Straub R E, Lipska B K, Egan M F, Goldberg T E, Callicott J H, Mayhew M B, Vakkalanka R K, Kolachana B S, Kleinman J E, Weinberger D R
Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, Intramural Research Program, National Institute of Mental Health, NIH, US Department of Health and Human Services, Bethesda, MD 20892-1379, USA.
Mol Psychiatry. 2007 Sep;12(9):854-69. doi: 10.1038/sj.mp.4001988. Epub 2007 May 1.
Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD(67)), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5' flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5' untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.
皮质GABA能功能障碍被认为是精神分裂症病理生理学的关键组成部分，并且在精神分裂症患者死后大脑中发现，由GAD1编码的γ-氨基丁酸（GABA）合成酶谷氨酸脱羧酶67（GAD(67)）表达降低。我们报告了在两个独立的基于精神分裂症家系的样本中，单核苷酸多态性（SNP）等位基因传递失真的证据。在这两个样本中，等位基因关联取决于受影响后代的性别，并且在临床脑疾病分支/国家心理健康研究所（CBDB/NIMH）样本中还取决于儿茶酚-O-甲基转移酶（COMT）Val158Met基因型。定量传递不平衡检验分析显示，GAD1的变异影响多个认知领域，包括陈述性记忆、注意力和工作记忆。影响家系中认知的一个5'侧翼SNP在无关健康个体中也与工作记忆任务期间背侧前额叶皮质（PFC）的低效BOLD功能磁共振成像激活相关，这是一种与精神分裂症和皮质抑制改变相关的生理表型。此外，5'非翻译（和预测的启动子）区域中一个也影响认知的SNP与精神分裂症大脑PFC中GAD1 mRNA表达降低相关。最后，我们观察到COMT中的两个SNP与GAD1中的SNP之间存在统计学上位性的证据，表明存在潜在的生物学协同作用导致风险增加。这些一致的结果表明GAD1参与精神分裂症的病因学，并提示其机制涉及皮质GABA抑制活性改变，可能受多巴胺能功能调节。
