Letter | Published:

Genome-wide meta-analysis identifies new susceptibility loci for migraine

Nature Genetics volume 45, pages 912917 (2013) | Download Citation

Abstract

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 × 10−8). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

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Acknowledgements

Study-specific acknowledgments appear in the Supplementary Note. We wish to thank A. Coffey, S. Hunt, R. Gwillian, P. Whittaker, S. Potter and A. Tashakkori-Ghanbarian for their invaluable help with this study, and we collectively thank everyone who has contributed to the collection, genotyping and analysis of the individual cohorts, as well as all the study participants.

Author information

Author notes

    • Verneri Anttila
    •  & Bendik S Winsvold

    These authors contributed equally to this work.

Affiliations

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

    • Verneri Anttila
    • , Bendik S Winsvold
    • , Padhraig Gormley
    • , Priit Palta
    • , Eija Hamalainen
    •  & Aarno Palotie
  2. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Verneri Anttila
    • , Priit Palta
    • , Eija Hamalainen
    • , Mari A Kaunisto
    • , Jaakko Kaprio
    • , Maija Wessman
    •  & Aarno Palotie
  3. Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Verneri Anttila
    • , Benjamin M Neale
    • , Elizabeth Rossin
    • , Kasper Lage
    •  & Mark J Daly
  4. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Benjamin M Neale
    • , Elizabeth Rossin
    • , Kasper Lage
    • , Suzanne B R Jacobs
    • , Mark J Daly
    •  & Aarno Palotie
  5. Department of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway.

    • Bendik S Winsvold
    •  & John-Anker Zwart
  6. Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 708–Neuroepidemiology, Bordeaux, France.

    • Tobias Kurth
  7. University of Bordeaux, Bordeaux, France.

    • Tobias Kurth
  8. Department of Medicine, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Tobias Kurth
    • , Lynda M Rose
    • , Julie E Buring
    • , Paul M Ridker
    •  & Daniel I Chasman
  9. deCODE Genetics, Reykjavik, Iceland.

    • Francesco Bettella
    • , Stacy Steinberg
    • , Hreinn Stefansson
    •  & Kari Stefansson
  10. University of Bristol/Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • George McMahon
    • , Wendy L McArdle
    • , Debbie A Lawlor
    • , David M Evans
    • , Susan M Ring
    •  & George Davey Smith
  11. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.

    • Mikko Kallela
    • , Markus Färkkilä
    •  & Ville Artto
  12. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany.

    • Rainer Malik
    • , Tobias Freilinger
    •  & Martin Dichgans
  13. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

    • Boukje de Vries
    • , Rune R Frants
    • , Claudia M Weller
    •  & Arn M J M van den Maagdenberg
  14. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Gisela Terwindt
    • , Anine H Stam
    • , Nadine Pelzer
    • , Ronald Zielman
    • , Michel D Ferrari
    •  & Arn M J M van den Maagdenberg
  15. Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Sarah E Medland
    • , Grant W Montgomery
    • , Nicholas G Martin
    •  & Dale R Nyholt
  16. Institute of Human Genetics, University of Ulm, Ulm, Germany.

    • Unda Todt
    • , Guntram Borck
    •  & Christian Kubisch
  17. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Lydia Quaye
    • , Frances M K Williams
    •  & Lynn Cherkas
  18. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Markku Koiranen
    • , Anneli Pouta
    •  & Marjo-Riitta Jarvelin
  19. Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

    • Markku Koiranen
    • , Anneli Pouta
    •  & Marjo-Riitta Jarvelin
  20. Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

    • M Arfan Ikram
    • , Joyce van den Ende
    • , Albert Hofman
    • , Najaf Amin
    •  & Cornelia van Duijn
  21. Department of Radiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

    • M Arfan Ikram
  22. Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

    • M Arfan Ikram
  23. Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.

    • Terho Lehtimäki
  24. Department of Biological Psychology, VU University, Amsterdam, The Netherlands.

