Review Probes Migraine’s Hereditary Nature

Although many preliminary studies exist identifying potential causative migraine genes and pathways, more comprehensive genomic and functional analyses may aid in superior diagnostic and treatment outcomes for migraineurs, according to a review published in Neuropsychiatric Disease and Treatment.

Current forms of migraine diagnosis can be complicated due to comorbidities and symptom overlap with other neurological disorders—leaving open an opportunity for genetic testing. It has been established that migraine has a large genetic component and studies have shown an increased familial risk for common migraine, considered to be polygenic, researchers wrote.

Studies on families with migraine revealed that a first-degree relative of an individual who suffers migraine without aura (MO) proband is 2 times as likely to suffer MO and 1.4 times as likely to have migraine with aura (MA). “However, a first-degree relative of an MA proband is 4 times more likely to have MA, but has no increased risk of MO,” authors noted.

One genome-wide association study (GWAS), including 59,674 migraineurs and 316,078 healthy controls, identified 44 single-nucleotide polymorphisms (SNPs) mapped to 38 loci associated with common polygenic migraine.

An additional approach used to study the genetic pathways of migraine is to examine monogenic subtypes, researchers wrote. For example, one study of “particular families which show strong inheritance of MA showed that a frameshift mutation of the KCNK18/TRESK gene segregated with migraine diagnosis, suggesting that it was causal.” This finding was corroborated by additional studies.

Patients with hemiplegic migraine (HM), a rare and severe subtype of MA, report symptoms of hemiparalysis or other motor disturbances accompanying migraine. HM also has sporadic (SHM) and familial forms (FHM) with FHM usually inherited in an autosomal dominant fashion with a 70%-90% penetrance, authors said.

Three main genes have been implicated in causing FHM and all encode for ion channels. They all also have been implicated in other disorders including spinocerebellar ataxia type 6 and epilepsy. “The common genetic mechanisms behind these disorders often lead to clinical presentation with similar symptoms, making molecular diagnosis through limited gene sequencing difficult,” researchers explained. To meet this challenge, increased use of next generation sequencing (NGF) has allowed for better screening of neurological diseases and increased diagnostic rates.

Several genetic overlaps have been documented in both migraineurs and those suffering from sleep disorders or circadian clock dysfunctions, although future investigations with larger cohorts are warranted to understand this relationship.

Gender also plays a fundamental role in migraine as global prevalence is significantly higher in women. According to researchers, this suggests either a hormonal link or a potential X-chromosomal link to migraine. Studies support the ladder hypothesis as several demonstrated localization of migraine susceptibility to the X chromosome. “However, genes and variants within these regions that may contribute to migraine risk are yet to be identified.”

Genetic analyses of mitochondrial DNA (mtDNA) could present an additional avenue of exploration for migraine susceptibility. Due to the fact mtDNA does not undergo recombination and is passed exclusively through the maternal line, mutations can be tracked across multiple generations. In addition, family studies have revealed clear causal variants in various mitochondrial diseases and also showed migraine is a frequent bi-product or comorbidity of mitochondrial disorders.

“Mitochondrial disorders result in decreased adenosine triphosphate (ATP) production which, in turn, causes oxidative stress. Given that the muscles and brain are highly dependent on oxidative metabolism, it stands to reason that these tissues will be the most adversely affected by any variations in mtDNA,” researchers explained.

Furthermore, “it has also been shown that decreased ATP resulting from mitochondrial disease can decrease the threshold for cortical spreading depression (CSD), which has been extensively linked to migraine.”

However, because migraine is complex and likely has a combination of factors contributing to risk and cause, more studies are needed to improve diagnoses and treatment of the disorder, authors concluded.

Reference

Bron C, Sutherland HG, and Griffiths LR. Exploring the hereditary nature of migraine. Neuropsychiatr Dis Treat. Published online April 22, 2021. doi:10.2147/NDT.S282562