Refined Causal Association Between Physical Activity Intensity and Depression: A Comprehensive Two-sample Mendelian Randomization Study

Depression remains a significant public health issue with high morbidity and mortality worldwide, making it crucial to investigate the role and causality of different types of physical activities in relieving depression. This study utilized a two-sample Mendelian randomization (MR) approach to evaluate the causal relationship between various physical activities, strenuous sports and walking for pleasure, and both general and major depression. We used summary statistics from large-scale genome-wide association studies involving European ancestry participants. Causal associations were estimated using the inverse-variance weighted model, with additional validation through extensive sensitivity analyses. Meta-analysis was conducted to comprehensively estimate the effects of multiple MR analyses. Results from single MR analyses and meta-analyses showed no significant causal effect of strenuous sports on depression (general depression: logOR=-0.1405, p = 0.2984; major depression: logOR = 0.0453, p = 0.9293). In contrast, walking for pleasure demonstrated a significant causal effect in reducing general depression (logOR=-0.5398, p = 0.0069) and major depression (logOR=-1.9786, p = 0.0103). Reverse MR analyses found no causal association between genetic liability to depression and the physical activities tested. Our findings underscore the significant role of walking for pleasure in alleviating and preventing both general and major depression. However, strenuous sports do not show a statistically significant causal effect. Further research is warranted to explore physical activities with intensities similar to walking for pleasure as potential preventive or rehabilitative measures in depression therapy, either alone or alongside psychotherapy or pharmacotherapy.