Association of Polyunsaturated Fatty Acids and Incident Glaucoma: The UK Biobank, Multi Omics, and Therapeutic Strategies Study

ABSTRACT Purpose To investigate the associations and causal effects of polyunsaturated fatty acids (PUFAs) with incident glaucoma and identify intervention thresholds and therapeutic strategies. Methods This prospective study included 451,199 glaucoma‐free UK Biobank participants of European ancestry. Associations between baseline plasma PUFAs and incident glaucoma were assessed using multivariable Cox models, with restricted cubic spline regression used to analyze nonlinear relationships and threshold effects. Associations of fish oil supplementation and oily fish intake with glaucoma were evaluated. The multi‐omics analysis framework incorporates genomics, transcriptomics, and epigenomic analyses, with data derived from the UK Biobank and the GEO database (GSE27276). Results Over 8.07 (mean) years, 8027 participants developed glaucoma. Circulating levels of PUFAs (PUFA: HR = 0.92, 95% CI: 0.88–0.96; omega‐3: HR = 0.90, 95% CI: 0.88–0.93; DHA: HR = 0.91, 95% CI: 0.88–0.93) were associated with a reduced risk of incident glaucoma. Omega‐3 and DHA exhibited an L‐shaped, nonlinear relationship with incident glaucoma, with risk reduction thresholds at 0.51 and 0.23 mmol/L, respectively. MR supported a causal effect of DHA (OR = 0.90, 95% CI: 0.83–0.97), partially mediated by lowering triglycerides in LDL. Multi‐omics analysis identified FADS2 as a key gene linking DHA and glaucoma. Fish oil supplementation (HR = 0.64, 95% CI: 0.53–0.76, p = 0.004) and oily fish consumption (HR = 0.75, 95% CI: 0.67–0.84, p < 0.001) showed protection for glaucoma. Conclusions Higher circulating PUFA, omega‐3 and DHA levels were associated with lower incident glaucoma risk; MR supported a causal association for DHA with overall glaucoma, while omega‐3 showed MR evidence only for POAG in the reported analysis.