Mendelian Randomization Study of Obesity and Cerebrovascular Disease
Corresponding Author
Sandro Marini MD
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Department of Neurology, Boston University Medical Center, Boston, MA
Address correspondence to
Dr Marini, Center for Genomic Medicine, 185 Cambridge Street, CPZN 6818, Boston, MA 02114. E-mail: [email protected]
Search for more papers by this authorJordi Merino PhD
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Diabetes Unit, Massachusetts General Hospital, Boston, MA
Department of Medicine, Harvard Medical School, Boston, MA
Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Rovira i Virgili University, Pere Virgili Health Research Institute, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders, Reus, Spain
Search for more papers by this authorBailey E. Montgomery BS
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorRainer Malik PhD
Institute for Stroke and Dementia Research, University Hospital of Ludwig Maximilian University, Munich, Germany
Search for more papers by this authorCatherine L. Sudlow BMBCh, MSc, DPhil, FRCPE
Center for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorMartin Dichgans MD
Institute for Stroke and Dementia Research, University Hospital of Ludwig Maximilian University, Munich, Germany
Munich Cluster for Systems Neurology, Munich, Germany
German Center for Neurodegenerative Diseases, Munich, Germany
Search for more papers by this authorJose C. Florez MD, PhD
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Diabetes Unit, Massachusetts General Hospital, Boston, MA
Department of Medicine, Harvard Medical School, Boston, MA
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
Search for more papers by this authorJonathan Rosand MD, MSc
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
Department of Neurology, Massachusetts General Hospital, Boston, MA
Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorDipender Gill MD, PhD
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
Search for more papers by this authorChristopher D. Anderson MD, MMSc
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
Department of Neurology, Massachusetts General Hospital, Boston, MA
Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA
Search for more papers by this authoron behalf of the International Stroke Genetics Consortium
Search for more papers by this authorCorresponding Author
Sandro Marini MD
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Department of Neurology, Boston University Medical Center, Boston, MA
Address correspondence to
Dr Marini, Center for Genomic Medicine, 185 Cambridge Street, CPZN 6818, Boston, MA 02114. E-mail: [email protected]
Search for more papers by this authorJordi Merino PhD
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Diabetes Unit, Massachusetts General Hospital, Boston, MA
Department of Medicine, Harvard Medical School, Boston, MA
Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Rovira i Virgili University, Pere Virgili Health Research Institute, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders, Reus, Spain
Search for more papers by this authorBailey E. Montgomery BS
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorRainer Malik PhD
Institute for Stroke and Dementia Research, University Hospital of Ludwig Maximilian University, Munich, Germany
Search for more papers by this authorCatherine L. Sudlow BMBCh, MSc, DPhil, FRCPE
Center for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorMartin Dichgans MD
Institute for Stroke and Dementia Research, University Hospital of Ludwig Maximilian University, Munich, Germany
Munich Cluster for Systems Neurology, Munich, Germany
German Center for Neurodegenerative Diseases, Munich, Germany
Search for more papers by this authorJose C. Florez MD, PhD
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Diabetes Unit, Massachusetts General Hospital, Boston, MA
Department of Medicine, Harvard Medical School, Boston, MA
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
Search for more papers by this authorJonathan Rosand MD, MSc
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
Department of Neurology, Massachusetts General Hospital, Boston, MA
Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorDipender Gill MD, PhD
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
Search for more papers by this authorChristopher D. Anderson MD, MMSc
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
Department of Neurology, Massachusetts General Hospital, Boston, MA
Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA
Search for more papers by this authoron behalf of the International Stroke Genetics Consortium
Search for more papers by this authorAbstract
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
Potential Conflicts of Interest
C.D.A.: consultancy, ApoPharma, Bayer; J.R: consultancy, One Mind.
Supporting Information
| Filename | Description |
|---|---|
| ana25686-sup-0001-Supinfo.docxWord 2007 document , 141.1 KB | Supplemental Table 1 Genome-wide significant (p < 5x10-8) and independent (r2 < 0.01) single nucleotide polymorphisms (SNP) that were used as instruments for Body Mass Index (BMI) and Waist to Hip Ratio (WHR). Supplemental Table 2: Mendelian Randomization associations between genetic instruments for Body Mass Index and Waist Hip Ratio and risk of all-cause ischemic stroke, ischemic stroke subtypes, and White Matter Hyperintensity. Supplemental Table 3: Bidirectional Mendelian Randomization. Associations between genetic instruments for cerebrovascular disease (instruments) and for Waist Hip Ratio (WHR). Supplemental Table 4: Effect of BMI and WHR on cerebrovascular disease mediated by SBP and FG, and HbA1c Supplemental Figure 1: Mediation analysis: estimates for the SBP mediating the effect of BMI on cerebrovascular disease outcomes. For any cerebrovascular disease, we report the average proportion mediated (dot), the 95% confidence intervals of the percentage mediated (gray bar) and p value. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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