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Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Nature Genetics volume 42, pages 869–873 (2010)Cite this article

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Abstract

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10−9, odds ratio = 1.23, 95% CI 1.150–1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10−11 (odds ratio = 1.18, 95% CI 1.127–1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10−5, permuted threshold for genome-wide significance 7.7 × 10−5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

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Figure 1: Cochran-Mantel-Haenszel association results for combined analysis of the three study populations between 97.5 Mb and 99.0 Mb on chromosome 8q22.1.
Figure 2: For each dataset, the horizontal line indicates the 95% CI, and the number above the line indicates the point estimate of the odds ratio.
Figure 3: A box-plot of the quantified expression values for MTDH, ordered based on the sample genotype of rs1835740.

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Acknowledgements

We wish to thank all individuals in the respective cohorts for their generous participation. This work was supported by the Wellcome Trust (grant number WT089062) and, among others, by the Academy of Finland (200923 to AP, 00213 to M.W.); the Helsinki University Central Hospital (to M. Kallela., M.F., V. Artto and S.V.); the Academy of Finland Center of Excellence for Complex Disease Genetics; the EuroHead project (LSM-CT-2004-504837); the Helsinki Biomedical Graduate School (to V. Anttila, P.T.-K.); the Finnish Cultural Foundation (to V. Anttila); the Finnish Neurology Foundation, Biomedicum Helsinki Foundation (to V. Anttila, P.T.-K. and V. Artto); the Cambridge Biomedical Research Centre (to S.C.); the Australian National Health and Medical Research Council Fellowship (339462 and 613674) and the Australian Research Council Future Fellowship (FT0991022) schemes (to D.R.N.); the German Federal Ministry of Education and Research (BMBF) (grant 01GS08121 to M. Dichgans, along with support to H.E.W. in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus) for the Heinz Nixdorf Recall study, and to C.K. (EMINet - 01GS08120) for the National Genome Research Network (Germany; NGFN-1 and NGFN-Plus)); the Center for Molecular Medicine Cologne (to C.K.); the Heinz Nixdorf Foundation for the Heinz Nixdorf Recall study, Deutsche Forschungsgemeinschaft (DFG; to C.K. and H.G.); the Netherlands Organization for the Health Research and Development (ZonMw) no. 90700217 (to G.M.T.) and to the Rotterdam Study (RIDE1 and RIDE2); the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants (to M.D.F.); 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 (to C.M.v.D., R.R.F., M.D.F. and A.M.J.M.v.d.M.) and project nos. 050-060-810 and 175.010.2005.011, 911-03-012 (to the Rotterdam Study). We thank the Health 2000 study for providing Finnish control genotypes. The Broad Institute Center for Genotyping and Analysis is supported by a grant from the National Center for Research Resources (US). The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria and is supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. We wish to thank S. Hunt, R. Gwillian, P. Whittaker, S. Potter and A. Tashakkori-Ghanbarian, as well as P. Marin-Garcia, for their invaluable help with this study. Finally, we wish to collectively thank everyone who has contributed to the collection, genotyping and analysis of the individual cohorts.

Author information

Author notes

  1. Leena Peltonen: Deceased.

Authors and Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

    Verneri Anttila, M Stella Calafato, Antigone S Dimas, Michael Inouye, Kirsi Alakurtti, Eija Hämäläinen, Jeffrey Barrett, Leena Peltonen & Aarno Palotie

  2. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    Verneri Anttila, Kirsi Alakurtti, Mari A Kaunisto, Eija Hämäläinen, Jaakko Kaprio, Leena Peltonen, Maija Wessman & Aarno Palotie

  3. Department of Population Genomics, deCODE genetics, Reykjavik, Iceland

    Hreinn Stefansson, Stacy Steinberg, Asgeir Björnsson & Kari Stefansson

  4. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

    Mikko Kallela, Ville Artto, Salli Vepsäläinen & Markus Färkkilä

  5. Institute of Human Genetics, University of Cologne, Cologne, Germany

    Unda Todt, Ingrid Goebel, Guntram Borck & Christian Kubisch

  6. Institute for Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    Unda Todt, Ingrid Goebel, Guntram Borck & Christian Kubisch

  7. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands

    Gisela M Terwindt, Anine H Stam, Michel D Ferrari & Arn M J M van den Maagdenberg

  8. National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK

    M Stella Calafato

  9. Neurogenetics Laboratory, Queensland Institute of Medical Research, Brisbane, Australia

    Dale R Nyholt

  10. Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK

    Antigone S Dimas

  11. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

    Antigone S Dimas & Emmanouil T Dermitzakis

  12. Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany

    Tobias Freilinger & Martin Dichgans

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

    Tobias Freilinger & Martin Dichgans

  14. Max Planck Institute of Psychiatry, Munich, Germany

    Bertram Müller-Myhsok, Christiane Wolf & Susanne Lucae

  15. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands

    Michael Inouye, Boukje de Vries, Claudia M Weller, Arn M J M van den Maagdenberg & Rune R Frants

