Hormonally modulated migraine is associated with single-nucleotide polymorphisms within genes involved in dopamine metabolism


Migraine is a complex trait in which multiple genetic loci, as well as environmental factors, likely contribute to its clinical manifestation. Many genetic associations reported in previous studies either have not been replicated to date or showed only marginal statistical significance, possibly due to the genetic heterogeneity of the common forms of migraine. One major phenotypic and possibly genetically identifiable migraine subgroup consists of women whose attacks are influenced by fluctuation in gonadal hormones. We hypothesized that for these women, the association between migraine attacks and the menstrual cycle might be attributable to an increased prevalence of genetic polymorphisms in the hypothalamic-pituitary-gonadal axis. We selected 21 such polymerphisms previously reported to be associated with the common forms of migraine and genotyped 1740 individuals (1132 migraineurs) to determine whether any of these selected polymorphisms occurred more frequently in females with hormonally modulated migraine. We were able to confirm the association of migraine with 3 genetic polymorphisms seen in previous studies (rs4680 [COMT], rs2283265 [DRD2], and rs7131056 [DRD2]). Interestingly, we found 2 additional genetic polymorphisms (rs2070762 [TH] and rs6356 [TH]) to be associated with migraine when defining the phenotype as hormonally modulated migraine.

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Sullivan, A. , Atkinson, E. and Cutrer, F. (2013) Hormonally modulated migraine is associated with single-nucleotide polymorphisms within genes involved in dopamine metabolism. Open Journal of Genetics, 3, 38-45. doi: 10.4236/ojgen.2013.32A3006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Lipton, R.B., Bigal, M.E., Diamond, M., Freitag, F., Reed, M.L. and Stewart, W.F. (2007) Migraine prevalence, disease burden, and the need for preventive therapy. Neurology, 68, 343-349. doi:10.1212/01.wnl.0000252808.97649.21
[2] Lipton, R.B. and Stewart, W.F. (1997) Prevalence and impact of migraine. Neurologic Clinics, 15, 1-13. doi:10.1016/S0733-8619(05)70291-7
[3] Hawkins, K., Wang, S. and Rupnow, M.F. (2007) Indirect cost burden of migraine in the United States. Journal of Occupational and Environmental Medicine, 49, 368-374. doi:10.1097/JOM.0b013e31803b9510
[4] Hawkins, K., Wang, S. and Rupnow, M. (2008) Direct cost burden among insured US employees with migraine. Headache, 48, 553-563. doi:10.1111/j.1526-4610.2007.00990.x
[5] Mulder, E.J., Van Baal, C., Gaist, D., Kallela, M., Kaprio, J., Svensson, D.A, et al. (2003) Genetic and environmental influences on migraine: A twin study across six countries. Twin Research, 6, 422-431.
[6] Wessman, M., Terwindt, G.M., Kaunisto, M.A., Palotie, A. and Ophoff, R.A. (2007) Migraine: A complex genetic disorder. Lancet Neurology, 6, 521-532. doi:10.1016/S1474-4422(07)70126-6
[7] Couturier, E.G., Bomhof, M.A., Neven, A.K. and van Duijn, N.P. (2003) Menstrual migraine in a representative Dutch population sample: Prevalence, disability and treatment. Cephalalgia, 23, 302-308. doi:10.1046/j.1468-2982.2003.00516.x
[8] Gupta, S., Mehrotra, S., Villalon, C.M., Perusquia, M., Saxena, P.R. and Maassen Van Den Brink, A. (2007) Potential role of female sex hormones in the pathophysiology of migraine. Pharmacology & Therapeutics, 113, 321-340. doi:10.1016/j.pharmthera.2006.08.009
[9] MacGregor, E.A., Chia, H., Vohrah, R.C. and Wilkinson, M. (1990) Migraine and menstruation: A pilot study. Cephalalgia, 10, 305-310. doi:10.1046/j.1468-2982.1990.1006305.x
[10] MacGregor, E.A. (2004) Oestrogen and attacks of migraine with and without aura. Lancet Neurology, 3, 354-361. doi:10.1016/S1474-4422(04)00768-9
[11] Martin, V.T. and Lipton, R.B. (2008) Epidemiology and biology of menstrual migraine. Headache, 48, S124-S130. doi:10.1111/j.1526-4610.2008.01310.x
[12] MacGregor, E.A. (1996) “Menstrual” migraine: Towards a definition. Cephalalgia, 16, 11-21. doi:10.1046/j.1468-2982.1996.1601011.x
[13] Stewart, W.F., Lipton, R.B., Chee, E., Sawyer, J. and Silberstein, S.D. (2000) Menstrual cycle and headache in a population sample of migraineurs. Neurology, 55, 1517-1523. doi:10.1212/WNL.55.10.1517
[14] Martin, V.T., Lee, J. and Behbehani, M.M. (2007) Sensi-tization of the trigeminal sensory system during different stages of the rat estrous cycle: Implications for menstrual migraine. Headache, 47, 552-563.
