Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia

Abstract

Treatment-resistant schizophrenia (TRS) continues to be a challenge. It was related to different factors, including alterations in the activity of brain dopaminergic system, which could be influenced by the dopamine-degrading enzyme, catechol-O-methyltransferase (COMT). Variants of the COMT gene have been extensively studied as risk factors for schizophrenia; however, their association with TRS has been poorly investigated. The aim of the present study was to determine the haplotypic and genotypic association of COMT rs4680 and rs4818 polymorphisms with the presence of TRS. Overall, 931 Caucasian patients diagnosed with schizophrenia (386 females and 545 males) were included, while 270 participants met the criteria for TRS. In males, no significant haplotypic and genotypic associations between COMT rs4680 and rs4818 polymorphisms and TRS were detected. However, genotypic analyses demonstrated higher frequency of COMT rs4680 AA genotype carriers compared to G-allele carriers (p = 0.033) and higher frequency of COMT rs4818 CC genotype carriers than G-allele carriers (p = 0.014) in females with TRS. Haplotype analyses confirmed that the presence of the G allele in females was associated with lower risk of TRS. In women with TRS, the high activity G-G/G-G haplotype was rare, while carriers of other haplotypes were overrepresented (p = 0.009). Such associations of COMT rs4680 and rs4818 high-activity (G variants), as well as G-G/G-G haplotype, with the lower risk of TRS in females, but not in males, suggest significant, but sex-specific influence of COMT variants on the development of treatment-resistance in patients with schizophrenia. However, due to relatively low number of females, those findings require replication in a larger sample.

Catechol-O-methyltransferase rs4680 and rs4818 haplotype association with treatment response to olanzapine in patients with schizophrenia

“…In our previous study on the treatment resistant schizophrenia 7 , the G alleles of the COMT rs4680 and rs4818, as well as the high activity COMT G-G/G-G haplotype, had lower risk to become treatment resistant only in female but not in male patients with schizophrenia. In contrast to these data 7 , in the present study the genotype distribution for the COMT rs4680 and rs4818 did not differ according to gender. However, when male and female subjects were evaluated separately, no significant association was detected between the COMT rs4680 and rs4818 genotypes and haplotypes and treatment response to olanzapine, risperidone, clozapine or other antipsychotics (Supplementary Tables S1-S12).…”

“…The differences between these studies are in the design, since present study was longitudinal while our previous study was cross-sectional, and, unlike the current investigation, previous study did not exclude patients who received ECT, as well as different antipsychotic combinations 7 . Large heterogeneity across studies, adherence to treatment, population stratification 6 , as well as influence of other functional variants in the COMT gene 7,31,32 , interactions with other gene polymorphisms, such as DRD4 (120-bp duplication) 33 , might explain some of the inconsistent findings. In addition, recent studies 34,35 discussed the disadvantages of the candidate gene association studies compared to genome-wide association studies (GWAS), pointing to the problems of high false discovery rate, low replication rates and insufficient knowledge to correctly identify possible candidate genes.…”

“…However, when male and female subjects were evaluated separately, no significant association was detected between the COMT rs4680 and rs4818 genotypes and haplotypes and treatment response to olanzapine, risperidone, clozapine or other antipsychotics (Supplementary Tables S1-S12). In addition, in contrast to our previous study 7 , in the present study we evaluated treatment response and not treatment resistance. The differences between these studies are in the design, since present study was longitudinal while our previous study was cross-sectional, and, unlike the current investigation, previous study did not exclude patients who received ECT, as well as different antipsychotic combinations 7 .…”

“…In addition, in contrast to our previous study 7 , in the present study we evaluated treatment response and not treatment resistance. The differences between these studies are in the design, since present study was longitudinal while our previous study was cross-sectional, and, unlike the current investigation, previous study did not exclude patients who received ECT, as well as different antipsychotic combinations 7 . Large heterogeneity across studies, adherence to treatment, population stratification 6 , as well as influence of other functional variants in the COMT gene 7,31,32 , interactions with other gene polymorphisms, such as DRD4 (120-bp duplication) 33 , might explain some of the inconsistent findings.…”

The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research

“…57 A study of two single-nucleotide polymorphisms (SNPs) in the dopamine-degrading enzyme catechol-O-methyltransferase (COMT) demonstrated that a higher-activity haplotype was protective against TRS in women but not men. 58 Genetic polymorphisms in DRD2 may also affect a patient's risk of developing DSP TRS or the likelihood that a patient will respond to non-clozapine antipsychotic medications. 36,59 However, another study showed no association between TRS and SNPs in DRD1, DRD2, DRD3, or COMT.…”