Attention-deficit/hyperactivity disorder and ischemic stroke: A Mendelian randomization study

Background: Observational studies have found an association between attention-deficit/hyperactivity disorder (ADHD) and ischemic stroke. Aims: The purpose of this study was to investigate whether genetic liability to ADHD has a causal effect on ischemic stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (nine single-nucleotide polymorphisms; P < 5 x 10(-8)) using as instrumental variables for the analysis was obtained from a genome-wide association study of ADHD with 19,099 cases and 34,194 controls. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium, with 40,585 cases and 406,111 controls. MR inverse variance-weighted method was conducted to investigate the effect of genetic liability to ADHD on ischemic stroke and its subtypes. Sensitivity analyses (median-based methods, MR-Egger, MR-robust adjusted profile scores, MR-pleiotropy residual sum and outlier) were also utilized to assess horizontal pleiotropy and remove outliers. Multivariable MR (MVMR) analyses were conducted to explore potential mediators. Results: Genetically determined ADHD (per 1 SD) was significantly associated with a higher risk of any ischemic stroke (AIS) (odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.05-1.25, P = 0.002) and large-artery atherosclerotic stroke (LAS) (OR = 1.40, 95% CI = 1.10-1.76, P = 0.005). The significant association was also found in sensitivity analyses and MVMR analyses. Conclusions: Genetic liability to ADHD was significantly associated with an increased risk of AIS, especially LAS. The association between ADHD and LAS was independent of age of smoking initiation but mediated by coronary artery disease.