Genetics of Migraine

Migraine is a prevalent neurological disorder characterized by moderate to severe unilateral headaches, often accompanied by nausea, vomiting, phonophobia, and/or photophobia. In up to one-third of patients, these attacks are preceded by an aura — a phase marked by temporary focal neurological symptoms. Visual disturbances are the most common manifestations of aura, although sensory changes and speech difficulties may also occur. When aura includes motor weakness, it is classified as hemiplegic migraine.

Understanding the Mechanisms Behind Migraine

One of the proposed mechanisms underlying migraine is cortical spreading depression — a wave of neuronal and glial cell depolarization that originates in the occipital cortex and slowly propagates across the cerebral cortex, followed by a prolonged period of suppressed brain activity. This phenomenon is believed to play a key role in the development of migraine with aura.

The Role of Genetics in Migraine

Migraine has a strong genetic component. Individuals with a robust family history of migraine are more likely to experience migraine with aura, have an earlier age of onset, and require longer medication use. These patterns suggest a higher genetic predisposition to certain types of migraine. A large-scale study in Finland further reinforced the genetic link between hemiplegic migraine and migraine with aura. Using polygenic risk scores based on common genetic variants identified in the latest genome-wide association studies (GWAS), researchers found that individuals with familial migraine with aura and those with hemiplegic migraine had higher risk scores compared to those with familial migraine without aura. This implies that the presence of common genetic variants contributes significantly to these migraine subtypes.

Genetic Variants Associated with Migraine

While the genetic load in hemiplegic migraine appeared higher than in migraine with aura, the difference was not statistically significant. Studies have identified seven gene loci — near TSPAN2, TRPM8, PHACTR1, FHL5, ASTN2, near FGF6, and LRP1 — that are associated with migraine without aura. The only GWAS specifically focused on migraine with aura identified a single nucleotide polymorphism (SNP) near MTDH and PGCP that reached genome-wide significance.

Insights from Monogenic Syndromes

Most genetic discoveries related to migraine with aura have emerged from studies of monogenic syndromes such as familial hemiplegic migraine (FHM), CADASIL, and FASPS. These conditions have highlighted the involvement of both neuronal signaling and vascular pathways in migraine pathophysiology. Compared to migraine without aura, both hemiplegic and aura-positive migraine types show a higher genetic burden, underscoring the spectrum of migraine as a genetically complex disorder.