Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

Abstract

Genetic variation in the catechol-O-methyltransferase (COMT) gene may influence the susceptibility to schizophrenia and the response to neuroleptic treatment. The authors tested for an association between a COMT haplotype and schizophrenia-spectrum disorders and for an eventual influence of a specific COMT genotype in the clinical outcome and in the response to treatment. The genotypes for single nucleotide polymorphisms rs737865, rs4633, rs6267, rs4680 (Val 158 Met) and rs165599 were determined in 207 patients with schizophrenia-spectrum disorders and 204 paired controls. Statistical tests for linkage disequilibrium and for case-control differences in haplotype frequencies were performed using log-linear modelling embedded within the expectation-maximization algorithm. P-values based on permutations were calculated using the software UNPHASED, and odds ratios were estimated using the SHEsis platform. The response to neuroleptic treatment was assessed by the Global Assessment of Functioning scale and the severity of psychotic symptoms by the positive and negative syndrome scale (PANSS) scale. The overall disease status was significantly associated with the T-G (Val) diplotype for rs4633-rs4680 (P ¼ 0.0049). A significant association was observed between schizophrenia, but not other related disorders, and genotypes GG (Val/Val) for rs4680 and TT for rs4633. Val/Val patients with schizophrenia showed a higher severity of the psychotic symptoms and a worse response to the neuroleptic treatment. COMT genetic variation seems to be involved in the psychotic symptomatology of the schizophreniaspectrum disorders and specifically in the narrow schizophrenia phenotype. Our results show an influence of the Val 158 Met polymorphism on the severity of psychotic symptoms and on the response to treatment.

Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population

“…[27][28][29][30] Many studies have evaluated the possible association of this common polymorphism with antipsychotic response. 6,27,[31][32][33] In this study, the AA genotype of rs4680 was observed to be overrepresented in poor responders. Nevertheless, rs4680 is not the only variation in the gene, and several other variations have also been observed to be associated with antipsychotic response in our study (Table 5).…”

Neurobiological background of negative symptoms

“…An association of the rs4633-rs4680 (Val158Met) haplotype of the COMT gene with negative symptoms was also reported in Han Chinese chronic schizophrenia patients [212]. However, there have also been negative findings for the same SNPs [213][214][215][216]. Other COMT gene SNPs were found in association with SANS scores in Han Chinese subjects with schizophrenia [217].…”

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…The authors speculate that the finding may be due to a reduced viability of female fetuses carrying this allele. However, to our knowledge, a sex difference in rs165599 allele frequency has not been replicated (eg Sweet et al, 2005; see also Molero et al, 2007)Falbeit no other study has reported on such a large sampleFand so its significance remains unclear. Table 1 is an extensive but not exhaustive list of the studies that have reported a sex difference in the impact of COMT genotype on a psychiatric phenotype.…”