{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:41:40Z","timestamp":1790959300199,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T00:00:00Z","timestamp":1582070400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["18POST34080063"],"award-info":[{"award-number":["18POST34080063"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK110550"],"award-info":[{"award-number":["DK110550"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["K23NS086873"],"award-info":[{"award-number":["K23NS086873"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["R01NS093870"],"award-info":[{"award-number":["R01NS093870"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["R01NS103924"],"award-info":[{"award-number":["R01NS103924"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used summary statistics from genome\u2010wide association studies for body mass index (BMI), waist\u2010to\u2010hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2\u2010sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44\u2013113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29\u201391%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59\u2013457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (\u03b2 = 0.11, 95% CI = 0.01\u20130.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one\u2010tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4\u201320%), but no evidence of mediation was found for average blood glucose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. <jats:bold>ANN NEUROL 2020;87:516\u2013524<\/jats:bold><\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25686","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T08:32:14Z","timestamp":1579854734000},"page":"516-524","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":151,"title":["Mendelian Randomization Study of Obesity and Cerebrovascular Disease"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1702-8168","authenticated-orcid":false,"given":"Sandro","family":"Marini","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine Massachusetts General Hospital  Boston MA"},{"name":"Department of Neurology Boston University Medical Center  Boston 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for Stroke and Dementia Research University Hospital of Ludwig Maximilian University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Sudlow","sequence":"additional","affiliation":[{"name":"Center for Medical Informatics, Usher Institute of Population Health Sciences and Informatics University of Edinburgh  Edinburgh United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Dichgans","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research University Hospital of Ludwig Maximilian University  Munich Germany"},{"name":"Munich Cluster for Systems Neurology  Munich Germany"},{"name":"German Center for Neurodegenerative Diseases  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose C.","family":"Florez","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine Massachusetts General Hospital  Boston 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