Identification of Key Modules and Genes Associated with Major Depressive Disorder in Adolescents

Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide. Adolescence is a crucial period for the occurrence and development of depression. There are essential distinctions between adolescent and adult depression patients, and the etiology of depressive disorder is unclear. The interactions of multiple genes in a co-expression network are likely to be involved in the physiopathology of MDD. In the present study, RNA-Seq data of mRNA were acquired from the peripheral blood of MDD in adolescents and healthy control (HC) subjects. Co-expression modules were constructed via weighted gene co-expression network analysis (WGCNA) to investigate the relationships between the underlying modules and MDD in adolescents. In the combined MDD and HC groups, the dynamic tree cutting method was utilized to assign genes to modules through hierarchical clustering. Moreover, functional enrichment analysis was conducted on those co-expression genes from interested modules. The results showed that eight modules were constructed by WGCNA. The blue module was significantly associated with MDD after multiple comparison adjustment. Several Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with stress and inflammation were identified in this module, including histone methylation, apoptosis, NF-kappa β signaling pathway, and TNF signaling pathway. Five genes related to inflammation, immunity, and the nervous system were identified as hub genes: CNTNAP3, IL1RAP, MEGF9, UBE2W, and UBE2D1. All of these findings supported that MDD was associated with stress, inflammation, and immune responses, helping us to obtain a better understanding of the internal molecular mechanism and to explore biomarkers for the diagnosis or treatment of depression in adolescents.

RPS6KA5 methylation predict response to 6-week treatment for adolescent MDD patients

“…In a recent review, the author suggested that RPS5KA might regulate key plasticity-related genes through epigenetic mechanisms to potentially avoid depression, which also supported our results [ 35 ]. As part of this neurotrophic factor cascades, MAPK signaling pathway and TNF signaling pathway might play a crucial role in immune and inflammatory response [ 36 , 37 ]. This agrees with the conclusions from previous studies that strong inflammation in MDD patients might be associated with drug resistance [ 38 ].…”

Evaluation of Inflammatory Response System (IRS) and Compensatory Immune Response System (CIRS) in Adolescent Major Depression

“…62 Further, the genome-wide association analyses identified the 44 risk gene variants in MDD with 4 of them (namely LACC1, OLFM4, TIAF1, and NR4A2) being associated with immune responses. 63 Besides, a recent weighted gene co-expression network analysis (WGCNA) identified three genes related to immune responses (IL1RAP, UBE2W, and UBE2D1) as hub genes of adolescent 64 Further research involving genome-wide association studies, transcriptomics and WGCNA is needed to exactly shed light on the genetic contributions of inflammation-related depression.…”

“… 63 Besides, a recent weighted gene co-expression network analysis (WGCNA) identified three genes related to immune responses ( IL1RAP, UBE2W, and UBE2D1 ) as hub genes of adolescent MDD. 64 Further research involving genome-wide association studies, transcriptomics and WGCNA is needed to exactly shed light on the genetic contributions of inflammation-related depression.…”

Inflammation and immune system pathways as biological signatures of adolescent depression—the IDEA-RiSCo study

“…Overall, this review showed: a positive correlation between an upregulated expression of pro-inflammatory genes with the presence of MDD together with an altered expression of stress-related genes in MDD patients [ 33 ]. However, it is noteworthy to mention that the majority of the studies investigating gene expression in MDD were conducted so far in adult individuals, whereas only a small number of them included adolescents [ 31 , 34 – 36 ]. Nevertheless, similar findings between adults’ and adolescents’ transcriptomic profiles have been observed, specifically a dysregulation of inflammatory-related pathways and genes in both adults and adolescents with depression [ 33 ].…”

“…Nevertheless, similar findings between adults’ and adolescents’ transcriptomic profiles have been observed, specifically a dysregulation of inflammatory-related pathways and genes in both adults and adolescents with depression [ 33 ]. Among the studies conducted in adolescents, Zhao and colleagues identified enrichments in genes involved in apoptosis, TNF signaling pathway, and NF-kb signaling pathway in MDD adolescents compared with controls [ 36 ], and the study by Chiang and colleagues observed an up-regulation of inflammation-related genes and a down-regulation of antiviral-related genes in adolescents with depression compared with their non-depressed peers [ 34 ].…”