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 previo usly associated with schizophrenia. The deleted region includes proxim ally the region harboring genes involved in DiGeorge and velocardiofac ial syndromes. Distally, it includes the gene for catechol-O-methyl-tr ansferase (COMT), an enzyme that catalyzes the O-methylation of catech olamine 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 co ntrols, using single-strand conformation polymorphism and chemical cle avage methodologies. Results: No mutations were found, but several seq uence variants were identified including the genetic polymorphism that underlies the high/low activity ofthe enzyme (a Val(158) --> Met chan ge, 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 resul ts presented here argue against a major role of COMT in schizophrenia in general (although a minor effect could not be excluded) and represe nt a first step toward a more refined delineation of the phenotype/gen otype relationship between 22q11 microdeletions and schizophrenia susc eptibility. (C) 1998 Society of Biological Psychiatry.