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Publications

Journal Article Epublish

PubMed: 42064014 DOI: 10.1016/j.xops.2026.101165

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

Ophthalmol Sci 6(6):101165

Authors: Kazuya Morino, Akira Meguro, Masao Nagasaki, Ikuko N Motoike, Masato Akiyama, Takahisa Kawaguchi, Shogo Numa, Yuki Mori, Shota Yasukura, Masahiro Akada, Shin-Ya Nakao, Takuro Kamei, Ai Nakata, Masaki Takeuchi, Norihiro Yamada, Yuki Mizuki, Takeshi Yoshida, Yukihide Momozawa, Yoichiro Kamatani, Hayato Anzawa, Yasuharu Tabara, Fumihiko Matsuda, Kengo Kinoshita, Kyoko Ohno-Matsui, Nobuo Fuse, Masayuki Yamamoto, Akitaka Tsujikawa, Nobuhisa Mizuki, Masahiro Miyake

Affiliations

  • Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • Department of Advanced Medicine for Ocular Diseases, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
  • Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan.
  • Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
  • Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
  • Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan.

Abstract

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.

FINANCIAL DISCLOSURES

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

MeSH

Eye, Genes, Glaucoma, Open-Angle, Genome, Glaucoma, Myopia