[15] Varlibas, A. and Erdemoglu, A.K. (2009) Altered trige-minal system excitability in menstrual migraine patients. Journal of Headache and Pain, 10, 277-282. doi:10.1007/s10194-009-0132-4
[16] Joshi, G., Pradhan, S. and Mittal, B. (2010) Role of the oestrogen receptor (ESR1 PvuII and ESR1 325 C->G) and progesterone receptor (PROGINS) polymorphisms in genetic susceptibility to migraine in a North Indian population. Cephalalgia, 30, 311-320.
[17] Oterino, A., Toriello, M., Cayon, A., Castillo, J., Colas, R., Alonson-Arranz, A., et al. (2008) Multilocus analyses reveal involvement of the ESR1, ESR2 and FSHR genes in migraine. Headache, 48, 1438-1450. doi:10.1111/j.1526-4610.2008.01294.x
[18] Lee, H., Sininger, L., Jen, J.C., Cha, Y.H., Baloh, R.W. and Nelson, S.F. (2007) Association of progesterone receptor with migraine-associated vertigo. Neurogenetics, 8, 195-200. doi:10.1007/s10048-007-0091-3
[19] Oterino, A., Pascual, J., Ruiz de Alegria, C., Valle, N., Castillo, J., Bravo, Y., et al. (2006) Association of migraine and ESR1 G325C polymorphism. NeuroReport, 17, 61-64. doi:10.1097/01.wnr.0000192735.85287.f4
[20] Colson, N.J., Lea, R.A., Quinlan, S., MacMillan, J. and Griffiths, L.R. (2005) Investigation of hormone receptor genes in migraine. Neurogenetics, 6, 17-23. doi:10.1007/s10048-004-0205-0
[21] Colson, N.J., Lea, R.A., Quinlan, S., MacMillan, J. and Griffiths, L.R. (2004) The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups. Neurogenetics, 5, 129-133. doi:10.1007/s10048-004-0181-4
[22] Silberstein, S.D. and Merriam, G.R. (2000) Physiology of the menstrual cycle. Cephalalgia, 20, 148-154. doi:10.1046/j.1468-2982.2000.00034.x
[23] Zacur, H.A. (2006) Hormonal changes throughout life in women. Headache, 46, S49-S54. doi:10.1111/j.1526-4610.2006.00554.x
[24] Martin, V.T. and Behbehani, M. (2006) Ovarian hormones and migraine headache: Understanding mechanisms and pathogenesis: Part I. Headache, 46, 3-23. doi:10.1111/j.1526-4610.2006.00309.x
[25] Martin, V.T. and Behbehani, M. (2006) Ovarian hormones and migraine headache: Understanding mechanisms and pathogenesis: Part 2. Headache, 46, 365-386. doi:10.1111/j.1526-4610.2006.00370.x
[26] Speroff, L. and Fritz, M.A. (2005) Clinical Gynecologic Endocrinology and Infertility. 7th Edition, Lippincott Williams & Wilkins, Philadelphia.
