Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1.
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.
Anttila
Verneri
V
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK. verneri.anttila@sanger.ac.uk
Stefansson
Hreinn
H
Kallela
Mikko
M
Todt
Unda
U
Terwindt
Gisela M
GM
Calafato
M Stella
MS
Nyholt
Dale R
DR
Dimas
Antigone S
AS
Freilinger
Tobias
T
Müller-Myhsok
Bertram
B
Artto
Ville
V
Inouye
Michael
M
Alakurtti
Kirsi
K
Kaunisto
Mari A
MA
Hämäläinen
Eija
E
de Vries
Boukje
B
Stam
Anine H
AH
Weller
Claudia M
CM
Heinze
Axel
A
Heinze-Kuhn
Katja
K
Goebel
Ingrid
I
Borck
Guntram
G
Göbel
Hartmut
H
Steinberg
Stacy
S
Wolf
Christiane
C
Björnsson
Asgeir
A
Gudmundsson
Gretar
G
Kirchmann
Malene
M
Hauge
Anne
A
Werge
Thomas
T
Schoenen
Jean
J
Eriksson
Johan G
JG
Hagen
Knut
K
Stovner
Lars
L
Wichmann
H-Erich
HE
Meitinger
Thomas
T
Alexander
Michael
M
Moebus
Susanne
S
Schreiber
Stefan
S
Aulchenko
Yurii S
YS
Breteler
Monique M B
MM
Uitterlinden
Andre G
AG
Hofman
Albert
A
van Duijn
Cornelia M
CM
Tikka-Kleemola
Päivi
P
Vepsäläinen
Salli
S
Lucae
Susanne
S
Tozzi
Federica
F
Muglia
Pierandrea
P
Barrett
Jeffrey
J
Kaprio
Jaakko
J
Färkkilä
Markus
M
Peltonen
Leena
L
Stefansson
Kari
K
Zwart
John-Anker
JA
Ferrari
Michel D
MD
Olesen
Jes
J
Daly
Mark
M
Wessman
Maija
M
van den Maagdenberg
Arn M J M
AM
Dichgans
Martin
M
Kubisch
Christian
C
Dermitzakis
Emmanouil T
ET
Frants
Rune R
RR
Palotie
Aarno
A
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
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
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