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New genetic evidence for involvement of the dopamine system in migraine with aura

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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.

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Acknowledgment

We thank Doris Wegner for support in database maintenance and all participating individuals for cooperation. This study was supported by grants of the Deutsche Forschungsgemeinschaft (DFG) to C.K. and H.G. (FOR 423, TPA2), the National Genome Network (NGFN-1 and NGFNplus) by the Bundesministerium für Bildung und Forschung (BMBF) to C.K., and the Center for Molecular Medicine Cologne to C.K. C.N. was supported by an EFIC-Grünenthal research grant (from the European Federation of Chapters of the International Association for the Study of Pain and the pharmaceutical company Grünenthal). J.F. was supported by a Young Investigator Grant of the National Alliance on Research in Schizophrenia and Depression (NARSAD).

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Authors and Affiliations

  1. Institute of Human Genetics, University of Cologne, Kerpener Strasse 34, 50931, Cologne, Germany

    Unda Todt, Christian Netzer, Ingrid Goebel & Christian Kubisch

  2. Institute for Genetics, University of Cologne, Cologne, Germany

    Unda Todt, Christian Netzer, Mohammad Toliat, Ingrid Goebel, Peter Nürnberg & Christian Kubisch

  3. Center for Molecular Medicine, University of Cologne, Cologne, Germany

    Unda Todt, Christian Netzer, Ingrid Goebel & Christian Kubisch

  4. Cologne Center for Genomics, University of Cologne, Cologne, Germany

    Mohammad Toliat & Peter Nürnberg

  5. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Peter Nürnberg & Christian Kubisch

  6. Kiel Pain and Headache Centre, Kiel, Germany

    Axel Heinze & Hartmut Göbel

  7. Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Northshore-LIJ University Hospital, New York, USA

    Jan Freudenberg

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  1. Unda Todt
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  2. Christian Netzer
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Correspondence to Christian Kubisch.

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U. Todt and C. Netzer contributed equally to this work.

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Todt, U., Netzer, C., Toliat, M. et al. New genetic evidence for involvement of the dopamine system in migraine with aura. Hum Genet 125, 265–279 (2009). https://doi.org/10.1007/s00439-009-0623-z

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  • DOI: https://doi.org/10.1007/s00439-009-0623-z

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