title: Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies.
abstract: BACKGROUND
  There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls.
  
  
  METHODS
  Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated (p < 5 × 10(-8); thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs.
  
  
  RESULTS
  Significant heterogeneity of SNP effects (p het < 1.4 × 10(-3)) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genome-wide SNP effects to be in the same direction across the subgroups.
  
  
  CONCLUSIONS
  Any differences in common genetic risk across these subgroups are outweighed by the similarities. Meta-analysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.
authors.affiliation: Neurogenetics Laboratory, QIMR Berghofer, Australia Dale.Nyholt@qimrberghofer.edu.au.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, USA Harvard Medical School, USA Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, USA.
authors.forename: Verneri
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authors.lastname: Anttila
authors.affiliation: FORMI and Department of Neurology, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Bendik S
authors.initials: BS
authors.lastname: Winsvold
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Research Center for Epidemiology and Biostatistics (U897) - Team Neuroepidemiology, France University of Bordeaux, France Department of Medicine, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, USA.
authors.forename: Tobias
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authors.lastname: Kurth
authors.affiliation: deCODE Genetics, Iceland.
authors.forename: Hreinn
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authors.lastname: Stefansson
authors.affiliation: Department of Neurology, Helsinki University Central Hospital, Finland.
authors.forename: Mikko
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authors.lastname: Kallela
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany.
authors.forename: Rainer
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authors.lastname: Malik
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, the Netherlands.
authors.forename: Boukje de
authors.initials: Bd
authors.lastname: Vries
authors.affiliation: Department of Neurology, Leiden University Medical Centre, the Netherlands.
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, the Netherlands Department of Radiology, Erasmus University Medical Centre, the Netherlands Department of Neurology, Erasmus University Medical Centre, the Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Department of Neurology, Leiden University Medical Centre, the Netherlands.
authors.forename: Anine H
authors.initials: AH
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authors.affiliation: Department of Biological Psychology, VU University, the Netherlands EMGO+ Institute for Health and Care Research, VU University Medical Centre, the Netherlands.
authors.forename: Lannie
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authors.lastname: Ligthart
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany Department of Neurology, Klinikum der Universität München, Germany.
authors.forename: Tobias
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authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Germany Institute of Human Genetics, University of Bonn, Germany.
authors.forename: Michael
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authors.affiliation: Max Planck Institute of Psychiatry, Germany Munich Cluster for Systems Neurology (SyNergy), Germany.
authors.forename: Bertram
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authors.lastname: Muller-Myhsok
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University, Germany Department of Internal Medicine I, Christian Albrechts University, Germany.
authors.forename: Stefan
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authors.lastname: Schreiber
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, Germany Institute of Human Genetics, Klinikum Rechts der Isar, Technische Universität München, Germany.
authors.forename: Thomas
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authors.affiliation: National Institute for Health and Welfare, Finland.
authors.forename: Arpo
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authors.affiliation: National Institute for Health and Welfare, Finland Institute of Genetics, Folkhälsan Research Center, Finland Department of General Practice, Helsinki University Central Hospital, Helsinki, Finland Vaasa Central Hospital, Finland Department of General Practice and Primary Health Care, University of Helsinki, Finland.
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland Department of Public Health, Hjelt Institute, University of Helsinki, Finland Department of Mental Health and Alcohol Research, National Institute for Health and Welfare, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Department of Biological Psychology, VU University, the Netherlands.
authors.forename: Dorret I
authors.initials: DI
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authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, the Netherlands.
authors.forename: Cornelia van
authors.initials: Cv
authors.lastname: Duijn
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital, Finland Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Finland.
authors.forename: Olli
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authors.lastname: Raitakari
authors.affiliation: Institute of Health Sciences, University of Oulu, Finland Unit of Primary Care, Oulu University Hospital, Finland Department of Children, Young People and Families, National Institute for Health and Welfare, Finland Department of Epidemiology and Biostatistics, School of Public Health, MRC-Health Protection Agency (HPA) Centre for Environment and Health, Faculty of Medicine, Imperial College, UK Biocenter Oulu, University of Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: FORMI and Department of Neurology, Oslo University Hospital and University of Oslo, Norway.
authors.forename: John-Anker
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authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, UK.
authors.forename: Lydia
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authors.affiliation: Division of Population Health Sciences and Education, St George's, University of London, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Germany Institute of Human Genetics, University of Ulm, Germany.
authors.forename: Christian
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authors.lastname: Kubisch
authors.affiliation: Department of Neurology, Leiden University Medical Centre, the Netherlands.
authors.forename: Michel D
authors.initials: MD
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authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, the Netherlands Department of Neurology, Leiden University Medical Centre, the Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany Munich Cluster for Systems Neurology (SyNergy), Germany.
authors.forename: Martin
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authors.affiliation: Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Institute of Genetics, Folkhälsan Research Center, Finland.
authors.forename: Maija
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authors.lastname: Wessman
authors.affiliation: Medical Research Council Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, UK.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: deCODE Genetics, Iceland School of Medicine, University of Iceland, Iceland.
authors.forename: Kari
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authors.lastname: Stefansson
authors.affiliation: Department of Medicine, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, USA.
authors.forename: Daniel I
authors.initials: DI
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authors.affiliation: Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, USA Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, USA Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, USA Department of Neurology, Massachusetts General Hospital, USA.
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mesh_terms: D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000145:classification* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
keywords: Migraine; association; genetic; genome-wide; heterogeneity; subgroups