Longitudinal Analysis of Peripheral MicroRNA Expression and Depressive Symptom Severity Change in a Community Cohort

Background: Depression is a heterogeneous and recurrent condition, whose underlying biological mechanisms remain poorly understood. MicroRNAs (miRNAs), small non-coding RNAs that regulate post-transcriptional gene expression, are increasingly implicated in cross sectional miRNA studies of depression and depressive symptoms; however, longitudinal studies capturing miRNA changes over time in relation to depression are scarce. Methods: We conducted small RNA sequencing of leukocyte-derived miRNAs at two timepoints in a prospective community-based cohort (n = 185) to assess associations between within-person changes in depressive symptom severity (ΔPHQ-9) and longitudinal miRNA expression. Differential expression analyses were performed using a paired limma-voom framework, adjusting for covariates (baseline PHQ-9, sex, age, DNAm-derived immune cell covariates and ancestry components derived from matched blood samples) and within-subject correlation. Results: Although no miRNAs survived multiple-testing correction, 68 mature unique miRNAs showed nominal associations (p < 0.05) with depressive symptom severity change (ΔPHQ-9). Several top candidates, including miR-493-3p, miR-409-3p, and miR-323a-3p, displayed expression patterns aligning with prior reports implicating these miRNAs in stress responsivity, synaptic plasticity, and neurodevelopmental regulation. Exploratory follow-up of predicted targets of the nominally symptom-associated miRNAs converged on genes in pathways central to depression biology, including neurotransmission, HPA axis/inflammatory signaling, neuroplasticity, and circadian regulation. Enrichment analyses highlighted receptor tyrosine kinase and intracellular signaling cascades, hypothalamic–pituitary–adrenal axis feedback, and inflammatory pathways. Conclusions: These findings provide preliminary evidence that peripheral miRNA expression changes may reflect depressive symptom trajectories, highlighting potential molecular pathways involved in depression. Further studies with larger samples and broader symptom severity are warranted to validate these dynamic miRNA signatures.