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

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 b-catenin binding sites. Expression of Fat, Catnb (b-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.

No influence of FAT polymorphisms in response to aripiprazole

“…In this study, we preliminarily investigated the potential influence of a set of markers in the FAT gene on clinical outcome and risk for side effects associated to aripiprazole treatment in a sample of 7,8 and some have suggested an involvement of FAT in schizophrenia, 3,4 . However, no work has yet confirmed neither an association between FAT gene and response to moodstabilizing agents nor an association between FAT and schizophrenia.…”

“…Further, we did not investigate a number of factors potentially influencing the course of symptoms over time independently from treatment, such as psychosocial status or environmental stressors. Also, the choice of SNPs was based on previous research 7,8 and focused only on the 3¢ of FAT gene; for this reason, further research is needed to provide a more complete coverage of FAT gene and to investigate further variants that could have a role on the expression of the gene and/or functionality of the protein.…”

“…Although current studies mainly focused on the role of classical cadherins and FAT in cancer, 5,6 there is consistent evidence suggesting a possible role of FAT in the development of psychiatric disorders. [7][8][9][10][11] Blair et al 8 recently reported FAT as a susceptibility gene for bipolar disorder. They found that a haplotype block at the 3¢ end of the cadherin gene FAT (rs2306987, rs1298865, rs2306990, rs2637777 and rs2304865) associated to bipolar disorder in an Australian patientcontrol sample of 137 families.…”

“…However, negative results have been also reported. 8 Increasing evidence suggests that bipolar disorder and schizophrenia could share many risk genes, [12][13][14] although evidence for cadherins is still limited. 4 Note, however, that the role of FAT in neuronal migration and positioning during development makes it a good candidate gene for schizophrenia.…”

A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26

“…[23][24][25][26][27][28] The cadherin gene FAT on chromosome 4q35 is a recent example of a bipolar susceptibility gene identified through a strategy of genetic linkage and association analysis in several independent cohorts. 29 Considering the number of loci reproducibly linked to bipolar disorder, and the mixed results from association studies among cohorts of various ethnicities, it is clear that precise genetic determinants of BP are yet to be elucidated.…”