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

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.