Abstract
Stroke is a leading cause of long-term disability and mortality worldwide. Modifiable lifestyle factors (including physical activity, diet, sleep, and psychological health) may influence poststroke recovery. However, evidence from observational studies is limited by confounding and reverse causation. We conducted a 2-sample Mendelian randomization (MR) analysis to investigate causal associations between 12 lifestyle-related exposures and stroke recovery outcomes. Genetic instruments (11-26 single nucleotide polymorphisms, all F-statistics > 10) were obtained from the MRC-IEU consortium (sample sizes 64,949-461,460), and outcome data were derived from the GISCOME consortium (6021 ischemic stroke patients, mean age ~65 years, predominantly middle-aged and older adults). Harmonization procedures ensured allele alignment, with palindromic and weak instruments removed. Causal estimates were obtained using inverse variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode methods. Sensitivity analyses included heterogeneity tests, MR-PRESSO, and leave-one-out analyses. Sedentary behavior was associated with poorer recovery (IVW odds ratio [OR] = 0.01, 95% confidence interval [CI]: 0.01-0.03, P < .05), whereas moderate-intensity physical activity showed beneficial associations (IVW OR = 4.91, 95% CI: 2.13-11.34, P = .01). Higher body mass index was negatively associated with recovery (IVW OR = 0.04, 95% CI: 0.01-0.09, P < .05). A low-calorie diet demonstrated significant benefit (IVW OR = 18.37, 95% CI: 1.05-3.20 × 10², P < .05). Smoking (IVW OR = 0.01, 95% CI: 0.01-0.09, P < .05), psychological distress (IVW OR = 0.01, 95% CI: 0.01-0.03, P < .05), and insomnia (IVW OR = 0.01, 95% CI: 0.01-0.02, P < .05) were negatively associated with recovery. No significant associations were observed for low- or high-intensity activity, alcohol abstinence, coffee intake, or household income. Sensitivity analyses indicated no heterogeneity or directional pleiotropy (MR-Egger intercept P > .05), and MR-PRESSO confirmed the robustness of causal estimates. This MR study provides genetic evidence that sedentary behavior, high body mass index, smoking, psychological distress, and insomnia may impair stroke recovery, whereas moderate-intensity physical activity and low-calorie diets may improve recovery. These findings emphasize the importance of integrating lifestyle modification into personalized stroke rehabilitation strategies.