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. © 2000 Wiley‐Liss, Inc.