Exploring the Hereditary Nature of Migraine

Abstract

Migraine is a common neurological disorder which affects 15-20% of the population; it has a high socioeconomic impact through treatment and loss of productivity. Current forms of diagnosis are primarily clinical and can be difficult owing to comorbidity and symptom overlap with other neurological disorders. As such, there is a need for better diagnostic tools in the form of genetic testing. Migraine is a complex disorder, encompassing various subtypes, and has a large genetic component. Genetic studies conducted on rare monogenic subtypes, including familial hemiplegic migraine, have led to insights into its pathogenesis via identification of causal mutations in three genes (CACNA1A, ATP1A2 and SCN1A) that are involved in transport of ions at synapses and glutamatergic transmission. Study of familial migraine with aura pedigrees has also revealed other causal genes for monogenic forms of migraine. With respect to the more common polygenic form of migraine, large genome-wide association studies have increased our understanding of the genes, pathways and mechanisms involved in susceptibility, which are largely involved in neuronal and vascular functions. Given the preponderance of female migraineurs (3:1), there is evidence to suggest that hormonal or X-linked components can also contribute to migraine, and the role of genetic variants in mitochondrial DNA in migraine has been another avenue of exploration. Epigenetic studies of migraine have shown links between hormonal variation and alterations in DNA methylation and gene expression. While there is an abundance of preliminary studies identifying many potentially causative migraine genes and pathways, more comprehensive genomic and functional analysis to better understand mechanisms may aid in better diagnostic and treatment outcomes.

Keywords: X-linked; epigenetics; familial hemiplegic migraine; migraine; migraine with aura; migraine without aura; mitochondrial variants.

Figure 1

GWAS-identified genes associated with migraine. The figure shows the major studies identifying the genes associated with polygenic forms of migraine, which largely fall into either neuronal or vascular function. Genes displayed in black text were new discoveries of each study, while the grey text highlights those that have been replicated for existing studies.–

Figure 2

Mitochondrial dysfunction leads to CSD. The image demonstrates how mechanical disruptions to the mitochondrion’s energy production could cause migraine by lowering the threshold for propagation of CSD.