We employed gene-network analysis34,35 for each factor to identify genes that are part of the implicated biological networks, even if they are not directly identified by the GWAS (Figure 4a; see Supplemental Text for more detail). The Externalizing and Behavioral Disinhibition networks were similar to one another, whereas the SUD network shared few genes, likely due to the limited power of the SUD gene set. We then used hierarchical clustering36 and gene ontology37,38 enrichment to identify the gene communities within these networks (Supplementary Table 16). We found that the Externalizing network contains gene communities that function in post-synaptic protein localization, organization, and signaling, as well as vesicle-mediated transport, and cytoskeleton-dependent transport (Figure 4b). We further validated our findings using annotations in the GWAS catalog. We found that the Externalizing network was significantly enriched for genes identified in psychiatric disorders (p = 2.2x10−7), substance-related disorders (p = 2.5x10−10), and substance abuse (p = 4.5x10−14; Supplementary Table 17). The Behavioral Disinhibition network showed a similar pattern of enrichment, whereas the SUD network was not significantly enriched for genes identified in any traits in the GWAS catalog.
