Transcriptomics and miRNomics data integration in lymphoblastoid cells highlights the key role of immune-related functions in lithium treatment response in Bipolar disorder

Abstract

Abstract Background Bipolar Disorder (BD) is a complex mental disease characterized by recurrent episodes of mania and depression. Lithium (Li) represents the mainstay of BD pharmacotherapy, despite the narrow therapeutic index and the high variability in treatment response. However, although several studies have been conducted, the molecular mechanisms underlying Li therapeutic effects remain unclear. Methods In order to identify molecular signatures and biological pathways associated with Li treatment response, we conducted transcriptome and miRNome microarray analyses on lymphoblastoid cell lines (LCLs) from 20 patients diagnosed with BD classified as Li responders (n = 11) or non-responders (n = 9). Results We found 335 mRNAs and 77 microRNAs (miRNAs) significantly modulated in BD responders versus non-responders. Interestingly, pathway and network analyses on these differentially expressed molecules suggested a modulatory effect of Li on several immune-related functions. Indeed, among the functional molecular nodes, we found NF-κB and TNF. Moreover, networks related to these molecules resulted overall inhibited in BD responder patients, suggesting anti-inflammatory properties of Li. From the integrative analysis between transcriptomics and miRNomics data carried out using miRComb R package on the same samples from patients diagnosed with BD, we found 97 significantly and negatively correlated mRNA-miRNA pairs, mainly involved in inflammatory/immune response. Conclusions Our results highlight that Li exerts modulatory effects on immune-related functions and that epigenetic mechanisms, especially miRNAs, can influence the modulation of different genes and pathways involved in Li response. Moreover, our data suggest the potentiality to integrate data coming from different high-throughput approaches as a tool to prioritize genes and pathways.

Keywords

• Bipolar disorder
• Lymphoblastoid cell line
• Lithium
• Gene expression
• microRNAs
• Transcriptome and miRNome integrative analysis