    • Lannie Ligthart
    • , Jouke-Jan Hottenga
    • , Jacqueline M Vink
    •  & Dorret I Boomsma
  25. EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands.

    • Lannie Ligthart
    •  & Brenda W Penninx
  26. Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.

    • Juho Wedenoja
    • , Kauko Heikkilä
    •  & Jaakko Kaprio
  27. European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Cambridge, UK.

    • Ian Dunham
    •  & Ewan Birney
  28. Department of Neurology, University Hospital Essen, Essen, Germany.

    • Markus Schürks
  29. Department of Epidemiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Paul M Ridker
  30. Department of Neurology, Landspitali University Hospital, Reykjavik, Iceland.

    • Finnbogi Jakobsson
  31. Folkhälsan Research Center, Helsinki, Finland.

    • Mari A Kaunisto
    • , Johan G Eriksson
    •  & Maija Wessman
  32. Department of Neurology, Klinikum der Universität München, Munich, Germany.

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

    • Jean Schoenen
  34. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Andrew C Heath
    •  & Pamela A F Madden
  35. Kiel Pain and Headache Center, Kiel, Germany.

    • Hartmut Göbel
    • , Axel Heinze
    •  & Katja Heinze-Kuhn
  36. Department of Clinical Sciences/Obstetrics and Gynecology, University Hospital of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
    •  & Anneli Pouta
  37. Department of Children, Young People and Families, National Institute for Health and Welfare, Helsinki, Finland.

    • Anna-Liisa Hartikainen
    •  & Anneli Pouta
  38. Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.

    • Anneli Pouta
    •  & Marjo-Riitta Jarvelin
  39. Genetic Epidemiology Unit, Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.

    • Andre G Uitterlinden
  40. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

    • Michael Alexander
  41. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Michael Alexander
  42. Max Planck Institute of Psychiatry, Munich, Germany.

    • Bertram Muller-Myhsok
  43. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

    • Bertram Muller-Myhsok
    •  & Martin Dichgans
  44. Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.

    • Stefan Schreiber
  45. Department of Internal Medicine I, Christian Albrechts University, Kiel, Germany.

    • Stefan Schreiber
  46. Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany.

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

    • Thomas Meitinger
  48. Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, Munich, Germany.

    • Heinz Erich Wichmann
  49. Institute of Epidemiology I, Helmholtz Center Munich, Neuherberg, Germany.

    • Heinz Erich Wichmann
  50. Klinikum Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany.

    • Heinz Erich Wichmann
  51. National Institute for Health and Welfare, Helsinki, Finland.

    • Arpo Aromaa
    •  & Johan G Eriksson
  52. Department of General Practice, Helsinki University Central Hospital, Helsinki, Finland.

    • Johan G Eriksson
  53. Vaasa Central Hospital, Vaasa, Finland.

    • Johan G Eriksson
  54. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan G Eriksson
  55. Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Bryan J Traynor
    •  & J Raphael Gibbs
  56. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.

    • Daniah Trabzuni
    •  & J Raphael Gibbs
  57. Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

    • Daniah Trabzuni
  58. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Elizabeth Rossin
  59. Pediatric Surgical Research Laboratories, Massachusetts General Hospital for Children, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Kasper Lage
  60. Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.

    • Kasper Lage
  61. Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.

    • Kasper Lage
  62. Department of Mental Health and Alcohol Research, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Kaprio
  63. Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands.

    • Brenda W Penninx
  64. Department of Psychiatry, University Medical Centre Groningen, Groningen, The Netherlands.

    • Brenda W Penninx
  65. Department of Psychiatry, VU University Medical Centre, Amsterdam, The Netherlands.

    • Brenda W Penninx
  66. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital, Turku, Finland.

    • Olli Raitakari
  67. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

    • Olli Raitakari
  68. Department of Epidemiology and Biostatistics, School of Public Health, MRC–Health Protection Agency (HPA) Centre for Environment and Health, Faculty of Medicine, Imperial College, London, UK.

