Article | Published:

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Nature Genetics volume 48, pages 856866 (2016) | Download Citation

  • A Corrigendum to this article was published on 28 September 2016

This article has been updated

Abstract

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

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Change history

  • 18 July 2016

    In the version of this article initially published online, the affiliations for Bertram Muller-Myhsok and Patricia Pozo-Rosich were incorrect or incomplete. These errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping, and genotyping for each of the individual cohorts. We also acknowledge the important contribution to research made by the study participants. We are grateful to H. Zhao (QIMR Berghofer Medical Research Institute) for helpful correspondence on the pathway analyses. We acknowledge the GTEx Consortium for support and contribution of pilot data. A list of study-specific acknowledgments and funding information can be found in the Supplementary Note.

Author information

Author notes

    • Padhraig Gormley
    •  & Verneri Anttila

    These authors contributed equally to this work.

    • Benjamin M Neale
    • , Jes Olesen
    • , Daniel I Chasman
    • , Dale R Nyholt
    •  & Aarno Palotie

    These authors jointly supervised this work.

Affiliations

  1. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Padhraig Gormley
    • , Ester Cuenca-Leon
    • , Mitja I Kurki
    • , Phil H Lee
    •  & Aarno Palotie
  2. Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Padhraig Gormley
    • , Verneri Anttila
    • , Tonu Esko
    • , Tune H Pers
    • , Kai-How Farh
    • , Ester Cuenca-Leon
    • , Mitja I Kurki
    • , Hailiang Huang
    • , Andrea E Byrnes
    • , Phil H Lee
    • , Mitja Kurki
    • , Benjamin M Neale
    • , Aarno Palotie
    •  & Mark J Daly
  3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Padhraig Gormley
    • , Verneri Anttila
    • , Ester Cuenca-Leon
    • , Mitja I Kurki
    • , Hailiang Huang
    • , Andrea E Byrnes
    • , Phil H Lee
    • , Mitja Kurki
    • , Benjamin M Neale
    • , Aarno Palotie
    •  & Mark J Daly
  4. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Padhraig Gormley
    • , Jie Huang
    •  & Aarno Palotie
  5. Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Verneri Anttila
    • , Kai-How Farh
    • , Hailiang Huang
    • , Andrea E Byrnes
    • , Mark J Daly
    • , Benjamin M Neale
    •  & Aarno Palotie
  6. FORMI, Oslo University Hospital, Oslo, Norway.

    • Bendik S Winsvold
    • , Linda M Pedersen
    •  & John-Anker Zwart
  7. Department of Neurology, Oslo University Hospital, Oslo, Norway.

    • Bendik S Winsvold
    •  & John-Anker Zwart
  8. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Bendik S Winsvold
    •  & John-Anker Zwart
  9. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Priit Palta
    • , Mikko Muona
    • , Antti-Pekka Sarin
    • , Mari Kaunisto
    • , Mitja I Kurki
    • , Eija Hämäläinen
    • , Eija Hamalainen
    • , Risto Kajanne
    • , Jaakko Kaprio
    • , Maija Wessman
    •  & Aarno Palotie
  10. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tonu Esko
    • , Mart Kals
    • , Reedik Mägi
    • , Kalle Pärn
    • , Evelin Mihailov
    • , Lili Milani
    •  & Andres Metspalu
  11. Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Tonu Esko
    •  & Tune H Pers
  12. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

    • Tune H Pers
  13. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

    • Tune H Pers
  14. Illumina, San Diego, California, USA.

    • Kai-How Farh
  15. Pediatric Neurology, Vall d'Hebron Research Institute, Barcelona, Spain.

    • Ester Cuenca-Leon
    • , Alfons Macaya
    •  & Marta Vila-Pueyo
  16. Folkhälsan Institute of Genetics, Helsinki, Finland.

    • Mikko Muona
    • , Marjo Hiekkala
    • , Mari Kaunisto
    •  & Maija Wessman
  17. Neuroscience Center, University of Helsinki, Helsinki, Finland.

    • Mikko Muona
  18. Molecular Neurology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.

    • Mikko Muona
  19. 23andMe, Inc., Mountain View, California, USA.

    • Nicholas A Furlotte
    • , David A Hinds
    • , Nadia Litterman
    • , Carrie Northover
    •  & Nicholas Eriksson
  20. Institute of Public Health, Charité–Universitätsmedizin Berlin, Berlin, Germany.

    • Tobias Kurth
  21. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

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

    • Andres Ingason
    • , Stacy Steinberg
    • , Hreinn Stefansson
    •  & Kari Stefansson
  23. Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • George McMahon
    • , Susan M Ring
    • , Evie Stergiakouli
    •  & George Davey Smith
  24. Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.

    • Lannie Ligthart
    • , Jouke-Jan Hottenga
    •  & Dorret I Boomsma
  25. Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.

