title: Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1.
abstract: Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10⁻⁹, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10⁻¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10⁻⁵, permuted threshold for genome-wide significance 7.7 × 10⁻⁵. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK. verneri.anttila@sanger.ac.uk
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Mikko
authors.initials: M
authors.lastname: Kallela
authors.forename: Unda
authors.initials: U
authors.lastname: Todt
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.forename: M Stella
authors.initials: MS
authors.lastname: Calafato
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: Antigone S
authors.initials: AS
authors.lastname: Dimas
authors.forename: Tobias
authors.initials: T
authors.lastname: Freilinger
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Ville
authors.initials: V
authors.lastname: Artto
authors.forename: Michael
authors.initials: M
authors.lastname: Inouye
authors.forename: Kirsi
authors.initials: K
authors.lastname: Alakurtti
authors.forename: Mari A
authors.initials: MA
authors.lastname: Kaunisto
authors.forename: Eija
authors.initials: E
authors.lastname: Hämäläinen
authors.forename: Boukje
authors.initials: B
authors.lastname: de Vries
authors.forename: Anine H
authors.initials: AH
authors.lastname: Stam
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Weller
authors.forename: Axel
authors.initials: A
authors.lastname: Heinze
authors.forename: Katja
authors.initials: K
authors.lastname: Heinze-Kuhn
authors.forename: Ingrid
authors.initials: I
authors.lastname: Goebel
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.forename: Hartmut
authors.initials: H
authors.lastname: Göbel
authors.forename: Stacy
authors.initials: S
authors.lastname: Steinberg
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolf
authors.forename: Asgeir
authors.initials: A
authors.lastname: Björnsson
authors.forename: Gretar
authors.initials: G
authors.lastname: Gudmundsson
authors.forename: Malene
authors.initials: M
authors.lastname: Kirchmann
authors.forename: Anne
authors.initials: A
authors.lastname: Hauge
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Jean
authors.initials: J
authors.lastname: Schoenen
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: Knut
authors.initials: K
authors.lastname: Hagen
authors.forename: Lars
authors.initials: L
authors.lastname: Stovner
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Michael
authors.initials: M
authors.lastname: Alexander
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: Monique M B
authors.initials: MM
authors.lastname: Breteler
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Päivi
authors.initials: P
authors.lastname: Tikka-Kleemola
authors.forename: Salli
authors.initials: S
authors.lastname: Vepsäläinen
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.forename: Federica
authors.initials: F
authors.lastname: Tozzi
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Muglia
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Barrett
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.forename: Markus
authors.initials: M
authors.lastname: Färkkilä
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: John-Anker
authors.initials: JA
authors.lastname: Zwart
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.forename: Maija
authors.initials: M
authors.lastname: Wessman
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
mesh_terms: D000954:Antigens, Surface / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics; D002478:Cells, Cultured; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D043425:Glutamate Carboxypeptidase II / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D018895:Microsatellite Repeats / Q000235:genetics*; D008881:Migraine Disorders / Q000235:genetics*; D040641:Quantitative Trait Loci; D016601:RNA-Binding Proteins
chemical_list: D000954:Antigens, Surface; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
references.citation: Nat Genet. 2003 Feb;33(2):192-6
references.pmid: 12539047
references.citation: Hum Genet. 2009 Jul;126(1):115-32
references.pmid: 19455354
references.citation: Nature. 2000 Jun 15;405(6788):847-56
references.pmid: 10866211
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4687-92
references.pmid: 11287655
references.citation: Cell. 1996 Nov 1;87(3):543-52
references.pmid: 8898206
references.citation: Nat Genet. 2006 Mar;38(3):320-3
references.pmid: 16415884
references.citation: Bioinformatics. 2007 Oct 15;23(20):2741-6
references.pmid: 17846035
references.citation: J Neurosci. 2007 Apr 11;27(15):3946-55
references.pmid: 17428968
references.citation: Science. 1997 Jun 13;276(5319):1699-702
references.pmid: 9180080
references.citation: Nat Genet. 2003 Oct;35(2):131-8
references.pmid: 14517540
references.citation: Autism Res. 2009 Apr;2(2):78-97
references.pmid: 19418574
references.citation: Lancet. 2005 Jul 30-Aug 5;366(9483):371-7
references.pmid: 16054936
references.citation: Cephalalgia. 2007 Mar;27(3):193-210
references.pmid: 17381554
references.citation: PLoS Genet. 2009 Jun;5(6):e1000529
references.pmid: 19543373
references.citation: Neuron. 2009 Mar 12;61(5):762-73
references.pmid: 19285472
references.citation: Nat Clin Pract Neurol. 2006 May;2(5):252-63
references.pmid: 16932562
references.citation: Neuroscience. 2009 Jun 30;161(2):327-41
references.pmid: 19303917
references.citation: Nat Genet. 2007 Oct;39(10):1217-24
references.pmid: 17873874
references.citation: Hum Mol Genet. 2008 Nov 1;17(21):3318-31
references.pmid: 18676988
references.citation: N Engl J Med. 2002 Jan 24;346(4):257-70
references.pmid: 11807151
references.citation: Gene. 2005 Jun 20;353(1):8-15
references.pmid: 15927426
references.citation: Am J Hum Genet. 2004 Apr;74(4):765-9
references.pmid: 14997420
references.citation: Brain. 1994 Feb;117 ( Pt 1):199-210
references.pmid: 7908596
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21300-5
references.pmid: 19940250
references.citation: Glia. 2008 Jul;56(9):998-1004
references.pmid: 18381653
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: Eur J Neurol. 2006 Apr;13(4):333-45
references.pmid: 16643310
references.citation: Trends Genet. 2009 Aug;25(8):361-7
references.pmid: 19665252
references.citation: Brain. 2000 Aug;123 ( Pt 8):1703-9
references.pmid: 10908199
references.citation: Cancer Biol Ther. 2009 Oct;8(19):1791-7
references.pmid: 19770591
references.citation: Neurotherapeutics. 2007 Apr;4(2):274-84
references.pmid: 17395138
references.citation: Arch Neurol. 2009 Jan;66(1):97-101
references.pmid: 19139306
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Neurology. 2005 Aug 23;65(4):529-34
references.pmid: 16116111
references.citation: Hum Mol Genet. 2007 Jul 15;16(14):1682-98
references.pmid: 17519220
references.citation: Cephalalgia. 2004;24 Suppl 1:9-160
references.pmid: 14979299
references.citation: BMC Med Genomics. 2009 Sep 22;2:62
references.pmid: 19772658
references.citation: Science. 2009 Sep 4;325(5945):1246-50
references.pmid: 19644074