title: Gene-based pleiotropy across migraine with aura and migraine without aura patient groups.
abstract: BACKGROUND
  It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related.
  
  
  OBJECTIVE
  Using a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO.
  
  
  METHODS
  Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO.
  
  
  RESULTS
  We found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value (pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) (pbinomial-test = 1.5 × 10(-4)). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue.
  
  
  CONCLUSIONS
  Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both types of migraine.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
authors.forename: Else
authors.initials: E
authors.lastname: Eising
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
authors.forename: Boukje
authors.initials: B
authors.lastname: de Vries
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
authors.forename: Lisanne S
authors.initials: LS
authors.lastname: Vijfhuizen
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
authors.initials: V
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
authors.initials: T
authors.lastname: Kurth
authors.affiliation: deCODE Genetics, Iceland.
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.affiliation: Department of Neurology, Helsinki University Central Hospital, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Kallela
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Malik
authors.affiliation: Department of Neurology, Leiden University Medical Centre, The Netherlands.
authors.forename: Anine H
authors.initials: AH
authors.lastname: Stam
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 Biological Psychology, VU University, The Netherlands EMGO+ Institute for Health and Care Research, VU University Medical Centre, The Netherlands.
authors.forename: Lannie
authors.initials: L
authors.lastname: Ligthart
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany Department of Neurology and Epileptology and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Freilinger
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Germany Institute of Human Genetics, University of Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Alexander
authors.affiliation: Max Planck Institute of Psychiatry, Germany Munich Cluster for Systems Neurology (SyNergy), Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University, Germany Department of Internal Medicine I, Christian Albrechts University, Germany.
authors.forename: Stefan
authors.initials: S
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
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: National Institute for Health and Welfare, Finland.
authors.forename: Arpo
authors.initials: A
authors.lastname: Aromas
authors.affiliation: National Institute for Health and Welfare, Finland Institute of Genetics, Folkhälsan Research Center, Finland Department of General Practice, Helsinki University Central Hospital, 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: Department of Biological Psychology, VU University, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: FORMI and Department of Neurology, Oslo University Hospital and University of Oslo, Norway.
authors.forename: John-Anker
authors.initials: JA
authors.lastname: Zwart
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Quaye
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
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
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Institute of Genetics, Folkhälsan Research Center, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Wessman
authors.affiliation: deCODE Genetics, Iceland School of Medicine, University of Iceland, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
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.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Department of Neurology, Leiden University Medical Centre, The Netherlands.
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
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 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 of Health and Biomedical Innovation, Queensland University of Technology, Australia QIMR Berghofer Medical Research Institute, Brisbane, Australia d.nyholt@qut.edu.au.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
mesh_terms: D000328:Adult; D005260:Female; D058685:Genetic Pleiotropy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020325:Migraine with Aura / Q000235:genetics*; D020326:Migraine without Aura / Q000235:genetics*; D018013:Receptors, Neuropeptide / Q000235:genetics*
chemical_list: D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor
keywords: Migraine; association; aura; gene-based; genome-wide; pleiotropy