Genetically identified mediators associated with increased risk of stroke and cardiovascular disease in individuals with autism spectrum disorder

Growing evidence suggested that individuals with autism spectrum disorder (ASD) associated with stroke and cardiovascular disease (CVD). However, the causal association between ASD and the risk of stroke and CVD remains unclear. To validate this, we performed two-sample Mendelian randomization (MR) and two-step mediation MR analyses, using relevant genetic variants sourced from the largest genome-wide association studies (GWASs). Two-sample MR evidence indicated causal relationships between ASD and any stroke (OR=1.1184, 95% CI: 1.0302-1.2142, P < 0.01), ischemic stroke (IS) (OR=1.1157, 95% CI: 1.0237-1.2160, P = 0.01), large-artery atherosclerotic stroke (LAS) (OR=1.2902, 95% CI: 1.0395-1.6013, P = 0.02), atrial fibrillation (AF) (OR=1.0820, 95% CI: 1.0019-1.1684, P = 0.04), and heart failure (HF) (OR=1.1018, 95% CI: 1.0007-1.2132, P = 0.05). Additionally, two-step mediation MR suggested that type 2 diabetes mellitus (T2DM) partially mediated this effect (OR=1.14, 95%CI: 1.02-1.28, P = 0.03). The mediated proportion were 10.96% (95% CI: 0.58%-12.10%) for any stroke, 11.77% (95% CI: 10.58%-12.97%) for IS, 10.62% (95% CI: 8.04%-13.20%) for LAS, and 7.57% (95% CI: 6.79%-8.36%) for HF. However, no mediated effect was observed between ASD and AF risk. These findings have implications for the development of prevention strategies and interventions for stroke and CVD in patients with ASD.