[27] Nahmias, J., Burley, M.W., Povey, S., Porter, C., Craig, I. and Wolfe, J. (1992) A 19 bp deletion polymorphism adjacent to a dinucleotide repeat polymorphism at the human dopamine beta-hydroxylase locus. Human Molecular Genetics, 1, 286. doi:10.1093/hmg/1.4.286
[28] Ebstein, R.P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., et al. (1996) Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nature Genetics, 12, 78-80. doi:10.1038/ng0196-78
[29] Emin Erdal, M., Herken, Y., Yilmaz, M. and Bayazit, Y.A. (2001) Significance of the catechol-O-methyltransferase gene polymorphism in migraine. Brain Research. Molecular Brain Research, 94, 193-196. doi:10.1016/S0169-328X(01)00219-4
[30] Park, J.W., Lee, K.S., Kim, J.S., Kim, Y.I. and Shin, H.E. (2007) Genetic contribution of catechol-o-methyltransferase polymorphism in patients with migraine without aura. Journal of Clinical Neurology, 3, 24-30. doi:10.3988/jcn.2007.3.1.24
[31] Corominas, R., Ribases, M., Camina, M., Cuenca-Leon, E., Pardo, J., Boronat, S., et al. (2009) Two-stage casecontrol association study of dopamine-related genes and migraine. BMC Medical Genetics, 10, 95. doi:10.1186/1471-2350-10-95
[32] Todt, U., Netzer, C., Toliat, M., Heinze, A., Goebel, I., Nurnberg, P., et al. (2009) New genetic evidence for involvement of the dopamine system in migraine with aura. Human Genetics, 125, 265-279. doi:10.1007/s00439-009-0623-z
[33] Corominas, R., Sobrido, M.J., Ribases, M., Cuenca-Leon, E., Blanco-Arias, P., Narberhaus, B., et al. (2010) Association study of the serotoninergic system in migraine in the Spanish population. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 153B, 177-184.
[34] Fernandez, F., Colson, N., Quinlan, S., MacMillan, J., Lea, R.A. and Griffiths, L.R. (2009) Association between migraine and a functional polymorphism at the dopamine beta-hydroxylase locus. Neurogenetics, 10, 199-208. doi:10.1007/s10048-009-0176-2
[35] Fernandez, F., Lea, R.A., Colson, N.J., Bellis, C., Quinlan, S. and Griffiths, L.R. (2006) Association between a 19 bp deletion polymorphism at the dopamine beta-hydroxylase (DBH) locus and migraine with aura. Journal of the Neurological Sciences, 251, 118-123. doi:10.1016/j.jns.2006.09.013
[36] Lea, R.A., Dohy, A., Jordan, K., Quinlan, S., Brimage, P.J. and Griffiths, L.R. (2000) Evidence for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility to typical migraine. Neurogenetics, 3, 35-40.
[37] Mochi, M., Cevoli, S., Cortelli, P., Pierangeli, G., Soriani, S., Scapoli, C., et al. (2003) A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes. Neurological Sciences, 23, 301-305. doi:10.1007/s100720300005
[38] Peroutka, S.J., Wilhoit, T. and Jones, K. (1997) Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles. Neurology, 49, 201-206. doi:10.1212/WNL.49.1.201
[39] Headache Classification Subcommittee of the International Headache Society (2004) The international classification of headache disorders. 2nd Edition, Cephalalgia, 24, 24-36.
