Figure 1
Principal analysis steps to identify and score gene/protein subnetwork modules containing CAD candidate genes. (A) Analysis steps to identify subnetwork modules with CAD candidate genes. (I) In step 1, 171 tissue-specific and cross-tissue co-expression networks inferred from the Stockholm Atherosclerosis Gene Expression (STAGE) study7,35. (II) In step II to account also for gene-protein and protein-protein interactions (PPIs), the ConsensusPathDB8 was used to add protein nodes to the STAGE gene networks conserving tissue integrity. (III) In step III, to extract smaller, likely functional, units Girvan-Newman algorithm was used to identify gene/protein modules within each networks resulting in 953 modules. (IV) In step IV, 286 modules affected by genome-wide significant loci (p < 5 × 10−8) were selected (Supplementary Table 1b). Squares indicate genes nodes from STAGE data. Diamonds represent protein nodes from ConsensusPathDB database. Color-coding highlight different modules. Yellow nodes are CAD candidate genes (LDLR, CETP, APOB and PCSK9 (p < 5 × 10−8), APOE and MAPK14 (FDR ≤ 5%)). (B), Principles for scoring gene/protein subnetwork modules with CAD candidate genes. The scoring theme was set to prioritize modules in relevant tissues and biological processes harboring druggable targets against CAD. Specifically, individual nodes were scored according to (I) distance to CAD candidate gene in module, (II) genetic modification of the mouse ortholog displaying an atherosclerotic phenotype (III) expression in CAD relevant tissues (green, positive score) or in tissues commonly displaying drug toxicity (red, negative score), and (IV) the CAD druggability potential of the gene. The final CAD-feasibility score for each module was calculated from the sum of individual gene/protein node scores divided by the total number of nodes/module. Several figures in panels II-IV have been obtained and adapted from Servier Medical Art (www.servier.com) which are distributed under Creative Commons license (https://creativecommons.org/licenses/by/3.0/).
