AbstractBackgroundObservational studies have shown that moderate-to-vigorous physical activity (MVPA), vigorous physical activity (VPA), sedentary behaviours, and sleep duration were associated with cardiovascular diseases (CVDs) and lipid levels. However, whether such observations reflect causality remain largely unknown. We aimed to investigate the causal associations of physical activity, sedentary behaviours, and sleep duration with coronary artery disease (CAD), myocardial infarction (MI), stroke and lipid levels.MethodsWe conducted a Mendelian randomization (MR) study using genetic variants as instruments which are associated with physical activity, sedentary behaviours, and sleep duration to examine the causal effects on CVDs and lipid levels. This study included analyses of 4 potentially modifiable factors and 7 outcomes. Thus, the threshold of statistical significance isP = 1.8 × 10^{− 3}(0.05/4 × 7) after Bonferroni correction.ResultsIn the present study, there was suggestive evidence for associations of genetically predicted VPA with CAD (odds ratio, 0.65; 95% confidence intervals, 0.47–0.90;P = 0.009) and MI (0.74; 0.59–0.93;P = 0.010). However, genetically predicted VPA, MVPA, sleep duration and sedentary behaviours did not show significant associations with stroke and any lipid levels.ConclusionsOur findings from the MR approach provided suggestive evidence that vigorous exercise decreased risk of CAD and MI, but not stroke. However, there was no evidence to support causal associations of MVPA,sleep duration or sedentary behaviours with cardiovascular risk and lipid levels.Translational perspectiveThe findings of this study did not point out specific recommendations on increasing physical activity required to deliver significant health benefits. Nevertheless, the findings allowed clinicians and public health practitioners to provide advice about increasing the total amount of excising time by demonstrating that such advice can be effective. Reliable assessment of the association of physical activity levels with different subtypes of CVDs is needed to provide the basis for a comprehensive clinical approach on CVDs prevention, which can be achieved through lifestyle interventions in addition to drug therapy.