[40] Wood, P.B. (2008) Role of central dopamine in pain and analgesia. Expert Review of Neurotherapeutics, 8, 781-797. doi:10.1586/14737175.8.5.781
[41] Viisanen, H., Ansah, O.B. and Pertovaara, A. (2012) The role of the dopamine D2 receptor in descending control of pain induced by motor cortex stimulation in the neuronpathic rat. Brain Research Bulletin, 89, 133-143. doi:10.1016/j.brainresbull.2012.08.002
[42] Charbit, A.R., Akerman, S. and Goadsby, P.J. (2010) Dopamine: What’s new in migraine? Current Opinion in Neurology, 23, 275-281. doi:10.1097/WCO.0b013e3283378d5c
[43] Bergerot, A., Storer, R.J. and Goadsby, P.J. (2007) Dopamine inhibits trigeminovascular transmission in the rat. Annals of Neurology, 61, 251-262. doi:10.1002/ana.21077
[44] Charbit, A.R., Akerman, S., Holland, P.R. and Goadsby, P.J. (2009) Neurons of the dopaminergic/calcitonin generelated peptide A11 cell group modulate neuronal firing in the trigeminocervical complex: An electrophysiological and immunohistochemical study. Journal of Neuroscience, 29, 12532-12541. doi:10.1523/JNEUROSCI.2887-09.2009
[45] Kambur, O., Talka, R., Ansah, O.B., Kontinen, V.K., Pertovaara, A., Kalso, E., et al. (2010) Inhibitors of catechol-O-methyltransferase sensitize mice to pain. British Journal of Pharmacology, 161, 1553-1565. doi:10.1111/j.1476-5381.2010.00999.x
[46] Kambur, O., Mannisto, P.T., Viljakka, K., Reenila, I., Lemberg, K., Kontinen, V.K., et al. (2008) Stress-induced analgesia and morphine responses are changed in catechol-O-methyltransferase-deficient male mice. Basic & Clinical Pharmacology & Toxicology, 103, 367-373. doi:10.1111/j.1742-7843.2008.00289.x
[47] Knobil, E. and Neill, J.D. (1994) The physiology of reproduction. 2nd Edition, Raven Press, New York.
[48] Panek, D.U. and Dixon, W.R. (1986) Effect of continuous intraventricular estrogen or catechol estrogen treatment on catecholamine turnover in various brain regions. Journal of Pharmacology and Experimental Therapeutics, 236, 646-652.
[49] Marcano de Cotte, D., De Menezes, C.E., Bennett, G.W. and Edwardson, J.A. (1980) Dopamine stimulates the degradation of gonadotropin releasing hormone by rat synaptosomes. Nature, 283, 487-489. doi:10.1038/283487a0
[50] Zohar, Y., Munoz-Cueto, J.A., Elizur, A. and Kah, O. (2010) Neuroendocrinology of reproduction in teleost fish. General and Comparative Endocrinology, 165, 438-455. doi:10.1016/j.ygcen.2009.04.017
[51] Dufour, S., Sebert, M.E., Weltzien, F.A., Rousseau, K. and Pasqualini, C. (2010) Neuroendocrine control by dopamine of teleost reproduction. Journal of Fish Biology, 76, 129-160. doi:10.1111/j.1095-8649.2009.02499.x
[52] Popesku, J.T., Martyniuk, C.J., Denslow, N.D. and Trudeau, V.L. (2010) Rapid dopaminergic modulation of the fish hypothalamic transcriptome and proteome. PLoS One, 5, e12338. doi:10.1371/journal.pone.0012338
[53] Rasmussen, D.D., Liu, J.H., Wolf, P.L. and Yen, S.S. (1986) Gonadotropin-releasing hormone neurosecretion in the human hypothalamus: In vitro regulation by dopamine. Journal of Clinical Endocrinology and Metabolism, 62, 479-483. doi:10.1210/jcem-62-3-479
[54] Boesgaard, S., Hagen, C., Hangaard, J., Andersen, A.N. and Eldrup, E. (1991) Pulsatile gonadotropin secretion and basal prolactin levels during dopamine D-1 receptor stimulation in normal women. Fertility and Sterility, 55, 281-286.

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