Abstract
Myopia has been extensively documented as a significant risk factor for cataracts; however, the relationship between hyperopia and cataract development remains poorly understood. Given the distinct refractive profiles of myopia and hyperopia, hyperopia may confer a protective effect against cataracts. In this study, we employed Mendelian randomization (MR) to examine the causal association between hyperopia and cataracts. A 2-sample MR framework was utilized to examine the causal relationship between hyperopia and cataracts, with multivariable MR implemented to account for potential confounding variables. The inverse variance weighted (IVW) method served as the primary analytical tool, complemented by multiple sensitivity analyses to ensure the robustness and reliability of the findings. Enrichment analyses were conducted to elucidate the underlying biological pathways, while Bayesian colocalization analysis pinpointed shared genetic loci that influence both hyperopia and cataracts. In our study, we found that hyperopia may exert a protective effect against cataracts (IVW odds ratio, 0.920 [95% confidence interval, 0.872-0.972]; P = .0029) and cataract surgery (IVW odds ratio, 0.811 [95% confidence interval, 0.754-0.873]; P < .0001). Multivariable MR, adjusting for confounding factors such as smoking, glaucoma, and diabetes, confirmed hyperopia's protective association with cataracts. Bayesian colocalization identified rs12193446 as a high-probability shared causal variant, while enrichment analyses revealed potential biological mechanisms linking hyperopia to cataract development. Genetic evidence suggests that higher levels of hyperopia are associated with a reduced risk of age-related nuclear cataracts, cataract extraction, and lens implants. Given the opposite refractive states of myopia and hyperopia and their opposite effects on cataracts, these findings provide new insights into the pathogenesis of age-related cataracts.