Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders

Abstract

Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2, and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome-wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients.

Identifying Natural Subgroups of Migraine Based on Comorbidity and Concomitant Condition Profiles: Results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study

“…For example, migraine may cause cranial autonomic features including rhinorrhea that may lead to misdiagnosis of sinusitis. 20,[42][43][44] Identification of classes with shared genetic factors may help identify genetically heterogeneous predictors of migraine in future analyses, and may enable the targeting of treatments, preliminary evidence of which has been demonstrated in a Danish population. 39,40 A more significant possibility is that the subtypes identified in these analyses have shared underlying pathophysiologic mechanisms that link migraine with the associated comorbidities, probably as a result of shared genetic factors.…”

Abdominal migraine

“…No studies suggest vasospasm of small gut vessels as the cause of the periumbilical pain, but regional or central changes2829 in blood flow may be important, as they are for other forms of migraine 26. The strong familial incidence in abdominal and other migraine suggests an important genetic role,30 particularly for mutations involving cell membrane transport (channelopathies) 3132…”

Correlation between MTHFR Genotype Polymorphisms and Different Types of Migraine Headache in Iranian Patients: A Case Control Study

“…Migraine is a common neurovascular disorder affecting around one in every five women and around one in every 15 men, which usually begins in early adulthood. There are several types of migraine, including migraine with aura, where there are specific warning signs immediately before the migraine begins, and migraine without aura (the most common type), where the migraine occurs without any specific warning sign [1].…”