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<p>Normal-tension glaucoma (NTG) is an age-related cause of irreversible vision loss, yet the contribution of genetic variants to susceptibility across the lifespan remains unclear. The splice-site variant <i>METTL23</i> c.84+60delAT (delAT), which induces aberrant exon skipping, has been implicated in NTG. We evaluated the age-dependent genetic risk associated with delAT by integrating age-stratified carrier frequency analyses in population datasets with age-specific case control association analyses in 3843 individuals. In the gnomAD database, the frequency of delAT carriers declined sharply with age, decreasing approximately sixfold in individuals aged ≥40 years. Consistent with this finding, case-control analyses demonstrated increasing effect sizes with advancing age, with odds ratios of 1.84 in individuals aged ≥40 years and 2.59 in those ≥50 years (<i>P</i> = 0.039). These complementary analyses provide convergent evidence that delAT confers an age-dependent increase in NTG risk, underscoring the importance of incorporating age into genetic analyses of late-onset disease.</p>

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Age-dependent association of the METTL23 c.84+60delAT variant with normal-tension glaucoma

  • 期刊论文

  • 发表日期：

    2026年7月3日

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  • Yang Pan,
  • Kazutoshi Yoshitake,
  • Naoko Minematsu,
  • Fumihiko Mabuchi,
  • Mitsuko Takamoto,
  • Yukihiro Shiga,
  • Kenji Kashiwagi,
  • Makoto Aihara,
  • Toru Nakazawa,
  • Takeshi Iwata

摘要

Normal-tension glaucoma (NTG) is an age-related cause of irreversible vision loss, yet the contribution of genetic variants to susceptibility across the lifespan remains unclear. The splice-site variant METTL23 c.84+60delAT (delAT), which induces aberrant exon skipping, has been implicated in NTG. We evaluated the age-dependent genetic risk associated with delAT by integrating age-stratified carrier frequency analyses in population datasets with age-specific case control association analyses in 3843 individuals. In the gnomAD database, the frequency of delAT carriers declined sharply with age, decreasing approximately sixfold in individuals aged ≥40 years. Consistent with this finding, case-control analyses demonstrated increasing effect sizes with advancing age, with odds ratios of 1.84 in individuals aged ≥40 years and 2.59 in those ≥50 years (P = 0.039). These complementary analyses provide convergent evidence that delAT confers an age-dependent increase in NTG risk, underscoring the importance of incorporating age into genetic analyses of late-onset disease.