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

Molecular Psychiatry volume 11, pages 372–383 (2006)Cite this article

Abstract

A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case–control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent–proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case–control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 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 β-catenin binding sites. Expression of Fat, Catnb (β-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). 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.

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Acknowledgements

We thank all patients and family members who participated in this study. Tissues were received from the Rebecca L Cooper Research Laboratories at the Mental Health Research Institute of Victoria, and the NSW Tissue Resource Centre, which is supported by The University of Sydney, Neuroscience Institute of Schizophrenia and Allied Disorders, National Institute of Alcohol Abuse and Alcoholism and NSW Department of Health. IPB was supported by a National Health and Medical Research Council (Australia) (NHMRC) postdoctoral fellowship and a NARSAD Young Investigator Award. PRS was supported by an NHMRC Senior Principal Research Fellowship. This study was supported by NHMRC project grant 230802 and NHMRC program grant 2223708.

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Authors and Affiliations

  1. Neurobiology Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia

    I P Blair, A F Chetcuti, R F Badenhop, A Scimone, M J Moses, L J Adams, J B J Kwok & P R Schofield

  2. Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

    I P Blair, J B J Kwok & P R Schofield

  3. Neuroscience Institute of Schizophrenia and Allied Disorders, Sydney, NSW, Australia

    A F Chetcuti & P R Schofield

  4. Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK

    N Craddock, E Green, G Kirov & M J Owen

  5. Department of Biological Sciences, Macquarie University, Sydney, NSW, Australia

    J A Donald

  6. School of Psychiatry, University of New South Wales, Sydney, NSW, Australia

    P B Mitchell

  7. Mood Disorders Unit, Black Dog Institute, Prince of Wales Hospital, Sydney, NSW, Australia

    P B Mitchell

  8. Prince of Wales Medical Research Institute, Sydney, NSW, Australia

    P R Schofield

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Blair, I., Chetcuti, A., Badenhop, R. et al. Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele. Mol Psychiatry 11, 372–383 (2006). https://doi.org/10.1038/sj.mp.4001784

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