Differences in the Circuitry-Based Association of Copy Numbers and Gene Expression Between the Hippocampi of Patients With Schizophrenia and the Hippocampi of Patients With Bipolar Disorder

Figure 1. Analysis of DNA copy number changes at the GAD67 -encompassing segment of chromosome 2q in sectors CA3/2 and CA1 in 15 healthy controls (Control), 15 patients with bipolar disorder (BD), and patients with schizophrenia (SZ). A, Heat map of copy number intensity (CNI) changes in the stratum oriens of sector CA3/2. Each column represents 1 sample and each row represents a specific gene, according to their physical order in the chromosome. Red indicates copy gain, and blue indicates copy loss. Copy numbers are displayed in the log₂ ratio in a color code from −2 to 2. The GAD67 -encompassing segment is highlighted by the dotted line. The upper arrow points to the close-up view of CNIs at the GAD67 - encompassing segment at chromosome 2q (B). C, The CNIs of each patient are represented as squares (Control), circles (SZ), and triangles (BD), respectively. The horizontal bars indicate the mean. Mean values were compared using 1-way analysis of variance with the Tukey post hoc test. The SZ group had less copy numbers than the control group (mean [SD], 1.74 [0.27] vs 1.99 [0.05]; P < .01) but not the BD group. D, Heat map of CNIs in the stratum oriens of sector CA1. The lower arrow points to the close-up view of CNIs at the GAD67 -encompassing segment at chromosome 2q (E). F, The CNIs of each patient are represented as squares (Control), circles (SZ), and triangles (BD), respectively. The horizontal bars indicate the mean. Similar to the findings in sector CA3/2, the SZ group in sector CA1 had less copy numbers than the control group (mean [SD], 1.84 [0.15] vs 2.04 [0.09]; P < .05) but not the BD group.

Figure 2. Heat Maps of DNA copy number changes for GAD67 regulatory genes in the stratum oriens of sector CA3/2 (A) and sector CA1 (B). The copy number intensities of 6 critical GAD67 regulatory genes are compared by performing the Fisher exact test between 15 healthy controls (Controls), 15 patients with schizophrenia (SZ), and 15 patients with bipolar disorder (BD). In the heat maps, red represents copy gain, and blue represents copy loss, in units of log₂. The blue curves in the middle graphs indicate the degree of gain (right) or loss (left) of each gene. The red vertical line indicates a copy number of 2. Also shown are the probabilities that changes are significant; the arrows indicate whether copy number intensities are increased (red arrows) or decreased (blue arrows).

Figure 3. Association of fold changes as a measure of gene expression and DNA copy number intensity (CNI) changes in the stratum oriens of sectors CA3/2 and CA1.The x-axis shows CNI changes, and the y-axis displays fold changes, from microarray data. Individual data points are connected with a line using linear regression analysis performed with GraphPad Prism version 4.0. In the stratum oriens of sector CA3/2, significant associations between CNI changes and fold changes are evident in patients with schizophrenia (SZ), patients with bipolar disorder (BD), and combined patients (SZ+BD), respectively. There are no significant associations between CNI changes and fold changes in any patient groups in sector CA1.

Figure 4. Association of fold changes as a measure of gene expression and DNA copy number intensity (CNI) changes for GAD67 and non- GAD67 regulatory genes in the stratum oriens of sectors CA3/2 and CA1. The x-axis shows CNI changes, and the y-axis displays fold changes, from microarray data. Individual data points are connected with a line using linear regression analysis performed with GraphPad Prism version 4.0. In sector CA3/2, both clusters showed a significant association between CNI changes and fold changes, but the GAD67 regulatory network has a higher correlation efficiency than does the non- GAD67 regulatory network. However, there is no significant association between CNI changes and fold changes in any gene cluster in sector CA1.