Fig. 4.

Integrating hub, CTS, and genetic information to implicate new genes in ASD risk. a, b Disrupted hubs are highly a expressed and b co-expressed with ASD genes in neuronal cell types. Cell types that are significant after Bonferroni correction are noted with their P values. c A unified framework DAWN integrating CTS co-expression, hub, and TADA to identify ASD genes in a CTS context. Three CTS-DAWN analyses were performed for three neuronal cell types. For presentation purposes, c–h present results of ExN-DAWN, and results of InN- and NPC-DAWN are provided in Additional file 1: Figs. 2 and 3, respectively. d, e, ExN-DAWN genes versus other genes evaluated on two loss-of-function tolerance metrics: pLI (d) and LOEUF (e). T/S stands for TADA/SFARI genes also identified by DAWN, Novel for DAWN genes not found in the T/S list, Other genes for expressed genes not found in the T/S or DAWN lists. f–h, ASD probands carrying a de novo protein-truncating or missense variant on ExN-DAWN genes exhibit severe ASD symptoms, with f reduced intelligence, g impaired social ability, and h delayed age of walking. i CTS-DAWN genes are enriched in neurodevelopmental processes. The top 10 enriched GO terms of each cell type are shown (FDR ≤ 0.05, ranked by fold-enrichment). CTS cell-type-specific, ExN excitatory neurons, InN inhibitory neurons, NPC neural progenitor cells, TADA transmission and de novo association, DAWN detecting association with networks, pLI probability of being loss-of-function intolerant, LOEUF loss-of-function observed/expected upper bound fraction, PTV protein-truncating variant