[en] 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 x 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 x 10(-4); combined P = 7.06 x 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 x 10(-4); combined P = 1.17 x 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 x 10(-8) and P = 0.02; combined P = 3.86 x 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.
Disciplines :
Neurology
Author, co-author :
Freilinger, Tobias
Anttila, Verneri
de Vries, Boukje
Malik, Rainer
Kallela, Mikko
Terwindt, Gisela M.
Pozo-Rosich, Patricia
Winsvold, Bendik
Nyholt, Dale R.
van Oosterhout, Willebrordus P. J.
Artto, Ville
Todt, Unda
Hamalainen, Eija
Fernandez-Morales, Jessica
Louter, Mark A.
Kaunisto, Mari A.
SCHOENEN, Jean ; Centre Hospitalier Universitaire de Liège - CHU > Neurologie CHR
Launer, L.J., Terwindt, G.M. & Ferrari, M.D. The prevalence and characteristics of migraine in a population-based cohort: the GEM study. Neurology 53, 537-542 (1999). (Pubitemid 29382048)
Stovner, L.J., Zwart, J.A., Hagen, K., Terwindt, G.M. & Pascual, J. Epidemiology of headache in Europe. Eur. J. Neurol. 13, 333-345 (2006).
Stovner, L. et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27, 193-210 (2007). (Pubitemid 46354128)
Olesen, J., Lekander, I., Andlin-Sobocki, P. & Jönsson, B. Funding of headache research in Europe. Cephalalgia 27, 995-999 (2007). (Pubitemid 47296033)
Anttila, V. et al. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat. Genet. 42, 869-873 (2010).
Chasman, D.I. et al. Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat. Genet. 43, 695-698 (2011).
Dimas, A.S. et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246-1250 (2009).
Nica, A.C. et al. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 7, e1002003 (2011).
Lin, X., Shah, S. & Bulleit, R.F. The expression of MEF2 genes is implicated in CNS neuronal differentiation. Brain Res. Mol. Brain Res. 42, 307-316 (1996). (Pubitemid 27035761)
Flavell, S.W. et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008-1012 (2006). (Pubitemid 43271729)
Aurora, S.K. & Wilkinson, F. The brain is hyperexcitable in migraine. Cephalalgia 27, 1442-1453 (2007). (Pubitemid 350150807)
Martínez, F., Castillo, J., Rodríguez, J.R., Leira, R. & Noya, M. Neuroexcitatory amino acid levels in plasma and cerebrospinal fluid during migraine attacks. Cephalalgia 13, 89-93 (1993). (Pubitemid 23116117)
Tottene, A. et al. Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Cav2.1 knockin migraine mice. Neuron 61, 762-773 (2009).
Flavell, S.W. et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60, 1022-1038 (2008).
Morrow, E.M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218-223 (2008). (Pubitemid 351989087)
Pfeiffer, B.E. et al. Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66, 191-197 (2010).
Schytz, H.W. et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 132, 16-25 (2009).
Markovics, A. et al. Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol. Dis. 45, 633-644 (2012).
Goadsby, P.J., Lipton, R.B. & Ferrari, M.D. Migraine-current understanding and treatment. N. Engl. J. Med. 346, 257-270 (2002).
Lin, H.Y., Wang, X.F., Ng-Eaton, E., Weinberg, R.A. & Lodish, H.F. Expression cloning of the TGF-β type 2 receptor, a functional transmembrane serine/threonine kinase. Cell 68, 775-785 (1992).
Law, C. et al. Clinical features in a family with an R460H mutation in transforming growth factor β receptor 2 gene. J. Med. Genet. 43, 908-916 (2006). (Pubitemid 46080187)
Rist, P.M., Diener, H.C., Kurth, T. & Schürks, M. Migraine, migraine aura, and cervical artery dissection: a systematic review and meta-analysis. Cephalalgia 31, 886-896 (2011).
Allen, P.B., Greenfield, A.T., Svenningsson, P., Haspeslagh, D.C. & Greengard, P. Phactrs 1-4: a family of protein phosphatise 1 and actin regulatory proteins. Proc. Natl. Acad. Sci. USA 101, 7187-7192 (2004). (Pubitemid 38596464)
Greengard, P., Allen, P.B. & Nairn, A.C. Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23, 435-447 (1999). (Pubitemid 29359916)
Jarray, R. et al. Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis. Biochimie 93, 1668-1675 (2011).
Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334-341 (2009).
Tietjen, G.E. Migraine as a systemic vasculopathy. Cephalalgia 29, 987-996 (2009).
Wilson, P.M., Fryer, R.H., Fang, Y. & Hatten, M.E. Astn2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. J. Neurosci. 30, 8529-8540 (2010).
DaSilva, A.F., Granziera, C., Snyder, J. & Hadjikhani, N. Thickening in the somatosensory cortex of patients with migraine. Neurology 69, 1990-1995 (2007). (Pubitemid 350145091)
Kruit, M.C. et al. Migraine as a risk factor for subclinical brain lesions. J. Am. Med. Assoc. 291, 427-434 (2004). (Pubitemid 38129746)
Proudfoot, C.J. et al. Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr. Biol. 16, 1591-1605 (2006). (Pubitemid 44233290)
Caspani, O., Zurborg, S., Labuz, D. & Heppenstall, P.A. The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain. PLoS ONE 4, e7383 (2009).
d'Agostino, V.C., Francia, E., Licursi, V. & Cerbo, R. Clinical and personality features of allodynic migraine. Neurol. Sci. 31 (suppl. 1), S159-S161 (2010).
Lillis, A.P., van Duyn, L.B., Murphy-Ullrich, J.E. & Strickland, D.K. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 88, 887-918 (2008).
May, P. et al. Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. Mol. Cell. Biol. 24, 8872-8883 (2004). (Pubitemid 39313893)
Russell, M.B., Rasmussen, B.K., Fenger, K. & Olesen, J. Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population. Cephalalgia 16, 239-245 (1996). (Pubitemid 26189249)
Kallela, M., Wessman, M., Havanka, H., Palotie, A. & Färkkilä, M. Familial migraine with and without aura: clinical characteristics and co-occurrence. Eur. J. Neurol. 8, 441-449 (2001). (Pubitemid 34203436)
Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851-861 (2007). (Pubitemid 47598626)
Teo, Y.Y. et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23, 2741-2746 (2007). (Pubitemid 350048339)
Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
Altshuler, D.M. et al. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52-58 (2010).
Mägi, R. & Morris, A.P. GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010).
Cochran, W.G. The combination of estimates from different experiments. Biometrics 10, 101-129 (1954).
Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539-1558 (2002). (Pubitemid 34746062)
Ioannidis, J.P., Patsopoulos, N.A. & Evangelou, E. Heterogeneity in meta-analyses of genome-wide association investigations. PLoS ONE 2, e841 (2007).
DerSimonian, R. & Laird, N. Meta-analysis in clinical trials. Control. Clin. Trials 7, 177-188 (1986). (Pubitemid 17189972)
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559-575 (2007). (Pubitemid 47330214)
Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 1217-1224 (2007). (Pubitemid 47482691)