Identification of Potential Drug Targets for Myopia Through Mendelian Randomization

Abstract

Purpose: The purpose of this study was to identify potential drug targets for myopia and explore underlying mechanisms.

Methods: Mendelian randomization (MR) was implemented to assess the effect of 2684 pharmacologically targetable genes in the blood and retina on the risk of myopia from a genomewide association study (GWAS) for age-at-onset of spectacle wearing-inferred mean spherical equivalent (MSE; discovery cohort, N = 287,448, European), which was further validated in a GWAS for autorefraction-measured MSE (replication cohort, N = 95,619, European). The reliability of the identified significant potential targets was strengthened by colocalization analysis. Additionally, enrichment analysis, protein-protein interaction network, and molecular docking were performed to explore the functional roles and the druggability of these targets.

Results: This systematic drug target identification has unveiled 6 putative genetically causal targets for myopia-CD34, CD55, Wnt3, LCAT, BTN3A1, and TSSK6-each backed by colocalization evidence in adult blood eQTL datasets. Functional analysis found that dopaminergic neuron differentiation, cell adhesion, Wnt signaling pathway, and plasma lipoprotein-associated pathways may be involved in myopia pathogenesis. Finally, drug prediction and molecular docking corroborated the pharmacological value of these targets with LCAT demonstrating the strongest binding affinity.

Conclusions: Our study not only opens new avenues for the development of therapeutic interventions for myopia but may also help to understand the underlying mechanisms of myopia.

Figure 1.

Study design overview.

Figure 2.

Manhattan plot in the discovery cohort (AOSW-inferred MSE). Names of significant genes were labeled. The blue and red lines signify the nominal P value threshold of 5.00E-02 and the Bonferroni-corrected significance threshold of 2.05E-5 in the blood and 2.00E-03 in the retina for statistical significance, respectively. AOSW, age-at-onset of spectacle wearing; MSE, mean spherical equivalent; eGenes, eQTL target genes.

Figure 3.

Forest plot displaying MR results of the 14 successfully replicated genes in the blood in the discovery and replication phase. The x-axis is the beta value which represents the risk of MSE as per SD increase in gene levels. A beta greater than 0 indicates that the upregulation of a specific gene is associated with less myopic MSE. Error bars represent 95% confidence intervals. MR, Mendelian randomization; MSE, mean spherical equivalent.

Figure 4.

Forest plot displaying MR results of the 4 successfully replicated genes in the retina in the discovery and replication phase. The x-axis is the beta value which represents the risk of MSE as per SD increase in gene levels. A beta greater than 0 indicates that the upregulation of a specific gene is associated with less myopic MSE. Error bars represent 95% confidence intervals. MR, Mendelian randomization; MSE, mean spherical equivalent.

Figure 5.

PPI network constructed by GeneMANIA. The circles are chromatically denoted to signify the functional pathways implicated by the respective genes. PPI, protein-protein interaction.

Figure 6.

Molecular docking. (A) LCAT docking with testosterone. (B) LCAT docking with prednisolone. (C) CD55 docking with Chembl35482. (D) CD34 docking with prednisolone.