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This study aimed to explore the causal impact of sarcopenia\u2010related traits on IS and to identify key mediators of this association.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted univariable, multivariable two\u2010sample, and two\u2010step Mendelian randomization (MR) analyses using genome\u2010wide association study (GWAS) data. This included data for appendicular lean mass (ALM), hand grip strength (HGS), and usual walking pace (UWP) from the UK Biobank, and IS data from the MEGASTROKE consortium. Additionally, 21 candidate mediators were analyzed based on their respective GWAS data sets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Each 1\u2010SD increase in genetically proxied ALM was associated with a 7.5% reduction in the risk of IS (95% CI: 0.879\u20130.974), and this correlation remained after controlling for levels of physical activity and adiposity\u2010related indices. Two\u2010step MR identified that six mediators partially mediated the protective effect of higher ALM on IS, with the most significant being coronary heart disease (CHD, mediating proportion: 39.94%), followed by systolic blood pressure (36.51%), hypertension (23.87%), diastolic blood pressure (15.39%), type\u20102 diabetes mellitus (T2DM, 12.71%), and low\u2010density lipoprotein cholesterol (7.97%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study revealed a causal protective effect of higher ALM on IS, independent of physical activity and adiposity\u2010related indices. Moreover, we found that higher ALM could reduce susceptibility to IS partially by lowering the risk of vascular risk factors, including CHD, hypertension, T2DM, and hyperlipidemia. In brief, we elucidated another modifiable factor for IS and implied that maintaining sufficient muscle mass may reduce the risk of such disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14759","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T05:45:04Z","timestamp":1715924704000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The causal relationship between sarcopenia\u2010related traits and ischemic stroke: Insights from univariable and multivariable Mendelian randomization analyses"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7809-0187","authenticated-orcid":false,"given":"Jiahao","family":"Song","sequence":"first","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital Capital Medical University  Beijing China"},{"name":"Advanced Center of Stroke Beijing Institute for Brain Disorders  Beijing China"},{"name":"National 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