Causal effects of mental disorders on stroke subtypes: A proteome-wide Mendelian randomization and mediation analysis

Observational studies have demonstrated associations between mental disorders and stroke, yet causal relationships and potential molecular mechanisms remain elusive. To clarify this, we performed a bidirectional 2-sample Mendelian randomization (MR) analysis using genome-wide association studies summary statistics to assess the causal effects of 7 major mental disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder [ADHD], Alzheimer disease, and Parkinson disease) on stroke subtypes. Analyses were divided into discovery and validation cohorts of European ancestry, followed by MRlap and meta-analysis to obtain pooled estimates. To explore potential circulating protein mediators, 4907 plasma cis-protein quantitative trait loci (cis-pQTLs) from deCODE Genetics were screened, followed by Bayesian co-localization and 2-step MR mediation analyses. Our findings revealed that ADHD was consistently associated with an increased risk of any stroke (AS), any ischemic stroke (AIS), and particularly large-artery atherosclerotic stroke (LAS; odds ratio = 1.455; 95% confidence interval: 1.077-1.967). Mediators screening showed genetic liability to ADHD was linked to elevated circulating matrix metallopeptidase-12 (MMP12; β = 0.141, P = .005), which conferred protection against AIS and LAS, potentially lowering LAS risk by 7.5%. In conclusion, this MR study suggests ADHD is a causal risk factor for ischemic stroke, especially LAS. Paradoxically, circulating MMP12 acts as a protective mediator, modestly reducing this risk by 7.5%. These findings require validation in future experimental and cohort studies.