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Linkage analysis of schizophrenia controlling for population substructure

Authors

  • Tiina Paunio,

    1. Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
    2. Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland
    3. Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
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  • Ritva Arajärvi,

    1. Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland
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  • Joseph D. Terwilliger,

    1. Department of Psychiatry, Columbia University, New York, New York
    2. Department of Genetics and Development, Columbia University, New York, New York
    3. Columbia Genome Center, Columbia University, New York, New York
    4. Division of Medical Genetics, New York State Psychiatric Institute, New York, New York
    5. Faculty of Medicine, University of Helsinki, Helsinki, Finland
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  • Tero Hiekkalinna,

    1. Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
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  • Perttu Haimi,

    1. Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
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  • Timo Partonen,

    1. Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland
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  • Jouko Lönnqvist,

    1. Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland
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  • Leena Peltonen,

    1. Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
    2. Department of Medical Genetics, University of Helsinki, Helsinki, Finland
    3. The Broad Institute of MIT and Harvard University, Cambridge, Massachusetts
    4. Welcome Trust Sanger Institute, Hinxton, Cambridge, UK
    5. Institute for Molecular Medicine Finland FIMM, Helsinki, Finland
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  • Teppo Varilo

    Corresponding author
    1. Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
    2. Department of Medical Genetics, University of Helsinki, Helsinki, Finland
    3. Institute for Molecular Medicine Finland FIMM, Helsinki, Finland
    • Faculty of Medicine, Department of Medical Genetics, Biomedicum, University of Helsinki, P.O. Box 63, Helsinki 00014, Finland.
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  • Please cite this article as follows: Paunio T, Arajärvi R, Terwilliger JD, Hiekkalinna T, Haimi P, Partonen T, Lönnqvist J, Peltonen L, Varilo T. 2009. Linkage Analysis of Schizophrenia Controlling for Population Substructure. Am J Med Genet Part B 150B:827–835.

Abstract

Etiological heterogeneity and complexity has hampered attempts to identify predisposing genes for schizophrenia. We sought to minimize the number of segregating genes involved by focusing on a population isolate with elevated disease prevalence. We exploited the well-established population history, and searched for disease susceptibility loci in families from two alternative founder lineages. We studied 28 schizophrenia pedigrees (123 nuclear families) from an outlying municipality on the eastern border of Finland. We divided the families based on their genealogy and defined two routes of immigration: southern and northern. We examined the kinship coefficients and allele frequency distributions within each group, and performed a linkage analysis based on 497 microsatellite markers across the genome. A high degree of historical relatedness was demonstrated by higher sharing of alleles than predicted by the relationships we identified within the previous four generations alone, as would be expected. Between the two subpopulations, allele frequencies were significantly different, consistent with their isolated genealogies. The southern families showed some evidence of linkage in a schizophrenia locus at 4q23 (Z = 3.3) near our previous finding with quantitative variation in verbal learning and memory [Paunio et al. (2004); Hum Mol Genet 13: 1693–1702], while the northern pedigrees gave most significant evidence on 10q21 (Z = 2.53). Joint analysis of families from both lineages suggested evidence of linkage only at 3p14 (Z = 3.18). Thus the detailed genealogical information led us to identification of distinct linkage signals for schizophrenia susceptibility loci between the three analyses we performed. © 2008 Wiley-Liss, Inc.

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