Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood

Abstract

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

Abstract

INTRODUCTION

Stress-related disorders arise from the interplay between genetic susceptibility and stress exposure, occurring throughout the lifespan. Progressively, these interactions lead to epigenetic modifications in the human genome, shaping the expression of genes and proteins. Prior postmortem brain studies have attempted to elucidate the molecular pathology of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) compared with neurotypical controls (NCs) in a single-omic manner, revealing genomic overlap, sex differences, and immune and interneuron signaling involvement. However, without integrative systems approaches, progress in understanding the molecular underpinnings of these prevalent and debilitating disorders is hindered.

RATIONALE

To tackle this roadblock, we have created a brain multiregion, multiomic database of individuals with PTSD and MDD and NCs (77 per group, n = 231) to describe molecular alterations across three brain regions: the central nucleus of the amygdala (CeA), medial prefrontal cortex (mPFC), and hippocampal dentate gyrus (DG) at the transcriptomic, methylomic, and proteomic levels. By using this multiomic strategy that merges information across biological layers and organizational strata and complementing it with single-nucleus RNA sequencing (snRNA-seq), genetics, and blood plasma proteomics analyses, we sought to reveal an integrated-systems perspective of PTSD and MDD.

RESULTS

We found molecular differences primarily in the mPFC, with differentially expressed genes (DEGs) and exons carrying the most disease signals. However, altered methylation was seen mainly in the DG in PTSD subjects, in contrast to the CeA in MDD subjects. Replication analysis substantiated these findings with multiomic data from two cohorts ( n = 114). Moreover, we found a moderate overlap between the disorders, with childhood trauma and suicide being primary drivers of molecular variations in both disorders, and sex specificity being more notable in MDD. Pathway analyses linked disease-associated molecular signatures to immune mechanisms, metabolism, mitochondria function, neuronal or synaptic regulation, and stress hormone signaling with low concordance across omics. Top upstream regulators and transcription factors included IL1B, GR, STAT3, and TNF. Multiomic factor and gene network analyses provided an underlying genomic structure of the disorders, suggesting latent factors and modules related to aging, inflammation, vascular processes, and stress.

To complement the multiomics analyses, our snRNA-seq analyses in the dorsolateral PFC ( n = 118) revealed DEGs, dysregulated pathways, and upstream regulators in neuronal and non-neuronal cell-types, including stress-related gene signals. Examining the intersection of brain multiomics with blood proteins (in >50,000 UK Biobank participants) revealed significant correlation, overlap, and directional similarity between brain-to-blood markers. Fine-mapping of PTSD and MDD genome-wide association studies’ (GWASs’) results showed a limited overlap between risk and disease processes at the gene and pathway levels .

Ultimately, prioritized genes with multiregion, multiomic, or multitrait disease associations were members of pathways or networks, showed cell-type specificity, had blood biomarker potential, or were involved in genetic risk for PTSD and MDD.

CONCLUSION

Our findings unveil shared and distinct brain multiomic molecular dysregulations in PTSD and MDD, elucidate the involvement of specific cell types, pave the way for the development of blood-based biomarkers, and distinguish risk from disease processes. These insights not only implicate established stress-related pathways but also reveal potential therapeutic avenues.