Elsevier

The Lancet Neurology

Volume 6, Issue 6, June 2007, Pages 521-532
The Lancet Neurology

Review
Migraine: a complex genetic disorder

https://doi.org/10.1016/S1474-4422(07)70126-6Get rights and content

Summary

Although family and twin studies show that there is a genetic component to migraine, no genes predisposing to common forms of the disorder have been identified. The most encouraging findings have emerged from the identification of genes causing rare mendelian traits that phenotypically resemble migraine. These studies have pointed migraine research towards ion-transport genes; however, there is no direct evidence of the involvement of these genes in common forms of migraine. Family-based linkage studies have identified several chromosomal regions linked to common forms of migraine, but there is little consistency between studies. The modest success in the identification of contributing gene variants has stimulated research into more effective strategies. These include new phenotyping methods for genetic studies and new study designs—such as case–control and whole-genome association studies—to identify common variants contributing to the trait.

Introduction

Migraine is a common disorder characterised by recurrent disabling attacks of headache associated with nausea, vomiting, hypersensitivity to light, sound, and smell (migraine without aura), and, in a third of patients, neurological aura symptoms (migraine with aura).1 These aura symptoms generally include visual disturbances and last for up to an hour or sometimes for several days. The underlying neurobiological mechanism for aura is cortical spreading depression.2 More severe neurological symptoms, such as hemiparesis, are part of the clinical aura spectrum (familial or sporadic hemiplegic migraine; FHM or SHM). The International Headache Society has established criteria for the diagnosis and classification of migraine symptoms (Panel 1, Panel 2).1 The diagnosis relies on a combination of traits or symptoms, and the individual traits are not completely independent of each other.

Migraine affects about 15% of people in developed countries3 and is three times more common in women than in men. Patients have a median of one attack per month and 25% have at least two attacks per month.4 Patients with more than one attack per month are at increased risk of brain lesions.5 More than one in four people with migraine are candidates for preventive therapy, and a substantial proportion of those who might benefit from prevention do not receive it.6 Furthermore, preventive therapy may not be fully effective.7 Migraine has a profound effect on wellbeing and general functioning, not only during the acute attack, but also in terms of work performance, family and social relationships, and school achievement. Migraine is rated by WHO as being among the most disabling chronic disorders8 and has been estimated to be the most costly neurological disorder in Europe.9

Careful diagnosis and subclassification are essential for genetic studies of complex diseases and can be especially demanding when no laboratory or other diagnostic test is available, as is the case with migraine. The difficulty in uncovering gene variants associated with migraine has stimulated a search for new research strategies. In this Review, we discuss diagnosis, the genetic background of migraine, and new phenotyping strategies that might help in the search for genes.

Section snippets

Diagnosis

The diagnosis of migraine, and thus adequate treatment decisions, is severely hampered by the lack of objective biomarkers and the episodic nature of the disease: signs and symptoms are present for periods of only several hours or days after which they fully disappear in most cases. Although the diagnostic criteria of the International Headache Society1 have greatly improved the validity of migraine diagnosis, differentiation from other neurological disorders—such as tension-type headache,

Clinical spectrum

A migraine attack may consist of five phases: prodrome (eg, food craving), aura (eg, visual, sensory, or motor symptoms preceding the headache), headache (usually unilateral, pulsating), resolution (pain wanes), and recovery.10 Not all the phases are needed to constitute a migraine attack and the presentation of phases varies among patients. Many clinicians support the view that migraine with aura (with FHM as a subtype) and migraine without aura are variants of the same disorder on the basis

Comorbidity

Several rare inherited neurological diseases are associated with migraine and might serve as models to study migraine-related mechanisms; these include CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy), which begins with migraine with aura in 33% of patients,15 and MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes). Epilepsy is another paroxysmal neurological disorder that might be associated with migraine.16

Genetic mechanisms

Both familial clustering and twin studies suggest that significant genetic mechanisms underlie migraine. Unfortunately, most studies lack the validated diagnostic criteria of the International Headache Society and make no distinction between migraine with and migraine without aura. A Danish population-based study addressed the heredity of migraine using the International Headache Society criteria20 and found a different pattern of familial risk for both entities. The first-degree relatives of

Mendelian forms of migraine and cellular mechanisms

The rare mendelian form of migraine FHM is the most successful model for the identification of migraine-associated cellular mechanisms. FHM is an autosomal dominant form of migraine with aura in which the aura is characterised by motor weakness of variable intensity.1 Symptoms include both typical migraine and severe episodes with prolonged aura, impaired consciousness ranging from confusion to profound coma, fever, and meningismus. Attacks may be triggered by head trauma.29 In some patients or

Other susceptibility genes

Several case–control association studies have indicated various susceptibility genes for migraine with and migraine without aura (table 1).102, 103, 104, 105, 106, 107, 108, 109, 110, 111 In these association studies, migraine has been associated with variants in oestrogen, progesterone, and insulin receptor genes and the gene for methylenetetrahydrofolate reductase (MTHFR), as well as promoter variants of the tumour necrosis factor α and angiotensin-converting enzyme, low-density lipoprotein

Other loci indicated in migraine

Genome-wide linkage analysis has become a widely used, yet somewhat controversial, tool in genetic studies on complex traits since the first published scan on type 1 diabetes in the early 1990s.129 In migraine, five genome-wide screens have found several loci with significant evidence of linkage to migraine with and migraine without aura.130, 131, 132, 133, 134 A susceptibility locus to migraine on chromosome 4q has been identified in two studies. A Finnish study131 found significant evidence

Phenotyping strategies

Identification of complex disease genes is obviously difficult. The lack of consensus among the identified migraine susceptibility loci is probably an indication of clinical and genetic heterogeneity. This situation is also common in other complex traits with incomplete penetrance, phenocopies, and locus heterogeneity.143 Most molecular genetic studies on migraine have used the International Headache Society classification as phenotypes. This might be an oversimplified picture of migraine

Conclusion

The identification of susceptibility variants underlying migraine is still in its early stages. The most encouraging approach has been the identification of genes causing rare mendelian forms that phenotypically resemble migraine. These studies have pinpointed channelopathies, although direct evidence for the involvement of the genes in common forms of migraine has not been found. The situation with migraine might resemble those of hypertension and epilepsy in which several mendelian traits

Search strategy and selection criteria

References for this Review were identified through searches of PubMed from 1966, to November, 2006, with the terms “migraine”, “migraine with aura”, “migraine without aura”, “familial hemiplegic migraine”, “gene”, “ion channel”, “genome-wide”, “linkage”, “association”, “complex disease”, “latent class analysis”, and “trait component”. Articles were also identified through searches of the authors' own files. Only papers published in English and accepted by peer-reviewed journals were

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