Abstract

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10−6) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10−9; rs10166942, OR = 0.85, P = 5.5 × 10−12; and rs11172113, OR = 0.90, P = 4.3 × 10−9). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

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Acknowledgements

This study is supported by a grant from the National Institute of Neurological Disorders and Stroke (NS-061836). The Women's Health Study and the Women's Genome Health Study are supported by grants from the National Heart, Lung, and Blood Institute (HL-043851, HL-080467 and HL-099355) and the National Cancer Institute (CA-47988). Part of the research for this work was supported by grants from the Donald W. Reynolds Foundation and the Leducq Foundation. Genome-wide genotyping and collaborative scientific support was provided by Amgen.

Genotyping in the Genetic Epidemiology of Migraine Study was supported by the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants and the Center for Medical Systems Biology (CMSB) established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO), project no. 050-060-409. The GEM study was supported by the Ministry of Health, Welfare and Sport and the National Institute of Public Health and the Environment, The Netherlands.

SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The SHIP authors are grateful to the contribution of A. Teumer, A. Hoffmann and A. Petersmann in generating the SNP data. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of Siemens AG.

The IHGC study was supported, among others, by the Academy of Finland (200923 to A.P.), the Wellcome Trust (grant number 089062), the European Community's Seventh Framework Programme (FP7/2007-2013) (through the SYNSYS Consortium (grant agreement no. 242167) and the ENGAGE Consortium (grant agreement no. 201413)), the Helsinki University Central Hospital (to M.K.) and the Finnish Culture Foundation (to V.A.). Funding by the German Federal Ministry of Education and Research (BMBF) within the National Genome Research Network (NGFNplus, EMINet-01GS08120 for C.K., 01GS08121 to M. Dichgans), the Deutsche Forschungsgemeinschaft (to C.K.) and the Center for Molecular Medicine Cologne (to C.K.). For a full list of acknowledgements, please see reference 5.

Author information

Author notes

    • Verneri Anttila
    • , Mikko Kallela
    • , Tobias Freilinger
    • , Christian Kubisch
    •  & Aarno Palotie

    On behalf of the International Headache Genetics Consortium (IHGC) (full list of consortium members appears in the Supplementary Note).

    • Daniel I Chasman
    •  & Markus Schürks

    These authors contributed equally to this work.

    • Robert Y L Zee
    •  & Tobias Kurth

    These authors jointly directed this work.

Affiliations

  1. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel I Chasman
    • , Markus Schürks
    • , Julie E Buring
    • , Paul M Ridker
    • , Robert Y L Zee
    •  & Tobias Kurth
  2. Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel I Chasman
    •  & Paul M Ridker
  3. Department of Neurology, University Hospital Essen, Essen, Germany.

    • Markus Schürks
  4. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Verneri Anttila
    •  & Aarno Palotie
  5. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Verneri Anttila
    •  & Aarno Palotie
  6. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

    • Boukje de Vries
    •  & Arn M J M van den Maagdenberg
  7. Department of Neurology, Ernst-Moritz-Arndt University, Greifswald, Germany.

    • Ulf Schminke
  8. National Institute of Aging, Laboratory for Epidemiology, Demography, and Biometry, Bethesda, Maryland, USA.

    • Lenore J Launer
  9. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Gisela M Terwindt
    • , Arn M J M van den Maagdenberg
    •  & Michel D Ferrari
  10. Institute for Community Medicine, Section Epidemiology of Health Care and Community Health, Ernst-Moritz-Arndt University, Greifswald, Germany.

    • Konstanze Fendrich
    •  & Wolfgang Hoffmann
  11. Institute for Community Medicine, Section Clinical Epidemiological Research, Ernst-Moritz-Arndt University, Greifswald, Germany.

    • Henry Völzke
  12. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University, Greifswald, Germany.

    • Florian Ernst
  13. Genomics Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Queensland, Australia.

    • Lyn R Griffiths
  14. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.

    • Mikko Kallela
  15. Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität and Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.

    • Tobias Freilinger
  16. Institute of Human Genetics, University of Ulm, Ulm, Germany.

    • Christian Kubisch
  17. Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

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

    • Aarno Palotie
  19. The Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.

    • Aarno Palotie
  20. INSERM Unit 708—Neuroepidemiology, Paris, France.

    • Tobias Kurth
  21. UPMC Univ Paris 06, F-75005, Paris, France.

    • Tobias Kurth

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Contributions

Obtained funding: J.E.B., M.D.F., W.H., T.K., A.M.J.M.v.d.M., A.P., P.M.R., U.S., H.V., R.Y.L.Z. Overall study design: D.I.C., T.K., M.S. Cohort supervision and phenotyping: V.A., J.E.B., K.F., M.D.F., T.F., W.H., M.K., C.K., T.K., L.J.L., A.P., P.M.R., U.S., M.S., G.M.T., H.V. Analysis and genotyping: V.A., D.I.C., K.F., L.R.G., W.H., A.M.J.M.v.d.M., P.M.R., U.S., M.S., F.E., B.d.V., R.Y.L.Z. Manuscript writing: D.I.C., M.S. 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 Markus Schürks or Tobias Kurth.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–9 and Supplementary Figures 1 and 2.

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DOI

https://doi.org/10.1038/ng.856

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