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

BACKGROUND: 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. We investigated potential causality between genetically instrumented liability to migraine and cardiovascular disease outcomes using two-sample Mendelian randomization.

METHODS: The exposure comprised 35 independent, genome-wide significant genetic variants identified in the largest published migraine GWAS (Ncases = 59,674 / Ncontrols =316,078). The outcome datasets included GWAS of CAD (76,014 / 264,785), myocardial infarction (MI) (43,676 / 128,199), angina (10,618 / 326,065), and AF (60,620 / 970,216). MR estimates were generated using inverse-variance weighted random-effects meta-analysis, and further assessed with conventional MR sensitivity analyses.

RESULTS: We found evidence for a protective effect of migraine liability on CAD (odds ratio 0.86, 95% confidence interval 0.76-0.96, p=0.003), MI (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 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: We identified a potentially protective effect of genetically instrumented liability to migraine on CAD risk. Mechanistic research investigating this link is warranted.