Abstract: Bipolar disorder (BPD) is a severe mental disorder with a significant burden on public health. MiRNAs arehighly expressed in the brain and have been shown by us and others to play a role in the neuropathology of BPDand other psychiatric disorders. However to date all published postmortem brain miRNA expression studies ofBPD have been hampered by small sample sizes older detection platforms and a lack of comprehensive dataintegration with other genomic resources. To address these limitations we propose a translational approach that will apply miRNA sequencing in theamygdala and subgenual cingulate anterior cortex (sAAC) in 150 patients diagnosed with bipolar disorder andmatched 150 neurotypical controls followed by a replication study in an independent sample of 100 matchedcase/control sample. Our aims are designed to take full advantage of this large and exceptionally well clinicallycharacterized sample. With our large discovery and replication samples we are powered to identify moderate tosmall effect sizes typically observed in neuropsychiatric disorders. By leveraging other pre-existing genomicdatasets (i.e. GWAS data and RNA-seq) generated in our sample we will apply a state-of-art series ofbioinformatic and statistical approaches for the comprehensive integration of these genomic data. Thisintegration 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 mechanismsby which genome-wide significant risk variants contribute to the etiology of bipolar disorder e.g. variantsaffecting miRNA expression between BPD cases and controls. Integrating the miRNA-Seq and RNA-Seq datawill identify miRNA gene targets with important functions in the etiology of bipolar disorder. Finally we will identifya set of high confidence risk miRNA of BPD (i.e. miRNAs with convergent evidence from the discovery eQTLbioinformatic and replication analyses) and deliver these in mice models to delineate the disease-specificfunctions and roles these miRNA play in BPD neuropathology. In summary the neurobiological mechanisms by which polymorphisms associated with BPD increase the riskfor bipolar disorder are unknown. We hypothesize that one of the mechanisms contributing to the neuropathologyof BPD is the ability of risk BPD variants to affect miRNA expression. Using such large discovery and replicationbrain samples of BPD we will identify miRNA whose expression is robustly associated with bipolar disorder andunder the control of risk variants for BPD and further validate their disease functions by testing their impact onbehavioral measures in mice models.