Genome-wide Meta-analysis for Myopic Macular Neovascularization Identified a Novel Susceptibility Locus and Revealed a Shared Genetic Susceptibility with Age-related Macular Degeneration

Abstract

PURPOSE: To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia. DESIGN: A genome-wide association study (GWAS) meta-analysis (meta-GWAS). PARTICIPANTS: We included 2783 highly myopic individuals, including 608 patients with mMNV and 2175 control participants without mMNV. METHODS: We performed a meta-analysis of 3 independent GWASs conducted according to the genotyping platform (Illumina Asian Screening Array [ASA] data set, Illumina Human610 BeadChip [610K] data set, and whole genome sequencing [WGS] data set), adjusted for age, sex, axial length, and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors (TFs) to DNA sequences around the susceptibility of single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. MAIN OUTCOME MEASURES: The association between SNPs and mMNV in patients with high myopia. RESULTS: The meta-GWAS identified rs56257842 at TEX29 - LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR]ₘₑₜₐ = 0.62, Pₘₑₜₐ = 4.63 × 10⁻⁸, I² = 0.00), which was consistently associated with mMNV in all data sets (OR[ASA] = 0.59, P[ASA] = 1.71 × 10⁻⁴; OR₆₁₀ₖ = 0.63, P₆₁₀ₖ = 5.53 × 10⁻⁴; OR[WGS] = 0.66, P[WGS] = 4.38 × 10⁻²). Transcription factor-wide analysis showed that the TFs ZNF740 and EGR1 lost their binding affinity to this locus when rs56257842 had the C allele (alternative allele), and the WNT signaling-related TF ZBTB33 gained binding affinity when rs56257842 had the C allele. When we examined the associations of AMD susceptibility loci, rs12720922 at CETP showed a statistically significant association with mMNV (ORₘₑₜₐ = 0.52, Pₘₑₜₐ = 1.55 × 10⁻⁵), whereas rs61871745 near ARMS2 showed a marginal association (ORₘₑₜₐ = 1.25, Pₘₑₜₐ = 7.79 × 10⁻³). CONCLUSIONS: Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD.