Migraine genetics: New opportunities, new challenges

Abstract

As migraine runs in families and has a strong genetic component, many investigations have aimed to identify the genetic factors that confer susceptibility to this disease. Initial studies of rare monogenic migraine disorders led to the identification of the first migraine genes (1). Specific mutations in the genes CACNA1A, ATP1A2 and SCN1A, which all encode subunits of ion transporters that play a part in neurotransmission, have been identified for familial hemiplegic migraine, an autosomal dominant subtype of migraine with aura characterized by a transient hemiparesis during the aura. Genes with an apparent vascular function were identified by studying monogenic diseases in which migraine is prominent, such as NOTCH3 in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and CSNK1D in familial advanced sleep phase syndrome. As a result of a recent technical revolution in the way DNA analyses are performed, which allows costeffective massive genotyping in large cohorts of many thousands of patients, it is now feasible to identify causal genetic variants for common polygenic disorders. This technical breakthrough has led to what is often referred to as the genome-wide association study (GWAS) era. As a consequence, in the last decade, numerous GWASs have been performed, which have led to the discovery of thousands of genes and gene variants for hundreds of traits, including various common neurological diseases (2). An essential factor for a GWAS to be successful in migraine was the fact that clinicians and geneticists with an interest in migraine organized themselves in the International Headache Genetics Consortium (IHGC) (http:// www.headachegenetics.org/). The IHGC connects no less than 34 research groups from 12 countries from Europe, the USA and Australia and brings together an ever-increasing wealth of well-characterized genetic information and high-quality diagnostic data, as well as analysis expertise, to discover the basis for future treatments of migraine and other headache disorders. The success of IHGC’s gene discovery efforts is evident from four GWASs that investigated over 23,000 patients and hundreds of thousands of control subjects. Migraine-associated single nucleotide polymorphisms (SNPs) were identified in 13 loci and the assigned genes suggest the involvement of vascular (C7orf10, PHACTR1, TGFBR2) and neuronal (ASTN2, FHL5, LRP1, MEF2D, MMP16, MTDH, PHACTR1, PRDM16) pathways, as well as metalloproteinases (AJAP1, MMP16, TSPAN2) and a pain nociceptor (TRPM8) in migraine pathophysiology (3–6). As the identified gene variants, without exception, have small effect sizes (odds ratio< 1.2), a legitimate question is whether they will really further our understanding of migraine pathophysiology and have practical clinical applications. This special issue of Cephalalgia contains reviews that present recent findings and viewpoints on how genetic data can be used in research and the clinic. In addition, it contains several studies with original data, most of which were initiated by the IHGC, which address issues related to, for example, the genetic architecture of migraine subtypes, gene variants in relation to drug response and disease pathophysiology. The review by Chasman et al. (7) discusses the importance of the appropriate ascertainment of the migraine status of individual patients enrolled in genetic studies. Challenges and solutions in diagnosing patients in very large population-based cohorts and how this is different from clinic-based cohorts, where clinical information is, in general, more detailed, are extensively discussed. Because an increase in sample