Causal effect of gastroesophageal reflux disease on cataracts: A Mendelian Randomization Study

Cataracts, the leading cause of blindness globally, have been linked to genetic variants in regions also implicated in gastroesophageal reflux disease (GERD), suggesting potential pleiotropic effects. While observational studies have hinted at a possible association, the direction and causality of this link remain unclear. To date, no studies have systematically evaluated whether GERD causally contributes to cataract development. We applied univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) to evaluate the causal effect of GERD on cataracts, using publicly available GWAS summary data from European-ancestry populations, including the GWAS catalog Consortium and the FinnGen consortium. Genetic instruments for GERD were selected from a GWAS meta-analysis involving 602,604 individuals, using genome-wide significance (p < 5×10 -8 ) and linkage disequilibrium pruning (r 2 < 0.001). To explore potential mediating pathways, we additionally performed two-step MR analysis to quantify indirect effects through coronary heart disease and diabetes. UVMR analysis showed a significant association between GERD and increased cataract risk (OR: 1.13, p = 4.01×10-6 from the GWAS catalog Consortium; OR: 1.12, p = 2.43 × 10 -2 from the FinnGen consortium). MVMR analysis indicated that GERD independently increased the odds of cataracts, even after adjusting for factors like Barrett’s esophagus (OR:1.127, p = 9.39×10-6; OR:1.100, p = 4.53 × 10 -2 ) and coronary heart disease (OR: 1.107, p = 4.64×10-4; OR:1.099, p = 5.61 × 10 -2 ) in the GWAS catalog Consortium and FinnGen consortium. Sensitivity analyses confirmed these findings. A meta-analysis across both GWAS datasets reinforced the association (OR: 1.11, p = 2.58×10 -7 ). Coronary heart disease (15.23%) and diabetes (16.03%) were identified as key mediators. This Mendelian randomization study provides genetic evidence supporting a causal effect of GERD on cataract risk. Furthermore, coronary heart disease and diabetes were found to partially mediate this relationship. These findings highlight the potential importance of managing systemic comorbidities in patients with GERD as a supportive strategy to reduce the risk of cataract development and warrant further research into underlying mechanisms.