Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine (original) (raw)

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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

  1. Padhraig Gormley, Verneri Anttila and William Wrenthal: These authors contributed equally to this work.
  2. Bertram Muller-Myhsok, Bertram Muller-Myhsok, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt and Aarno Palotie: These authors jointly supervised this work.

Authors and 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, Verneri Anttila, Ester Cuenca-Leon, Padhraig Gormley, Mitja Kurki, Benjamin M Neale, Aarno Palotie, Mark J Daly, Benjamin M Neale & Aarno Palotie
  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, Verneri Anttila, Ester Cuenca-Leon, Padhraig Gormley, Mitja Kurki, Benjamin M Neale, Aarno Palotie, Mark J Daly, Benjamin M Neale & Aarno Palotie
  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, Linda M Pedersen, Bendik S Winsvold, John-Anker Zwart & John-Anker Zwart
  7. Department of Neurology, Oslo University Hospital, Oslo, Norway
    Bendik S Winsvold, Bendik S Winsvold, John-Anker Zwart & John-Anker Zwart
  8. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    Bendik S Winsvold, Bendik S Winsvold, John-Anker Zwart & 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, Priit Palta, 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, Tonu Esko & 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 & 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, Nicholas A Furlotte, 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, Andres Ingason, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg & 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, George McMahon & George Davey Smith
  24. Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands
    Lannie Ligthart, Jouke-Jan Hottenga, Dorret I Boomsma, Lannie Ligthart & 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, Gisela M Terwindt, Michel D Ferrari & Arn M J M van den Maagdenberg
  26. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
    Mikko Kallela, Markus Färkkilä, Ville Artto, Salli Vepsäläinen, Ville Artto & Mikko Kallela
  27. Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
    Tobias M Freilinger & 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, 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 & Marjo-Riitta Järvelin
  33. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
    Lydia Quaye, Lynn Cherkas, Lynn Cherkas, Massimo Mangino, Lydia Quaye & 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 & M Arfan Ikram
  35. Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands
    Hieab H H Adams, M Arfan Ikram & 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 & Daniel I Chasman
  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. Department of Physiology, MRC Functional Genomics Unit, 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 & 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. Department of Neurology, Danish Headache Center, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
    Ann-Louise Esserlind, Anne Francke Christensen, Anne Francke Christensen, Ann-Louise Esserlind, Thomas Folkmann Hansen, Jes Olesen & 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 & 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 & Marjo-Riitta Järvelin
  72. Unit of Primary Care, Oulu University Hospital, Oulu, Finland
    Marjo-Riitta Järvelin & Marjo-Riitta Järvelin
  73. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Christian Kubisch, Davor Lessel & Christian Kubisch
  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, 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 & 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 & Bertram Muller-Myhsok
  91. Neurology Department, Headache Unit, Vall d'Hebron University Hospital, Barcelona, Spain
    Patricia Pozo-Rosich

Authors

  1. Padhraig Gormley
  2. Verneri Anttila
  3. Bendik S Winsvold
  4. Priit Palta
  5. Tonu Esko
  6. Tune H Pers
  7. Kai-How Farh
  8. Ester Cuenca-Leon
  9. Mikko Muona
  10. Nicholas A Furlotte
  11. Tobias Kurth
  12. Andres Ingason
  13. George McMahon
  14. Lannie Ligthart
  15. Gisela M Terwindt
  16. Mikko Kallela
  17. Tobias M Freilinger
  18. Caroline Ran
  19. Scott G Gordon
  20. Anine H Stam
  21. Stacy Steinberg
  22. Guntram Borck
  23. Markku Koiranen
  24. Lydia Quaye
  25. Hieab H H Adams
  26. Terho Lehtimäki
  27. Antti-Pekka Sarin
  28. Juho Wedenoja
  29. David A Hinds
  30. Julie E Buring
  31. Markus Schürks
  32. Paul M Ridker
  33. Maria Gudlaug Hrafnsdottir
  34. Hreinn Stefansson
  35. Susan M Ring
  36. Jouke-Jan Hottenga
  37. Brenda W J H Penninx
  38. Markus Färkkilä
  39. Ville Artto
  40. Mari Kaunisto
  41. Salli Vepsäläinen
  42. Rainer Malik
  43. Andrew C Heath
  44. Pamela A F Madden
  45. Nicholas G Martin
  46. Grant W Montgomery
  47. Mitja I Kurki
  48. Mart Kals
  49. Reedik Mägi
  50. Kalle Pärn
  51. Eija Hämäläinen
  52. Hailiang Huang
  53. Andrea E Byrnes
  54. Lude Franke
  55. Jie Huang
  56. Evie Stergiakouli
  57. Phil H Lee
  58. Cynthia Sandor
  59. Caleb Webber
  60. Zameel Cader
  61. Bertram Muller-Myhsok
  62. Stefan Schreiber
  63. Thomas Meitinger
  64. Johan G Eriksson
  65. Veikko Salomaa
  66. Kauko Heikkilä
  67. Elizabeth Loehrer
  68. Andre G Uitterlinden
  69. Albert Hofman
  70. Cornelia M van Duijn
  71. Lynn Cherkas
  72. Linda M Pedersen
  73. Audun Stubhaug
  74. Christopher S Nielsen
  75. Minna Männikkö
  76. Evelin Mihailov
  77. Lili Milani
  78. Hartmut Göbel
  79. Ann-Louise Esserlind
  80. Anne Francke Christensen
  81. Thomas Folkmann Hansen
  82. Thomas Werge
  83. Jaakko Kaprio
  84. Arpo J Aromaa
  85. Olli Raitakari
  86. M Arfan Ikram
  87. Tim Spector
  88. Marjo-Riitta Järvelin
  89. Andres Metspalu
  90. Christian Kubisch
  91. David P Strachan
  92. Michel D Ferrari
  93. Andrea C Belin
  94. Martin Dichgans
  95. Maija Wessman
  96. Arn M J M van den Maagdenberg
  97. John-Anker Zwart
  98. Dorret I Boomsma
  99. George Davey Smith
  100. Kari Stefansson
  101. Nicholas Eriksson
  102. Mark J Daly
  103. Benjamin M Neale
  104. Jes Olesen
  105. Daniel I Chasman
  106. Dale R Nyholt
  107. Aarno Palotie

Consortia

International Headache Genetics Consortium

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.

Corresponding author

Correspondence toAarno Palotie.

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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.

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

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Gormley, P., Anttila, V., Winsvold, B. et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.Nat Genet 48, 856–866 (2016). https://doi.org/10.1038/ng.3598

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