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Yu Qian,1,* Ding Ye,1,* David JH Wu,1,2 Chen Feng,3 Zhen Zeng,1 Lihong Ye,1 Rui Zhu,4 Zhenyu Zhang,5 Yingying Mao11School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 2University of Minnesota Medical School, Minneapolis, MN 55455, USA; 3The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 4College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 5Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA*These authors contributed equally to this workPurpose: Numerous studies have indicated that smokers have an increased risk of developing ischemic stroke. However, less is known about the causal relationship between cigarette smoking and ischemic stroke subtypes. In the present study, we aim to determine whether genetically predicted cigarette smoking was associated with subtypes of ischemic stroke using Mendelian randomization (MR).Patients and methods: We used summary-level genetic association data from the MEGASTROKE consortium, including 438,847 individuals of European ancestry (34,217 cases of ischemic stroke and 404,630 controls). We used 176 single nucleotide polymorphisms as instrumental variables, which were previously identified to be associated with smoking in the Study of the Social Science Genetic Association Consortium (n=518,633). MR analyses were performed using inverse-variance-weighted method, weighted-median method, and MR-Egger regression.Results: We found that genetically predicted smoking was associated with a higher risk of ischemic stroke (odds ratio (OR): 1.24, 95% CI: 1.10–1.39) and large artery ischemic stroke (OR: 1.52, 95% CI: 1.14–2.02), but not with risk of cardioembolic ischemic stroke or small vessel ischemic stroke. Sensitivity analyses using alternative MR approaches produced similar results.Conclusion: Genetic predisposition toward smoking is causally associated with a higher incidence of large artery ischemic stroke. Further work is warranted to clarify the underlying mechanism of smoking in the development of large artery ischemic stroke.Keywords: ischemic stroke, Mendelian randomization, polymorphism, single nucleotide, smoking