Figure 5.
Interactomes and omnigenic model of complex polygenic hematological phenotypes. (A) An interactome of 366 nodes and 1559 edges was generated using the proteins encoded by the 93 BTPD DGGs and the 658 proteins encoded by the genes harboring GWAS-variants for platelet count as “seeds” for retrieving their first-order interactors. (B) A similar interactome of 73 nodes and 374 edges was generated for venous thrombotic events (VTE) using the 93 DGG-encoded proteins and 297 proteins encoded by genes harboring GWAS-variants for VTE as seeds.30 For panels A-B, only interactions from the IntAct database31 are shown, in order to simplify the network visualization. Nodes and edges were arranged using Cytoscape software circular layout. Seed genes (ie, DGG genes) were positioned in the center of the circles. The nodes in the outer rings are first-order interactors of the seed genes. Although the algorithm used for platelet traits and thrombosis is the same, the number of nodes is much larger in platelet genes, which led to a better resolution of the outer circle. The outer circle highlights genes that interact with BTPD genes but are not BTPD genes themselves. The radii of nodes are proportional to the estimated effect size, in SD, of the GWAS-variant residing in the gene. Nodes have been colored purple, green and orange for genes/proteins implicated in platelet, bleeding, and thrombotic disorders or in gray if the gene/protein does not belong to one of these DGG domains. (C) Barplots showing the results of the expansion analysis using the entire human interactome of 18 410 nodes and 571 917 edges, showing the enrichment in effect sizes of GWAS-variants as a function of the distance from the core seed genes. x-axis shows the OR of the proximity to the core seed genes/proteins, with >90 to 50 to 60 groups representing the nodes (proteins) most proximal and most distal from seed proteins (panels A-B). Group “>90” consists of the seed genes/proteins and their close protein interactors estimated via propagation score. The reported ORs are calculated using the most distant proteins (<50%) as a reference. The effect sizes of GWAS-variants for platelets and VTE (panel C) are split into 4 quartile effects described for the PGS analysis for VTE and platelets.30,31 The top quartile (ie, 75%) contains the variants that have been associated with the largest effect sizes in the relevant GWAS. The y-axis shows the enrichment (in OR) for a set of effect-size quartile bins, in a given distance from the center of the expansion network (in comparison to the periphery of the interaction network). For example, the top quartile of large effect variants for PLT has an OR of >2 of being in close proximity to seed genes (bin group “>90”). Results of the expansion analyses for the count (PLT) and mean volume (MPV) of platelets are in purple and for VTE in orange.

Interactomes and omnigenic model of complex polygenic hematological phenotypes. (A) An interactome of 366 nodes and 1559 edges was generated using the proteins encoded by the 93 BTPD DGGs and the 658 proteins encoded by the genes harboring GWAS-variants for platelet count as “seeds” for retrieving their first-order interactors. (B) A similar interactome of 73 nodes and 374 edges was generated for venous thrombotic events (VTE) using the 93 DGG-encoded proteins and 297 proteins encoded by genes harboring GWAS-variants for VTE as seeds.30 For panels A-B, only interactions from the IntAct database31 are shown, in order to simplify the network visualization. Nodes and edges were arranged using Cytoscape software circular layout. Seed genes (ie, DGG genes) were positioned in the center of the circles. The nodes in the outer rings are first-order interactors of the seed genes. Although the algorithm used for platelet traits and thrombosis is the same, the number of nodes is much larger in platelet genes, which led to a better resolution of the outer circle. The outer circle highlights genes that interact with BTPD genes but are not BTPD genes themselves. The radii of nodes are proportional to the estimated effect size, in SD, of the GWAS-variant residing in the gene. Nodes have been colored purple, green and orange for genes/proteins implicated in platelet, bleeding, and thrombotic disorders or in gray if the gene/protein does not belong to one of these DGG domains. (C) Barplots showing the results of the expansion analysis using the entire human interactome of 18 410 nodes and 571 917 edges, showing the enrichment in effect sizes of GWAS-variants as a function of the distance from the core seed genes. x-axis shows the OR of the proximity to the core seed genes/proteins, with >90 to 50 to 60 groups representing the nodes (proteins) most proximal and most distal from seed proteins (panels A-B). Group “>90” consists of the seed genes/proteins and their close protein interactors estimated via propagation score. The reported ORs are calculated using the most distant proteins (<50%) as a reference. The effect sizes of GWAS-variants for platelets and VTE (panel C) are split into 4 quartile effects described for the PGS analysis for VTE and platelets.30,31 The top quartile (ie, 75%) contains the variants that have been associated with the largest effect sizes in the relevant GWAS. The y-axis shows the enrichment (in OR) for a set of effect-size quartile bins, in a given distance from the center of the expansion network (in comparison to the periphery of the interaction network). For example, the top quartile of large effect variants for PLT has an OR of >2 of being in close proximity to seed genes (bin group “>90”). Results of the expansion analyses for the count (PLT) and mean volume (MPV) of platelets are in purple and for VTE in orange.

Close Modal
This Feature Is Available To Subscribers Only

or Create an Account

Close Modal
Close Modal