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Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Abstract

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10−6) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10−9; rs10166942, OR = 0.85, P = 5.5 × 10−12; and rs11172113, OR = 0.90, P = 4.3 × 10−9). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

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Figure 1: Association P values and genomic context for candidate SNPs.

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Acknowledgements

This study is supported by a grant from the National Institute of Neurological Disorders and Stroke (NS-061836). The Women's Health Study and the Women's Genome Health Study are supported by grants from the National Heart, Lung, and Blood Institute (HL-043851, HL-080467 and HL-099355) and the National Cancer Institute (CA-47988). Part of the research for this work was supported by grants from the Donald W. Reynolds Foundation and the Leducq Foundation. Genome-wide genotyping and collaborative scientific support was provided by Amgen.

Genotyping in the Genetic Epidemiology of Migraine Study was supported by the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants and the Center for Medical Systems Biology (CMSB) established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO), project no. 050-060-409. The GEM study was supported by the Ministry of Health, Welfare and Sport and the National Institute of Public Health and the Environment, The Netherlands.

SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The SHIP authors are grateful to the contribution of A. Teumer, A. Hoffmann and A. Petersmann in generating the SNP data. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of Siemens AG.

The IHGC study was supported, among others, by the Academy of Finland (200923 to A.P.), the Wellcome Trust (grant number 089062), the European Community's Seventh Framework Programme (FP7/2007-2013) (through the SYNSYS Consortium (grant agreement no. 242167) and the ENGAGE Consortium (grant agreement no. 201413)), the Helsinki University Central Hospital (to M.K.) and the Finnish Culture Foundation (to V.A.). Funding by the German Federal Ministry of Education and Research (BMBF) within the National Genome Research Network (NGFNplus, EMINet-01GS08120 for C.K., 01GS08121 to M. Dichgans), the Deutsche Forschungsgemeinschaft (to C.K.) and the Center for Molecular Medicine Cologne (to C.K.). For a full list of acknowledgements, please see reference 5.

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Obtained funding: J.E.B., M.D.F., W.H., T.K., A.M.J.M.v.d.M., A.P., P.M.R., U.S., H.V., R.Y.L.Z. Overall study design: D.I.C., T.K., M.S. Cohort supervision and phenotyping: V.A., J.E.B., K.F., M.D.F., T.F., W.H., M.K., C.K., T.K., L.J.L., A.P., P.M.R., U.S., M.S., G.M.T., H.V. Analysis and genotyping: V.A., D.I.C., K.F., L.R.G., W.H., A.M.J.M.v.d.M., P.M.R., U.S., M.S., F.E., B.d.V., R.Y.L.Z. Manuscript writing: D.I.C., M.S. All authors participated in critical review of the manuscript for intellectual content.

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Correspondence to Markus Schürks or Tobias Kurth.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Tables 1–9 and Supplementary Figures 1 and 2. (PDF 192 kb)

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Chasman, D., Schürks, M., Anttila, V. et al. Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 43, 695–698 (2011). https://doi.org/10.1038/ng.856

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