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Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1


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 rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10−9, odds ratio = 1.23, 95% CI 1.150–1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10−11 (odds ratio = 1.18, 95% CI 1.127–1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, 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 rs1835740 (P = 3.96 × 10−5, permuted threshold for genome-wide significance 7.7 × 10−5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

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Figure 1: Cochran-Mantel-Haenszel association results for combined analysis of the three study populations between 97.5 Mb and 99.0 Mb on chromosome 8q22.1.
Figure 2: For each dataset, the horizontal line indicates the 95% CI, and the number above the line indicates the point estimate of the odds ratio.
Figure 3: A box-plot of the quantified expression values for MTDH, ordered based on the sample genotype of rs1835740.


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We wish to thank all individuals in the respective cohorts for their generous participation. This work was supported by the Wellcome Trust (grant number WT089062) and, among others, by the Academy of Finland (200923 to AP, 00213 to M.W.); the Helsinki University Central Hospital (to M. Kallela., M.F., V. Artto and S.V.); the Academy of Finland Center of Excellence for Complex Disease Genetics; the EuroHead project (LSM-CT-2004-504837); the Helsinki Biomedical Graduate School (to V. Anttila, P.T.-K.); the Finnish Cultural Foundation (to V. Anttila); the Finnish Neurology Foundation, Biomedicum Helsinki Foundation (to V. Anttila, P.T.-K. and V. Artto); the Cambridge Biomedical Research Centre (to S.C.); the Australian National Health and Medical Research Council Fellowship (339462 and 613674) and the Australian Research Council Future Fellowship (FT0991022) schemes (to D.R.N.); the German Federal Ministry of Education and Research (BMBF) (grant 01GS08121 to M. Dichgans, along with support to H.E.W. in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus) for the Heinz Nixdorf Recall study, and to C.K. (EMINet - 01GS08120) for the National Genome Research Network (Germany; NGFN-1 and NGFN-Plus)); the Center for Molecular Medicine Cologne (to C.K.); the Heinz Nixdorf Foundation for the Heinz Nixdorf Recall study, Deutsche Forschungsgemeinschaft (DFG; to C.K. and H.G.); the Netherlands Organization for the Health Research and Development (ZonMw) no. 90700217 (to G.M.T.) and to the Rotterdam Study (RIDE1 and RIDE2); the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants (to M.D.F.); 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 (to C.M.v.D., R.R.F., M.D.F. and A.M.J.M.v.d.M.) and project nos. 050-060-810 and 175.010.2005.011, 911-03-012 (to the Rotterdam Study). We thank the Health 2000 study for providing Finnish control genotypes. The Broad Institute Center for Genotyping and Analysis is supported by a grant from the National Center for Research Resources (US). The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria and is supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. We wish to thank S. Hunt, R. Gwillian, P. Whittaker, S. Potter and A. Tashakkori-Ghanbarian, as well as P. Marin-Garcia, for their invaluable help with this study. Finally, we wish to collectively thank everyone who has contributed to the collection, genotyping and analysis of the individual cohorts.

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Correspondence to Verneri Anttila or Aarno Palotie.

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the International Headache Genetics Consortium. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet 42, 869–873 (2010).

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