    • Marjo-Riitta Jarvelin
  69. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  70. Division of Population Health Sciences and Education, St George's, University of London, London, UK.

    • David P Strachan
  71. School of Medicine, University of Iceland, Reykjavik, Iceland.

    • Kari Stefansson

Consortia

  1. North American Brain Expression Consortium

  2. UK Brain Expression Consortium

  3. the International Headache Genetics Consortium

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A. Palotie, D.I.C., D.R.N., M.J.D., K.S., G.D.S., M.W., M.D., A.M.J.M.v.d.M., M.D.F., C.K., T.K., D.P.S., L.C., J.-A.Z., M.-R.J., C.v.D., D.I.B., J.K., L.Q. and G.T. jointly supervised research. A. Palotie, D.I.C., D.R.N., V. Anttila, B.S.W., M.J.D., M.W., M.D., A.M.J.M.v.d.M., C.K., L.C., J.-A.Z., M.-R.J., C.v.D., D.I.B., J.K., T.K., M. Kallela, R.M., B.d.V., G.T., L.Q., M.A.I., L.L., E.H., M.S., H.S., K.S., F.J., T.F. and B.M.-M. conceived and designed the study. V. Anttila, B.S.W., A. Palotie, D.R.N., G.D.S., M.W., M.D., A.M.J.M.v.d.M., C.K., J.-A.Z., M.-R.J., O.R., C.v.D., D.I.B., J.K., E.B., M. Kallela, B.d.V., G.T., E.H., T.F., R.R.F., N.G.M., A.G.U., T.M. and J.G.E. performed the experiments. V. Anttila, B.S.W., P.G., D.I.C., D.R.N., M.J.D., D.P.S., E.B., J.R.G., S.B.R.J., T.K., F.B., G.M., R.M., B.d.V., L.Q., M.A.I., L.L., I.D., P.P., M.S., S. Steinberg, T.F. and B.M.-M. performed statistical analysis. V. Anttila, B.S.W., P.G., A. Palotie, D.I.C., D.R.N., L.C., J.R.G., S.B.R.J., K.L., T.K., F.B., G.M., R.M., B.d.V., S.E.M., L.Q., M.A.I., L.L., J.W., P.P., M.S., S. Steinberg, H.S., T.F., N.A., B.M.-M. and D.T. analyzed the data. D.I.C., D.R.N., M.J.D., A. Palotie, G.D.S., M.W., M.D., A.M.J.M.v.d.M., M.D.F., C.K., D.P.S., L.C., J.-A.Z., M.-R.J., O.R., C.v.D., D.I.B., B.W.P., J.K., E.B., J.R.G., K.L., E.R., V. Anttila, B.S.W., P.G., T.K., F.B., G.M., M. Kallela, R.M., B.d.V., G.T., U.T., W.L.M., L.Q., M. Koiranen, M.A.I., T.L., A.H.S., L.L., I.D., B.M.N., M.S., L.M.R., J.E.B., P.M.R., S. Steinberg, H.S., F.J., D.A.L., D.M.E., S.M.R., M.F., V. Artto, M.A.K., T.F., J.S., R.R.F., N.P., C.M.W., R.Z., A.C.H., P.A.F.M., G.W.M., N.G.M., G.B., H.G., A. Heinze, K.H.-K., F.M.K.W., A.-L.H., A. Pouta, J.v.d.E., A.G.U., A. Hofman, J.-J.H., J.M.V., K.H., M.A., B.M.-M., S. Schreiber, T.M., H.E.W., A.A., J.G.E., B.J.T. and D.T. contributed reagents and/or materials and/or analysis tools. V. Anttila, B.S.W., A. Palotie, D.I.C., D.R.N., A.M.J.M.v.d.M. and C.K. wrote the manuscript. All authors contributed to the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Verneri Anttila or Aarno Palotie.

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https://doi.org/10.1038/ng.2676

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