Abstract: Bipolar disorder (BPD) is a severe mental disorder with a significant burden on public health. MiRNAs are highly expressed in the brain and have been shown by us and others to play a role in the neuropathology of BPD and other psychiatric disorders. However, to date, all published postmortem brain miRNA expression studies of BPD have been hampered by small sample sizes, older detection platforms, and a lack of comprehensive data integration with other genomic resources. To address these limitations, we propose a translational approach that will apply miRNA sequencing in the amygdala and subgenual cingulate anterior cortex (sAAC) in 150 patients diagnosed with bipolar disorder and matched 150 neurotypical controls, followed by a replication study in an independent sample of 100 matched case/control sample. Our aims are designed to take full advantage of this large and exceptionally well clinically characterized sample. With our large discovery and replication samples, we are powered to identify moderate to small effect sizes typically observed in neuropsychiatric disorders. By leveraging other pre-existing genomic datasets (i.e., GWAS data and RNA-seq) generated in our sample, we will apply a state-of-art series of bioinformatic and statistical approaches for the comprehensive integration of these genomic data. This integration will lead to the generation of specific and testable hypotheses. As an example, integrating the miRNA- seq data with GWAS of BPD (from the Psychiatric Genomics Consortium) will reveal the genetic mechanisms by which genome-wide significant risk variants contribute to the etiology of bipolar disorder, e.g., variants affecting miRNA expression between BPD cases and controls. Integrating the miRNA-Seq and RNA-Seq data will identify miRNA gene targets with important functions in the etiology of bipolar disorder. Finally, we will identify a set of high confidence risk miRNA of BPD (i.e., miRNAs with convergent evidence from the discovery, eQTL, bioinformatic, and replication analyses) and deliver these in mice models to delineate the disease-specific functions and roles these miRNA play in BPD neuropathology. In summary, the neurobiological mechanisms by which polymorphisms associated with BPD increase the risk for bipolar disorder are unknown. We hypothesize that one of the mechanisms contributing to the neuropathology of BPD is the ability of risk BPD variants to affect miRNA expression. Using such large discovery and replication brain samples of BPD, we will identify miRNA, whose expression is robustly associated with bipolar disorder and under the control of risk variants for BPD and further validate their disease functions by testing their impact on behavioral measures in mice models.