Causal inference between physical activity and chronic diseases: Insights from a two-sample Mendelian randomization study

Chronic diseases are major causes of global death and disability, significantly impacting individual health and imposing economic burdens. This study aims to investigate the causal relationship between physical activity (PA) and the development of chronic diseases. Using a Mendelian randomization (MR) approach, we incorporated average PA and its subtypes (more than 450 ​000 participants) as exposure measures and eight chronic diseases as outcome measures. Data were obtained from the European Genome-Wide Association Study (GWAS). The primary causal analysis technique employed was the inverse variance weighting (IVW) method, with MR-Egger, weighted median, weighted mode, and simple mode used to validate the results. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. The IVW approach results show that vigorous physical activity (VPA) is associated with a modest reduction in the risk of major coronary heart disease (<i>OR</i> ​= ​0.95, 95% <i>CI</i>: 0.91-0.99, <i>p</i> ​= ​0.01). The causal directions of the other four MR methods are consistent with this result and validated by sensitivity analysis. No substantial associations were found between other levels of PA and chronic disease. Our findings underscore the importance of VPA in preventive cardiology and suggest its potential role in public health initiatives. Further research should explore the impact of PA on different demographic groups and the dose-response relationship of VPA on heart health.