Figure 2: Collagen gene sets are coordinately regulated downstream of TGF-beta with respect to brain laterality in a disease-dependent manner.

(A) Leading edges of collagen-related gene sets with significant interaction between SCZ or BD(+) with laterality. Linear modeling was performed to assign t statistics to each gene with respect to the interaction of SCZ or BD(+) with laterality, and GSEA was performed to identify Gene Ontology (GO) terms or BioCarta, KEGG or Reactome pathways with coordinate regulation in either or both disease states with respect to laterality that differs significantly from that in controls. The expression of the genes in any of the “leading edges” of each set (i.e., the genes that contributed the most to the significance of the result) is shown across all subjects (including non-psychotic BD, which was not included in the analysis). Rows and columns correspond to genes and samples, respectively. Expression values were scaled by z-normalizing expression values to a mean of zero and standard deviation of one across all samples in each row, with red and blue indicating z-scores ≥ 2 or ≤ −2, respectively. Genes are arranged in descending order from top to bottom by the magnitude of the t statistic used to rank genes for GSEA. The membership of each gene in the leading edge of each gene set for each disease state (SCZ or BD(+)) in each analysis is denoted in a separate color (orange or yellow) for each gene set. (B) Mechanistic network of TGFB2-driven regulation of genes with significant SCZ:laterality interaction. Ingenuity Pathway Analysis was used to predict upstream regulators of the 265 genes with SCZ:laterality p< 0.05 and called Present in ≥ 3 samples. TGFB2 and SMAD3 were predicted to be activated, and SMAD7 was predicted to be inhibited, leading to coordinate downregulation of genes such as collagens in the right brain of controls only.