Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene

Authors

  • Anna K. Kähler,

    Corresponding author
    1. TOP Project, Institute of Psychiatry, University of Oslo, Oslo, Norway
    2. Department of Medical Genetics, Ulleval University Hospital, Oslo, Norway
    3. Department of Psychiatry, Ulleval University Hospital, Oslo, Norway
    • Research Fellow, Section for Psychosis Research, Department for Research and Development, Division of Psychiatry, Ulleval University Hospital, Building 49, Kirkeveien 166, N-0407 Oslo, Norway.
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  • Srdjan Djurovic,

    1. TOP Project, Institute of Psychiatry, University of Oslo, Oslo, Norway
    2. Department of Medical Genetics, Ulleval University Hospital, Oslo, Norway
    3. Department of Psychiatry, Ulleval University Hospital, Oslo, Norway
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  • Bettina Kulle,

    1. Department of Biostatistics, University of Oslo, Oslo, Norway
    2. Department of Mathematics, University of Oslo, Oslo, Norway
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  • Erik G. Jönsson,

    1. Department of Clinical Neuroscience, HUBIN Project, Psychiatry Section, Karolinska Institutet and Hospital, Stockholm, Sweden
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  • Ingrid Agartz,

    1. TOP Project, Institute of Psychiatry, University of Oslo, Oslo, Norway
    2. Department of Clinical Neuroscience, HUBIN Project, Psychiatry Section, Karolinska Institutet and Hospital, Stockholm, Sweden
    3. Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
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  • Håkan Hall,

    1. Department of Clinical Neuroscience, HUBIN Project, Psychiatry Section, Karolinska Institutet and Hospital, Stockholm, Sweden
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  • Stein Opjordsmoen,

    1. TOP Project, Institute of Psychiatry, University of Oslo, Oslo, Norway
    2. Department of Psychiatry, Ulleval University Hospital, Oslo, Norway
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  • Klaus D. Jakobsen,

    1. Research Institute of Biological Psychiatry, H:S Sct. Hans Hospital, Roskilde, Denmark
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  • Thomas Hansen,

    1. Research Institute of Biological Psychiatry, H:S Sct. Hans Hospital, Roskilde, Denmark
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  • Ingrid Melle,

    1. TOP Project, Institute of Psychiatry, University of Oslo, Oslo, Norway
    2. Department of Psychiatry, Ulleval University Hospital, Oslo, Norway
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  • Thomas Werge,

    1. Research Institute of Biological Psychiatry, H:S Sct. Hans Hospital, Roskilde, Denmark
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  • Vidar M. Steen,

    1. Dr. Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway
    2. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
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  • Ole A. Andreassen

    1. TOP Project, Institute of Psychiatry, University of Oslo, Oslo, Norway
    2. Department of Psychiatry, Ulleval University Hospital, Oslo, Norway
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  • Please cite this article as follows: Kähler AK, Djurovic S, Kulle B, Jönsson EG, Agartz I, Hall H, Opjordsmoen S, Jakobsen KD, Hansen T, Melle I, Werge T, Steen VM, Andreassen OA. 2008. Association Analysis of Schizophrenia on 18 Genes Involved in Neuronal Migration: MDGA1 as a New Susceptibility Gene. Am J Med Genet Part B 147B:1089–1100.

Abstract

Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P < 0.05) in either a genotypic or allelic association test. All of these genes, except transcription factor DLX1, are involved in the adhesion between neurons and radial glial cells. Eight markers obtained nominal significance in both tests, and were located in intronic or 3′UTR regions of adhesion molecule MDGA1 and previously reported SZ candidate RELN. The most significant result was attained for MDGA1 SNP rs9462341 (unadjusted association results: genotypic P = 0.00095; allelic P = 0.010). Several haplotypes within MDGA1, RELN, ITGA3, and ENAH were nominally significant. Further studies in independent samples are needed, including upcoming genome wide association study results, but our data suggest that MDGA1 is a new SZ susceptibility gene, and that altered neuronal migration is involved in SZ pathology. © 2008 Wiley-Liss, Inc.

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