Figure 3. Network-level convergence resulting from ASD LoF genes is cell-type-specific, greatest in glutamatergic neurons, largely reflects unique hub genes in each cell type, and is enriched for rare and common psychiatric risk in glutamatergic neurons.

(A) Schematic explaining cross-KO cell-type specific convergence at the network level using Bayesian bi-clustering and undirected network reconstruction. (B) Testing the strength of network convergence across all possible combinations of 9 ASD/NDD KO perturbations, (i) the mean strength of network convergence is significantly different by cell-type, with the highest convergence present in immature iGLUTs. However, the same KO combinations test in one cell type may not resolve convergence in another cell type – indicating cell-type specificity. Each point represents the calculated convergence strength of one resolved network. Dots that represent the same combinations of KO perturbations, but tested in each cell type, are connected by a line. (ii) Testing the strength of network convergence across a subset of random combinations of 2–10 genes from the total 23 ASD/NDD KO perturbations, The mean strength of network convergence is significantly different by cell-type, with the highest convergence present in immature and mature iGLUTs, confirming the pattern seen with gene-level convergence (B) Venn diagrams of (i) the total number of networks resolved of the 502 combinations tested across 9 KOs further demonstrate that some KO combinations are only convergent in one cell-type – for example 6 are unique to NPCs. (ii) While overlap of the total number of unique node genes within those networks by cell-type demonstrate that even if the same combination of KOs resolve convergence, the node genes within their networks will be cell-type specific.(E) Enrichment of cell-type specific convergent node genes for rare variant targets revealed significant associations of immature iGLUTs with SCZ non-synonymous (NS) targets and nominal enrichments of mature iGLUTs and ASD LoF targets. (F) Although not significantly enriched, many node genes overlapped with GWAS common variant targets; heatmap representing the percent overlap of unique node genes for each cell-type that are targets of. Number in the center of each tile represent the absolute number of overlapping genes.