Testing the causal relationships of physical activity and sedentary behaviour with mental health and substance use disorders: A Mendelian Randomisation study

ABSTRACT Importance Observational studies suggest that physical activity can reduce the risk of mental health and substance use disorders. However, it is unclear whether this relationship is causal or explained by confounding (e.g., common underlying causes or reverse causality). Objective We investigated bidirectional causal relationships of physical activity (PA) and sedentary behaviour (SB) with mental health and substance use disorders, applying a genetically informed causal inference method. Design, Setting, and Participants This two-sample Mendelian Randomisation (MR) study used genetic instruments for the exposures and outcomes that were derived from the largest available, non-overlapping genome-wide association studies (GWAS). Summary-level data for objectively assessed PA (accelerometer-based average activity, moderate activity, and walking) and SB (assessed over 7 consecutive days) and self-reported moderate-to-vigorous PA were obtained from the UK Biobank. Data for mental health/substance use disorders were obtained from the Psychiatric Genomics Consortium and the GWAS and Sequencing Consortium of Alcohol and Nicotine Use. MR estimates were combined using inverse variance weighted meta-analysis (IVW). Several sensitivity analyses were conducted to assess the robustness of the results (e.g., MR-Egger, weighted median/mode, MR-RAPS, MR-PRESSO). Exposures Objectively assessed/self-reported PA and objectively assessed SB. Main Outcomes and Measures Mental health and substance use disorders. Results Accelerometer-based average PA had a causal protective effect on the risk of depression (b=-0.043, 95%CI: -0.071 to -0.016, effect size[OR]=0.957), and on the number of cigarettes smoked per day (b=-0.026; 95%CI: -0.035 to -0.017, effect size[β]=-0.022). Accelerometer-based SB was causally related to a lower risk of anorexia (b=-0.341, 95%CI: -0.530 to -0.152, effect size[OR]=0.711) and schizophrenia (b=-0.230; 95%CI: -0.285 to -0.175, effect size[OR]=0.795). However, we found evidence of reverse causality in the effect of SB on schizophrenia. Further, PTSD, bipolar disorder, anorexia, and ADHD were all causally related to increased PA. Conclusions and Relevance This study provides evidence consistent with a causal protective effect of objectively assessed but not self-reported PA on reduced depression and cigarette smoking. Objectively assessed SB had a protective effect on anorexia. Enhancing PA may be an effective prevention strategy for specific types of psychiatric disorders. KEY POINTS Question Do heightened physical activity and low sedentary behaviour have causal protective effects on the risk of mental health and substance use disorders? Findings Applying two-sample Mendelian Randomisation to summary-level data from large-scale genome-wide association studies to strengthen causal inferences, we found evidence that objectively assessed but not self-reported physical activity was causally related to a lower risk of depression and cigarette smoking, whereas sedentary behaviour had a protective effect on anorexia. Meaning Interventions that enhance physical activity may be effective in reducing the risk of depression and cigarette smoking, whereas those that increase sedentary behaviours may be effective to reduce the risk of anorexia nervosa.