mise à jour du 22 mai 2003
1998; 51; 3; 781-6
Association between dopamine receptor genes and migraine without aura in a Sardinian sample
Del Zompo, M., A. Cherchi, et al
Headache center, Department of neurosciences BB Brodie; University Caligari Italy


Migraine is a common, debilitating disorder that affects approximately 15% of the adult population. There are two main types of migraine: migraine without aura (MO), which occurs in 85% of patients, and migraine with aura (MA).

Altered monoaminergic neurotransmission is involved in the pathogenesis of migraine. 5-Hydroxytryptamine has long been implicated in migraine pathophysiology. Abnormalities in the serotoninergic system have been observed before and during migraine attacks and have been the target of therapeutic developments. Clinical and pharmacologic evidence supports the hypothesis that dopamine (DA) is also involved in the pathogenesis of migraine, and it could therefore be considered the second putative protagonist in headache. In particular, dopaminergic hypersensitivity in migraineurs is suggested due to the possibility of eliciting several symptoms by dopaminergic agonists at doses that do not affect nonmigraineurs

All studies on the familial occurrence of migraine have found an increased frequency of familial patients, suggesting the presence of a genetic factor. Twin studies produced conflicting results with respect to the inheritability of migraine. A recent report suggests that both MO and MA seem to be caused by a combination of genetic and environmental factors. Nevertheless, the mode of inheritance has not been clarified and the causative genes have not been identified. In 1993, a gene for familial hemiplegic migraine, a rare autosomal dominant subtype of MA, was mapped to chromosome 19pl3. Subsequently, a gene encoding an alpha 1 (ion-conducting) subunit of a voltage-gated calcium channel was identified. The human gene was designated CACNA1A.Various studies conducted to test this locus for linkage with MO or MA produced conflicting results.

Association studies using polymorphic candidate genes are important strategies ln the detection of genes that contribute only partially toward an overall susceptibility to developing complex diseases such as migraine. One of the limitations of the latter design is that population stratification can often produce spurious results. Moreover, unless the gene has a major effect, it may be difficult to replicate independently even true genetic association results. With regard to genes for dopamine receptors (DR), five of which (DRD1, DRD2, DRD3, DRD4, and DRD5) have been cloned and characterized to date, only one study of association with migraine has been published. This recent study reported an association between MA and a DA-related gene-DRD2-using the classic case-control design.

As an alternative to case-control association studies, a different design has been proposed recently that is robust in the face of geographic stratification because it is based on families of affected individuals whose parental, nontransmitted chromosomes serve as ethnically matched controls. Nuclear families represent the unit structure for such studies. Data can be analyzed subsequently using methods such as the Transmission Disequilibrium. Test (TDT). The original use intended for the TDT was to test for linkage with a marker located near a candidate gene in subjects in whom disease association had already been found. However, even in the absence of previous evidence of association, the TDT is a valid tool that can be used to test any marker (or a set of markers) for which data are available from parents and affected offspring.

The assumption that the disorder within the isolate is less heterogeneous genetically compared with similar syndromes in outbred groups contributed to the success of population isolate mapping. In this regard Cavalli-Sforza and Piazza reported that Sardinians are one of the most genetically deviant populations in Europe.

We applied the family-based association methodTDT to a sample of 50 nuclear Sardinian families with MO to test an association between this type of migraine and some candidate genes related to the dopaminergic system. Moreover, to increase the probability of detecting an association with DArelated genes, a subgroup of probands with enhanced DA sensitivity based on the presence of both nausea and yawning during the migraine attack was analyzed.

The current article reports the findings of a genetie study used to test the DA receptor genes DRD2, DRD3, and DRD4 for an involvement in migraine using, for the first time, an isolated population and a family-based association method (TDT).


Discussion. The current study, carried out using the family-based method (TDT), demonstrated a positive association between allele 1 of DRD2 and the subgroup of dopaminergic migraine. Considerable evidence supports an involvement of the dopaminergic system in the control of nausea and yawning as well as their importance as core symptoms in migraine. Therefore, our a priori hypothesis of an association between DA-related genes and dopaminergic migraine was warranted.

Several arguments suggest a possible involvement of DA in migraine pathophysiology. Apomorphine, a classic dopaminergic agonist, is able to trigger true migraine attacks in patients affected by PD disease and migraine. Moreover, dopaminergic agonists induce exaggerated dopaminergic-associated phenomena of migraine such as yawning, nausea, vomiting, hypotension, and syncope in migraineurs at a dosage that is ineffective in nonmigraineurs. Dopaminergic antagonists have been proposed as antimigraine drugs. Apomorphine bas a cerebral vasodilatory effect and increases blood flow significantly in the middle cerebral artery in migraineurs. This increase is not present with placebo. The antidopaminergic property of flunarizine, a widely used prophylactic drug in migraine, suggests that the dopaminergic system may play a role in its clinical efficacy.

An increased density of dopamine D5 receptors in peripheral blood lymphocytes of migraineurs has been reported recently, further suggesting the presence of an altered dopaminergic function in migraine. All these observations support the hypothesis that migraine is, at least in part, characterized by dopaminergie hypersensitivity.

Our data should be interpreted while bearing several considerations in mind. Although allele 1 is the less common form. of DRD2, it is unlikely that it represents the sole or major factor in the development of MO. Nevertheless we cannot ignore the fact that in a subgroup of MO, the gene of the D2 receptor plays a pathogenetic role in the illness. The intronic noncoding position of the polymorphisin studied might be linked closely to a funetional mutation, modifying the expression of the DRD2 gene. Alternatively, the same might be in linkage disequilibrium with another closely linked locus. Allelic frequencies may vary between populations of different origin. In our study the allelic frequencies observed in the control group are similar to those reported previously for a white population. Thus we may conclude that the functional significance of this DRD2 allelic association might be related to DA hypersensitivity in migraine.

To our knowledge, this is the first study of candidate genes related to the dopaminergic system-such as DRD2, DRD3, and DRD4-in migraine using a family-based association approach. Very recently the first case-control association study performed in white population suggested a positive association between MA and the DRD2 NeoI alleles. In particular, Peroutka et al. suggested that the presence of the DRD2 NcoI C allele has a significant effect on susceptibility to MA compared with a control group as well as with individuals with MO. The apparent discrepancies with our data may be explained by the fact that we used a different statistical approach and a population with a high genetic homogeneity. Moreover, our finding of a positive association between MO and the DRD2 gene was obtained in a subgroup of migraineurs enriched with dopaminergic symptoms.

Our data, in agreement with the cited report, suggest that a genetic approach could be useful in providing molecular support to the hypothesis that hypersensitivity of the dopaminergic system may represent the pathophysiologic basis of migraine, at least in a subgroup of patients. Moreover, these data may be relevant to the usefulness of very low doses of D2 agonists as prophylactic agents in migraine.

Because of the small size of the sample examined, the recruitment of additional triads and the replication of data in other populations is necessary to clarify further the role of DRD2 in migraine.

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