Investigating causal associations between serum metabolites and cataract by Mendelian randomization

Early studies have demonstrated that systemic metabolic changes can significantly contribute to the development and progression of cataract, however, the causal effects of specific human serum metabolites on cataract have not been fully elucidated. The causal effects of 7 serum metabolites, including proline, serine, 3-dehydrocarnitine, N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide, octanoylcarnitine, decanoylcarnitine, and citrate, on cataract were analyzed using a 2-sample multivariable Mendelian randomization (MR). Using data from multiple genome-wide association study datasets, which fall under the broad category of the studied serum metabolites, we identified instrumental variables following strict criteria. We then analyzed a FinnGen genome-wide association study dataset, which included 39,519 European cataract cases and 452,358 European controls, employing the inverse variance weighted method, and rigorous tests for horizontal pleiotropy and heterogeneity as well as sensitivity analysis, to ensure robustness of the results. The MR analysis uncovered that 3-dehydrocarnitine and citrate have significant positive causal associations with cataract, while proline, serine, N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide, octanoylcarnitine, and decanoylcarnitine, have significant negative causal associations with cataract (P < .05). Notably, no significant pleiotropy or heterogeneity was detected (P > .05) in the MR analysis, and sensitivity analysis confirmed the robustness of the results. This research uncovered significant causal associations between several serum metabolites and cataract, indicating altered metabolic pathways involved in cataract pathogenesis. These findings further suggest the studied serum metabolites may serve as biomarkers for early disease diagnosis and highlight promising targets for developing effective management and treatment strategies in cataract.