Many candidate gene association studies and recently also genome-wide association studies (GWAS) have searched for genetic factors underlying migraine heritability. Some genetic factors increasing migraine susceptibility have direct links to epigenetic mechanisms. For instance, DNA polymorphisms in
MTHFR (the gene for 5',10'-methylenetetrahydrofolate reductase), a gene required for DNA methylation, show a slight association with migraine in some studies [
47]. More recently, GWAS have identified several single nucleotide polymorphisms linked to migraine pathophysiology [
48‐
50] in genes or in regulatory regions of genes involved in epigenetic processes, including
MTDH,
MEF2D and
PRDM16. For example, metadherin (MTDH) associates with nuclear factor κB (NFκB) and a HAT to promote the expression of NFκB target genes [
51]. Myocyte enhancer factor 2D (MEF2D) can target methyltransferase complexes to specific genes to mark them for gene expression [
52].
MEF2 has recently been shown to be regulated via the glucocorticoid receptor [
53], which may be one of the mechanisms by which stress hormones affect the epigenome. Finally, PR domain containing 16 (PRDM16) is involved in positioning and removing specific chromatin modifications at enhancer regions of Notch target genes during olfactory neuron differentiation in drosophila [
54]. These studies suggest that some of the migraine GWAS hits may contribute to developing migraine through epigenetic modifications at their target genes. Despite great efforts, GWAS have until now only explained a fraction of the total heritability of migraine. One explanation for this so-called 'missing heritability' is the fact that GWA approaches are unsuited for capturing disease susceptibility DNA variants with a low allele frequency, but which are expected to have a larger effect size [
55]; next generation sequencing is currently used to identify such variants. Another possible explanation could be that DNA is not the only carrier of heritable information; epigenetic information can also be transmitted across cell divisions and possibly even transgenerationally. Recent techniques that couple array-based analysis or next generation sequencing to methods to study epigenetic marks enable genome-wide and high-throughput analysis of epigenetic marks. These techniques can analyze histone modifications (that is, by chromatin immunoprecipitation (ChIP)) as well as DNA methylation (that is, by bisulfite conversion of unmethylated cytosines or by immunoprecipitation of methylated DNA using antibodies (MeDIP) or methyl binding domains (MBD)) [
56]. It therefore seems likely that the recently proposed epigenome-wide association studies, that can associate epigenetic marks to a trait (in addition to genetic variations found by GWAS) [
57], will soon be put to use to further discover factors involved in migraine heritability. Because brain tissue from migraine patients is scarcely available, it may be feasible to use DNA banks consisting of large collections of stored DNA samples of migraine sufferers as a resource for identification of heritable DNA methylation marks that predispose to migraine.