Analysis of genetic networks regulating refractive eye development in collaborative cross progenitor strain mice reveals new genes and pathways underlying human myopia

Population studies suggest that genetic factors play an important role in refractive error development; however, the precise role of genetic background and the composition of the signaling pathways underlying refractive eye development remain poorly understood. Here, we analyzed normal refractive development and susceptibility to form-deprivation myopia in the eight progenitor mouse strains of the Collaborative Cross (CC). Genetic background strongly influenced both baseline refractive development and susceptibility to environmentally-induced myopia. Baseline refractive errors ranged from -21.2 diopters (D) in 129S1/svlmj mice to +22.0 D in CAST/EiJ mice and represented a continuous distribution typical of a quantitative genetic trait. The extent of induced form-deprivation myopia ranged from -5.6 D in NZO/HILtJ mice to -20.0 D in CAST/EiJ mice and also followed a continuous distribution. Whole-genome (RNA-seq) gene expression profiling in retinae from CC progenitor strains identified genes whose expression level correlated with either baseline refractive error or susceptibility to myopia. Expression levels of 2,302 genes correlated with the baseline refractive state of the eye, whereas 1,917 genes correlated with susceptibility to induced myopia. Genome-wide gene-based association analysis in the CREAM and UK Biobank human cohorts revealed that 985 of the above genes were associated with refractive error development in humans, including 847 genes which were implicated in the development of human myopia for the first time. Although the gene sets controlling baseline refractive development and those regulating susceptibility to myopia overlapped, these two processes appeared to be controlled by largely distinct sets of genes. Comparison with data for other animal models of myopia revealed that the genes identified in this study comprise a well-defined set of retinal signaling pathways, which are highly conserved across different species. These results provide attractive targets for the development of anti-myopia drugs. Author SummarySeveral lines of evidence suggest that variations in genetic background have a strong impact on a default (baseline) trajectory of eye growth and refractive development. Many studies also highlighted differences in susceptibility of different individuals to environmentally induced changes in refractive eye development, suggesting that genetic background plays an important role in visual regulation of eye growth. However, genes and signaling pathways that control the baseline trajectory of refractive eye development and those that regulate the impact of visual environment on refractive eye development are still poorly understood. Our data suggest that both processes are regulated by elaborate retinal genetic networks. Surprisingly, we found that although genes that control baseline refractive eye development and genes regulating the impact of visual environment on refractive development overlap, there is a large number of genes and pathways which exclusively control either the baseline trajectory of refractive eye development or the impact of visual environment on refractive development. Moreover, we found that many of the genes and pathways, which we found to be associated with either baseline refractive development or susceptibility to environmentally induced myopia in mice, are also associated with refractive error development in the human population and are highly conserved across different species. Identification of genes and pathways that underlie visual regulation of eye growth versus genes and pathways that control default trajectory of refractive eye development sheds light on the basic mechanisms of eye emmetropization and provides previously unexplored possibilities for the development of new treatment options for myopia.