Causal Effects of Sleep Traits on Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study

Huan Cai,1,* Jialin Liang,2,* Zhonghua Liu,1 Liang Fang,1 Jinghong Zheng,3 Jiahe Xu,3 Liyi Chen,1 Wen Sun,4 Hao Zhang5 1Department of Rehabilitation, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong, People’s Republic of China; 2Department of Endocrinology and Metabolism, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong, People’s Republic of China; 3Department of Neurology, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong, People’s Republic of China; 4Division of Life Sciences and Medicine, Stroke Center and Department of Neurology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230026, Anhui, People’s Republic of China; 5Department of Neurology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hao ZhangDepartment of Neurology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, People’s Republic of ChinaTel +86-13450989238Fax +86 760-87727692Email zh_hao_neurol@163.comZhonghua LiuDepartment of Rehabilitation, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong, People’s Republic of ChinaTel 86-13923308898Email zhonghua_reha@163.comBackground: Unfavorable sleep habits have been linked with ischemic stroke in observational studies, but the causality remains unclear. The aim of this study is to investigate the potential causal role of three sleep traits, including sleep duration, insomnia, and chronotype, in ischemic stroke and its subtypes.Methods: We conducted two-sample Mendelian randomization (MR) analysis using single nucleotide polymorphisms associated with sleep duration, insomnia, and chronotype as instruments to estimate causal associations with ischemic stroke and its subtypes, among 34,217 ischemic stroke cases and 406,111 controls from the MEGASTROKE consortium. Inverse-variance weighted method was used as the main analyses. Alternative MR methods and sensitivity analyses were further performed.Results: We found suggestive evidence that per doubling of genetic liability for short sleep duration (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.01– 1.58) and frequent insomnia symptoms (OR, 1.19; 95% CI, 1.00– 1.41) were associated with a modest increase in risk of large artery stroke (LAS) but not with small vessel stroke, cardioembolic stroke, or any ischemic stroke. The association of frequent insomnia symptoms with LAS was stronger after the exclusion of the outlier (OR, 1.25; 95% CI, 1.04– 1.50). No significant association was observed for chronotype with any ischemic stroke subtype. Results were overall robust to sensitivity analyses, and there was little evidence of horizontal pleiotropy.Conclusion: We provided suggestive evidence for a potential causal role of short sleep duration and insomnia symptoms in LAS. Future researches are required to investigate whether improved sleep habits could help to mitigate LAS risk.Keywords: sleep, large artery stroke, ischemic stroke, Mendelian randomization