IMI - Myopia Genetics Report

Abstract

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.

Figure 1

Historic overview of myopia gene finding. Genes identified using WES are marked as purple. Other loci (linkage studies, GWAS) are marked as red.

Figure 2

Effect sizes of common and rare variants for myopia and refractive error. Overview of SNPs and annotated genes found in the most recent GWAS meta-analysis. The x-axis displays the minor allele frequency of each SNP; y-axis displays the effect size of the individual SNP in diopters; We transformed the z-scores of the fixed effect meta-analysis between CREAM (refractive error) and 23andMe (age of diagnosis of myopia) into effect sizes in diopters with the following formula: .

Figure 3

Schematic overview of expression in retinal cells of refractive error and syndromic myopia genes according to literature. Bold: genes identified for both common refractive error and in syndromic myopia.