Effect of genetic liability to migraine on coronary artery disease and atrial fibrillation: a Mendelian randomization study

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 (N-cases = 59 674/N-controls = 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.