The allelic association of the human dopamine D2 receptor gene and alcoholism was evaluated in 20 male alcoholics and 20 controls (sex, race, and geographic place of birth matched). This study further examines the issue of alcoholism severity and A1 allele frequency. No difference in A1 allele frequency was observed between these two groups. Similarly, no relationship between alcoholism severity and A1 frequency within the alcoholics was demonstrated.

The principal brain synaptic vesicular monoamine transporter (VMAT2) is responsible for the reuptake of serotonin, dopamine, norepinephrine, epinephrine, and histamine from the cytoplasm into synaptic vesicles, thus contributing to determination of the size of releasable neurotransmitter vesicular pools. Potential involvement of VMAT2 gene variants in the etiology of schizophrenia and related disorders was tested using polymorphic VMAT2 gene markers in 156 subjects from 16 multiplex pedigrees with schizophrenia, schizophreniform, schizoaffective, and schizotypal disorders and mood incongruent psychotic depression. Assuming genetic homogeneity, complete (theta = 0.0) linkage to the schizophrenia spectrum was excluded under both dominant and recessive models. Allelic variants at the VMAT2 locus do not appear to provide major genetic contributions to the etiology of schizophrenia spectrum disorders in these pedigrees.

A pseudoautosomal locus for schizophrenia has been proposed based on observations of an excess of same-sex affected sibling pairs over opposite-sex pairs when the transmitting parent is the father. Such a pattern of partial concordance by sex related to paternal transmission would be difficult to explain by any biologic mechanism other than pseudoautosomal transmission of schizophrenia. To test the pseudoautosomal hypothesis, 37 sibling pairs concordant for the schizophrenia spectrum were identified from 24 nuclear pedigrees. No significant difference in concordance for sex was found between sibships of paternal and maternal transmission of schizophrenia. Next, a linkage analysis was performed in 12 informative pedigrees, examining seven marker loci spanning the pseudoautosomal region. Both strict schizophrenia and a broader schizophrenia spectrum were analyzed as the affected phenotype, and both autosomal dominant and autosomal recessive models were tested. None of the markers supported linkage to either schizophrenia or the schizophrenia spectrum. Lod scores of less than -4 were obtained across the entire pseudoautosomal region by means of multipoint linkage analyses in the autosomal dominant model. In the autosomal recessive model, the respective lod scores were less than -2. We conclude that there is no evidence of a pseudoautosomal locus for schizophrenia in our pedigrees in any of the genetic models we tested.

Cholecystokinin tetrapeptide (CCK4) is known to induce panic attacks in patients with panic disorder at a lower dose than in normal controls. Therefore, the cholecystokinin B (CCKB) receptor gene is a candidate gene for panic disorder. We searched for mutations in the CCKB gene in 22 probands of panic disorder pedigrees, using single-strand conformation polymorphism (SSCP) analysis. Two polymorphisms were detected. A polymorphism in an intron (2491 C-->A) between exons 4 and 5 was observed in 10 of 22 probands. A missense mutation in the extracellular loop of exon 2 (1550 G-->A, Val125-->Ile) was found in only one proband. This mutation was also examined in additional 34 unrelated patients with panic disorder and 112 controls. The prevalence rate of this mutation was 8.8% in patients with panic disorder (3/34) and 4.4% in controls (5/112). The mutation did not segregate with panic disorder in two families where this could be tested. These results suggest no pathophysiological significance of this mutation in panic disorder.

The long arm of chromosome 11 is of interest in schizophrenia research because of three independent reports of balanced 11q translocations cosegregating with schizophrenia and other major psychiatric illness in pedigrees. In addition, a number of candidate genes for psychosis are located in the translocated regions. These include the dopamine D2 receptor, porphobilinogen deaminase, which has shown an allelic association with schizophrenia, and neural cell adhesion molecule, a cell surface glycoprotein involved in neuronal cell-cell recognition during brain development. To search for a schizophrenia locus on chromosome 11q, we conducted linkage analyses in 12 multiplex pedigrees. Sixteen DNA markers, including the above three candidate genes, were used to screen the entire long arm of chromosome 11. None of these markers were supportive of linkage to schizophrenia regardless of whether the affected phenotype was defined narrowly or broadly, whether high or low penetrance was assumed. Both dominant and recessive models tested more than 130 centimorgans of chromosome 11q, and therefore, the reported translocation regions. The results provide no evidence for a susceptibility locus for schizophrenia on chromosome 11q in these pedigrees.