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

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 1 , 8 , 9 , 1 , 10 , 11 , 12 , 13 , 4 , 1 , 14 , 1 , 2 , 2 , 15 , 1 , 2 , 14 , 7 , 14 , 16 , 16 , 5 , 6 , 5 , 6 , 16 , 3 , 13 , 3 , 17 , 18 , 18 , 19 , 20 , 15 , 21 , 22 , 23 , 24 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 35 , 36 , 35 , 35 , 37 , 4 , 13 , 38 , 38 , 39 , 1 , 2 , 23 , 40 , 4 , 1 , 2 , 41 , 3 , 23 , 42 , 7 , 18 , 41 , 2 , 15 , 7 , 14 , 12 , 5 , 6 , 43 , 11 , 14 , 1 , 2 , 41 , 44 , 45
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          Abstract

          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=5.12 × 10 −9, OR 1.23 [1.150-1.324]) in a genome-wide association study of 2,748 migraineurs 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 1.60 × 10 −11 (OR 1.18 [1.127 – 1.244]). rs1835740 is located between the astrocyte elevated gene 1 ( MTDH/AEG-1) and plasma glutamate carboxypeptidase ( PGCP). In an expression quantitative trait study in lymphoblastoid cell lines transcript levels of the MTDH/AEG-1 were found to have a significant correlation to rs1835740. Our data establish rs1835740 as the first genetic risk factor for migraine.

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          Most cited references30

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          The International Classification of Headache Disorders: 2nd edition.

          (2004)
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            The global burden of headache: a documentation of headache prevalence and disability worldwide.

            This study, which is a part of the initiative 'Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide', assesses and presents all existing evidence of the world prevalence and burden of headache disorders. Population-based studies applying International Headache Society criteria for migraine and tension-type headache, and also studies on headache in general and 'chronic daily headache', have been included. Globally, the percentages of the adult population with an active headache disorder are 46% for headache in general, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. Our calculations indicate that the disability attributable to tension-type headache is larger worldwide than that due to migraine. On the World Health Organization's ranking of causes of disability, this would bring headache disorders into the 10 most disabling conditions for the two genders, and into the five most disabling for women.
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              • Record: found
              • Abstract: found
              • Article: not found

              Common regulatory variation impacts gene expression in a cell type-dependent manner.

              Studies correlating genetic variation to gene expression facilitate the interpretation of common human phenotypes and disease. As functional variants may be operating in a tissue-dependent manner, we performed gene expression profiling and association with genetic variants (single-nucleotide polymorphisms) on three cell types of 75 individuals. We detected cell type-specific genetic effects, with 69 to 80% of regulatory variants operating in a cell type-specific manner, and identified multiple expressive quantitative trait loci (eQTLs) per gene, unique or shared among cell types and positively correlated with the number of transcripts per gene. Cell type-specific eQTLs were found at larger distances from genes and at lower effect size, similar to known enhancers. These data suggest that the complete regulatory variant repertoire can only be uncovered in the context of cell-type specificity.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                6 August 2010
                29 August 2010
                October 2010
                01 April 2011
                : 42
                : 10
                : 869-873
                Affiliations
                [1 ] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
                [2 ] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki.Finland.
                [3 ] Department of Population Genomics, deCODE genetics, Reykjavik, Iceland.
                [4 ] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
                [5 ] Institute of Human Genetics, University of Cologne, Cologne, Germany.
                [6 ] Institute for Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
                [7 ] Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
                [8 ] National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
                [9 ] Neurogenetics Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
                [10 ] Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.
                [11 ] Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
                [12 ] Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany.
                [13 ] Max Planck Institute of Psychiatry, Munich, Germany.
                [14 ] Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
                [15 ] Folkhälsan Research Center, Helsinki, Finland.
                [16 ] Kiel Pain and Headache Center, Kiel, Germany.
                [17 ] Department of Neurology, Landspitali University Hospital, Reykjavik, Iceland.
                [18 ] Department of Neurology, Glostrup Hospital and the Danish Headache Center, Glostrup, Denmark.
                [19 ] Research Institute of Biological Psychiatry, University of Copenhagen, Roskilde, Denmark.
                [20 ] Headache Research Unit. Department of Neurology and GIGA-Neurosciences, Liège University, Liège, Belgium.
                [21 ] Department of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
                [22 ] Vaasa Central Hospital, Vaasa, Finland.
                [23 ] National Institute for Health and Welfare, Helsinki, Finland.
                [24 ] Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
                [25 ] Institute of Epidemiology, HelmholtzCenter Munich, Neuherberg, Germany.
                [26 ] Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, Munich, Germany.
                [27 ] Klinikum Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany.
                [28 ] Institute of Human Genetics, HelmholtzCenter Munich, Neuherberg, Germany.
                [29 ] Institute of Human Genetics, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
                [30 ] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
                [31 ] Institute of Human Genetics, University of Bonn, Bonn, Germany.
                [32 ] Institute of Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
                [33 ] Department of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
                [34 ] Department Internal Medicine I, Christian Albrechts University, Kiel, Germany.
                [35 ] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
                [36 ] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
                [37 ] Research Program in Molecular Medicine, University of Helsinki, Helsinki, Finland.
                [38 ] Drug Discovery, GlaxoSmithKline R&D, Verona, Italy.
                [39 ] Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Canada.
                [40 ] Department of Public Health, University of Helsinki, Helsinki, Finland
                [41 ] The Broad Institute of MIT and Harvard, Boston, MA, USA.
                [42 ] Department of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway.
                [43 ] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
                [44 ] Department of Medical Genetics, University of Helsinki, Helsinki, Finland
                [45 ] Department of Medical Genetics, Helsinki University Central Hospital, Helsinki, Finland
                Author notes
                Correspondence and requests for materials should be addressed to V.A. ( verneri.anttila@ 123456sanger.ac.uk ) or A.P. ( aarno.palotie@ 123456sanger.ac.uk ).
                [*]

                Deceased

                Author contributions. All authors contributed to the current version of the paper.

                Article
                UKMS31703
                10.1038/ng.652
                2948563
                20802479
                7fa96f3c-6436-4e04-9e57-b7e35a39959c

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                History
                Funding
                Funded by: Wellcome Trust :
                Award ID: 089062 || WT
                Categories
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                Genetics
                Genetics

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