Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba-shi, Chiba, 260-8670, Japan.
Mol Biol Rep. 2022 Mar;49(3):2015-2024. doi: 10.1007/s11033-021-07019-z. Epub 2021 Nov 29.
GABAergic system dysfunction has been implicated in the etiology of schizophrenia and of cognitive impairments in particular. Patients with treatment-resistant schizophrenia (TRS) generally suffer from profound cognitive impairments in addition to severe positive symptoms, suggesting that GABA system dysfunction could be involved more closely in patients with TRS.
In the present study, exome sequencing was conducted on fourteen TRS patients, whereby four SNPs were identified on GAD1, GABBR1 and GABBR2 genes. An association study for five SNPs including these 4 SNPs and rs3749034 on GAD1 as then performed among 357 patients with TRS, 682 non-TRS patients and 508 healthy controls (HC). The results revealed no significant differences in allelic and/or genetic distributions for any of the five SNPs. However, several subanalyses in comparisons between schizophrenia and HC groups, as well as between the three groups, showed nominal-level significance for rs3749034 on GAD1 and rs10985765/rs3750344 on GABBR2. In particular, in comparisons of female subjects, rigorous analysis for rs3749034 showed a statistical difference between the schizophrenia and HC groups and between the TRS and HC groups.
Several positive results in subanalyses suggested that genetic vulnerability in the GABA system to schizophrenia or TRS could be affected by sex or sampling area, and overall, that rs3749034 on GAD1 and rs10985765 on GABBR2 could be related to TRS. In the present study, only a few SNPs were examined; it is possible that other important genetic variants in other regions of GABA-related genes were not captured in this preliminary study.
γ-氨基丁酸（GABA）能系统功能障碍与精神分裂症的病因学以及认知障碍有关。除了严重的阳性症状外，治疗抵抗性精神分裂症（TRS）患者通常还患有严重的认知障碍，这表明 GABA 系统功能障碍可能与 TRS 患者的关系更为密切。
本研究对 14 名 TRS 患者进行了外显子组测序，在 GAD1、GABBR1 和 GABBR2 基因上发现了 4 个单核苷酸多态性（SNP）。然后，对包括这 4 个 SNP 在内的 5 个 SNP 进行了 357 名 TRS 患者、682 名非 TRS 患者和 508 名健康对照者（HC）的关联研究。结果显示，这 5 个 SNP 的等位基因和/或遗传分布均无显著差异。然而，在精神分裂症组与 HC 组以及三组之间的比较中，几个亚组分析显示 GAD1 上的 rs3749034 和 GABBR2 上的 rs10985765/rs3750344 存在名义水平上的显著性。特别是，在女性受试者的比较中，对 rs3749034 的严格分析显示，精神分裂症组与 HC 组以及 TRS 组与 HC 组之间存在统计学差异。
亚组分析中的一些阳性结果表明，GABA 系统对精神分裂症或 TRS 的遗传易感性可能受到性别或采样区域的影响，总的来说，GAD1 上的 rs3749034 和 GABBR2 上的 rs10985765 可能与 TRS 有关。在本研究中，只检查了少数几个 SNP；在这个初步研究中，可能没有捕获到 GABA 相关基因其他区域的其他重要遗传变异。
