Fig. 4: KEGG pathway enrichment analysis result of the top 500-proximal gene network. | Molecular Psychiatry

Fig. 4: KEGG pathway enrichment analysis result of the top 500-proximal gene network.

From: Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Fig. 4

a, b Significantly enriched KEGG pathways (B-H q-value ≤ 0.05) identified in KEGG pathway enrichment analysis of the top 500-proximal gene network derived from the 41 protein-coding DE genes. The KEGG pathway analysis (containing at least one seed gene and one GWAB gene) identified a total of 37 KEGG pathways, including a subset of 17 KEGG pathways relevant to BD/neuronal system, which were significantly enriched (B-H q-value ≤ 0.05) in the top 500-proximal gene network. Details for each pathway are listed in Supplementary Table 15. The distribution of genes for each pathway is summarized in Supplementary Fig. 7. a Summary of significantly enriched KEGG pathways and gene sets in the top 500-proximal gene network. Pie charts display the number of genes from each source that comprise the top 500-proximal gene network (left), a set of 196 genes of the 37 enriched KEGG pathways (middle), and a set of 130 genes of the 17 relevant enriched KEGG pathways (right). Each pie represents the proportion of gene types as both numbers and percentages. Colors represent gene types. Solid and stripe patterns indicate function (participating) and non-function (non-participating) of genes, respectively, in each gene set of either 37 or 17 enriched KEGG pathways. b KEGG pathway classification and enrichment statistics of significantly enriched KEGG pathways for the top 500-proximal gene network. A total of 37 enriched KEGG pathways is on the left panel, and a subset of 17 relevant enriched KEGG pathways is on the right panel. These pathways were classified into four classes: cellular processes (yellow), environmental information processing (blue), human diseases (grey), and organismal systems (green). Of the 37 enriched KEGG pathways, the most significant enrichment was ‘pathways in cancer’ (hsa05200; B-H q = 1.05E–21; see red box). The second most significant enrichment was ‘focal adhesion’ (hsa04510; B-H q = 8.04E–20; see red box), which was also the most significant one among the 17 relevant enriched KEGG pathways. Of the 17 relevant enriched KEGG pathways, the top 3 significant enrichment were ‘focal adhesion’ (as mentioned), ‘ECM-receptor interaction’ (hsa04512; B-H q = 1.57E–13), and ‘PI3K-Akt signaling pathway’ (hsa04151; B-H q = 9.62E–13), respectively. Pie charts (top panel) show the distribution of KEGG pathway classification. Each pie displays the proportion of KEGG classes as both numbers and percentages, colored by KEGG classes. Bar and bubble plots (bottom panel) show the distribution of genes and/or the statistical enrichment for each of the enriched KEGG pathways, respectively. Bar plots show the distribution of genes for each KEGG pathway. The x-axis represents the number of genes contributing to each corresponding pathway. The y-axis corresponds to significantly enriched KEGG pathways categorized into KEGG classes and shown in text colors. For the 37 enriched KEGG pathways (bottom left panel), the color scale on bars indicates the degree of significance (B-H q-value ≤ 0.05) of enrichment (low, blue; high, red). An asterisk (*) on bars specifies the KEGG pathways that are relevant to BD/neuronal system. Whereas, for a subset of the 17 relevant enriched KEGG pathways ranked by the degree of significance in enrichment (bottom middle panel), colors on bars indicate gene types. Bubble plot (bottom right panel) shows the statistical enrichment of a subset 17 relevant enriched KEGG pathways. The size of bubbles represents the number of genes (gene counts) in each corresponding KEGG pathway. The bubble coordinate on the x-axis represents the degree of enrichment for DE genes known as ‘DE gene rich factor’. The DE gene rich factor is the ratio of DE genes in each pathway to total genes in each pathway. The larger rich factor represents the greater enrichment. The color scale indicates the degree of significance (B-H q-value ≤ 0.05) in enrichment for each corresponding pathway (low, dark purple; high, yellow). The significance of enrichment is presented as the -log transformed B-H q-value. c–e Identification and summarizing features of the top 3 significantly enriched KEGG pathways relevant to BD/neuronal system (B-H q-value ≤ 0.05). The top 3 of the 17 relevant significantly enriched KEGG pathways are ‘top 1’ – focal adhesion (hsa04510; light blue), ‘top 2’ – ECM-receptor interaction (hsa04512; light yellow), and ‘top 3’ – PI3K-Akt signaling pathway (hsa04151; light pink), respectively. A subset of 54 genes (out of the top 500 proximal network genes) are present in the top 3 relevant enriched KEGG pathways. c Sub-networks among the 54 genes in the top 3 significantly enriched KEGG pathways relevant to BD/neuronal system. A propagation-based network illustrates sub-networks among a set of 54 genes (out of the top 500 proximal network genes) present in the top 3 relevant enriched KEGG pathways. This network included 54 genes (nodes) connected with 506 edges, containing 3 DE, 1 DE/GWAB, 12 GWAB, and 38 network genes. Shapes represent gene types (DE, filled triangle; DE/GWAB, filled outlined triangle; GWAB, filled outlined square; network, filled circle). Color scale indicates the degree of connectivity calculated from the top 500 proximal network genes (low degree/poorly connected, yellow; high degree/highly connected, dark purple). Background colors are specified for the top 3 relevant enriched KEGG pathways. The connectivity of the 54 proximal network genes of the top 3 relevant enriched KEGG pathways is presented in Supplementary Table 16. The interactive graph exclusively displayed the connectivity degree of the top 500 proximal network genes can be accessed at https://www.ndexbio.org/viewer/networks/16809bed-82ed-11ec-b3be-0ac135e8bacf. d Venn diagram of the 54 genes in the top 3 significantly enriched KEGG pathways relevant to BD/neuronal system. A total of 54 gene names are listed and categorized into gene types. There are 42, 23, and 44 genes involved in the top 1, top 2, and top 3 relevant enriched KEGG pathways, respectively, including 20 overlapping genes and four ‘hub-like’ genes. Venn diagram colors indicate the top 3 relevant enriched KEGG pathways. e Pathview of focal adhesion (hsa04510), the top significantly enriched KEGG pathway relevant to BD/neuronal system. The top relevant significantly enriched KEGG pathway, ‘focal adhesion’ (B-H q-value = 8.04E–20), contained a total of 42 genes (including three ‘hub-like’ genes), which are listed and categorized into gene types. This figure also illustrates several KEGG pathways connected with focal adhesion. Those relevant significantly enriched pathways (B-H q-value ≤ 0.05) identified in our study are highlighted in blue. The color scale indicates the degree of network proximity to seed genes (more proximal/farther, yellow; less proximal/nearer, red). Pathview map created by the R-based Pathview [82] software from Bioconductor (https://www.bioconductor.org/). For Fig. 4a, b, d, and e, gene types are indicated by colors: DE, orange; DE/GWAB, yellow; GWAB, green; network, purple. An asterisk (*) in dark red represents the ‘hub-like’ genes. B-H Benjamini and Hochberg, DE differentially expressed, ECM the extracellular matrix, GWAB genome-wide association boosting, KEGG Kyoto Encyclopedia of Genes and Genomes pathways (https://www.genome.jp/kegg/pathway.html).

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