Migraines are a common chronic neurovascular disease caused by the combined effects of genetic and environmental factors, affecting at least 1 billion people worldwide.1,2 Spontaneous coronary artery dissection (SCAD) is a rare acute coronary syndrome unrelated to atherosclerosis or iatrogenic catheter-induced events, characterized by the spontaneous separation of the coronary artery wall and the formation of a false lumen.3,4 In a retrospective study of 20,195 patients with acute coronary syndrome, 0.31 % of patients presented with SCAD.5 Fibromuscular dysplasia (FMD) is a rare, non-atherosclerotic, non-inflammatory arterial disease characterized by “string of beads” vascular changes.6, 7, 8, 9 According to data from the French “DISCO” registry, 45 % of patients with SCAD were found to have FMD.10 Additionally, data show that 70 % of patients with FMD report migraines, and among patients with both FMD and SCAD, 27 % have a history of migraines.11, 12, 13 People are becoming increasingly interested in the connections among these diseases.

However, the complex relations among these three diseases are only partially understood, and no definitive conclusions have been reached regarding their causal relations. Migraines and FMD are widely regarded as considerable risk factors for SCAD and its recurrence, and migraine is considered a potential pathogenic factor for FMD. Therefore, it can be inferred that there may be a causal relation among these three diseases.14 However, the research on these aspects is insufficient. In 2019, Saw et al. analyzed data from 750 patients with SCAD and found that 50.1 % of patients did not have definite risk factors.15 Whether SCAD originates from coronary artery FMD is also a subject of controversy. It is important to note that the aforementioned viewpoints come from observational studies, and the identified correlation does not equate to a causal relation.

Mendelian randomization (MR) is an emerging approach that uses genetic variants as instrumental variables (IV) to assess the causal effects of exposures and outcomes. Compared with traditional observational studies, MR can still obtain reliable causal inferences even when all confounding factors are not fully understood, and there is no issue of reverse causation. In this study, we used two-sample and multivariate MR analysis methods to address the following two key questions from a genetic perspective: (1) Is there a causal association and mediating effect among migraine, SCAD, and FMD? (2) Do currently perceived potential risk factors for SCAD and FMD mediate the aforementioned causal association?