Sandro Marini1,2, Jordi Merino1,3,4,5, Bailey E Montgomery1, Rainer Malik6, Catherine L Sudlow7, Martin Dichgans6,8,9, Jose C Florez1,3,4,10, Jonathan Rosand1,10,11,12, Dipender Gill13, Christopher D Anderson1,10,11,12. 1. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA. 2. Department of Neurology, Boston University Medical Center, Boston, MA. 3. Diabetes Unit, Massachusetts General Hospital, Boston, MA. 4. Department of Medicine, Harvard Medical School, Boston, MA. 5. 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. 6. Institute for Stroke and Dementia Research, University Hospital of Ludwig Maximilian University, Munich, Germany. 7. Center for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom. 8. Munich Cluster for Systems Neurology, Munich, Germany. 9. German Center for Neurodegenerative Diseases, Munich, Germany. 10. Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA. 11. Department of Neurology, Massachusetts General Hospital, Boston, MA. 12. Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA. 13. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
Abstract
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.
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.
Authors: Alice R Carter; Dipender Gill; Neil M Davies; Amy E Taylor; Taavi Tillmann; Julien Vaucher; Robyn E Wootton; Marcus R Munafò; Gibran Hemani; Rainer Malik; Sudha Seshadri; Daniel Woo; Stephen Burgess; George Davey Smith; Michael V Holmes; Ioanna Tzoulaki; Laura D Howe; Abbas Dehghan Journal: BMJ Date: 2019-05-22
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Authors: Robert A Scott; Vasiliki Lagou; Ryan P Welch; Eleanor Wheeler; May E Montasser; Jian'an Luan; Reedik Mägi; Rona J Strawbridge; Emil Rehnberg; Stefan Gustafsson; Stavroula Kanoni; Laura J Rasmussen-Torvik; Loïc Yengo; Cecile Lecoeur; Dmitry Shungin; Serena Sanna; Carlo Sidore; Paul C D Johnson; J Wouter Jukema; Toby Johnson; Anubha Mahajan; Niek Verweij; Gudmar Thorleifsson; Jouke-Jan Hottenga; Sonia Shah; Albert V Smith; Bengt Sennblad; Christian Gieger; Perttu Salo; Markus Perola; Nicholas J Timpson; David M Evans; Beate St Pourcain; Ying Wu; Jeanette S Andrews; Jennie Hui; Lawrence F Bielak; Wei Zhao; Momoko Horikoshi; Pau Navarro; Aaron Isaacs; Jeffrey R O'Connell; Kathleen Stirrups; Veronique Vitart; Caroline Hayward; Tõnu Esko; Evelin Mihailov; Ross M Fraser; Tove Fall; Benjamin F Voight; Soumya Raychaudhuri; Han Chen; Cecilia M Lindgren; Andrew P Morris; Nigel W Rayner; Neil Robertson; Denis Rybin; Ching-Ti Liu; Jacques S Beckmann; Sara M Willems; Peter S Chines; Anne U Jackson; Hyun Min Kang; Heather M Stringham; Kijoung Song; Toshiko Tanaka; John F Peden; Anuj Goel; Andrew A Hicks; Ping An; Martina Müller-Nurasyid; Anders Franco-Cereceda; Lasse Folkersen; Letizia Marullo; Hanneke Jansen; Albertine J Oldehinkel; Marcel Bruinenberg; James S Pankow; Kari E North; Nita G Forouhi; Ruth J F Loos; Sarah Edkins; Tibor V Varga; Göran Hallmans; Heikki Oksa; Mulas Antonella; Ramaiah Nagaraja; Stella Trompet; Ian Ford; Stephan J L Bakker; Augustine Kong; Meena Kumari; Bruna Gigante; Christian Herder; Patricia B Munroe; Mark Caulfield; Jula Antti; Massimo Mangino; Kerrin Small; Iva Miljkovic; Yongmei Liu; Mustafa Atalay; Wieland Kiess; Alan L James; Fernando Rivadeneira; Andre G Uitterlinden; Colin N A Palmer; Alex S F Doney; Gonneke Willemsen; Johannes H Smit; Susan Campbell; Ozren Polasek; Lori L Bonnycastle; Serge Hercberg; Maria Dimitriou; Jennifer L Bolton; Gerard R Fowkes; Peter Kovacs; Jaana Lindström; Tatijana Zemunik; Stefania Bandinelli; Sarah H Wild; Hanneke V Basart; Wolfgang Rathmann; Harald Grallert; Winfried Maerz; Marcus E Kleber; Bernhard O Boehm; Annette Peters; Peter P Pramstaller; Michael A Province; Ingrid B Borecki; Nicholas D Hastie; Igor Rudan; Harry Campbell; Hugh Watkins; Martin Farrall; Michael Stumvoll; Luigi Ferrucci; Dawn M Waterworth; Richard N Bergman; Francis S Collins; Jaakko Tuomilehto; Richard M Watanabe; Eco J C de Geus; Brenda W Penninx; Albert Hofman; Ben A Oostra; Bruce M Psaty; Peter Vollenweider; James F Wilson; Alan F Wright; G Kees Hovingh; Andres Metspalu; Matti Uusitupa; Patrik K E Magnusson; Kirsten O Kyvik; Jaakko Kaprio; Jackie F Price; George V Dedoussis; Panos Deloukas; Pierre Meneton; Lars Lind; Michael Boehnke; Alan R Shuldiner; Cornelia M van Duijn; Andrew D Morris; Anke Toenjes; Patricia A Peyser; John P Beilby; Antje Körner; Johanna Kuusisto; Markku Laakso; Stefan R Bornstein; Peter E H Schwarz; Timo A Lakka; Rainer Rauramaa; Linda S Adair; George Davey Smith; Tim D Spector; Thomas Illig; Ulf de Faire; Anders Hamsten; Vilmundur Gudnason; Mika Kivimaki; Aroon Hingorani; Sirkka M Keinanen-Kiukaanniemi; Timo E Saaristo; Dorret I Boomsma; Kari Stefansson; Pim van der Harst; Josée Dupuis; Nancy L Pedersen; Naveed Sattar; Tamara B Harris; Francesco Cucca; Samuli Ripatti; Veikko Salomaa; Karen L Mohlke; Beverley Balkau; Philippe Froguel; Anneli Pouta; Marjo-Riitta Jarvelin; Nicholas J Wareham; Nabila Bouatia-Naji; Mark I McCarthy; Paul W Franks; James B Meigs; Tanya M Teslovich; Jose C Florez; Claudia Langenberg; Erik Ingelsson; Inga Prokopenko; Inês Barroso Journal: Nat Genet Date: 2012-08-12 Impact factor: 38.330
Authors: Dipender Gill; Verena Zuber; Jesse Dawson; Jonathan Pearson-Stuttard; Alice R Carter; Eleanor Sanderson; Ville Karhunen; Michael G Levin; Robyn E Wootton; Derek Klarin; Philip S Tsao; Konstantinos K Tsilidis; Scott M Damrauer; Stephen Burgess; Paul Elliott Journal: Int J Obes (Lond) Date: 2021-05-17 Impact factor: 5.551