Differential microRNA expression profiling of peripheral blood L1CAM neural-enriched and bulk extracellular vesicles in individuals with bipolar disorder

Bipolar disorder (BD) is a common and yet poorly elucidated psychiatric disorder, with emerging evidence implicating a role for epigenetic mechanisms, including microRNAs (miRNAs), in its pathophysiology. These molecules are secreted from cells in extracellular vesicles (EVs), which can be isolated from bodily fluids and tested as potential biomarkers. In individuals with BD and control participants (CON), we characterized the miRNA expression profiles of peripheral blood EVs selected for L1CAM, a putative neuronal marker, as well as bulk peripheral blood EVs. Peripheral blood EVs were isolated from n=20 BD and 20 CON (L1CAM) and n=21 BD and 20 CON (bulk). Within each study, analyses identified miRNAs that were differentially expressed between BD and CON, followed by functional interrogation and testing for associations with clinical features. Results were then compared to better understand the relative specificity of bulk and L1CAM EV analyses. Thirty-four miRNAs were differentially expressed between groups in L1CAM EVs, whereas 10 differentially expressed miRNAs were identified in bulk EVs. Across both analyses, biological pathways attributed to the differentially expressed miRNAs included insulin receptor pathway and type II diabetes mellitus. Importantly, associations of differentially expressed miRNAs with clinical features were only significant in L1CAM EVs. Our results reiterate a crucial role for miRNAs in the pathophysiology of BD and suggest that miRNA signatures of putative neuronal origin more closely correspond to clinical features.