The Neuronal Transcriptome of Suicide in Bipolar Disorder

Among the strongest factors associated with suicide risk is the presence of psychiatric disorders, especially bipolar disorder (BD). BD affects around 1-2% of the population and is currently among the most disabling medical conditions worldwide. Specifically, the risk for suicide in patients with BD is among the highest of all psychiatric disorders; between 25-50% of adult patients make at least one suicide attempt in their lifetime and between 8 and 19% of patients with BD will die from suicide. Although BD and suicide seem to share a genetic risk, the mechanisms by which some patients are more vulnerable to suicidal behavior than others and the molecular underpinnings of the clinically heterogeneous phenotype of suicide in BD are vastly unknown. The continued existence of this knowledge gap and the absence of biomarkers that can be used to predict suicidality in this susceptible population represent an important problem because it limits our ability to identify patients at high risk and/or provide targeted early interventions. Among possible mechanisms currently under investigation are genetic and epigenetic markers, especially based on the known familial aggregation of suicidal behavior. Of note, although genetic variation may contribute to suicide risk, the mechanisms by which these variations disrupt the regulatory processes or molecular pathways to contribute to pathophysiological dysfunction belong to the field of transcriptomics. In fact, several studies have described suicide-associated alterations on gene expression, although such an analysis has never been performed in isolated post-mortem neurons with a focus on bipolar disorder while integrating with genetic risk and DNA methylation markers. To this effect, the overarching goal of this study is to identify brain gene expression alterations associated with suicidality in BD. Our working hypothesis is that neuronal gene expression alterations will inform upon the pathophysiological mechanisms underlying suicide death in BD. This hypothesis will be tested by pursuing two specific aims. In Aim 1, we will identify and characterize gene expression alterations in a sample of post-mortem dorsolateral prefrontal cortex tissues (BA9 region) from patients with BD that committed suicide or died of other causes. We will also integrate these transcriptomic findings with genome-wide DNA methylation levels measured in the same samples. In Aim 2, we will determine the association between genetic risk for BD and suicide attempt (as measured by polygenic risk scores) and gene expression alterations in post-mortem prefrontal cortex. As expected outcomes, we anticipate the identification of clinically-relevant transcriptome-based biomarkers of suicidality in BD. A better understanding of suicide death in BD can help to shed light on its cause, identify individuals at high risk for the development of incident suicidal behavior, and frame targets for intervention and prevention, ultimately reducing the impact and development of suicidal behavior in this vulnerable population. Finally, this study will also provide the basis for testing suicide transcriptomic biosignatures in other disorders known to have an increased rate of suicidal behavior, further exploring the specificity of these alterations and their potential clinical use in other populations.