Mendelian Randomization Study of Obesity and Cerebrovascular Disease

• Published in: Annals of neurology 2020-04, Vol.87 (4), p.516-524
• Main Authors: Marini, Sandro, Merino, Jordi, Montgomery, Bailey E., Malik, Rainer, Sudlow, Catherine L., Dichgans, Martin, Florez, Jose C., Rosand, Jonathan, Gill, Dipender, Anderson, Christopher D.
• Format: Article
• Language: English
• Subjects: Adipose tissue; Blood Glucose - genetics; Blood pressure; Blood Pressure - genetics; Blood vessels; Body mass; Body Mass Index; Body size; Cerebral Hemorrhage - epidemiology; Cerebral Hemorrhage - genetics; Cerebral Small Vessel Diseases - epidemiology; Cerebral Small Vessel Diseases - genetics; Cerebrovascular diseases; Cerebrovascular Disorders - epidemiology; Cerebrovascular Disorders - genetics; Confidence intervals; Genome-wide association studies; Genomes; Glucose; Health risk assessment; Health risks; Hemorrhage; Hip; Humans; Hyperglycemia; Hypertension; Ischemia; Mendelian Randomization Analysis; Obesity; Obesity - epidemiology; Obesity - genetics; Phenotypes; Randomization; Risk; Statistical methods; Stroke; Stroke - epidemiology; Stroke - genetics; Substantia alba; Waist-Hip Ratio; White Matter - diagnostic imaging
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25686

Objective 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. Methods 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 2‐sample 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. Results 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% (95% CI = 29–91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59–457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% 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 (proportion mediated: 12%, 95% CI = 4–20%), but no evidence of mediation was found for average blood glucose. Interpretation 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. ANN NEUROL 2020;87:516–524