A dopamine D4 receptor exon 3 VNTR allele protecting against migraine without aura

Social, Genetic and Developmental Centre, Institute of Psychiatry, University of London, London, United Kingdom.
Annals of Neurology (Impact Factor: 9.98). 06/2007; 61(6):574-8. DOI: 10.1002/ana.21140
Source: PubMed


As dopamine plays an important role in the pathophysiology of migraine and antimigraine drugs have an effect on the dopamine system, the objective of this study was to examine the dopamine D4 receptor gene for involvement in the cause of migraine.
We tested a VNTR-polymorphism in the dopamine D4 receptor gene, the exon 3 VNTR, in a sample of 190 family trios each with a proband with childhood migraine by using transmission disequilibrium test tests.
We found a trend for transmission distortion of this marker in migraine, with the common seven-repeat allele of the VNTR transmitted 58 times and not transmitted 82 times (global likelihood ratio score (LRS) = 12.27, degress of freedom (DF) = 6, p = 0.06; for the 7-repeat allele: chi(2) = 5.1, p = 0.02). This effect came only from migraine without aura (145 trios), with the common 7-repeat allele transmitted 45 times and not transmitted 69 times (global LRS = 15.18; DF = 6, p = 0.019; for the 7-repeat allele: chi(2) = 6.4, p = 0.01; odds ratio, 0.47), whereas in migraine with aura (45 trios) there was no transmission distortion of the 7-repeat allele.
We conclude that seven-repeat allele of the dopamine D4 receptor VNTR is a protective factor for migraine without aura. Because migraine is a common disorder, this protective effect may have contributed to the positive selection acting on the dopamine D4 receptor exon 3 VNTR seven-repeat allele in recent human history. We speculate that dopamine function in the lateral parabrachial nucleus is involved in migraine without aura.

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Available from: Christian Wöber, Dec 23, 2014
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    • "It is worth mentioning, however, that a (TG)n repeat variant in DRD2 was found associated with yawning and nausea in a small subgroup of migraine patients [30]. We analyzed DRD2 rs2242592, in strong LD with rs6275, that belonged to a risk haplotype identified in population 1 but not confirmed in population 2. Subsequent studies found association between migraine phenotypes and polymorphisms in DRD4 [31,32] and DBH [9,25,33,34], although negative associations have also been described [9,30,31,33]. No associations have been identified in any of the polymorphisms analyzed in genes DRD1, DRD3, DRD5 or COMT [9,27,30,35-38]. "
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    ABSTRACT: We previously reported risk haplotypes for two genes related with serotonin and dopamine metabolism: MAOA in migraine without aura and DDC in migraine with aura. Herein we investigate the contribution to migraine susceptibility of eight additional genes involved in dopamine neurotransmission. We performed a two-stage case-control association study of 50 tag single nucleotide polymorphisms (SNPs), selected according to genetic coverage parameters. The first analysis consisted of 263 patients and 274 controls and the replication study was composed by 259 cases and 287 controls. All cases were diagnosed according to ICHD-II criteria, were Spanish Caucasian, and were sex-matched with control subjects. Single-marker analysis of the first population identified nominal associations of five genes with migraine. After applying a false discovery rate correction of 10%, the differences remained significant only for DRD2 (rs2283265) and TH (rs2070762). Multiple-marker analysis identified a five-marker T-C-G-C-G (rs12363125-rs2283265-rs2242592-rs1554929-rs2234689) risk haplotype in DRD2 and a two-marker A-C (rs6356-rs2070762) risk haplotype in TH that remained significant after correction by permutations. These results, however, were not replicated in the second independent cohort. The present study does not support the involvement of the DRD1, DRD2, DRD3, DRD5, DBH, COMT, SLC6A3 and TH genes in the genetic predisposition to migraine in the Spanish population.
    BMC Medical Genetics 09/2009; 10(1):95. DOI:10.1186/1471-2350-10-95 · 2.08 Impact Factor
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    • "Many migraine candidate genes have been analyzed in case-control or family based association studies during the past 10 years, among these several genes from the dopamine pathway (Asuni et al. 2007; Cevoli et al. 2006; de Sousa et al. 2007; Del Zompo et al. 1998; Dichgans et al. 1998; Lea et al. 2000; Maude et al. 2001; Mochi et al. 2003; Noble 2003; Peroutka et al. 1997, 1998; Rebaudengo et al. 2004; Shepherd et al. 2002; Stochino et al. 2003). However, most of the results of these association studies were negative, and positive Wndings could very often not be replicated. "
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    ABSTRACT: In order to systematically test the hypothesis that genetic variation in the dopamine system contributes to the susceptibility to migraine with aura (MA), we performed a comprehensive genetic association study of altogether ten genes from the dopaminergic system in a large German migraine with aura case-control sample. Based on the genotyping results of 53 variants across the ten genes in 270 MA cases and 272 controls, three genes-DBH, DRD2 and SLC6A3-were chosen to proceed to additional genotyping of 380 MA cases and 378 controls. Four of the 26 genotyped polymorphisms in these three genes displayed nominally significant allelic P-values in the sample of 650 MA patients and 650 controls. Three of these SNPs [rs2097629 in DBH (uncorrected allelic P value = 0.0012, OR = 0.77), rs7131056 in DRD2 (uncorrected allelic P value = 0.0018, OR = 1.28) and rs40184 in SLC6A3 (uncorrected allelic P value = 0.0082, OR = 0.81)] remained significant after gene-wide correction for multiple testing by permutation analysis. Further consideration of imputed genotype data from 2,937 British control individuals did not affirm the association with DRD2, but supported the associations with DBH and SLC6A3. Our data provide new evidence for an involvement of components of the dopaminergic system-in particular the dopamine-beta hydroxylase and dopamine transporter genes-to the pathogenesis of migraine with aura.
    Human Genetics 02/2009; 125(3):265-79. DOI:10.1007/s00439-009-0623-z · 4.82 Impact Factor
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    • "They found no association except for a significantly different distribution of alleles for the DRD4 gene in migraine without aura (MO) compared to migraine with aura (MA) and control groups. However, Campos de Sousa et al. (2007) recently found the seven-repeat allele of the DRD4 VNTR being a protective factor for MO. Fernandez et al. (2006) examined two DBH polymorphisms, a functional insertion= deletion promote and a coding SNP A444G polymorphism and found an association with the insertion=deletion variant, but not with the SNP polymorphism. "
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    ABSTRACT: Because of the role of dopamine in triggering migraine attacks, genes of the dopamine system are candidates for involvement in migraine. We examined three VNTR polymorphisms in the dopamine transporter, the 5'UTR VNTR, the intron 8 VNTR and the intron 14 VNTR, in a sample of 205 family trios. We used the transmission disequilibirium test (TDT) to examine the transmission of these three markers and their haplotypes to offspring affected by migraine. We found no significant transmission distortion of any marker. Likewise haplotypes of the three markers did not show significant overall or individual association with migraine. Finally we examined migraine with and without aura, and likewise found no association between dopamine transporter VNTRs or their haplotypes and either classification of the disease. We conclude that functional genetic variation in the dopamine transporter does not act as a significant risk factor for migraine.
    Journal of Neural Transmission 02/2008; 115(1):91-5. DOI:10.1007/s00702-007-0799-0 · 2.40 Impact Factor
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