Sheng Guoqing, Demers Matthew, Subburaju Sivan, Benes Francine M
Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, Harvard Medical School, Boston, MA 02478, USA.
Arch Gen Psychiatry. 2012 Jun;69(6):550-61. doi: 10.1001/archgenpsychiatry.2011.1882.
GAD67 regulation involves a network of genes implicated in schizophrenia and bipolar disorder. We have studied the copy number intensities of these genes in specific hippocampal subregions to clarify whether abnormalities of genomic integrity covary with gene expression in a circuitry-based manner.
To compare the copy number intensities of genes associated with GAD67 regulation in the stratum oriens of sectors CA3/2 and CA1 in patients with schizophrenia, patients with bipolar disorder, and healthy controls.
Samples of sectors CA3/2 and CA1 were obtained from patients with schizophrenia, patients with bipolar disorder, and healthy controls. Genomic integrity was analyzed using microarrays, and the copy number intensities identified were correlated with the gene expression profile from a subset of these cases previously reported.
Harvard Brain Tissue Resource Center at McLean Hospital, Belmont, Massachusetts.
A total of 15 patients with schizophrenia, 15 patients with bipolar disorder, and 15 healthy controls.
The copy number intensities for 28 target genes were individually examined using single-nucleotide polymorphism microarrays and correlated with homologous messenger RNA (mRNA) fold changes.
The copy number intensities examined using both microarrays and quantitative real-time polymerase chain reaction for the GAD67 gene were significantly decreased in sector CA3/2 of patients with schizophrenia and patients with bipolar disorder. Other genes associated with GAD67 regulation also showed changes in copy number intensities, and these changes were similar in magnitude and direction to those previously reported for mRNA fold changes in sector CA3/2 but not sector CA1. Moreover, the copy number intensities and mRNA fold changes were significantly correlated for both patients with schizophrenia (r=0.649; P=.0003) and patients with bipolar disorder (r=0.772; P=.0002) in sector CA3/2 but not in sector CA1.
Insertions and deletions of genomic DNA in γ-aminobutyric acid cells at a key locus of the hippocampal circuit are reflected in transcriptional changes in GAD67 regulation that are circuitry-based and diagnosis-specific.
GAD67的调控涉及一个与精神分裂症和双相情感障碍相关的基因网络。我们研究了这些基因在特定海马亚区的拷贝数强度，以阐明基因组完整性异常是否以基于神经回路的方式与基因表达共变。
比较精神分裂症患者、双相情感障碍患者和健康对照者CA3/2区和CA1区梨状细胞层中与GAD67调控相关基因的拷贝数强度。
从精神分裂症患者、双相情感障碍患者和健康对照者中获取CA3/2区和CA1区的样本。使用微阵列分析基因组完整性，并将鉴定出的拷贝数强度与先前报道的这些病例子集中的基因表达谱相关联。
马萨诸塞州贝尔蒙特麦克莱恩医院的哈佛脑组织资源中心。
共15例精神分裂症患者、15例双相情感障碍患者和15名健康对照者。
使用单核苷酸多态性微阵列单独检测28个靶基因的拷贝数强度，并与同源信使核糖核酸（mRNA）的倍数变化相关联。
使用微阵列和定量实时聚合酶链反应检测，精神分裂症患者和双相情感障碍患者CA3/2区GAD67基因的拷贝数强度显著降低。其他与GAD67调控相关的基因也显示出拷贝数强度的变化，这些变化在幅度和方向上与先前报道的CA3/2区mRNA倍数变化相似，但与CA1区不同。此外，CA3/2区精神分裂症患者（r = 0.649；P = 0.0003）和双相情感障碍患者（r = 0.772；P = 0.0002）的拷贝数强度与mRNA倍数变化显著相关，而CA1区则无此相关性。
海马回路关键位点的γ-氨基丁酸能细胞中基因组DNA的插入和缺失反映在基于神经回路且具有诊断特异性的GAD67调控转录变化中。
