Candidate Blood Transcriptomic Markers of Early Onset Major Depression Derived from Etiological Animal Models of Depression

Abstract

Early onset Major Depressive Disorder (MDD) is a serious and prevalent psychiatric illness in adolescents and young adults. Current treatments are not universally effective. Biological markers of early onset MDD could increase diagnostic specificity, but no such biomarker exists. Our innovative approach to biomarker discovery for early onset MDD combined results from genome-wide transcriptomic profiles in the blood of two animal models of depression, representing the genetic and the environmental, stress-related, etiology of MDD. The genetic animal model is bred by bidirectional selection in a test for depressive behavior from the accepted animal model of depression, the Wistar Kyoto rat. The “depressed” WMI (Wistar Kyoto More Immobile) strain responds to tricyclic antidepressants and MAOIs by normalized behavior, and has dysfunctions in connectivity in the brain similar to human depressed patients. The genetically close Wistar Kyoto Less Immobile (WLI) strain serves as the non-depressed control. Transcriptomic differences between these strains, that showed the same directional expression differences in the blood as in the hippocampus or amygdala, were selected as potential blood markers for MDD. The chronic stress model employed four genetically distinct strains of rats and established the transcriptional consequences of chronic stress in the blood regardless of genotype or vulnerability to stress. Some of these chronic stress-related transcripts were also selected as candidate blood markers for MDD.
We carried out unbiased analyses of the 26 candidate blood transcriptomic markers, selected from the two models, in a sample of 15-19- year-old subjects with MDD and subjects with no disorder (ND). A panel of 11 blood markers differentiated participants with early onset MDD from the ND group. Additionally, a separate, but partially overlapping panel of 18 transcripts distinguished subjects with MDD with or without comorbid anxiety. Based on an interacting protein network analysis, transcripts were differentiated as markers of MDD alone, MDD and anxiety and anxiety alone, suggesting overlapping and separate molecular mechanisms for MDD with and without comorbid anxiety. Four transcripts, based on the chronic stress animal model, correlated with maltreatment scores in youths. Thus, our approach can lead to clinically valid diagnostic panels of blood transcripts for early onset MDD, which could reduce diagnostic heterogeneity in this population and has the potential to advance individualized treatment strategies.