Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients.

Disturbances in dopaminergic transmission have been implicated in the etiology of psychotic disorders. Interindividual differences in deoxyribonucleic acid (DNA) sequences coding for dopamine receptor proteins might contribute to the genetic background of these diseases. We have identified a variation in exon 1 of the dopamine D4 receptor (DRD4) gene, which is characterized by a polymorphic 12 base pair (bp) repeat. This repeat codes for a sequence of four amino acids in the extracellular N-terminal part of the receptor, which borders the first putative transmembrane domain. The 12bp repeat occurs as a two-fold repeat in the more common variant (A1 allele) and is represented only once in the rarer one (A2 allele). The frequency of this DNA polymorphism was determined in a sample of 59 patients suffering from delusional disorder, in 79 schizophrenic patients, and in 75 control subjects. Sixteen (27%) of the 59 patients with delusional disorder carried the A2 allele compared with six (8%) of the controls. The observed difference in genotype frequencies between patients with delusional disorder and controls was highly significant. There were no significant differences in genotype frequencies between schizophrenics and controls: Our results strongly suggest the involvement of genetic variation in the DRD4 gene in conferring susceptibility to delusional disorder.