MicroRNA expression profiling of lymphoblasts from bipolar disorder patients who died by suicide, pathway analysis and integration with postmortem brain findings.

ABSTRACT

Post-mortem brain studies suggest that miRNAs may be involved in suicide, but their role as peripheral biomarkers or targets of preventive pharmacological treatments in suicide has yet to be elucidated. We used nCounter miRNA Expression assay to measure miRNAs expression in lymphoblastoid cell lines (LCLs) from patients with Bipolar Disorder (BD) who died by suicide (SC, n = 7) and with low risk of suicide (LR, n = 11). Five miRNAs were differentially expressed in SC compared to LR (false discovery rate p<0.05). The two most significant miRNAs were measured with RT-qPCR in the same sample and in 12 healthy controls (HC) miR-4286 was increased while miR-186-5p was decreased in SC compared to LR and HC (ANOVA F = 14.92, p = 0.000043 and F = 3.95, p = 0.032 respectively). miR-4286 was also decreased in postmortem brains from 12 patients with BD who died by suicide compared to 13 controls, even though it did not reach statistical significance (FC=0.51, p = 0.07). Treatment with lithium of human neural progenitor cells reduced the expression of miR-4286 (FC=0.30, p = 0.038). Pathway analysis on predicted miR-4286 targets showed that "insulin resistance" was significantly enriched after correction for multiple testing. This pathway comprised 17 genes involved in lipid and glucose metabolism, several of which were also dysregulated in postmortem brains from patients with BD who died by suicide from the Stanley-foundation array collection. In conclusion, our study suggests that miR-4286 could be a biomarker of suicide but further studies are warranted to investigate its targeted genes and how these could be involved in the neurobiology of suicide.