Novel polymorphisms of the human cholecystokinin A receptor gene: an association analysis with schizophrenia

The cholecystokinin A receptor (CCK-AR) modulates CCK-stimulated dopamine release in the posterior nucleus accumbens, and its gene is mapped to 4p15.2-15.1 with the dopamine receptor 5 (DR5) gene. We speculated that alterations in the CCK-AR lead to an increase in dopamine release, which may in turn constitute a predisposition in schizophrenia. We investigated genetic variations in the promoter region and the coding region of the CCK-AR gene. An association analysis was conducted between 83 unrelated schizophrenic patients and 80 healthy controls. Novel polymorphisms (201A-->G, 246G-->A in the promoter region, 1260T-->A, 1266T-->C in intron 1 within the 3' mRNA splice acceptor site consensus sequence, and Leu306Leu in exon 5) were found in addition to the variants (608G-->A in intron 1, 3849C-->T [Ile296Ile] in exon 5) reported previously. Significant differences were found in the allele frequencies of the 201A-->G nucleotide substitution in the promoter region between patients and controls (P = 0.0181, odds ratio: 1.972, after Bonferroni correction: P = 0.0543). These differences were also found between the patients with paranoid type and controls (P = 0.0274, odds ratio = 3.667, after Bonferroni correction: P = 0.0822). Our analyses suggest that the 201A allele frequency was higher in the schizophrenic group, especially in the paranoid type, than in the control group at a rate that was not quite significant after Bonferroni correction. Am J. Med Genet. (Neuropsychiatr. Genet.) 96:141-145, 2000.