Genome-wide association analysis identifies susceptibility loci for migraine without aura.
Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.
Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.
Tobias
T
Freilinger
Verneri
V
Anttila
Boukje
B
de Vries
Rainer
R
Malik
Mikko
M
Kallela
Gisela M
GM
Terwindt
Patricia
P
Pozo-Rosich
Bendik
B
Winsvold
Dale R
DR
Nyholt
Willebrordus P J
WP
van Oosterhout
Ville
V
Artto
Unda
U
Todt
Eija
E
Hämäläinen
Jèssica
J
Fernández-Morales
Mark A
MA
Louter
Mari A
MA
Kaunisto
Jean
J
Schoenen
Olli
O
Raitakari
Terho
T
Lehtimäki
Marta
M
Vila-Pueyo
Hartmut
H
Göbel
Erich
E
Wichmann
Cèlia
C
Sintas
Andre G
AG
Uitterlinden
Albert
A
Hofman
Fernando
F
Rivadeneira
Axel
A
Heinze
Erling
E
Tronvik
Cornelia M
CM
van Duijn
Jaakko
J
Kaprio
Bru
B
Cormand
Maija
M
Wessman
Rune R
RR
Frants
Thomas
T
Meitinger
Bertram
B
Müller-Myhsok
John-Anker
JA
Zwart
Markus
M
Färkkilä
Alfons
A
Macaya
Michel D
MD
Ferrari
Christian
C
Kubisch
Aarno
A
Palotie
Martin
M
Dichgans
Arn M J M
AM
van den Maagdenberg
D000328:Adult; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics; D026161:MADS Domain Proteins / Q000235:genetics; D064326:MEF2 Transcription Factors; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D020326:Migraine without Aura / Q000235:genetics*; D018006:Myogenic Regulatory Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics
C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D008840:Microfilament Proteins; D018006:Myogenic Regulatory Factors; C570134:PHACTR1 protein, human; D018125:Receptors, Transforming Growth Factor beta; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II