Co-expression network of mRNA and DNA methylation in first-episode and drug-naive adolescents with major depressive disorder

Abstract

ObjectiveWe explored the DNA methylation and messenger RNA (mRNA) co-expression network and hub genes in first-episode, drug-naive adolescents with major depressive disorder (MDD). To preliminarily explore whether adolescent MDD has unique mechanisms compared with adult MDD.MethodsWe compared DNA methylation and mRNA profiles of peripheral blood mononuclear cells from four first-episode and drug-naive adolescents with MDD and five healthy adolescent controls (HCs). We performed differential expression analysis, constructed co-expression network, and screened the hub genes. And enrichment analysis was performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We also downloaded DNA methylation and mRNA datasets of adults with MDD (GSE113725/GSE38206) from the GEO database, and performed differential expression and enrichment analysis.ResultsOur clinical data showed that 3034 methylation sites and 4190 mRNAs were differentially expressed in first-episode, drug-naive adolescents MDD patients compared with HCs. 19 hub genes were screened out according to the high degree value in the co-expression network. The results from the GEO database showed that compared with adult HCs, there were 290 methylation sites and 127 mRNAs were differentially expressed in adult MDD patients.ConclusionCompared with adolescent HCs and adult MDD patients, the DNA methylation and mRNA expression patterns of first-episode, drug-naive adolescent MDD patients were different. The co-expression network of DNA methylation and mRNA and the screened hub genes may play an important role in the pathogenesis of MDD in first-episode, drug-naive adolescents. Compared with adult MDD, adolescent MDD is more enriched in metabolism in terms of function and pathways.

Sex-specific and multiomic integration enhance accuracy of peripheral blood biomarkers of major depressive disorder

“…In males, they were notably related to: immune responses, such as phagocytosis (NES = 2.14, FDR < 10 − 4 ), Toll-like receptor signaling (NES = 1.67, FDR = 1.8x10 − 2 ), leukocyte transendothelial migration, necroptosis (NES = 1.72, FDR = 1.19x10 − 2 ), IL-17 signaling pathway (NES = 1.76, FDR = 7.22 10 − 3 ); energy metabolism, including oxidative phosphorylation (NES = 1.81, FDR = 3.81x10 − 3 ) glycolysis (NES = 1.71, FDR = 1.37x10 − 2 ), pentose phosphate pathway (NES = 1.84, FDR = 2.96x10 − 3 ), carbon metabolism (NES = 1.82, FDR = 3.99x10 − 3 ); the proteasome (NES = 2.21, FDR < 10 − 4 ); mTOR signaling (NES = 1.56, FDR = 4.59x10 − 2 ); and the synaptic vesicle cycle (NES = 1.88, FDR = 1.61x10 − 3 ). These results are consistent with previous peripheral blood studies of MDD, which identi ed similar GO terms related to the stress axis, immunity and brain neuronal physiology [17,54]. They also further document signi cant sex differences in MDD, which we further characterized using RRHO2.…”

“…Importantly, despite the moderate number of genome-wide signi cant DMPs in our conservative approach, concordance with results from previous studies was still detectable using the GSEA threshold-free algorithm (TableS4). Accordingly, signi cant enrichments were observed for DMPs identi ed by Tao et al when comparing drug-naive adolescents presenting a rst MDD episode with healthy controls [54]. Used as gene sets, these probes were signi cantly enriched among those with methylation changes in both our male (normalized enrichment score, NES = 1.04, padj = 5.74×10 − 2) and female (NES = 1.05, padj = 2.70×10 − 3) cohorts.…”

Identification of 17 novel epigenetic biomarkers associated with anxiety disorders using differential methylation analysis followed by machine learning-based validation

“…Four out of eleven genes associated with methylation biomarkers have been reported as relevant in previous research. [10,[69][70][71][72][73][74][75][76] In previous studies, the altered methylation patterns of the INPP5A gene were associated with cognitive functions in both blood and the hippocampus samples. [69,70] The DIP2C gene has been previously reported to undergo changes in its methylation patterns in studies related to anxiety disorder, post-traumatic stress disorder (PTSD), and major depressive disorder.…”

“…[69,70] The DIP2C gene has been previously reported to undergo changes in its methylation patterns in studies related to anxiety disorder, post-traumatic stress disorder (PTSD), and major depressive disorder. [10,[71][72][73][74] Furthermore, despite their distinct genomic positions, both INPP5A and DIP2C have been identified as markers in a blood-based study for diagnosing anxiety disorders. [75] The methylation and gene expression patterns of the ATP5F1A gene are known to be associated with Alzheimer's disease.…”