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Nat Genet. 2016 Aug;48(8):856-66. doi: 10.1038/ng.3598. Epub 2016 Jun 20.

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

Gormley P1,2,3,4, Anttila V2,3,5, Winsvold BS6,7,8, Palta P9, Esko T2,10,11, Pers TH2,11,12,13, Farh KH2,5,14, Cuenca-Leon E1,2,3,15, Muona M9,16,17,18, Furlotte NA19, Kurth T20,21, Ingason A22, McMahon G23, Ligthart L24, Terwindt GM25, Kallela M26, Freilinger TM27,28, Ran C29, Gordon SG30, Stam AH25, Steinberg S22, Borck G31, Koiranen M32, Quaye L33, Adams HH34,35, Lehtimäki T36, Sarin AP9, Wedenoja J37, Hinds DA19, Buring JE21,38, Schürks M39, Ridker PM21,38, Hrafnsdottir MG40, Stefansson H22, Ring SM23, Hottenga JJ24, Penninx BW41, Färkkilä M26, Artto V26, Kaunisto M9, Vepsäläinen S26, Malik R28, Heath AC42, Madden PA42, Martin NG30, Montgomery GW30, Kurki MI1,2,3,9,43, Kals M10, Mägi R10, Pärn K10, Hämäläinen E9, Huang H2,3,5, Byrnes AE2,3,5, Franke L44, Huang J4, Stergiakouli E23, Lee PH1,2,3, Sandor C45, Webber C45, Cader Z46,47, Muller-Myhsok B48,49,50, Schreiber S51, Meitinger T52,53, Eriksson JG54,55, Salomaa V55, Heikkilä K56, Loehrer E34,57, Uitterlinden AG58, Hofman A34, van Duijn CM34, Cherkas L33, Pedersen LM6, Stubhaug A59,60, Nielsen CS59,61, Männikkö M32, Mihailov E10, Milani L10, Göbel H62, Esserlind AL63, Christensen AF63, Hansen TF64, Werge T65,66,67; International Headache Genetics Consortium, Kaprio J9,37,68, Aromaa AJ55, Raitakari O69,70, Ikram MA34,35,71, Spector T33, Järvelin MR32,72,73,74, Metspalu A10, Kubisch C75, Strachan DP76, Ferrari MD25, Belin AC29, Dichgans M28,49, Wessman M9,16, van den Maagdenberg AM25,77, Zwart JA6,7,8, Boomsma DI24, Smith GD23, Stefansson K22,78, Eriksson N19, Daly MJ2,3,5, Neale BM2,3,5, Olesen J63, Chasman DI21,38, Nyholt DR79, Palotie A1,2,3,4,5,9,80.

Author information

1
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
3
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
5
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
6
FORMI, Oslo University Hospital, Oslo, Norway.
7
Department of Neurology, Oslo University Hospital, Oslo, Norway.
8
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
9
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
10
Estonian Genome Center, University of Tartu, Tartu, Estonia.
11
Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
12
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
13
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
14
Illumina, San Diego, California, USA.
15
Pediatric Neurology, Vall d'Hebron Research Institute, Barcelona, Spain.
16
Folkhälsan Institute of Genetics, Helsinki, Finland.
17
Neuroscience Center, University of Helsinki, Helsinki, Finland.
18
Molecular Neurology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
19
23andMe, Inc., Mountain View, California, USA.
20
Institute of Public Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.
21
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
22
deCODE Genetics, Reykjavik, Iceland.
23
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
24
Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
25
Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
26
Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
27
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
28
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
29
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
30
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
31
Institute of Human Genetics, Ulm University, Ulm, Germany.
32
Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland.
33
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
34
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
35
Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
36
Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland.
37
Department of Public Health, University of Helsinki, Helsinki, Finland.
38
Harvard Medical School, Boston, Massachusetts, USA.
39
Department of Neurology, University Duisburg-Essen, Essen, Germany.
40
Landspitali University Hospital, Reykjavik, Iceland.
41
Department of Psychiatry, VU University Medical Centre, Amsterdam, the Netherlands.
42
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
43
Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
44
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
45
MRC Functional Genomics Unit, Department of Physiology, Anatomy &Genetics, Oxford University, Oxford, UK.
46
Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.
47
Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK.
48
Max Planck Institute of Psychiatry, Munich, Germany.
49
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
50
Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
51
Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
52
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
53
Institute of Human Genetics, Technische Universität München, Munich, Germany.
54
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
55
National Institute for Health and Welfare, Helsinki, Finland.
56
Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
57
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
58
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
59
Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway.
60
Medical Faculty, University of Oslo, Oslo, Norway.
61
Department of Ageing and Health, Norwegian Institute of Public Health, Oslo, Norway.
62
Kiel Pain and Headache Center, Kiel, Germany.
63
Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
64
Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark.
65
Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark.
66
Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
67
iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
68
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
69
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
70
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
71
Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
72
Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
73
Biocenter Oulu, University of Oulu, Oulu, Finland.
74
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
75
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
76
Population Health Research Institute, St George's, University of London, London, UK.
77
Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
78
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
79
Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
80
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

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.

PMID:
27322543
PMCID:
PMC5331903
DOI:
10.1038/ng.3598
[Indexed for MEDLINE]
Free PMC Article

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