Association between migraine and a functional polymorphism at the dopamine β-hydroxylase locus
- 185 Downloads
Migraine is a common neurological disorder with a significant genetic component. Although a number of linkage and association studies have been undertaken, the number and identity of all migraine susceptibility genes has yet to be defined. The existence of dopaminergic hypersensitivity in migraine has been recognised on a pharmacological basis and some studies have reported genetic association between migraine and dopamine-related gene variants. Our laboratory has previously reported association of migraine with a promoter STR marker in the dopamine beta hydroxylase (DBH) gene. In the present study, we analysed two additional DBH markers in two independent migraine case–control cohorts. These two markers are putative functional SNPs, one within the promoter (−1021C→T) and another SNP (+1603C→T) in exon 11 of the DBH gene. The results showed a significant association for allelic and genotypic frequency distribution between the DBH marker in the promoter and migraine in the first (P = 0.004 and P = 0.012, respectively) and the second (P = 0.013 and P = 0.031, respectively) tested cohorts. There was no association observed between either genotype and/or allelic frequencies for the DBH marker located in exon 11 and migraine (P ≥ 0.05). The promoter DBH marker, reported associated with migraine in this study, has been shown to affect up to 52% of plasma DBH activity. Varying DBH activity levels have been postulated to be involved in migraine process with an increase of dopamine, resulting from a lower DBH activity shown positively correlated with migraine severity. It is plausible that the functional promoter variant of DBH may play a role in the migraine disorder.
KeywordsMigraine Genetic association DBH gene Functional polymorphism
The authors would like to thank Dr. Yi-lang Tang and Prof. Joseph Cubells for the helpful information regarding the studied polymorphisms. This work was supported by funding from an ARC Linkage Grant and Corbett Research.
- 6.Cubells JF, Kranzler HR, McCance-Katz E, Anderson GM, Malison RT, Price LH, Gelernter J (2000) A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia. Mol Psychiatry 5:56–63. doi: 10.1038/sj.mp.4000657 PubMedCrossRefGoogle Scholar
- 7.Cubells JF, Price LH, Meyers BS, Anderson GM, Zabetian CP, Alexopoulos GS, Nelson JC, Sanacora G, Kirwin P, Carpenter L, Malison RT, Gelernter J (2002) Genotype-controlled analysis of plasma dopamine beta-hydroxylase activity in psychotic unipolar major depression. Biol Psychiatry 51:358–364. doi: 10.1016/S0006-3223(01)01349-X PubMedCrossRefGoogle Scholar
- 8.Cubells JF, van Kammen DP, Kelley ME, Anderson GM, O’Connor DT, Price LH, Malison R, Rao PA, Kobayashi K, Nagatsu T, Gelernter J (1998) Dopamine beta-hydroxylase: two polymorphisms in linkage disequilibrium at the structural gene DBH associate with biochemical phenotypic variation. Hum Genet 102:533–540. doi: 10.1007/s004390050736 PubMedCrossRefGoogle Scholar
- 13.Dobrowolski SF, Ellingson C, Coyne T, Grey J, Martin R, Naylor EW, Koch R, Levy HL (2007) Mutations in the phenylalanine hydroxylase gene identified in 95 patients with phenylketonuria using novel systems of mutation scanning and specific genotyping based upon thermal melt profiles. Mol Genet Metab 91:218–227. doi: 10.1016/j.ymgme.2007.03.010 PubMedCrossRefGoogle Scholar
- 21.HCCIHS (2004) Headache Classification Committee for the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. 2nd edn. Cephalgia 24(Suppl 1):1–60Google Scholar
- 22.Healy DG, Abou-Sleiman PM, Ozawa T, Lees AJ, Bhatia K, Ahmadi KR, Wullner U, Berciano J, Moller JC, Kamm C, Burk K, Barone P, Tolosa E, Quinn N, Goldstein DB, Wood NW (2004) A functional polymorphism regulating dopamine beta-hydroxylase influences against Parkinson’s disease. Ann Neurol 55:443–446. doi: 10.1002/ana.20063 PubMedCrossRefGoogle Scholar
- 35.O’Connor DT, Cervenka JH, Stone RA, Levine GL, Parmer RJ, Franco-Bourland RE, Madrazo I, Langlais PJ, Robertson D, Biaggioni I (1994) Dopamine beta-hydroxylase immunoreactivity in human cerebrospinal fluid: properties, relationship to central noradrenergic neuronal activity and variation in Parkinson’s disease and congenital dopamine beta-hydroxylase deficiency. Clin Sci (Lond) 86:149–158Google Scholar
- 37.Pasay C, Arlian L, Morgan M, Vyszenski-Moher D, Rose A, Holt D, Walton S, McCarthy J (2008) High-resolution melt analysis for the detection of a mutation associated with permethrin resistance in a population of scabies mites. Med Vet Entomol 22:82–88. doi: 10.1111/j.1365-2915.2008.00716.x PubMedCrossRefGoogle Scholar
- 49.Tang Y, Anderson GM, Zabetian CP, Kohnke MD, Cubells JF (2005) Haplotype-controlled analysis of the association of a non-synonymous single nucleotide polymorphism at DBH (+ 1603C –> T) with plasma dopamine beta-hydroxylase activity. Am J Med Genet B Neuropsychiatr Genet 139:88–90. doi: 10.1002/ajmg.b.30220 Google Scholar
- 53.Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu T, Kim KS, Kim CH, Malison RT, Gelernter J, Cubells JF (2001) A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am J Hum Genet 68:515–522. doi: 10.1086/318198 PubMedCrossRefGoogle Scholar
- 54.Zabetian CP, Buxbaum SG, Elston RC, Kohnke MD, Anderson GM, Gelernter J, Cubells JF (2003) The structure of linkage disequilibrium at the DBH locus strongly influences the magnitude of association between diallelic markers and plasma dopamine beta-hydroxylase activity. Am J Hum Genet 72:1389–1400. doi: 10.1086/375499 PubMedCrossRefGoogle Scholar