Epigenetics in primary headaches: a new avenue for research

Sir,I read with great satisfaction and enthusiasm the reviewarticle by Professor Montagna, ‘‘The primary headaches:genetics, epigenetics and a behavioural genetic model [1].’’He presents a detailed outline of genetic studies in primaryheadaches, mostly migraine, and at the same time discussesthe limitations associated with each of the approaches asmirrored by the inconsistent results. In addition, a com-prehensive hypothesis on migraine pathophysiology,incorporating both the Darwinian perspective and recentadvances in epigenetics, is presented. This is satisfying intwo ways. First, it helps to understand why many of theresults are controversial. Most importantly he calls ourattention to something we all know: ‘migraine’ is a col-lective term for a set of symptoms, as deﬁned by theInternational Headache Society [2]. This etiological het-erogeneity is the main obstacle hampering genetic studiesand any small or moderate genetic effect, that may beimportant for a subgroup of migraines of the same origin(same underlying syndrome or disease), will inevitably bediluted when we look at all migraines. Furthermore, envi-ronmental aspects (nutrients, living conditions, etc., withthe potential to exert epigenetic changes) have so far beendisregarded in genetic studies. Second, this novel hypoth-esis on migraine pathophysiology incorporates existingknowledge into a new, more complex framework, ratherthan refuting prior studies. This encourages continuing tosearch for the origin of primary headaches.Epigenetics refers to the heritability of traits not attrib-utable to a change in DNA sequence. Two commonmechanisms are DNA methylation and post-translationalhistone modiﬁcation [3]. Although a relatively youngresearch branch, tremendous progress has been made inelucidating how, e.g., DNA methylation regulates geneexpression and how that impacts disease susceptibility, inparticular cancerogenesis [3]. In addition, pharmacologicalapproaches to modify DNA methylation and, thus, geneexpression have come into focus recently [4]. In extensionto Professor Montagna’s ‘behavioural genetic model’ ofmigraine and other primary headache disorders, I wouldalso like to suggest the idea of a epigenetic cause formedication response. In migraine abortive and preventivedrugs are effective in only about half of patients [5] and incluster headache subcutaneous sumatriptan is effective in80% of patients at best [6, 7]. These phenomena may beexplained by functional gene variants [8]. However,response to analgesics and triptans can also change overtime and depending on the frequency of usage (medicationoveruse headache impairing effectiveness of abortivemedication). This cannot be explained by simple altera-tions in the genetic code, but suggests epigenetic changesat target molecules. Such a ‘pharmaco(epi-)genetic’ modelwould acknowledge both DNA sequence variation andmethylation, etc., as determinants of drug treatmentresponse.This article [1] fuels headache research enthusiasm.Admittedly, the proportion epigenetics plays with regard todisease causation and drug response is unknown andepigenetics will unlikely provide answers to all openquestions in headache research. However, I consider this‘behavioural genetic model’ a very valuable framework