This study aimed to systematically evaluate the causal associations between various sleep disorders (SDs) and stroke risk by integrating cross-sectional observational analyses with Mendelian randomization (MR) approaches. A cross-sectional analysis was performed using data from the National Health and Nutrition Examination Survey (2015-2018), including 7,264 participants, 270 of whom had a history of stroke. Logistic regression models assessed the association between SD and stroke risk. Eight sleep disorders were examined: sleep terrors, sleep-wake schedule disorders, sleepwalking, sleep apnea, nonorganic sleep disorder, insomnia, trouble falling asleep, and daytime dozing. Genetic instruments (single nucleotide polymorphisms) for these exposures were retrieved from the IEU Open Genome-Wide Association Study (GWAS) database, and two-sample MR analysis was conducted to infer causality. SD showed a strong positive association with stroke in the crude model [odds ratio (OR) = 2.62, 95% confidence interval (CI): 1.88-3.64,< 0.001], which remained significant after adjusting for confounders (OR = 1.83, 95% CI: 1.28-2.63,= 0.007). MR analysis identified nonorganic sleep disorder (OR = 1.025,= 0.023) and sleep apnea (OR = 1.105,= 0.002) as significant risk factors for stroke. Conversely, sleepwalking showed a negative association (OR = 0.986,= 0.001). No evidence of horizontal pleiotropy or heterogeneity was detected, and reverse MR showed no causal effect of stroke on SD. Combining observational and genetic evidence, this study supports a causal relationship between certain SD subtypes and stroke risk. Nonorganic sleep disorders and sleep apnea may increase stroke risk, whereas sleepwalking may have a protective effect.This study uniquely combines cross-sectional analysis and Mendelian randomization to reveal a causal link between specific sleep disorders and stroke risk. It identifies nonorganic sleep disorders and sleep apnea as independent risk factors while suggesting a protective effect of sleepwalking. These findings offer novel genetic and observational evidence supporting targeted prevention strategies and highlight the need for further investigation into underlying mechanisms and clinical implications. P P P P P NEW & NOTEWORTHY
