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Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, Pers TH, Farh KH, Cuenca-Leon E, Muona M, Furlotte NA, Kurth T, Ingason A, McMahon G, Ligthart L, Terwindt GM, Kallela M, Freilinger TM, Ran C, Gordon SG, Stam AH, Steinberg S, Borck G, Koiranen M, Quaye L, Adams HHH, Lehtimäki T, Sarin AP, Wedenoja J, Hinds DA, Buring JE, Schürks M, Ridker PM, Hrafnsdottir MG, Stefansson H, Ring SM, Hottenga JJ, Penninx BWJH, Färkkilä M, Artto V, Kaunisto M, Vepsäläinen S, Malik R, Heath AC, Madden PAF, Martin NG, Montgomery GW, Kurki MI, Kals M, Mägi R, Pärn K, Hämäläinen E, Huang H, Byrnes AE, Franke L, Huang J, Stergiakouli E, Lee PH, Sandor C, Webber C, Cader Z, Muller-Myhsok B, Schreiber S, Meitinger T, Eriksson JG, Salomaa V, Heikkilä K, Loehrer E, Uitterlinden AG, Hofman A, van Duijn CM, Cherkas L, Pedersen LM, Stubhaug A, Nielsen CS, Männikkö M, Mihailov E, Milani L, Göbel H, Esserlind AL, Christensen AF, Hansen TF, Werge T, Kaprio J, Aromaa AJ, Raitakari O, Ikram MA, Spector T, Järvelin MR, Metspalu A, Kubisch C, Strachan DP, Ferrari MD, Belin AC, Dichgans M, Wessman M, van den Maagdenberg AMJM, Zwart JA, Boomsma DI, Smith GD, Stefansson K, Eriksson N, Daly MJ, Neale BM, Olesen J, Chasman DI, Nyholt DR, Palotie A. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 2016; 48:856-66. [PMID: 27322543 DOI: 10.1038/ng.3598] [Citation(s) in RCA: 444] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 05/26/2016] [Indexed: 12/16/2022]
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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Affiliation(s)
- Padhraig Gormley
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
| | - Verneri Anttila
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Bendik S Winsvold
- FORMI, Oslo University Hospital, Oslo, Norway.,Department of Neurology, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Priit Palta
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Tonu Esko
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Estonian Genome Center, University of Tartu, Tartu, Estonia.,Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Tune H Pers
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Kai-How Farh
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Illumina, San Diego, California, USA
| | - Ester Cuenca-Leon
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Pediatric Neurology, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Mikko Muona
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.,Folkhälsan Institute of Genetics, Helsinki, Finland.,Neuroscience Center, University of Helsinki, Helsinki, Finland.,Molecular Neurology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | | | - Tobias Kurth
- Institute of Public Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | - George McMahon
- Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Lannie Ligthart
- Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands
| | - Gisela M Terwindt
- Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Mikko Kallela
- Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
| | - Tobias M Freilinger
- Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.,Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Caroline Ran
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Scott G Gordon
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Anine H Stam
- Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | | | - Guntram Borck
- Institute of Human Genetics, Ulm University, Ulm, Germany
| | - Markku Koiranen
- Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland
| | - Lydia Quaye
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Hieab H H Adams
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland
| | - Antti-Pekka Sarin
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Juho Wedenoja
- Department of Public Health, University of Helsinki, Helsinki, Finland
| | | | - Julie E Buring
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Markus Schürks
- Department of Neurology, University Duisburg-Essen, Essen, Germany
| | - Paul M Ridker
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | | | | | - Susan M Ring
- Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Jouke-Jan Hottenga
- Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands
| | - Brenda W J H Penninx
- Department of Psychiatry, VU University Medical Centre, Amsterdam, the Netherlands
| | - Markus Färkkilä
- Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
| | - Ville Artto
- Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
| | - Mari Kaunisto
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Salli Vepsäläinen
- Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
| | - Rainer Malik
- Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Andrew C Heath
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Pamela A F Madden
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Nicholas G Martin
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Grant W Montgomery
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Mitja I Kurki
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.,Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland
| | - Mart Kals
- Estonian Genome Center, University of Tartu, Tartu, Estonia
| | - Reedik Mägi
- Estonian Genome Center, University of Tartu, Tartu, Estonia
| | - Kalle Pärn
- Estonian Genome Center, University of Tartu, Tartu, Estonia
| | - Eija Hämäläinen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Hailiang Huang
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Andrea E Byrnes
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Lude Franke
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jie Huang
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
| | - Evie Stergiakouli
- Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Phil H Lee
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Cynthia Sandor
- MRC Functional Genomics Unit, Department of Physiology, Anatomy &Genetics, Oxford University, Oxford, UK
| | - Caleb Webber
- MRC Functional Genomics Unit, Department of Physiology, Anatomy &Genetics, Oxford University, Oxford, UK
| | - Zameel Cader
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.,Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK
| | - Bertram Muller-Myhsok
- Max Planck Institute of Psychiatry, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.,Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.,Institute of Human Genetics, Technische Universität München, Munich, Germany
| | - Johan G Eriksson
- Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,National Institute for Health and Welfare, Helsinki, Finland
| | - Veikko Salomaa
- National Institute for Health and Welfare, Helsinki, Finland
| | - Kauko Heikkilä
- Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
| | - Elizabeth Loehrer
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Andre G Uitterlinden
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Albert Hofman
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Cornelia M van Duijn
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Lynn Cherkas
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | | | - Audun Stubhaug
- Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway.,Medical Faculty, University of Oslo, Oslo, Norway
| | - Christopher S Nielsen
- Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway.,Department of Ageing and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Minna Männikkö
- Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland
| | | | - Lili Milani
- Estonian Genome Center, University of Tartu, Tartu, Estonia
| | | | - Ann-Louise Esserlind
- Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Anne Francke Christensen
- Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Folkmann Hansen
- Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark
| | - Thomas Werge
- Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark.,Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark.,iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
| | | | - Jaakko Kaprio
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.,Department of Public Health, University of Helsinki, Helsinki, Finland.,Department of Health, National Institute for Health and Welfare, Helsinki, Finland
| | - Arpo J Aromaa
- National Institute for Health and Welfare, Helsinki, Finland
| | - Olli Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.,Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
| | - M Arfan Ikram
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Tim Spector
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Marjo-Riitta Järvelin
- Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland.,Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.,Biocenter Oulu, University of Oulu, Oulu, Finland.,Unit of Primary Care, Oulu University Hospital, Oulu, Finland
| | | | - Christian Kubisch
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David P Strachan
- Population Health Research Institute, St George's, University of London, London, UK
| | - Michel D Ferrari
- Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Andrea C Belin
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Martin Dichgans
- Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Maija Wessman
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.,Folkhälsan Institute of Genetics, Helsinki, Finland
| | - Arn M J M van den Maagdenberg
- Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.,Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands
| | - John-Anker Zwart
- FORMI, Oslo University Hospital, Oslo, Norway.,Department of Neurology, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Dorret I Boomsma
- Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands
| | - George Davey Smith
- Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Kari Stefansson
- deCODE Genetics, Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | | | - Mark J Daly
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Benjamin M Neale
- Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Jes Olesen
- Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Daniel I Chasman
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Dale R Nyholt
- Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia
| | - Aarno Palotie
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.,Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.,Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
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