Genome-Wide Meta-Analysis for High Myopia Provides Insights into Disease Mechanisms and Reveals a Causal Link to Primary Open-Angle Glaucoma.

Purpose

To investigate the genetic architecture of high myopia.

Design

A meta-analysis of genome-wide association studies (meta-GWASs).

Participants

A total of 7867 individuals with high myopic eyes and 21 700 controls were enrolled.

Methods

We performed a meta-GWAS comprising 3910 cases with high myopic eyes and 5718 controls in the discovery stage. A replication study included an independent set of 3957 participants with high myopic eyes and 15 982 control participants. Functional enrichment analysis was conducted using FUMA and ToppFun. We assessed shared genetic architectures between high myopia and 4 phenotypes (2 ocular diseases and 2 biometric features) using the LDSC software, followed by the evaluation of causality utilizing a bidirectional inverse variance-weighted Mendelian randomization (IVW-MR) analysis with sensitivity analyses.

Main outcome measures

The association between single-nucleotide polymorphisms and high myopia.

Results

We identified 10 loci exceeding genome-wide significance ( P < 5.0 × 10 -8 ); 2 of those, rs2727196 in ADAMTS17 (odds ratio [OR] = 1.13, P = 2.91 × 10 -8 ) and rs6564696 in MAFTRR (OR = 1.19, P = 1.78 × 10 -10 ), were novel. Functional enrichment analysis revealed a significant role of 8 pathways in the pathogenesis of high myopia, including 2 pathways regarding acetylcholine-gated channels (gene ontology [GO]:0005892 and GO:0022848) and 4 pathways regarding Golgi body (GO:0033116, GO:0032580, GO:0030134, and GO:0031985). Genetic correlation analysis revealed shared polygenic architecture between high myopia and primary open-angle glaucoma (POAG) ( r g [the measure of genetic correlation] = 0.41, P = 2.60 × 10 -3 ). In the IVW-MR analysis, a causal relationship from high myopia to POAG was confirmed (OR = 1.14, P = 3.92 × 10 -3 ), whereas an inverse causal relationship was not noticed ( P = 0.97).

Conclusions

Our study identified 2 novel high myopia-associated loci. Subsequent functional enrichment analysis offered important insights into the molecular biology of high myopia, demonstrating potential therapeutic targets. Previous studies could not definitively determine whether high myopia had a causal effect on POAG due to the potential influence of unmeasured confounders. By utilizing an MR method, which can control for even unmeasured confounders, this study provides data that support a causal association of high myopia on POAG.

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