A System-Level Transcriptomic Analysis of Schizophrenia Using Postmortem Brain Tissue Samples

Figure 1. Gene expression changes in the cerebral cortex of persons with schizophrenia (SZ). A, Venn diagram depicting the overlap of genes differentially expressed between persons with SZ and controls in Brodmann areas (BAs) 21, 32, 38, and 46. Differential expression was assessed with unpaired 2-class test analysis (using the significance analysis of microarrays package) at a false discovery rate of less than 0.05 and a fold change of greater than 1.3. B, Differentially expressed genes between persons with SZ and controls in each BA and paired overlap analysis between the 4 BAs assessed with the hypergeometric distribution. C, Heat map of top 200 genes differentially expressed between SZ and control samples of the cerebral cortex in BAs 21, 32, and 38. Scaled expression values are color-coded. The dendrogram depicts hierarchical clustering based on the Euclidean distance and the complete linkage method. The bars show variables for each sample: diagnosis (Dx) (green, persons with SZ; red, controls), BA (red, BA 21; green, BA 32; yellow, BA 38), sex (red, male; green, female), age of death (AOD), and postmortem interval (PMI). The corresponding scale for quantitative variables is shown on the left.

Figure 2. Gene coexpression modules associated with schizophrenia (ie, visualization of the OLIG₁ [A] and GABA [B] modules). The heat map of intramodular expression genes is shown in the top of the left side for each module, and the corresponding module eigengene values, across samples according to Brodmann area (BA), are shown on the middle left side (black, BA 21; red, BA 32; green, BA 38; blue, BA 46). Visualization of the OLIG₁ and GABA modules is provided on the right side. The top 1000 connections are shown for each module on the top right side, according to a degree-sorted circle layout. The intramodular hubs are shown in larger size at the bottom, where the relevant gene ontology categories enriched in the OLIG₁ and GABA modules are listed on the bottom left side.

Figure 3. Genome-wide association enrichment analysis of modules associated with schizophrenia (SZ). Several genome-wide association studies examining a variety of illnesses using several cohorts (eg, SZ from the Psychiatric Genomics Consortium [PGC_SZ],¹⁸ bipolar disorder from the PGC [PGC_BD],¹⁹ attention-deficit/hyperactivity disorder [ADHD],²⁰ and major depression disorder [MDD]²¹) and 3 nonpsychiatric disease studies as negative controls in human immunodeficiency virus (HIV),²² psoriasis,²³ and Parkinson disease (PD)²⁴ were included. Single-nucleotide polymorphisms located within the transcript boundaries and an additional 20 kilobase on the 5′ end and the 3′ end of the gene were included in the gene set analysis method.¹⁵ The analyses presented here are based on k = 5. For multiple testing corrections, a Benjamini-Hochberg correction was applied, and α was set at 10⁻⁴.

Figure 4. Cortical interregional differences shown as diminished in schizophrenia (SZ). A, Venn diagram depicting the overlap of differentially expressed genes between persons with SZ and controls in all regions (611 genes) and genes differentially expressed among the 4 different Brodmann areas (BAs) in controls (681 genes) and persons with SZ (82 genes). The 42 genes (in red font) are the genes that overlap between differentially expressed genes between persons with SZ and controls in all regions and genes differentially expressed among the 4 different BAs in controls. B, The 42 genes are differentially expressed among BAs in control samples and show different expression levels in control samples compared with SZ samples. The horizontal bars show the −log P values for differential expression among all BAs in SZ and control groups. The majority (n = 34) of these genes (ie, those with an asterisk) overlap with the cUNK₁ module, which is 1 of the 3 modules that show a different regional expression in controls. C, Visualization of the top 1000 connections for the cUNK₁ module is shown on the left side, and a more detailed view of the hub cUNK₁ genes is shown on the right. Three of the 42 genes (SCARNA9, SMC3, and TOP1) were intramodular hub genes in cUNK₁.

Figure 5. A hypothetical model based on the current data according to the disconnectivity hypothesis in schizophrenia.