Genome-wide association study of migraine implicates a common susceptibility variant on 8 q 22 . 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 rs 835740 on chromosome 8q22. to be associated with migraine (P = 5.38 × 0−9, odds ratio = .23, 95% CI . 50– .324) in a genome-wide association study of 2,73 migraine cases ascertained from three European headache clinics and 0,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of .69 × 0− (odds ratio = . 8, 95% CI . 27– .244). rs 835740 is located between MTDH (astrocyte elevated gene , 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 rs 835740 (P = 3.96 × 0−5, permuted threshold for genome-wide significance 7.7 × 0−5). To our knowledge, our data establish rs 835740 as the first genetic risk factor for migraine.

[1]  N. Risch.  Searching for genetic determinants in the new millennium , 2000, Nature.

[2]  J. Pascual,et al.  Epidemiology of headache in Europe , 2006, European journal of neurology.

[3]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[4]  H. Stefánsson,et al.  Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes , 2006, Nature Genetics.

[5]  Yinglei Lai,et al.  Gene expression profiling differentiates autism case–controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism , 2009, Autism research : official journal of the International Society for Autism Research.

[6]  P. Deloukas,et al.  Common Regulatory Variation Impacts Gene Expression in a Cell Type–Dependent Manner , 2009, Science.

[7]  Jes Olesen,et al.  The International Classification of Headache Disorders: 2nd edition. , 2004, Cephalalgia : an international journal of headache.

[8]  Stephen T Warren,et al.  Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. , 2007, Human molecular genetics.

[9]  M. Ferrari,et al.  Molecular genetics of migraine , 2009, Human Genetics.

[10]  Mark Gurney,et al.  The gene encoding phosphodiesterase 4D confers risk of ischemic stroke , 2003, Nature Genetics.

[11]  T. Strom,et al.  Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine , 2005, The Lancet.

[12]  B. Rosen,et al.  Mechanisms of migraine aura revealed by functional MRI in human visual cortex , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Ferrari,et al.  Enhanced Excitatory Transmission at Cortical Synapses as the Basis for Facilitated Spreading Depression in CaV2.1 Knockin Migraine Mice , 2009, Neuron.

[14]  R. Lipton,et al.  Migraine--current understanding and treatment. , 2002, The New England journal of medicine.

[15]  W. Frankel.  Genetics of complex neurological disease: challenges and opportunities for modeling epilepsy in mice and rats. , 2009, Trends in genetics : TIG.

[16]  D. Koller,et al.  Population genomics of human gene expression , 2007, Nature Genetics.

[17]  K. Khalili,et al.  Molecular mechanisms of necrosis in glioblastoma: The role of glutamate excitotoxicity , 2009, Cancer biology & therapy.

[18]  R. Lipton,et al.  The Global Burden of Headache: A Documentation of Headache Prevalence and Disability Worldwide , 2007, Cephalalgia : an international journal of headache.

[19]  P. Fisher,et al.  Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis , 2009, Proceedings of the National Academy of Sciences.

[20]  L. DeLisi,et al.  Exon expression in lymphoblastoid cell lines from subjects with schizophrenia before and after glucose deprivation , 2009, BMC Medical Genomics.

[21]  D. Nyholt.  A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. , 2004, American journal of human genetics.

[22]  M. Dallas,et al.  Hypoxia Suppresses Glutamate Transport in Astrocytes , 2007, The Journal of Neuroscience.

[23]  M. Daly,et al.  A high-density association screen of 155 ion transport genes for involvement with common migraine. , 2008, Human molecular genetics.

[24]  P. Fisher,et al.  Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. , 2005, Gene.

[25]  Michael Inouye,et al.  A genotype calling algorithm for the Illumina BeadArray platform , 2007, Bioinform..

[26]  Andrew Charles,et al.  The neurobiology of migraine. , 2010, Handbook of clinical neurology.

[27]  A. Ballabio,et al.  Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2 , 2003, Nature Genetics.

[28]  C. Peers,et al.  Differential involvement of TNFα in hypoxic suppression of astrocyte glutamate transporters , 2008, Glia.

[29]  Masahiko Watanabe,et al.  Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. , 1997, Science.

[30]  R. Baloh,et al.  Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake. , 2009, Archives of neurology.

[31]  D. Yarnitsky,et al.  The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. , 2000, Brain : a journal of neurology.

[32]  Michael G Hanna,et al.  Genetic neurological channelopathies , 2006, Nature Clinical Practice Neurology.

[33]  F. Tamanini,et al.  Familial hemiplegic migraine. , 1955, The Lancet.

[34]  T. Olsen,et al.  Pathophysiology of the migraine aura: the spreading depression theory. , 1995, Brain : a journal of neurology.

[35]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[36]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[37]  Dennis E Bulman,et al.  Familial Hemiplegic Migraine and Episodic Ataxia Type-2 Are Caused by Mutations in the Ca2+ Channel Gene CACNL1A4 , 1996, Cell.