Cannabis use disorder increases risk of large-artery atherosclerotic stroke and migraine with aura through mendelian randomization study

Observational studies have shown some association between cannabis use disorder (CUD) and neurological disorders, but their causal relationship is unclear. In this study, we tested the potential causal relationship between CUD and three common neurological disorders using two-sample Mendelian randomization (TSMR) and multivariate MR (MVMR) methods. Thirty-two genetic loci were extracted as exposure factors from the largest genome-wide association study (GWAS) summary statistics for CUD to date. TSMR results showed that genetic prediction of CUD with all stroke, ischemic stroke, large-artery atherosclerotic stroke, migraine with aura, and Alzheimer's disease (AD) had a positive causal relationship (P < 0.05), which was not found in several other diseases. The association between CUD and stroke, ischemic stroke, and AD in the MVMR study may have been influenced by confounding factors (P > 0.05). Subgroup analyses highlighted a causal relationship between genetically predicted CUD and large-artery atherosclerotic stroke (OR = 1.169; 95%CI 1.030-1.328; P = 0.016) and migraine with aura (OR = 1.142; 95% 1.021-1.278; P = 0.020). Our further functional mapping and annotation enrichment analyses using FUMA suggest that the brain-gut axis may serve as another layer of explanation for the existence of an association between CUD and neurological disorders.