Migraine is a common neurovascular brain disorder that is characterized by recurrent attacks of severe headache and various neurological symptoms. Main migraine subtypes, migraine with and without aura, are distinguished based on the presence of a phenomenon that is characterized as a wave of glial and neuronal depolarization that proceeds through the cortex and is thought to activate headache mechanisms, at least in those patients that also experience such events. Migraine runs in families and has a strong genetic component. Knowledge on migraine pathophysiology has advanced with the discovery of various genes for monogenic forms of migraine, that is familial hemiplegic migraine and disorders in which migraine is a prominent clinical feature. Identified gene mutations affect neuronal function, pointing towards neuronal hyperactivity, and glial cell and vascular dysfunction. Transgenic migraine mouse models that carry mutations previously identified in patients have been instrumental in dissecting underlying disease mechanisms, not only of migraine but also of its co-morbidities, such as epilepsy and stroke. So-called genome-wide association studies performed for common migraine forms have yielded already over a hundred gene variants and provided, to certain extent, support for involvement of similar disease mechanisms, as have surfaced for investigating the rare migraine types. Efforts are underway to assess whether and how genetic findings can be translated to clinical practice. Finally, the advent of the use of human induced pluripotent stem cell-derived brain cells and the use of brain organoids provide new exciting opportunities to bridge the whole spectrum from modeling disease in cells, animals and patients.

Arn van den Maagdenberg's Brain Prize seminar: Genetics of migraine and the use of genetic mouse models