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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