Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10−5 for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10−4; combined P = 7.06 × 1011) and at 3p24 (near TGFBR2; replication P = 1.0 × 10−4; combined P = 1.17 × 10−9). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10−8 and P = 0.02; combined P = 3.86 × 10−8, respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.

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We wish to thank all individuals in the respective cohorts for their generous participation. This work was supported by the German Federal Ministry of Education and Research (BMBF) (grant 01GS08121 to M.D., along with support to E.W. in the context of the German National Genome Research Network, (NGFN-2 and NGFN-plus) for the Heinz Nixdorf Recall Study); the Spanish Ministry of Science and Innovation (grant SAF2009-13182-C03 to A.M. and B.C.); the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (grants 2009SGR78 and 2009SGR971 to A.M. and B.C., respectively); an unrestricted grant of the Vascular Dementia Research Foundation (to M.D.); the Netherlands Organization for Health Research and Development (ZonMw) (90700217) and VIDI (ZonMw) (91711319 to G.M.T.); the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants (to M.D.F.); the Center for Medical Systems Biology (CMSB) established in the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO) (project 050-060-409 to C.M.v.D., R.R.F., M.D.F. and A.M.J.M.v.d.M. and 050-060-810 to C.M.v.D.) and the generation and management of GWAS genotype data for the Rotterdam Study (175.010.2005.011 and 911-03-012) (funded by the Erasmus Medical Center, Erasmus University Rotterdam and the Ministries of Education, Culture and Science, Health, Welfare and Sports), as well as the NGI-sponsored Netherlands Consortium for Healthy Aging (NCHA) and the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the German Federal Ministry of Education and Research (BMBF) within the framework of the National Genome Research Network (NGFN-Plus; grants 01GS08120 and 01GS1103 to C.K.); the German Federal Ministry of Education and Research and the State of Bavaria, supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ) for the KORA research platform, which was initiated by the Helmholtz Center Munich, German Research Center for Environmental Health; the National Health and Medical Research Council (NHMRC) Research Fellowship (613674) and the Australian Research Council (ARC) Future Fellowship (FT0991022) schemes (to D.R.N.); the Wellcome Trust (grant 098051 to A.P.); the Academy of Finland (grant 251704 to A.P. and 139795 to M.W.); the Academy of Finland, Center of Excellence in Complex Disease Genetics (grants 213506 and 129680 to A.P. and J.K.); the South-Eastern Norway Regional Health Authority (2010075 and 2011083 to B.W. and J.-A.Z.), the Unger-Vetlesen Medical Fund (to B.W.) and the Ullevaal fund (to B.W.); the European Community's Seventh Framework Programme (FP7/2007-2013), the ENGAGE Consortium, (grant agreement HEALTH-F4-2007- 201413); EU/SYNSYS–Synaptic Systems (grant 242167 to A.P.); the Sigrid Juselius Foundation, Finland (to A.P.); the Folkhälsan Research Foundation, Helsinki (to M.W.); and the Helsinki University Central Hospital (to M.K., V. Artto and M.F.).

Author information

Author notes

    • Tobias Freilinger
    • , Verneri Anttila
    •  & Boukje de Vries

    These authors contributed equally to this work.

    • Aarno Palotie
    • , Martin Dichgans
    •  & Arn M J M van den Maagdenberg

    These authors jointly directed this work.


  1. Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.

    • Tobias Freilinger
    • , Rainer Malik
    •  & Martin Dichgans
  2. Department of Neurology, Klinikum der Universität München, Munich, Germany.

    • Tobias Freilinger
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.

    • Verneri Anttila
    • , Bendik Winsvold
    • , Eija Hämäläinen
    • , Jèssica Fernández-Morales
    •  & Aarno Palotie
  4. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Verneri Anttila
    • , Eija Hämäläinen
    • , Mari A Kaunisto
    • , Jaakko Kaprio
    • , Maija Wessman
    •  & Aarno Palotie
  5. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

    • Boukje de Vries
    • , Rune R Frants
    •  & Arn M J M van den Maagdenberg
  6. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.

