Mendelian randomization study of obesity and cerebrovascular disease

Sandro Marini, Jordi Merino, Bailey E. Montgomery, Rainer Malik, Catherine L. Sudlow, Martin Dichgans, Jose C. Florez, Jonathan Rosand, Dipender Gill, Christopher D. Anderson

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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.
We used summary statistics from genome‐wide association studies for body mass index (BMI), waist‐to‐hip ratio (WHR) and multiple cerebrovascular disease phenotypes. We explored causal associations with two‐sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR; and assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels respectively.

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%‐113%) in risk for large artery ischemic stroke, a 57% (CI=29%‐91%) increase in risk for small vessel ischemic stroke, a 197% increase (CI=59%‐457%) in risk of intracerebral hemorrhage, as well as an increase in white matter hyperintensity volume (β=0.11; CI=0.01‐0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (12%; CI=4%‐20%), but no evidence of mediation was found for average blood glucose.
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.
Original languageEnglish
JournalAnnals of Neurology
Early online date24 Jan 2020
Publication statusE-pub ahead of print - 24 Jan 2020

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