  16. Folkhälsan Research Center, Helsinki, Finland

    Mari A Kaunisto, Johan G Eriksson & Maija Wessman

  17. Kiel Pain and Headache Center, Kiel, Germany

    Axel Heinze, Katja Heinze-Kuhn & Hartmut Göbel

  18. Department of Neurology, Landspítali University Hospital, Reykjavik, Iceland

    Gretar Gudmundsson

  19. Department of Neurology, Glostrup Hospital and the Danish Headache Center, Glostrup, Denmark

    Malene Kirchmann, Anne Hauge & Jes Olesen

  20. Research Institute of Biological Psychiatry, University of Copenhagen, Roskilde, Denmark

    Thomas Werge

  21. Department of Neurology and Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-Neurosciences, Headache Research Unit, Liège University, Liège, Belgium

    Jean Schoenen

  22. Department of General Practice, Helsinki University Central Hospital, Helsinki, Finland

    Johan G Eriksson

  23. Vaasa Central Hospital, Vaasa, Finland

    Johan G Eriksson

  24. National Institute for Health and Welfare, Helsinki, Finland

    Johan G Eriksson & Jaakko Kaprio

  25. Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway

    Knut Hagen, Lars Stovner & John-Anker Zwart

  26. Institute of Epidemiology, Helmholtz Center Munich, Neuherberg, Germany

    H-Erich Wichmann

  27. Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, Munich, Germany

    H-Erich Wichmann

  28. Klinikum Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany

    H-Erich Wichmann

  29. Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany

    Thomas Meitinger

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

    Thomas Meitinger

  31. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

    Michael Alexander

  32. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Michael Alexander

  33. Institute of Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany

    Susanne Moebus

  34. Department of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany

    Stefan Schreiber

  35. Department of Internal Medicine I, Christian Albrechts University, Kiel, Germany

    Stefan Schreiber

  36. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Yurii S Aulchenko, Monique M B Breteler, Albert Hofman & Cornelia M van Duijn

  37. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    Andre G Uitterlinden

  38. Research Program in Molecular Medicine, University of Helsinki, Helsinki, Finland

    Päivi Tikka-Kleemola

  39. Drug Discovery, GlaxoSmithKline Research and Development, Verona, Italy

    Federica Tozzi & Pierandrea Muglia

  40. Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    Pierandrea Muglia

  41. Department of Public Health, University of Helsinki, Helsinki, Finland

    Jaakko Kaprio

  42. The Broad Institute of MIT and Harvard, Boston, Massachusetts, USA

    Leena Peltonen, Mark Daly & Aarno Palotie

  43. Department of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway

    John-Anker Zwart

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

    Christian Kubisch

  45. Institute of Human Genetics, University of Ulm,

    Christian Kubisch

  46. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Aarno Palotie

  47. Department of Medical Genetics, Helsinki University Central Hospital, Helsinki, Finland

    Aarno Palotie

Consortia

the International Headache Genetics Consortium

  • Verneri Anttila
  • , Hreinn Stefansson
  • , Mikko Kallela
  • , Unda Todt
  • , Gisela M Terwindt
  • , M Stella Calafato
  • , Dale R Nyholt
  • , Antigone S Dimas
  • , Tobias Freilinger
  • , Bertram Müller-Myhsok
  • , Ville Artto
  • , Michael Inouye
  • , Kirsi Alakurtti
  • , Mari A Kaunisto
  • , Eija Hämäläinen
  • , Boukje de Vries
  • , Anine H Stam
  • , Claudia M Weller
  • , Axel Heinze
  • , Katja Heinze-Kuhn
  • , Ingrid Goebel
  • , Guntram Borck
  • , Hartmut Göbel
  • , Stacy Steinberg
  • , Christiane Wolf
  • , Asgeir Björnsson
  • , Gretar Gudmundsson
  • , Malene Kirchmann
  • , Anne Hauge
  • , Thomas Werge
  • , Jean Schoenen
  • , Johan G Eriksson
  • , Knut Hagen
  • , Lars Stovner
  • , H-Erich Wichmann
  • , Thomas Meitinger
  • , Michael Alexander
  • , Susanne Moebus
  • , Stefan Schreiber
  • , Yurii S Aulchenko
  • , Monique M B Breteler
  • , Andre G Uitterlinden
  • , Albert Hofman
  • , Cornelia M van Duijn
  • , Päivi Tikka-Kleemola
  • , Salli Vepsäläinen
  • , Susanne Lucae
  • , Federica Tozzi
  • , Pierandrea Muglia
  • , Jeffrey Barrett
  • , Jaakko Kaprio
  • , Markus Färkkilä
  • , Leena Peltonen
  • , Kari Stefansson
  • , John-Anker Zwart
  • , Michel D Ferrari
  • , Jes Olesen
  • , Mark Daly
  • , Maija Wessman
  • , Arn M J M van den Maagdenberg
  • , Martin Dichgans
  • , Christian Kubisch
  • , Emmanouil T Dermitzakis
  • , Rune R Frants
  •  & Aarno Palotie

Contributions

All authors contributed to the current version of the paper.

Corresponding authors

Correspondence to Verneri Anttila or Aarno Palotie.

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The author declare no competing financial interests.

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the International Headache Genetics Consortium. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet 42, 869–873 (2010). https://doi.org/10.1038/ng.652

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