To test our prediction that TYROBP can direct LOAD-associated gene networks, we contrast both the molecular function and genome-wide effects of TYROBP with those predicted by the structure of causal networks inferred from human LOAD brains. For this, microglia cells derived from mouse embryonic stem cells were genetically modified by lentiviral vectors to over-express either full length or a truncated version of Tyrobp which lacks both intracellular ITAM motifs (Extended Experimental Procedures and Figure S6). To assess the genome-wide gene expression changes in response to the perturbation of Tyrobp, we derived gene expression data from the RNA sequencing of mouse microglia cell lines over-expressing (1) vehicle, (2) the full length Tyrobp or (3) dominant negative truncated Tyrobp. We identified 2638 and 3415 differentially expressed genes for the over-expression of full length Tyrobp and truncated Tyrobp, respectively (Table S1), at FDR < 2.5%. Roughly one-third (858 to 1092) of these genes are found in the most variable gene set in the brain dataset used for the network reconstruction. The PFC variant of the human immune/microglia module was highly enriched for genes
