Bipolar affective disorder is a genetically complex psychiatric disorder with a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier's disease was mapped to chromosome 12q23-q24.1 and linkage studies by us and others have subsequently implicated this region as harbouring a susceptibility gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a potential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this hypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random clustering of missense mutations in ATP2A2 in neuropsychiatric Darier patients, and functional data demonstrating the role of SERCA2 in intracellular calcium regulation. 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 ATP2A2 coding sequence, promoter regions, and 3Ј untranslated region and identified six sequence variations. These were analysed in a large sample of bipolar patients (n ‫؍‬ 324) and control subjects (n ‫؍‬ 327). Analysis of allele and genotype distributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipolar disorder. Molecular Psychiatry (2001) 6, 92-97.

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.

Evidence for the involvement of genetic factors in the pathogenesis of bipolar affective disorder is now well established. 1 However, the mode of inheritance is nonmendelian and this makes the identification of susceptibility loci difficult. A short-cut to localisation of a disease gene for an oligogenic/multifactorial disorder such as bipolar disorder may come from observation of cosegregation with a monogenic trait. We have described a family (pedigree 324) in which there was cosegregation of major affective disorder and Darier's disease, a dominantly inherited skin disorder, and hypothesised that this reflects genetic linkage between genes involved in these disorders. 2 Genetic mapping studies have placed the locus for Darier's disease on chromosome 12q23-q24. 3-7 We conducted subsequent linkage studies (1995) upon 45 bipolar families (without Darier's disease). These results showed some evidence in favour of linkage with chromosome 12q markers with maximum evidence at a trinucleotide repeat marker within intron 1 of the phospholipase A2A (PLA2A) gene. 8 Evidence for linkage was more significant when analysing the 22 families comprising the Cardiff centre sample, which were expected to be most genetically similar to pedigree 324.Phospholipase A2 is a superfamily of distinct enzymes 9 that play a central role in a number of cellular processes including host defence, signal transduction and phospholipid digestion/metabolism. 10 They are a diverse class of enzymes with regard to localisation, regulation, sequence, structure and role of divalent metal ions. 10 All PLA2s perform the same enzymatic reaction involving the hydrolysis of the sn-2 fatty acid acyl bond of phospholipids to yield free fatty acids and lysophospholipids and have an important role in regulation of lipid membrane fluidity. 11 Hibbeln et al 11 proposed that excess PLA2 activity disrupts membrane fluidity and composition and therefore affects the activity of membranedependent proteins, such as neurotransmitter receptoreffector complexes.In the present study mutational analysis was performed on the human PLA2A gene on chromosome 12q. Linked polymorphisms were found within exon three and the upstream region. However, the allele and genotype frequencies of these polymorphisms in samples of individuals affected with bipolar disorder (n = 96) did not differ from those of control subjects (n = 96), suggesting that these variations are not associated with bipolar affective disorder.The PLA2A gene on chromosome 12 encodes a secretory form of PLA2 found predominantly in the pancreas. 12 This might seem to make it an implausible candidate for bipolar disorder. However, it has been shown that secretory PLA2 has significant effects upon neuronal cells 13 demonstrable in vitro and thought to have significance in vivo. 14 Glutamate receptors within the brain may be involved in the mode of action of some antidepressant drugs and therefore, may be involved in the pathogenesis of depression. 15 The presence of PLA2 has been shown to accompany a modulation in me...