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Bipolar disorder is a major psychiatric illness that has evidence for a significant genetic contribution toward its development. In recent years, the BalI RFLP (restriction fragment length polymorphism) in the dopamine D3 receptor gene has been examined as a possible susceptibility factor for both schizophrenia and bipolar disorder. While analysis in schizophrenia has produced examples of increased homozygosity in patients, less encouraging results have been found for bipolar disorder. Recently, however, a family-based association study has found a significant excess of allele 1 and allele 1–containing genotypes in transmitted alleles to bipolar probands over nontransmitted controls. In a large bipolar case control sample (n = 454), we have been unable to replicate the family-based association study (chi-square = 0.137, P = 0.71, 1 df) or detect an effect similar to the positive homozygosity findings in schizophrenia (chi-square = 0.463, P = 0.50, 1 df). A meta-analysis of previous association studies also revealed no difference in allele distributions between bipolar patients and controls for this polymorphism in ethnically homogeneous samples (odds ratio, OR, = 1.04; P = 0.60; 95% confidence interval, CI, = 0.89–1.20). In view of this evidence, we conclude that variation at the BalI RFLP is not an important factor influencing the susceptibility to bipolar disorder. It remains possible, however, that other sequence variations within the DRD3 gene could play a role. © 2001 Wiley-Liss, Inc.

We have previously reported cosegregation of bipolar affective disorder and Darier disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier disease was mapped to chromosome 12q23–q24.1 and linkage studies have subsequently implicated this region as harboring a susceptibility gene for bipolar affective disorder. We have genomically characterized the human homologue of murine Cux-2, a neuronal-specific transcription factor potentially involved in the regulation of neural cell adhesion molecule expression that maps to this region. Also, in a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23–q24.1 region, we performed mutational screening of the CUX2 coding sequence, and 5' untranslated region (5' UTR). Resulting sequence were analyzed in a large sample of bipolar patients (n = 218) and control subjects (n = 218). No evidence was found for the involvement of variants within the CUX2 coding, or 5' UTR sequence in producing susceptibility to bipolar disorder. © 2001 Wiley-Liss, Inc.