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Am J Ophthalmol. 2019 Mar 21. pii: S0002-9394(19)30124-2. doi: 10.1016/j.ajo.2019.03.018. [Epub ahead of print]

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

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School of Optometry & Vision Sciences, Cardiff University, Cardiff, Wales, UK. Electronic address:
School of Optometry & Vision Sciences, Cardiff University, Cardiff, Wales, UK.



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.


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.


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.


The risk AMD caused by a 1 diopter (D) change in refractive error.


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.


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.


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