    • Mikko Kallela
    • , Ville Artto
    •  & Markus Färkkilä
  7. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Gisela M Terwindt
    • , Willebrordus P J van Oosterhout
    • , Mark A Louter
    • , Michel D Ferrari
    •  & Arn M J M van den Maagdenberg
  8. Department of Neurology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.

    • Patricia Pozo-Rosich
  9. Headache Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

    • Patricia Pozo-Rosich
    •  & Jèssica Fernández-Morales
  10. Department of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway.

    • Bendik Winsvold
    •  & John-Anker Zwart
  11. Neurogenetics Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Dale R Nyholt
  12. Institute of Human Genetics, University of Ulm, Ulm, Germany.

    • Unda Todt
    •  & Christian Kubisch
  13. Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands.

    • Mark A Louter
  14. Folkhälsan Research Center, Helsinki, Finland.

    • Mari A Kaunisto
    •  & Maija Wessman
  15. Headache Research Unit, Department of Neurology and Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-Neurosciences, Liège University, Liège, Belgium.

    • Jean Schoenen
  16. Department of Clinical Physiology, University of Turku and Turku University Central Hospital, Turku, Finland.

    • Olli Raitakari
  17. Department of Clinical Chemistry, Tampere University Hospital and University of Tampere, Tampere, Finland.

    • Terho Lehtimäki
  18. Pediatric Neurology Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

    • Marta Vila-Pueyo
    •  & Alfons Macaya
  19. Kiel Pain and Headache Center, Kiel, Germany.

    • Hartmut Göbel
    •  & Axel Heinze
  20. Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

    • Erich Wichmann
  21. Department of Genetics, University of Barcelona, Barcelona, Spain.

    • Cèlia Sintas
    •  & Bru Cormand
  22. Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain.

    • Cèlia Sintas
    •  & Bru Cormand
  23. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Andre G Uitterlinden
    •  & Fernando Rivadeneira
  24. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Albert Hofman
    • , Fernando Rivadeneira
    •  & Cornelia M van Duijn
  25. Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.

    • Erling Tronvik
  26. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
  27. Department of Mental Health and Alcohol Research, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Kaprio
  28. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.

    • Bru Cormand
  29. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

    • Thomas Meitinger
  30. Institute of Human Genetics, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.

    • Thomas Meitinger
  31. Max Planck Institute of Psychiatry, Munich, Germany.

    • Bertram Müller-Myhsok
  32. The Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.

    • Aarno Palotie
  33. Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

    • Aarno Palotie
  34. Department of Medical Genetics, Helsinki University Central Hospital, Helsinki, Finland.

    • Aarno Palotie


  1. International Headache Genetics Consortium

    A full list of members and affiliations is provided in the Supplementary Note.


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Funding was obtained by M.D., M.D.F., A.P., A.M.J.M.v.d.M., C.K. and C.M.v.D. Overall study design was guided by T.F., V. Anttila, B.d.V., R.M., D.R.N., J.-A.Z., C.K., A.P., M.D. and A.M.J.M.v.d.M. Cohorts were supervised and phenotyped by T.F., M.K., G.M.T., P.P.-R., B.W., W.P.J.v.O., V. Artto, U.T., J.F.-M., M.A.L., M.A.K., J.S., O.R., T.L., M.V.-P., H.G., E.W., C.S., A.G.U., A. Heinze, A. Hoffman., E.T., C.M.v.D., J.K., B.C., T.M., J.-A.Z., M.F. and A.M. Analysis and genotyping were performed by V. Anttila, B.d.V., R.M., B.W., D.R.N., E.H., A.G.U., F.R., M.W., T.M. and B.M.-M. The manuscript was written by T.F., V. Anttila, B.d.V., D.R.N., B.C., M.W., R.R.F., J.-A.Z., C.K., A.P., M.D. and A.M.J.M.v.d.M. All authors participated in critical review of the manuscript for intellectual content.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Aarno Palotie or Arn M J M van den Maagdenberg.

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