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ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

Original publication




Journal article



Publication Date





e944 - e950


From the Unit of Cardiovascular and Nutritional Epidemiology (S.C.L.), Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Stroke Research Group, Department of Clinical Neurosciences (M.T., H.S.M.), MRC Biostatistics Unit (S.B.), and Department of Public Health and Primary Care (S.B.), University of Cambridge, UK; Department of Cerebrovascular Diseases (G.B.B.), Fondazione IRCCS-Istituto Neurologico Carlo Besta, Milano, Italy; Department of Clinical Pathology and Genetics (C.J.), Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg; and Department of Surgical Sciences (K.M.), Uppsala University, Sweden.


MEGASTROKE project of the International Stroke Genetics Consortium, Humans, Brain Ischemia, Intracranial Embolism, Calcium, Magnesium, Polymorphism, Single Nucleotide, Stroke, Mendelian Randomization Analysis