Integrative gene and isoform co-expression networks reveal regulatory rewiring in stress-related psychiatric disorders

Isoform-specific expression patterns have been linked to stress-related psychiatric disorders such as major depressive disorder (MDD). To further explore their involvement, we constructed co-expression networks using total gene expression (TE) and isoform ratio (IR) data from affected (n = 210, 81% with depressive symptoms) and unaffected (n = 95) individuals. Networks were validated using advanced graph generation methods. Our analysis revealed distinct differences in network topology and structure. Shared hubs exhibited unique co-regulatory patterns in each network, with key master hubs in the affected network showing association with psychiatric disorders. Gene Ontology enrichment highlighted condition-specific biological processes linked to each network's master hubs. Notably, isoform-level data uncovered unique co-regulatory interactions and enrichments not observed at the gene level. This is the first study to show network-level differences of gene and isoform co-expression between affected and unaffected individuals of stress-related psychiatric disorders, emphasizing the importance of isoforms in understanding the molecular mechanisms of these conditions.