Identification of Sequence Variants and Analysis of the Role of the Catechol-O-Methyl-Transferase Gene in Schizophrenia Susceptibility

Background: Deletions of 1.5–2 MB of chromosome 22q11 have been previously associated with schizophrenia. The deleted region includes proximally the region harboring genes involved in DiGeorge and velocardiofacial syndromes. Distally, it includes the gene for catechol-O-methyl-transferase (COMT), an enzyme that catalyzes the O-methylation of catecholamine neurotransmitters, including dopamine, and which therefore is considered a candidate gene for schizophrenia. Methods: We address the issue of a direct involvement of the COMT gene in the development of schizophrenia by employing the first extensive mutational analysis of this gene in a sample of 157 schizophrenia patients and 129 healthy controls, using single-strand conformation polymorphism and chemical cleavage methodologies. Results: No mutations were found, but several sequence variants were identified, including the genetic polymorphism that underlies the high/low activity of the enzyme (a Val158 → Met change, which results in the creation of an NlaIII restriction site in the low-activity allele). The distribution of the NlaIII genotypes among subsets of schizophrenia patients was analyzed. Conclusions: The results presented here argue against a major role of COMT in schizophrenia in general (although a minor effect could not be excluded) and represent a first step toward a more refined delineation of the phenotype/genotype relationship between 22q11 microdeletions and schizophrenia susceptibility.