Objective  To explore the causal relationship between sleep apnea syndrome (SAS) and stroke and the possible mediating role of serum metabolites from a genetic perspective based on Mendelian randomization (MR).

Methods  A two-sample bidirectional MR approach was used to explore the effect of SAS on stroke and its subtypes, and serum metabolites were used as mediators for MR analysis. The inverse-variance weighted (IVW) method was considered as the primary method to evaluate the causal relationship between exposure and outcome. Additionally, sensitivity analyses were performed to evaluate pleiotropy and heterogeneity.

Results  Two- sample bidirectional MR showed that there was a significant correlation between SAS and lacunar infarction [OR=1.144, 95%CI (1.014, 1.291), P<0.05] and large artery atherosclerotic ischemic stroke [OR=1.118, 95%CI (1.028, 1.371), P<0.05]. Mediating effects showed that SAS increased the risk of largeartery atherosclerotic ischemic stroke by increasing the levels of N6-carbamoylthreonyladenosine [β=0.020, 95%CI (0.001, 0.038), P=0.035] and 4-hydroxyphenylpyruvic acid [β=0.019, 95%CI (0.001, 0.036), P=0.037].

Conclusion  There is a causal relationship in genetics between SAS, lacunar infarction, and large artery atherosclerotic ischemic stroke, and changes in serum metabolite levels may be a potential mechanism underlying the causal relationship between SAS and large artery atherosclerotic ischemic stroke.

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