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.

从多巴胺能神经元到前额叶皮层中的 γ-氨基丁酸 (GABA) 中间神经元的投射与精神分裂症的病因有关。尚未研究多巴胺信号与 GABA 表达之间的相互作用对精神分裂症临床表型的影响。由于这些相互作用可能与前额叶皮层功能密切相关，因此具有这些相关分子的特定等位基因（导致遗传功能降低或脆弱）的患者可能会出现治疗难治性症状。我们针对难治性精神分裂症(TRS) 组 ( n =171)、非 TRS 组 ( n =592) 和健康对照组 (HC:n = 447），我们检查了 TRS 特有的等位基因组合。结果显示，在COMT基因上具有 rs4680 的 Met 等位基因和GAD1上具有 rs3470934 的C/C 纯合子的受试者百分比TRS组基因显着高于其他两组。非TRS组和HC组之间没有显着差异。考虑到先前研究揭示的这些单核苷酸多态性的功能方向，我们推测具有 Met/CC 等位基因组合的受试者可能在前额叶皮质中具有更高的多巴胺水平和更低的 GABA 表达。我们的研究结果表明，多巴胺能信号和 GABA 信号强度之间的相互作用在 TRS 患者和其他类型的精神分裂症患者和健康受试者之间可能不同。