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

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

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

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

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

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

Novel Myopia Genes and Pathways Identified From Syndromic Forms of Myopia

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

Exploiting genetics and genomics to improve the understanding of eye diseases [Editorial]

Editorial on the Research Topic Exploiting genetics and genomics to improve the understanding of eye disease

Clinical and Epidemiologic Research Time Outdoors and Physical Activity as Predictors of Incident Myopia in Childhood: A Prospective Cohort Study

PURPOSE. Time spent in &apos;&apos;sports/outdoor activity&apos;&apos; has shown a negative association with incident myopia during childhood. We investigated the association of incident myopia with time spent outdoors and physical activity separately. METHODS. Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed by noncycloplegic autorefraction at ages 7, 10, 11, 12, and 15 years, and classified as myopic (-1 diopters) or as emmetropic/ hyperopic ( ‡-0.25 diopters) at each visit (N ¼ 4,837-7,747). Physical activity at age 11 years was measured objectively using an accelerometer, worn for 1 week. Time spent outdoors was assessed via a parental questionnaire administered when children were aged 8-9 years. Variables associated with incident myopia were examined using Cox regression. RESULTS. In analyses using all available data, both time spent outdoors and physical activity were associated with incident myopia, with time outdoors having the larger effect. The results were similar for analyses restricted to children classified as either nonmyopic or emmetropic/hyperopic at age 11 years. Thus, for children nonmyopic at age 11, the hazard ratio (95% confidence interval, CI) for incident myopia was 0.66 (0.47-0.93) for a high versus low amount of time spent outdoors, and 0.87 (0.76-0.99) per unit standard deviation above average increase in moderate/vigorous physical activity. CONCLUSION. Time spent outdoors was predictive of incident myopia independently of physical activity level. The greater association observed for time outdoors suggests that the previously reported link between &apos;&apos;sports/outdoor activity&apos;&apos; and incident myopia is due mainly to its capture of information relating to time outdoors rather than physical activity. (Invest Ophthalmol Vis Sci. 2012;53:2856-2865) DOI:10.1167/ iovs.11-9091 M yopia arises from a mismatch between the axial length of the eye and the focal power of its refractive elements, the cornea and crystalline lens. This produces blurred distance vision that requires the use of spectacles, contact lenses or refractive surgery for correction. A high degree of myopia is associated with a number of sight-threatening pathologies. 9,10 Genetic factors also have been shown to be important, because-at least in chickens-they are the major determinant of an individual animal&apos;s susceptibility to myopia induced by the visual environment. 12-21 Many studies in humans are consistent with the above findings (but not all, 22,23 perhaps due to the complexity of the visual environment). For example, a shift towards myopia has been observed during childhood in eyes exposed to form deprivation, 24 hyperopic defocus, 37 Jones et al. found that the number of hours per week that children From th