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

Runming Du; Yi Zhou; Chong You; Kevin Liu; Daniel A King; Zhi-Sheng Liang; Janice M Ranson; David J Llewellyn; Jie Huang; Zhenyu Zhang

doi:10.1177/17474930221108272

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

Int J Stroke. 2023 Mar;18(3):346-353. doi: 10.1177/17474930221108272. Epub 2022 Jul 6.

Authors

Runming Du¹, Yi Zhou¹, Chong You², Kevin Liu³, Daniel A King⁴, Zhi-Sheng Liang¹, Janice M Ranson⁵, David J Llewellyn^{5

6}, Jie Huang⁷, Zhenyu Zhang^{1

8}

Affiliations

¹ Department of Global Health, Peking University School of Public Health, Beijing, China.
² Department of Biostatistics, Peking University School of Public Health, Beijing, China.
³ Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
⁴ Northwell Health Cancer Institute and Feinstein Institute of Research, Lake Success, NY, USA.
⁵ College of Medicine and Health, University of Exeter, Exeter, UK.
⁶ Alan Turing Institute, London, UK.
⁷ School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China.
⁸ Institute for Global Health and Development, Peking University, Beijing, China.

PMID: 35670701
DOI: 10.1177/17474930221108272

Abstract

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 × 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.

Keywords: Attention-deficit/hyperactivity disorder; Mendelian randomization; ischemic stroke.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Attention Deficit Disorder with Hyperactivity* / complications
Attention Deficit Disorder with Hyperactivity* / epidemiology
Attention Deficit Disorder with Hyperactivity* / genetics
Genome-Wide Association Study
Humans
Ischemic Stroke* / complications
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide / genetics
Stroke* / complications
Stroke* / epidemiology
Stroke* / genetics