I Daghlas1,2, Y Guo1,3, D I Chasman1. 1. Department of Medicine, Division of Preventive Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. 2. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. 3. Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Abstract
BACKGROUND AND PURPOSE: Observational studies have implicated migraine as a risk factor for coronary artery disease (CAD) and atrial fibrillation (AF); however, it is unclear whether migraine is causal in this relationship. Potential causality between genetically instrumented liability to migraine and cardiovascular disease outcomes was investigated using two-sample Mendelian randomization. METHODS: The exposure comprised 35 independent, genome-wide significant genetic variants identified in the largest published genome-wide association study of migraine (Ncases = 59 674/Ncontrols = 316 078). The outcome datasets included genome-wide association studies of CAD (76 014/264 785), myocardial infarction (43 676/128 199), angina (10 618/326 065) and AF (60 620/970 216). Mendelian randomization estimates were calculated using inverse-variance weighted regression, and were further assessed with conventional Mendelian randomization sensitivity analyses. RESULTS: Evidence was found for a protective effect of migraine liability on CAD (odds ratio 0.86, 95% confidence interval 0.76-0.96, P = 0.003), myocardial infarction (0.86, 0.74-0.96, P = 0.01) and angina (0.86, 0.75-0.99, P = 0.04), but not on AF (1.00, 0.95-1.05, P = 0.88). Analyses by migraine subtype showed an effect of liability to migraine without aura on CAD risk (0.91, 0.84-0.99, P = 0.014), but not of migraine with aura (1.00, 0.97-1.03, P = 0.89). Sensitivity analyses indicated minimal bias by horizontal pleiotropy, outliers, reverse causality or sample overlap. CONCLUSIONS: A potentially protective effect of genetically instrumented liability to migraine on CAD risk was identified. Mechanistic research investigating this link is warranted.
BACKGROUND AND PURPOSE: Observational studies have implicated migraine as a risk factor for coronary artery disease (CAD) and atrial fibrillation (AF); however, it is unclear whether migraine is causal in this relationship. Potential causality between genetically instrumented liability to migraine and cardiovascular disease outcomes was investigated using two-sample Mendelian randomization. METHODS: The exposure comprised 35 independent, genome-wide significant genetic variants identified in the largest published genome-wide association study of migraine (Ncases = 59 674/Ncontrols = 316 078). The outcome datasets included genome-wide association studies of CAD (76 014/264 785), myocardial infarction (43 676/128 199), angina (10 618/326 065) and AF (60 620/970 216). Mendelian randomization estimates were calculated using inverse-variance weighted regression, and were further assessed with conventional Mendelian randomization sensitivity analyses. RESULTS: Evidence was found for a protective effect of migraine liability on CAD (odds ratio 0.86, 95% confidence interval 0.76-0.96, P = 0.003), myocardial infarction (0.86, 0.74-0.96, P = 0.01) and angina (0.86, 0.75-0.99, P = 0.04), but not on AF (1.00, 0.95-1.05, P = 0.88). Analyses by migraine subtype showed an effect of liability to migraine without aura on CAD risk (0.91, 0.84-0.99, P = 0.014), but not of migraine with aura (1.00, 0.97-1.03, P = 0.89). Sensitivity analyses indicated minimal bias by horizontal pleiotropy, outliers, reverse causality or sample overlap. CONCLUSIONS: A potentially protective effect of genetically instrumented liability to migraine on CAD risk was identified. Mechanistic research investigating this link is warranted.
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