    • Gisela M Terwindt
    • , Anine H Stam
    • , Michel Ferrari
    • , Arn M J M van den Maagdenberg
    •  & Michel D Ferrari
  26. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.

    • Mikko Kallela
    • , Markus Färkkilä
    • , Ville Artto
    •  & Salli Vepsäläinen
  27. Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.

    • Tobias M Freilinger
  28. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.

    • Tobias M Freilinger
    • , Rainer Malik
    •  & Martin Dichgans
  29. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

    • Caroline Ran
    • , Andrea Carmine Belin
    •  & Andrea C Belin
  30. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Scott G Gordon
    • , Nicholas G Martin
    •  & Grant W Montgomery
  31. Institute of Human Genetics, Ulm University, Ulm, Germany.

    • Guntram Borck
  32. Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland.

    • Markku Koiranen
    • , Minna Männikkö
    •  & Marjo-Riitta Järvelin
  33. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Lydia Quaye
    • , Lynn Cherkas
    • , Massimo Mangino
    •  & Tim Spector
  34. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Hieab H H Adams
    • , Elizabeth Loehrer
    • , Albert Hofman
    • , Cornelia M van Duijn
    • , Cornelia van Duijn
    •  & M Arfan Ikram
  35. Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Hieab H H Adams
    •  & M Arfan Ikram
  36. Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland.

    • Terho Lehtimäki
    •  & Terho Lehtimaki
  37. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Juho Wedenoja
    •  & Jaakko Kaprio
  38. Harvard Medical School, Boston, Massachusetts, USA.

    • Julie E Buring
    • , Paul M Ridker
    • , Daniel I Chasman
    • , Tobias Kurth
    •  & Markus Schürks
  39. Department of Neurology, University Duisburg–Essen, Essen, Germany.

    • Markus Schürks
  40. Landspitali University Hospital, Reykjavik, Iceland.

    • Maria Gudlaug Hrafnsdottir
  41. Department of Psychiatry, VU University Medical Centre, Amsterdam, the Netherlands.

    • Brenda W J H Penninx
  42. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Andrew C Heath
    •  & Pamela A F Madden
  43. Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.

    • Mitja I Kurki
  44. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

    • Lude Franke
  45. MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, UK.

    • Cynthia Sandor
    •  & Caleb Webber
  46. Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.

    • Zameel Cader
  47. Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK.

    • Zameel Cader
  48. Max Planck Institute of Psychiatry, Munich, Germany.

    • Bertram Muller-Myhsok
  49. Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.

    • Stefan Schreiber
  50. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

    • Thomas Meitinger
  51. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Thomas Meitinger
  52. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

    • Johan G Eriksson
  53. National Institute for Health and Welfare, Helsinki, Finland.

    • Johan G Eriksson
    • , Veikko Salomaa
    •  & Arpo J Aromaa
  54. Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.

    • Kauko Heikkilä
  55. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Elizabeth Loehrer
  56. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Andre G Uitterlinden
  57. Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway.

    • Audun Stubhaug
    •  & Christopher S Nielsen
  58. Medical Faculty, University of Oslo, Oslo, Norway.

    • Audun Stubhaug
  59. Department of Ageing and Health, Norwegian Institute of Public Health, Oslo, Norway.

    • Christopher S Nielsen
  60. Kiel Pain and Headache Center, Kiel, Germany.

    • Hartmut Göbel
  61. Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.

    • Ann-Louise Esserlind
    • , Anne Francke Christensen
    • , Thomas Folkmann Hansen
    •  & Jes Olesen
  62. Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark.

    • Thomas Folkmann Hansen
  63. Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark.

    • Thomas Werge
  64. Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Thomas Werge
  65. iPSYCH—The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.

    • Thomas Werge
  66. Department of Health, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Kaprio
  67. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

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

    • Olli Raitakari
  69. Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • M Arfan Ikram
  70. Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Marjo-Riitta Järvelin
  71. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  72. Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

    • Marjo-Riitta Järvelin
  73. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Christian Kubisch
    •  & Davor Lessel
  74. Population Health Research Institute, St George's, University of London, London, UK.

    • David Strachan
    •  & David P Strachan
  75. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

    • Bertram Muller-Myhsok
    •  & Martin Dichgans
  76. Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.

    • Else Eising
    • , Rune R Frants
    •  & Arn M J M van den Maagdenberg
  77. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Kari Stefansson
  78. Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.

    • Dale R Nyholt
  79. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aarno Palotie
  80. Department of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway.

    • Sigrid Børte
  81. Department of Genetics, University of Barcelona, Barcelona, Spain.

    • Bru Cormand
    •  & Celia Sintas
  82. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

    • Lyn Griffiths
    • , Dale R Nyholt
    •  & Huiying Zhao
  83. National Institute on Aging, Bethesda, Maryland, USA.

    • Lenore Launer
  84. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Nancy Pedersen
  85. Department of Clinical Genetics, Vrije Universiteit, Amsterdam, the Netherlands.

