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

Abstract

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 bias (e.g., common underlying causes or reverse causality). We investigated the bidirectional causal relationship of physical activity (PA) and sedentary behaviour (SB) with ten mental health and substance use disorders, applying two-sample Mendelian Randomisation (MR). Genetic instruments for the exposures and outcomes 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 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). Sensitivity analyses were conducted to assess the robustness of the results. Accelerometer-based average PA was associated with a lower risk of depression (b = -0.043, 95% CI: -0.071 to -0.016, effect size[OR] = 0.957) and cigarette smoking (b = -0.026; 95% CI: -0.035 to -0.017, effect size[β] = -0.022). Accelerometer-based SB decreased the 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 relationship between SB and schizophrenia. Further, PTSD, bipolar disorder, anorexia, and ADHD were all associated with increased PA. 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 relationship with anorexia. Enhancing PA may be an effective intervention strategy to reduce depressive symptoms and addictive behaviours, while promoting sedentary or light physical activities may help to reduce the risk of anorexia in at-risk individuals.

Fig. 1. Study design and Mendelian Randomisation (MR) assumptions.

Study design: Solid paths are hypothesised to exist, whereas dotted paths are hypothesised not to exist according to MR assumptions; β is the causal relationship of interest to be estimated, where β = α/γ. γ and α are the estimated direct effects of a SNP on the exposure and the outcome, respectively. MR assumptions: MR relies on three core assumptions for valid instrumental variables. These include: Relevance (IV1) – the instrument is associated with the risk factor of interest; Exchangeability (IV2) – the instrument is not associated with any potentially confounding variable; and Exclusion Restriction (IV3) – the instrumental variable can only influence the outcome via the risk factor (Fig. 1). In light of the first assumption, the genetic instruments were constructed using top SNPs associated with the exposure variables. The second and third assumptions are violated if instrument SNPs show horizontal pleiotropy, influencing the outcome through other causal pathways than the exposure, or correlated pleiotropy, where genetic variants for the exposure are also associated with a confounder. Therefore, several sensitivity analyses were conducted to detect and remove possible pleiotropic genetic variants, as detailed in the Methods and Results. SNP single nucleotide polymorphism.

Fig. 2. MR estimates (IVW/Wald ratio) and 95% confidence intervals for the causal relationships of physical activity and sedentary behaviour with mental health and substance use disorders (Direction 1).

MR Mendelian randomisation, IVW inverse variance weighted, G1 = genome-wide significant genetic instrument (P < 5 × 10⁻⁸), G2 = more relaxed genetic instrument (P < 1 × 10⁻⁶); PA physical activity. IVW is used for analyses involving ≥ 2 SNPs, and Wald ratio for analyses involving 1 SNP. Effects marked with an asterisk (*) are robust to the correction for multiple testing (i.e., FDR-adjusted p < 0.05).

Fig. 3. MR estimates (IVW/Wald ratio) and 95% confidence intervals for the causal relationships of mental health and substance use disorders with physical activity and sedentary behaviour (Direction 2).

MR Mendelian randomisation, IVW inverse variance weighted, G1 genome-wide significant genetic instrument (P < 5 × 10⁻⁸); G2 = more relaxed genetic instrument (P < 1 × 10⁻⁶), PA physical activity. IVW is used for analyses involving ≥2 SNPs, and Wald ratio for analyses involving 1 SNP. Effects marked with an asterisk (*) are robust to the correction for multiple testing (i.e., FDR-adjusted p < 0.05).