1/3 Understanding PTSD through Postmortem Targeted Brain Multi-omics

Project Summary/Abstract Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are prevalent and disabling. Al- though trauma exposure is common and most trauma victims recover, the ~10% who develop chronic PTSD continue to have debilitating symptoms of re-experiencing, avoidance and hyperarousal as well as depression symptoms. It is critical to identify the underlying neurobiology of PTSD susceptibility and to further understand underlying differences between PTSD and MDD. Despite their clinical importance, there are limited human biol- ogy-focused postmortem brain studies of well-matched PTSD and MDD cases and controls to leverage the fact that these are well understood Psychiatric Disorders in terms of neural circuit regulation. This Competitive Re- newal utilizes a Collaborative R01 mechanism across 3-sites (University of Texas (1), Lieber Institute for Brain Development (2), and McLean Hospital (3)), to extend a postmortem, multi-omic study of brains (PTSD Brainom- ics Project), building on progress from data from the initial grant period with 300 additional new subjects in this proposal across the 3 diagnostic categories of 1) PTSD, 2) MDD, and 3) `neurotypical' controls. We will focus on targeted brain regions with known differential association with PTSD risk as a function of identified intermediate phenotypes, including amygdala, hippocampus, and dorsal raphe nucleus. We will conduct DNA genotyping (LIBD) and bulk-tissue DNA methylation and whole-genome bisulfite sequencing (on a subset), RNA-sequencing and protein expression across brain regions. We will also perform single nucleus (sn) Multiome-sequencing that combines snRNAseq and snATACseq to expand interpretation of the bulk multiomic data and spatial tran- scriptomics on select brain samples. Our new 900 samples from 300 new subjects will also support metaanalyses with prior samples for 1800 total brain samples from 600 total subjects. We will aim to investigate the roles of: 1) gene expression and alternative splicing in PTSD/MDD and trauma exposure in relation to upstream epigenetic regulation and downstream (phosphor)protein expression; 2) gene expression and chromatin accessibility in individual brain cells and spatial organization of molecular alterations in PTSD/MDD and trauma exposure; 3) polygenic risk and putative causal variants in PTSD/MDD and trauma exposed brains, and 4) to utilize systems biology, factor analysis and deep learning to understand traumatic stress related outcomes. We will use state- of-the-art statistical modeling, combined with rich psychological and biological phenotype measurements to de- termine disease-associated networks across brain regions and molecular pathways. This novel, integrated, and impactful linked R01 proposal will lead to identification of unknown trauma-associated genes and proteins, ncRNAs, and epigenetic marks in trauma related disorders and identify novel therapeutic targets. It will also expand understanding of cell-type-specific multiomic regulation. Our strategy has the potential to help redefine psychobiological subtypes of PTSD and reduce the burden of chronic PTSD.