Understanding Suicide through Postmortem Targeted Brain Multi-omics

Suicide is among the most prevalent causes of death in developed countries and the leading or second leading cause of death among young people. Psychiatric disorders are strongly linked to suicidal behavior. To date there are have been several genome-wide association studies (GWASs) on suicide attempt. These studies have examined individuals with comorbid psychiatric disorders (e.g. MDD) and have compared attempters with nonattempters to test for genetic variants that might contribute independently to suicide attempt. These studies have revealed inconsistent genetic findings and infrequent replication across studies, raising the possibility of different molecular changes in suicides with different psychiatric comorbidities. It is critical to identify the underlying neurobiology of suicide particular to specific psychiatric disorders because of the very significant medical and psychiatric morbidity and mortality, and the promise of new therapeutics based on its biological underpinnings. Despite its clinical importance, there have yet to be human biology-focused postmortem studies of well-matched cases and controls for suicide between major psychiatric disorders.

This proposal seeks to perform a postmortem, multi-omic study of brains from 75 total subjects: PTSD (n=15), MDD (n=15), PTSD-S (PTSD + suicide, n=15), MDD-S (MDD + suicide, n=15) and normal controls (n=15). We will focus on targeted brain regions with known differential association with suicide risk as a function of identified intermediate phenotypes (comorbid PTSD and MDD) including the amygdala and the prefrontal cortex. We will determine differential mRNA expression and chromatin assembly accessibility in single nuclei isolated across brain areas. We hypothesize that single cell-type, multi-modal genomic analysis across brain regions will reveal 1.) that pathways in MDD and PTSD will be differentially identified in specific cell types in suicide subjects with comorbid MDD and PTSD and 2.) that genome-wide exploratory approaches will identify novel epigenomically regulated gene pathways. Our main outcome will be a model of cell type-specific genetic, epigenomic, and transcriptomic profiles of brain regions from cases vs. controls. These data will allow an understanding of the cell type-specific and psychobiological subtypes of suicide transcriptional and epigenomic profiles, and findings will be integrated with detailed multi-omic data from other studies and genome wide-association studies of suicide.