Fig. 4: Perturbation of schizophrenia eGenes within functional categories results in non-additive effects on transcription, impacting the expression of genes linked to brain disorders and synaptic function.

A Schematic of differential expression analysis. Individual eGene perturbations, the implementation of the expected additive model based on the latter and the measured combinatorial perturbation permit the detection of interactive effects through comparison with the additive model. B Combinatorial perturbation of synaptic and regulatory eGenes resulted in non-additive effects on expression across 16.8% (synaptic) and 20.2% (regulatory) of the transcriptome. No significant non-additive effects were seen following joint perturbation of non-synaptic, non-transcriptional regulatory eGenes. Teal = proportion of genes showing significant non-additivity (two-tailed FDR < 0.1); blue = proportion of genes showing no significant non-additivity. C GSEA of non-additive genes in the Synaptic eGene set demonstrated significant enrichment for genes relating to brain disorders and synaptic function. GSEA of non-additive genes in the Regulatory eGene set demonstrated significant enrichment for genes relating to brain disorders and synaptic function. SCZ schizophrenia, CNV copy number variant, FMRP Fragile X Mental Retardation Protein, FDR false discovery rate. D Non-additive effects following combinatorial perturbation of sets of five, ten, and fifteen eGenes randomly assigned from the synaptic, regulatory, and multi-function eGene groups. The proportion of the transcriptome exhibiting significant non-additive effects increased with increasing numbers of perturbed eGenes (average of 5.1%, 10.0% and 19.2% of the transcriptome with non-additive FDR < 0.1 after joint perturbations of 5, 10, and 15 eGenes, respectively).