Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.
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.
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.
Padhraig
P
Gormley
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.
Verneri
0000-0002-0073-4675
V
Anttila
FORMI, Oslo University Hospital, Oslo, Norway.|Department of Neurology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Bendik S
BS
Winsvold
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Priit
P
Palta
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.
Tonu
0000-0003-1982-6569
T
Esko
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.
Tune H
TH
Pers
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.
Kai-How
KH
Farh
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.
Ester
E
Cuenca-Leon
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.
Mikko
0000-0002-0949-6650
M
Muona
23andMe, Inc., Mountain View, California, USA.
Nicholas A
NA
Furlotte
Institute of Public Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Tobias
T
Kurth
deCODE Genetics, Reykjavik, Iceland.
Andres
A
Ingason
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
George
G
McMahon
Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
Lannie
L
Ligthart
Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
Gisela M
GM
Terwindt
Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
Mikko
M
Kallela
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.
Tobias M
TM
Freilinger
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Caroline
0000-0003-0239-9871
C
Ran
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Scott G
SG
Gordon
Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
Anine H
AH
Stam
deCODE Genetics, Reykjavik, Iceland.
Stacy
S
Steinberg
Institute of Human Genetics, Ulm University, Ulm, Germany.
Guntram
0000-0003-2279-8052
G
Borck
Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland.
Markku
M
Koiranen
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Lydia
L
Quaye
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.|Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Hieab H H
0000-0003-3687-2508
HH
Adams
Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland.
Terho
T
Lehtimäki
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Antti-Pekka
AP
Sarin
Department of Public Health, University of Helsinki, Helsinki, Finland.
Juho
J
Wedenoja
23andMe, Inc., Mountain View, California, USA.
David A
DA
Hinds
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Julie E
JE
Buring
Department of Neurology, University Duisburg-Essen, Essen, Germany.
Markus
M
Schürks
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Paul M
PM
Ridker
Landspitali University Hospital, Reykjavik, Iceland.
Maria Gudlaug
MG
Hrafnsdottir
deCODE Genetics, Reykjavik, Iceland.
Hreinn
H
Stefansson
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Susan M
SM
Ring
Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
Jouke-Jan
JJ
Hottenga
Department of Psychiatry, VU University Medical Centre, Amsterdam, the Netherlands.
Brenda W J H
BW
Penninx
Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
Markus
M
Färkkilä
Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
Ville
V
Artto
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Mari
M
Kaunisto
Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
Salli
S
Vepsäläinen
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
Rainer
R
Malik
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
Andrew C
AC
Heath
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
Pamela A F
PA
Madden
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Nicholas G
NG
Martin
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Grant W
GW
Montgomery
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.
Mitja I
MI
Kurki
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Mart
M
Kals
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Reedik
R
Mägi
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Kalle
K
Pärn
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Eija
E
Hämäläinen
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.
Hailiang
0000-0003-1461-5762
H
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
AE
Byrnes
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Lude
0000-0002-5159-8802
L
Franke
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Jie
J
Huang
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Evie
E
Stergiakouli
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.
Phil H
PH
Lee
MRC Functional Genomics Unit, Department of Physiology, Anatomy &Genetics, Oxford University, Oxford, UK.
Cynthia
C
Sandor
MRC Functional Genomics Unit, Department of Physiology, Anatomy &Genetics, Oxford University, Oxford, UK.
Caleb
C
Webber
Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.|Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK.
Zameel
Z
Cader
Max Planck Institute of Psychiatry, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Bertram
B
Muller-Myhsok
Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
Stefan
S
Schreiber
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
Thomas
T
Meitinger
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.
Johan G
JG
Eriksson
National Institute for Health and Welfare, Helsinki, Finland.
Veikko
V
Salomaa
Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
Kauko
K
Heikkilä
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.
Elizabeth
E
Loehrer
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
Andre G
AG
Uitterlinden
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Albert
A
Hofman
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Cornelia M
CM
van Duijn
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Lynn
L
Cherkas
FORMI, Oslo University Hospital, Oslo, Norway.
Linda M
LM
Pedersen
Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway.|Medical Faculty, University of Oslo, Oslo, Norway.
Audun
A
Stubhaug
Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway.|Department of Ageing and Health, Norwegian Institute of Public Health, Oslo, Norway.
Christopher S
0000-0003-0678-331X
CS
Nielsen
Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland.
Minna
M
Männikkö
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Evelin
E
Mihailov
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Lili
0000-0002-5323-3102
L
Milani
Kiel Pain and Headache Center, Kiel, Germany.
Hartmut
H
Göbel
Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
Ann-Louise
AL
Esserlind
Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
Anne Francke
AF
Christensen
Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark.
Thomas Folkmann
0000-0001-6703-7762
TF
Hansen
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.
Thomas
T
Werge
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.
Jaakko
0000-0002-3716-2455
J
Kaprio
National Institute for Health and Welfare, Helsinki, Finland.
Arpo J
AJ
Aromaa
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.
Olli
O
Raitakari
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.
M Arfan
0000-0003-0372-8585
MA
Ikram
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Tim
T
Spector
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.
Marjo-Riitta
MR
Järvelin
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Andres
A
Metspalu
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christian
C
Kubisch
Population Health Research Institute, St George's, University of London, London, UK.
David P
0000-0001-7854-1366
DP
Strachan
Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
Michel D
MD
Ferrari
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Andrea C
AC
Belin
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Martin
M
Dichgans
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Folkhälsan Institute of Genetics, Helsinki, Finland.
Maija
M
Wessman
Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.|Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
Arn M J M
AM
van den Maagdenberg
FORMI, Oslo University Hospital, Oslo, Norway.|Department of Neurology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
John-Anker
JA
Zwart
Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
Dorret I
DI
Boomsma
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
George Davey
GD
Smith
deCODE Genetics, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Kari
K
Stefansson
23andMe, Inc., Mountain View, California, USA.
Nicholas
N
Eriksson
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.
Mark J
0000-0002-0949-8752
MJ
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
0000-0003-1513-6077
BM
Neale
Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
Jes
J
Olesen
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Daniel I
DI
Chasman
Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
Dale R
DR
Nyholt
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.
Aarno
A
Palotie
D016022:Case-Control Studies; D056426:Genetic Loci / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D008881:Migraine Disorders / Q000235:genetics*; D009130:Muscle, Smooth / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014652:Vascular Diseases / Q000235:genetics
D005819:Genetic Markers