The majority of the common causal regulators were located either in the ‘Fc’ pathway and associated/clustered genes (HCK, SERPINA1, S100A11, DOCK2 and FCER1G) or the ‘Complement’ pathway (TYROBP) in the immune/microglia network (Figure 5). Recent reports (we note that our submission predates these reports) show a striking association of a low-frequency DNA variant in TREM2 to LOAD (Guerreiro et al., 2013; Jonsson et al., 2013). More specifically, TREM2 is known to associate and signal via TYROBP, the key regulator of the immune/microglia network activated in LOAD. Thus our data-driven network-based approach places both TREM2 and TYROBP in a gene network that literally unifies them with previous top GWAS risk loci including MS4A4A, MS4A6A and CD33 (Figure 5). These new results provide exciting convergent evidence for the specific microglia network that we had directly implicated as activated in LOAD, and reinforce the potential causality of this pathway in LOAD pathology. In fact, the dissection of the immune/microglia module into distinct families and key causal regulators point towards an important function of the microglia pathways involving genes of the ‘Complement’ and/or ‘Fc’
