Causal relationships among seven cardiovascular-associated metabolic diseases: insights from a bidirectional Mendelian randomization study

Aim: Previous studies have suggested that metabolic diseases are gene- and heritability-related and there are potential cross-genetic correlations. We aim to elucidate the causal relationships among specific metabolic diseases. Methods: We investigated seven metabolic diseases by analyzing summary statistics from Genome-Wide Association Studies (GWAS). Genetic correlations and pleiotropic associations were identified, and biological functions were determined. In addition, two-sample bidirectional Mendelian randomization (MR) analysis was performed to establish causal inferences. Results: Most metabolic diseases shared common genetic components, and more than sixty percent of paired disorders presented significant positive genetic correlations. The primary MR analysis revealed that obesity causally induced a higher risk of type 2 diabetes (T2D). Both obesity and T2D increased the risk of hypertension, gout, and high triglyceride (TG) levels, whereas gout and TG could pose direct risks for hypertension. Significant differential expression of pleiotropic genes was found in the adrenal gland and brain, and the most enriched tissues were the pancreas, liver, and heart. Conclusion: This study identified causal relationships among a set of metabolic diseases and indicated potential mechanisms of disease comorbidities. These findings underscore the need for integrative strategies for metabolic disease management and provide insights for future development of targeted medical therapy.