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 × 1011) 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.

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Figure 1: Regional and forest plots for the newly identified loci associated with migraine.
Figure 2: Regional and forest plots for the previously reported loci associated with migraine that replicate in the current migraine without aura study.


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We wish to thank all individuals in the respective cohorts for their generous participation. This work was supported by the German Federal Ministry of Education and Research (BMBF) (grant 01GS08121 to M.D., along with support to E.W. in the context of the German National Genome Research Network, (NGFN-2 and NGFN-plus) for the Heinz Nixdorf Recall Study); the Spanish Ministry of Science and Innovation (grant SAF2009-13182-C03 to A.M. and B.C.); the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (grants 2009SGR78 and 2009SGR971 to A.M. and B.C., respectively); an unrestricted grant of the Vascular Dementia Research Foundation (to M.D.); the Netherlands Organization for Health Research and Development (ZonMw) (90700217) and VIDI (ZonMw) (91711319 to G.M.T.); the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants (to M.D.F.); the Center for Medical Systems Biology (CMSB) established in the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO) (project 050-060-409 to C.M.v.D., R.R.F., M.D.F. and A.M.J.M.v.d.M. and 050-060-810 to C.M.v.D.) and the generation and management of GWAS genotype data for the Rotterdam Study (175.010.2005.011 and 911-03-012) (funded by the Erasmus Medical Center, Erasmus University Rotterdam and the Ministries of Education, Culture and Science, Health, Welfare and Sports), as well as the NGI-sponsored Netherlands Consortium for Healthy Aging (NCHA) and the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the German Federal Ministry of Education and Research (BMBF) within the framework of the National Genome Research Network (NGFN-Plus; grants 01GS08120 and 01GS1103 to C.K.); the German Federal Ministry of Education and Research and the State of Bavaria, supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ) for the KORA research platform, which was initiated by the Helmholtz Center Munich, German Research Center for Environmental Health; the National Health and Medical Research Council (NHMRC) Research Fellowship (613674) and the Australian Research Council (ARC) Future Fellowship (FT0991022) schemes (to D.R.N.); the Wellcome Trust (grant 098051 to A.P.); the Academy of Finland (grant 251704 to A.P. and 139795 to M.W.); the Academy of Finland, Center of Excellence in Complex Disease Genetics (grants 213506 and 129680 to A.P. and J.K.); the South-Eastern Norway Regional Health Authority (2010075 and 2011083 to B.W. and J.-A.Z.), the Unger-Vetlesen Medical Fund (to B.W.) and the Ullevaal fund (to B.W.); the European Community's Seventh Framework Programme (FP7/2007-2013), the ENGAGE Consortium, (grant agreement HEALTH-F4-2007- 201413); EU/SYNSYS–Synaptic Systems (grant 242167 to A.P.); the Sigrid Juselius Foundation, Finland (to A.P.); the Folkhälsan Research Foundation, Helsinki (to M.W.); and the Helsinki University Central Hospital (to M.K., V. Artto and M.F.).

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Funding was obtained by M.D., M.D.F., A.P., A.M.J.M.v.d.M., C.K. and C.M.v.D. Overall study design was guided by T.F., V. Anttila, B.d.V., R.M., D.R.N., J.-A.Z., C.K., A.P., M.D. and A.M.J.M.v.d.M. Cohorts were supervised and phenotyped by T.F., M.K., G.M.T., P.P.-R., B.W., W.P.J.v.O., V. Artto, U.T., J.F.-M., M.A.L., M.A.K., J.S., O.R., T.L., M.V.-P., H.G., E.W., C.S., A.G.U., A. Heinze, A. Hoffman., E.T., C.M.v.D., J.K., B.C., T.M., J.-A.Z., M.F. and A.M. Analysis and genotyping were performed by V. Anttila, B.d.V., R.M., B.W., D.R.N., E.H., A.G.U., F.R., M.W., T.M. and B.M.-M. The manuscript was written by T.F., V. Anttila, B.d.V., D.R.N., B.C., M.W., R.R.F., J.-A.Z., C.K., A.P., M.D. and A.M.J.M.v.d.M. All authors participated in critical review of the manuscript for intellectual content.

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Correspondence to Aarno Palotie or Arn M J M van den Maagdenberg.

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Freilinger, T., Anttila, V., de Vries, B. et al. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet 44, 777–782 (2012).

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