    • Danielle Posthuma
  86. Headache Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

    • Patricia Pozo-Rosich
  87. Sutter Health, Sacramento, California, USA.

    • Alice Pressman
  88. Department of Medicine, University of Turku, Turku, Finland.

    • Olli Raitakari
  89. Broad Institute of MIT and Harvard, Cambridge, USA.

    • William Wrenthal
  90. Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

    • Bertram Muller-Myhsok
  91. Headache Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.

    • Patricia Pozo-Rosich

Consortia

  1. International Headache Genetics Consortium

    A full list of members and affiliations appears at the end of the paper and in the Supplementary Note.

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Contributions

P.G., V. Anttila, G.W.M., M.I.K., M. Kals, R. Mägi, K.P., E.H., E.L., A.G.U., L.C., E.M., L.M., A.-L.E., A.F.C., T.F.H., A.J.A., D.I.C., and D.R.N. performed the experiments. P.G., V. Anttila, B.S.W., P.P., T.E., T.H.P., K.-H.F., M. Muona, N.A.F., A.I., G.M., L.L., S.G.G., S. Steinberg, L.Q., H.H.H.A., D.A.H., J.-J.H., R. Malik, A.E.B., E.S., C.M.v.D., E.M., D.P.S., N.E., B.M.N., D.I.C., and D.R.N. performed the statistical analyses. P.G., V. Anttila, B.S.W., P.P., T.E., T.H.P., K.-H.F., E.C.-L., N.A.F., A.I., G.M., L.L., M. Kallela, T.M.F., S.G.G., S. Steinberg, M. Koiranen, L.Q., H.H.H.A., T.L., J.W., D.A.H., S.M.R., M.F., V. Artto, M. Kaunisto, S.V., R. Malik, M.I.K., M. Kals, R. Mägi, K.P., H.H., A.E.B., J.H., E.S., C.S., C.W., Z.C., K.H., E.L., L.M.P., A.-L.E., A.F.C., T.F.H., J.K., A.J.A., O.R., M.A.I., M.-R.J., D.P.S., M.W., G.D.S., N.E., M.J.D., B.M.N., J.O., D.I.C., D.R.N., and A.P. participated in data analysis and/or interpretation. P.G., V. Anttila, B.S.W., T.H.P., K.-H.F., E.C.-L., T.K., G.M.T., M. Kallela, C.R., A.H.S., G.B., M. Koiranen, T.L., M.S., M.G.H., M.F., V. Artto, M. Kaunisto, S.V., R. Malik, A.C.H., P.A.F.M., N.G.M., G.W.M., H.H., A.E.B., L.F., J.H., P.H.L., C.S., C.W., Z.C., B.M.-M., S. Schreiber, T.M., J.G.E., V.S., A.G.U., C.M.v.D., A.S., C.S.N., H.G., A.-L.E., A.F.C., T.F.H., T.W., A.J.A., O.R., M.-R.J., C.K., M.D.F., A.C.B., M.D., M.W., J.-A.Z., B.M.N., J.O., D.I.C., D.R.N., A.-P.S., J.E.B., P.M.R., and A.P. contributed materials and/or analysis tools. T.E., T.K., T.L., H.S., B.W.J.H.P., A.C.H., P.A.F.M., N.G.M., G.W.M., L.F., A.H., A.S., C.S.N., M. Männikkö, T.W., J.K., O.R., M.A.I., T.S., M.-R.J., A.M., C.K., D.P.S., M.D.F., A.M.J.M.v.d.M., J.-A.Z., D.I.B., G.D.S., K.S., N.E., B.M.N., J.O., D.I.C., D.R.N., and A.P. supervised the research. T.K., G.M.T., G.B., T.L., J.E.B., M.S., P.M.R., H.S., B.W.J.H.P., A.C.H., P.A.F.M., N.G.M., G.W.M., L.F., V.S., A.H., L.C., A.S., C.S.N., H.G., J.K., A.J.A., O.R., M.A.I., M.-R.J., A.M., C.K., D.P.S., M.D., A.M.J.M.v.d.M., D.I.B., G.D.S., N.E., M.J.D., B.M.N., D.I.C., D.R.N., and A.P. conceived and designed the study. P.G., V. Anttila, B.S.W., P.P., T.E., T.H.P., E.C.-L., H.H., B.M.N., J.O., D.I.C., D.R.N., and A.P. wrote the paper. All authors contributed to the final version of the manuscript.

Competing interests

T.W. has acted as a lecturer and consultant for H. Lundbeck A/S, Valby, Denmark. M.S. is a full-time employee of Bayer HealthCare, Germany.

Corresponding author

Correspondence to Aarno Palotie.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 3–15, and Supplementary Tables 1–25

  2. 2.

    Supplementary Figure 1

    Forest plots of the 44 independently associated SNPs

  3. 3.

    Supplementary Figure 2

    Regional plots of the 44 independently associated SNPs

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DOI

https://doi.org/10.1038/ng.3598