In:
Science, American Association for the Advancement of Science (AAAS), Vol. 384, No. 6698 ( 2024-05-24)
Abstract:
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. Systems biology dissection of PTSD and MDD. The interplay between genetic susceptibility and stress exposure, occurring both early and later in life, contributes to the pathogenesis of stress-related disorders and their progression after diagnosis until death. Our integrative systems approach combines multiregion, multiomic analyses with single-nucleus transcriptomics, blood plasma proteomics, and GWAS-based fine-mapping to provide deeper insights into molecular mechanisms associated with risk and those involved in the disease process.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.adh3707
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2024
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
SSG:
11
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