Positional cloning, association analysis, and expression studies provide convergent evidence that the cadherin gene fat contains a bipolar disorder susceptibility allele

IP Blair, AF Chetcuti, R. F. Badenhop, Anna Scimone, LJ Adams, N. Craddock, E Green, G. Kirov, MJ Owen, MA Kennedy, AL Miller, PR Joyce, R Olds, JA Donald, PB Mitchell, Peter R. Schofield

    Research output: Contribution to journalMeeting abstractpeer-review

    Abstract

    Introduction: A susceptibility locus for bipolar disorder was previously
    localized to chromosome 4q35 by linkage analysis. We now
    report identification of a susceptibility gene for bipolar disorder.
    Methods: Positional cloning and association analysis (in four independent
    cohorts) was used to identify potential susceptibility alleles.
    Microarray and quantitative expression studies were undertaken
    using mouse brain mRNA following administration of lithium and
    valproate.
    Results: The cadherin gene, FAT, is associated with susceptibility to
    bipolar disorder in four independent cohorts (allelic P values 0.003 to
    0.024). Pooled analysis of the case-control cohort data further
    supported association (P¼0.0002, summary OR¼2.31, 95% CI: 1.49–
    3.59). We localized the bipolar associated region of the FAT gene to an
    interval that encodes an intracellular EVH1 domain, a domain that
    interacts with Ena/VASP proteins, as well as putative ß-catenin
    binding sites. Expression of Fat, Catnb (ß-catenin), and the three
    genes (Enah, Evl, and Vasp) encoding the Ena/VASP proteins, was
    investigated. Fat was significantly downregulated (P¼0.027), and
    Catnb and Enah were significantly upregulated (P¼0.0003 and 0.005,
    respectively), in response to therapeutic doses of lithium. The
    expression of genes encoding murine homologues of FAT (ft) interacting
    proteins was investigated.Of 14 interactingmolecules that showed
    expression following microarray analysis, eight showed significantly
    altered expression in response to therapeutic doses of lithium (binomial
    P¼0.004).
    Conclusions: Together, these data provide convergent evidence that
    FAT and its protein partners may be components of a molecular
    pathway involved in susceptibility to bipolar disorder.
    Original languageEnglish
    Pages (from-to)26-27
    Number of pages2
    JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
    Volume138B
    Issue number1
    DOIs
    Publication statusPublished - 5 Sep 2005
    Event13th World Congress on Psychiatric Genetics - Boston, Morocco
    Duration: 4 Sep 20058 Sep 2005

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