Migraine has a strong genetic basis and includes both monogenic and polygenic forms. Some distinct rare familial sub-types, e.g. familial hemiplegic migraine (FHM), are caused by pathogenic variants in genes involved in ion transport and neurotransmitter release, suggesting an underlying vulnerability of the excitability/inhibitory balance in the brain. For more prevalent migraine sub-types, genetic studies have identified many susceptibility loci, implicating genes involved in both neuronal and vascular pathways. Nevertheless, the full spectrum of genomic factors involved in migraine susceptibility is yet to be uncovered.
We are utilising a variety of approaches to identify genes and pathways involved in migraine disorders. Firstly, in a cohort of hemiplegic migraine patients negative for pathogenic missense variants or small indels in the known FHM genes, we have used multiplex ligation-dependent probe amplification (MLPA) assays and Nanopore sequencing to investigate whether larger copy number or structural variations of these may play a role in some patients. We have also conducted whole exome sequencing (WES) of this cohort, and via targeted analyses, identified additional ion channel gene candidates for hemiplegic migraine. For example, rare missense variants in CACNA1I, encoding the voltage gated calcium channel Cav3.3, were present in a number of cases; electrophysiological testing of selected variants supported functional effects on channel activity.1 As there are known epidemiological and genetic relationships between sleep and migraine, WES data was also analysed for rare protein-altering variants in genes involved in circadian and sleep-wake cycles, revealing numerous genes and variants of interest. Furthermore, we have explored whether epigenetic factors, specifically DNA methylation, may also contribute to migraine susceptibility by using Illumina EPIC arrays to identify differentially methylated CpGs in a small cohort of twin pairs discordant for migraine. Altogether these studies support a complex aetiology for migraine, and highlight the role of ion channels and homeostasis.