Abstract
The projection from dopaminergic neurons to gamma-aminobutyric acid (GABA) interneurons in the prefrontal cortex is involved in the etiology of schizophrenia. The impact of interacting effects between dopamine signals and the expression of GABA on the clinical phenotypes of schizophrenia has not been studied. Since these interactions could be closely involved in prefrontal cortex functions, patients with specific alleles of these relevant molecules (which lead to lower or vulnerable genetic functions) may develop treatment-refractory symptoms. We conducted a genetic association study focusing on COMT and GAD1 genes for a treatment-resistant schizophrenia (TRS) group (n=171), a non-TRS group (n=592), and healthy controls (HC: n=447), and we examined allelic combinations specific to TRS. The results revealed that the percentage of subjects with Met allele of rs4680 on the COMT gene and C/C homozygote of rs3470934 on the GAD1 gene was significantly higher in the TRS group than the other two groups. There was no significant difference between the non-TRS group and HC groups. Considering the direction of functions of these single-nucleotide polymorphisms revealed by previous studies, we speculate that subjects with the Met/CC allelic combination could have a higher dopamine level and a lower expression of GABA in the prefrontal cortex. Our results suggest that an interaction between the dopaminergic signal and GABA signal intensities could differ between TRS patients and patients with other types of schizophrenia and healthy subjects.
Highlights
It has been considered that in brains of patients with schizophrenia in the acute phase, the synthesis and release of dopamine are increased in the mesolimbic dopamine system, and it has been suggested that all antipsychotics exhibit preferable actions by blocking post-synaptic dopamine D2 receptors (DRD2) [Howes et al, 2009]
We conducted a genetic association study focusing on COMT and glutamic acid decarboxylase1 (GAD1) genes for a treatment-resistant schizophrenia (TRS) group (n = 171), a non-TRS group (n = 592) and healthy controls (HC: n = 437), and we examined allelic combinations specific to TRS
The results revealed that the percentage of subjects with Met allele of rs4680 on the COMT gene and C/C homozygote of rs3470934 of the GAD1 gene was significantly higher in the TRS group than the other two groups
Summary
It has been considered that in brains of patients with schizophrenia in the acute phase, the synthesis and release of dopamine are increased in the mesolimbic dopamine system, and it has been suggested that all antipsychotics exhibit preferable actions by blocking post-synaptic dopamine D2 receptors (DRD2) [Howes et al, 2009]. Abnormalities in parvalbumin-positive GABA interneurons and lowered expressions of mRNA/protein of glutamic acid decarboxylase (GAD1) in the brains of individuals with schizophrenia have been consistently reported from multiple post-mortem studies, and these findings are suggested to be related to the lower expression of γ-oscillation and cognitive dysfunctions in living patients with schizophrenia [Tallon-Baudry et al, 1998; Fries et al, 2001; Lewis et al, 2008; Buzsáki et al, 2004]. The impact of interacting effects between dopamine signals and the expression of GABA on the clinical phenotypes of schizophrenia has not been studied Since these interactions could be closely involved in prefrontal cortex functions, patients with specific alleles of these relevant molecules (which lead to lower or vulnerable genetic functions) may develop treatment-refractory symptoms.
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