Figure 6. Gene targets of context-specific regulatory elements showed distinct associations with brain disorders and medications.

(A) Workflow of activity-by-contact enhancer-gene interaction scoring (made with BioRender). (1.) By integrating cell type and cue-specific MPRA enhancer activity, cell and cue-specific chromatin accessibility, and transcription factor binding affinities we (2.) predict cell-type and cue-specific genetically regulated genes (ABC genes) (B) Predicted ABC gene targets of active CREs across cues. Venn diagrams of overlapping ABC genes mapped to (i) active significantly enhancers across cue-exposures (FDR<0.1) and to (ii) differentially active CRE (nominal p-value <=0.05) by cue compared to baseline. (C) MAGMA enrichment analysis across psychiatric, substance use (SUD), neurological, and metabolic/immune disorders revealed unique association of cue specific genetically regulated genes with disorder risk. (D) GWAS catalogue over representation analysis (i) identified unique and shared trait enrichment across cues, including enrichments for psychiatric (ii), neurodegenerative (iii), and allergy/autoimmune enrichments (iv) (Supplemental Data 2). (E) Cue-specific ABC target genes resolved shared and unique drug reversers. (FDR<=0.08^#, FDR<0.05*, FDR<0.01**, FDR<0.001***).