Elsevier

The Lancet Neurology

Volume 1, Issue 5, September 2002, Pages 285-293
The Lancet Neurology

Review
The Genetics of Migraine

https://doi.org/10.1016/S1474-4422(02)00134-5Get rights and content

Summary

The search for genes involved in the pathophysiology of migraine poses major difficulties. First, there is no objective diagnostic method to assess the status of the individuals studied. Second, migraine is a polygenic multifactorial disorder. Familial hemiplegic migraine (FHM) is the only known autosomal dominant subtype of migraine. In half the families with FHM who have been studied, there are mutations in the calcium-channel gene CACNA1A, located on chromosome 19. In other families, a locus has been mapped on chromosome 1. The role of these loci in typical migraine is still unknown. A susceptibility locus for migraine with aura has been located on chromosome 19 (but is distinct from CACNA1A) and a genome-wide linkage analysis has mapped a susceptibility locus on chromosome 4. Another locus for migraine may be on the X chromosome. Finally, many positive association studies have been published, but few have been replicated.

Section snippets

Why is it so difficult to identify migraine genes?

Genetic studies face difficulties directly related to some of the characteristic features of migraine. First, researchers must establish the clinical status of each person studied—ie, find out whether the individual is affected or not. In the absence of any biological or radiological marker, the diagnosis of migraine is purely clinical. The International Headache Society (IHS) classification (panel), published in 1988,1

distinguishes different varieties of migraine, the two most frequent being

Is migraine a genetic condition?

In addition to genetic factors, familial aggregation of a pathological disorder may be due to environmental factors and may also, as previously mentioned, occur purely by chance in very common diseases. A major step in the study of migraine genetics was thus to show the existence of genetic factors by the means of genetic epidemiological surveys.28

Twin studies have been used to assess the respective roles of genetic and environmental factors. These studies are based on the comparison of

Strategies in the quest for migraine genes

In non-mendelian diseases, the identification of diseasecausing mutations can be achieved by different methods. In families, linkage analysis to candidate genes or markers can be used to map a susceptibility locus, followed by detection of the pathogenetic mutation and positional cloning. Modelfree or non-parametric linkage analyses have to be used in migraine because classic parametric linkage analyses require the definition of a precise genetic model, and such a definition is inaccurate in

Genetic heterogeneity of FHM

FHM is genetically heterogeneous.12, 14, 25, 26, 47, 48, 49 Joutel and coworkers47 localised the first gene on the short arm of chromosome 19 in 1993. In 1996, Ophoff and colleagues12 identified this gene as CACNA1A, which encodes the α1A subunit of the neuronal P/Q type voltage-gated calcium-ion channel. CACNA1A is implicated in about 50% of families with FHM and in all families with FHM and permanent cerebellar symptoms.14, 15, 16, 25, 26 In 1997, a second gene was mapped to chromosome 1q;

CACNA1A, α1A subunit, and P/Q-type channels

CACNA1A, the only known FHM gene, encodes the main subunit of the P/Q type voltage-gated calcium channel.12 These channels are large multimeric proteins located within the cell membrane; in the centre is a pore that opens in response to membrane depolarisation, letting calcium ions flow into the cell.50, 51 In neurons, they have a major role in the control of neuronal excitability and neurotransmitter release. Each channel is formed by a main α1 subunit associated with four auxiliary subunits

Consequences of CACNA1A mutations

Several methods can be used to understand the mechanisms leading from the different CACNA1A mutations to the observed phenotypes.

Seven CACNA1A mutations causing FHM have been studied electrophysiologically by comparison of the calcium currents between cells expressing the wild-type gene and cells expressing the mutant gene.67, 68, 69 All the mutations modify the density and the gating properties of P/Q-type currents. FHM mutations are thus “gain of function” mutations with the abnormal protein

Genotype–phenotype correlations in FHM

FHM is characterised by striking clinical variability. Age at onset, frequency, duration, and features of attacks may vary from one patient to another, even among affected members from a given family who all carry the same mutation in the same gene.16, 19 This variability suggests complex interactions between the consequences of the mutation and environmental factors or modifying genetic factors.

Several studies have shown that the various FHM genotypes have a role in producing this clinical

Are FHM genes implicated in migraine without aura and/or migraine with aura?

CACNA1A is the first gene for which an involvement in a subtype of migraine has been demonstrated. CACNA1A and the other FHM genes represent good candidate genes for migraine with aura and migraine without aura. Indeed, several clinical features support the hypothesis that migraine without aura and migraine with aura could also be neurological channelopathies, the main factor being paroxysmal presentation with attacks lasting a few hours to a few days. Several groups have tried to implicate

Are other loci or genes implicated in migraine with or without aura?

Nyholt and colleagues89, 90 have analysed X-chromosome markers in three large Australian pedigrees. They found positive non-parametric lod scores with Xq24–28 markers in two of these families.89, 90 According to these researchers, this locus may be involved in the higher female prevalence of this disorder. Further studies, including a much larger panel of families, are necessary to confirm the role of an X-chromosome locus in migraine susceptibility.

As previously discussed, Jones and colleagues

Summary

Migraine is a complex polygenic multifactorial disorder in which genetic factors interact with environmental factors. Several studies have suggested that genetic factors may be more important in migraine with aura than in migraine without aura. The number of different susceptibility loci and genes is still unknown (table 2). FHM, which is the only known monogenic variety of migraine, is caused by mutations in the calcium channel gene CACNA1A located on chromosome 19p13 in about 50% of families.

Search strategy and selection criteria

Data for this review were identified by searches of Medline and references from relevant articles using the search terms “migraine”, “hemiplegic migraine”, “familial”, “genetics”, “association study”, “polymorphism”, “linkage”, “gene”, and “calcium channel”. Many articles were also identified through searches of the extensive files of the authors. Abstracts were included only when they related directly to previous published work. In addition to papers published in English, a few papers

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