APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans

Abstract

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (“missing heritability”). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5’-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10 ⁻⁴) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10 ⁻³). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10 ⁻³). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10 ⁻⁴) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10 ⁻⁴) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10 ⁻⁴) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10 ⁻⁴). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10 ⁻⁴) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the “missing” myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.

Author Summary

Gene variants identified by GWAS studies to date explain only a small fraction of myopia cases because myopia represents a complex disorder thought to be controlled by dozens or even hundreds of genes. The majority of genetic variants underlying myopia seems to be of small effect and/or low frequency, which makes them difficult to identify using classical genetic approaches, such as GWAS, alone. Here, we combined gene expression profiling in a monkey model of myopia, human GWAS, and a gene-targeted mouse model of myopia to identify one of the “missing” myopia genes, APLP2. We found that a low-frequency risk allele of APLP2 confers susceptibility to myopia only in children exposed to large amounts of daily reading, thus, providing an experimental example of the long-hypothesized gene-environment interaction between nearwork and genes underlying myopia. Functional analysis of APLP2 using an APLP2 knockout mouse model confirmed functional significance of APLP2 in refractive development and implicated a potential role of synaptic transmission at the level of glycinergic amacrine cells of the retina for the development of myopia. Furthermore, mouse studies revealed that lack of Aplp2 has a dose-dependent suppressive effect on susceptibility to form-deprivation myopia, providing a potential gene-specific target for therapeutic intervention to treat myopia.