had robust independent evidence of non-additive effects (rs7829127 within ZMAT4, p = 4.76E−05) while a further 2 had suggestive evidence (rs35337422 in RD3L, p = 7.21E−03 and rs12193446 in LAMA2, p = 2.57E−02). Accounting for non-additive effects had minimal impact on the accuracy of a polygenic risk score for refractive error (R2 = 6.04% vs. 6.01%). Our findings demonstrate that very few GWAS variants for refractive error show evidence of a departure from an additive mode of action and that accounting for non-additive risk variants offers little scope to improve the accuracy of polygenic risk scores for myopia

The effect of unilateral disruption of the centrifugal visual system on normal eye development in chicks raised under constant light conditions

The centrifugal visual system (CVS) comprises a visually driven isthmic feedback projection to the retina. While its function has remained elusive, we have previously shown that, under otherwise normal conditions, unilateral disconnection of centrifugal neurons in the chick affected eye development, inducing a reduced rate of axial elongation that resulted in a unilateral hyperopia in the eye contralateral to the lesion. Here, we further investigate the role of centrifugal neurons in ocular development in chicks reared in an abnormal visual environment, namely constant light. The baseline ocular phenotype of constant light-reared chicks (n = 8) with intact centrifugal neurons was assessed over a 3-week post-hatch time period and, subsequently, compared to chicks raised in normal diurnal lighting (n = 8). Lesions of the isthmo-optic tract or sham surgeries were performed in another seventeen chicks, all raised under constant light. Ocular phenotyping was performed over a 21-day postoperative period to assess changes in refractive state (streak retinoscopy) and ocular component dimensions (A-scan ultrasonography). A pathway-tracing paradigm was employed to quantify lesion success. Chicks raised in constant light conditions with an intact CVS developed shallower anterior chambers combined with elongated vitreous chambers relative to chicks raised in normal diurnal lighting. Seven days following surgery to disrupt centrifugal neurons, a significant positive correlation between refractive error asymmetry between the eyes and lesion success was evident, characterized by hyperopia in the eye contralateral to the lesion. By 21 days post-surgery, these contralateral eyes had become emmetropic, while ipsilateral eyes had developed relative axial hyperopia. Our results provide further support for the hypothesis that the centrifugal visual system can modulate eye development

Genome-wide association studies for corneal and refractive astigmatism in UK Biobank demonstrate a shared role for myopia susceptibility loci

Previous studies have suggested that naturally occurring genetic variation contributes to the risk of astigmatism. The purpose of this investigation was to identify genetic markers associated with corneal and refractive astigmatism in a large-scale European ancestry cohort (UK Biobank) who underwent keratometry and autorefraction at an assessment centre. Genome-wide association studies for corneal and refractive astigmatism were performed in individuals of European ancestry (N = 86,335 and 88,005 respectively), with the mean corneal astigmatism or refractive astigmatism in fellow eyes analysed as a quantitative trait (dependent variable). Genetic correlation between the two traits was calculated using LD Score regression. Gene-based and gene-set tests were carried out using MAGMA. Single marker-based association tests for corneal astigmatism identified four genome-wide significant loci (P < 5 × 10−8) near the genes ZC3H11B (1q41), LINC00340 (6p22.3), HERC2/OCA2 (15q13.1) and NPLOC4/TSPAN10 (17q25.3). Three of these loci also demonstrated genome-wide significant association with refractive astigmatism: LINC00340, HERC2/OCA2 and NPLOC4/TSPAN10. The genetic correlation between corneal and refractive astigmatism was 0.85 (standard error = 0.068, P = 1.37 × 10−35). Here, we have undertaken the largest genome-wide association studies for corneal and refractive astigmatism to date and identified four novel loci for corneal astigmatism, two of which were also novel loci for refractive astigmatism. These loci have previously demonstrated association with axial length (ZC3H11B), myopia (NPLOC4), spherical equivalent refractive error (LINC00340) and eye colour (HERC2). The shared role of these novel candidate genes for astigmatism lends further support to the shared genetic susceptibility of myopia and astigmatism

Novel Myopia Genes and Pathways Identified From Syndromic Forms of Myopia

PURPOSE. To test the hypothesis that genes known to cause clinical syndromes featuring myopia also harbor polymorphisms contributing to nonsyndromic refractive errors. METHODS. Clinical phenotypes and syndromes that have refractive errors as a recognized feature were identified using the Online Mendelian Inheritance in Man (OMIM) database. One hundred fifty-four unique causative genes were identified, of which 119 were specifically linked with myopia and 114 represented syndromic myopia (i.e., myopia and at least one other clinical feature). Myopia was the only refractive error listed for 98 genes and hyperopia and the only refractive error noted for 28 genes, with the remaining 28 genes linked to phenotypes with multiple forms of refractive error. Pathway analysis was carried out to find biological processes overrepresented within these sets of genes. Genetic variants located within 50 kb of the 119 myopia-related genes were evaluated for involvement in refractive error by analysis of summary statistics from genome-wide association studies (GWAS) conducted by the CREAM Consortium and 23andMe, using both single-marker and gene-based tests. RESULTS. Pathway analysis identified several biological processes already implicated in refractive error development through prior GWAS analyses and animal studies, including extracellular matrix remodeling, focal adhesion, and axon guidance, supporting the research hypothesis. Novel pathways also implicated in myopia development included mannosylation, glycosylation, lens development, gliogenesis, and Schwann cell differentiation. Hyperopia was found to be linked to a different pattern of biological processes, mostly related to organogenesis. Comparison with GWAS findings further confirmed that syndromic myopia genes were enriched for genetic variants that influence refractive errors in the general population. Gene-based analyses implicated 21 novel candidate myopia genes (ADAMTS18, ADAMTS2, ADAMTSL4, AGK, ALDH18A1, ASXL1, COL4A1, COL9A2, ERBB3, FBN1, GJA1, GNPTG, IFIH1, KIF11, LTBP2, OCA2, POLR3B, POMT1, PTPN11, TFAP2A, ZNF469). CONCLUSIONS. Common genetic variants within or nearby genes that cause syndromic myopia are enriched for variants that cause nonsyndromic, common myopia. Analysis of syndromic forms of refractive errors can provide new insights into the etiology of myopia and additional potential targets for therapeutic interventions

A deficit in visits to the optometrist by preschool age children: implications for vision screening

Vision screening in children is aimed primarily at detecting non-strabismic amblyopia (other forms of vision defect are generally evident to parents). Such non-strabismic amblyopia occurs mostly as a result of uncorrected refractive errors.1,2 In the December 2003 report by the Child Health Sub-group3 it was recommended that all 4−5 year olds should receive vision screening. The Health For All Children 4 (HFAC4, 2003) “Hall Report”4 and the Children’s Eye Health Working Party guidelines5 similarly suggest vision screening should be undertaken in all 4–5 year olds. This advice is in accord with the results of the first randomised controlled trial of treatment for amblyopia,2 which found that treatment of moderate amblyopia (acuity 6/36−6/18) in preschool aged children was effective

Novel Myopia Genes and Pathways Identified From Syndromic Forms of Myopia

P URPOSE . To test the hypothesis that genes known to cause clinical syndromes featuring myopia also harbor polymorphisms contributing to nonsyndromic refractive errors