Nikolaos Daskalakis , Artemis Iatrou , Christos Chatzinakos , Aarti Jajoo , Clara Snijders , PGC PTSD Working Group , Charles Nemeroff , Joel Kleinman , Kerry Ressler
{"title":"PTSD 的系统生物学揭示了大脑多原子、脑细胞类型和血液水平的风险和疾病过程机制","authors":"Nikolaos Daskalakis , Artemis Iatrou , Christos Chatzinakos , Aarti Jajoo , Clara Snijders , PGC PTSD Working Group , Charles Nemeroff , Joel Kleinman , Kerry Ressler","doi":"10.1016/j.euroneuro.2024.08.015","DOIUrl":null,"url":null,"abstract":"<div><div>Stress-related disorders stem from the interplay of genetic susceptibility and stress exposure, shaping gene and protein expression through epigenetic modifications across the lifespan. Studies on postmortem brains of PTSD and MDD patients, compared to neurotypical controls, reveal genetic overlaps, sex disparities, and immune and interneuron signaling involvement, yet lack integrative analyses. To address this gap, we established a brain multi-omic, multi-region database comprising individuals with PTSD, MDD, and NCs (77/group, n = 231). We analyzed molecular changes across the central nucleus of the amygdala (CeA), medial prefrontal cortex (mPFC), and hippocampal dentate gyrus (DG) at transcriptomic, methylomic, and proteomic levels. Our approach is supplemented by single-nucleus RNA sequencing (snRNA-seq), genetics, and blood proteomics, aiming for a comprehensive systems perspective. Our findings highlight predominant molecular</div><div>changes in the mPFC, with differentially expressed genes (DEGs) and exons carrying disease signals. Notably, methylation alterations were concentrated in the DG for PTSD and CeA for MDD. Findings supported by replication analyses across two cohorts (n = 114). We observed a moderate overlap between disorders, with childhood trauma and suicide driving molecular variations, and sex-specificity was more notable in MDD. Pathway analyses link disease-associated molecular signatures to immune mechanisms, metabolism, mitochondria function, and stress hormone signaling, albeit with low concordance across omics. Top upstream regulators include IL1B, GR, STAT3, and TNF. Multi-omic factor and gene network analyses suggest latent factors and modules related to aging, inflammation, vascular processes, and stress.</div><div>Complementing multi-omics, our snRNA-seq in the dorsolateral PFC reveals dysregulated pathways and upstream regulators in neuronal and non-neuronal cell types, including stress-related genes. Examining brain multi-omics with blood proteins in the large UK Biobank cohort shows significant correlation, overlap, and directional similarity, implying potential blood-based biomarkers. Fine-mapping of PTSD and MDD genome-wide association study results reveals limited overlap between risk and disease processes at the gene and pathway level.</div><div>Ultimately, prioritized genes with multi-omic, multi-region, or multi-trait associations are implicated in pathways/networks, exhibit cell-type specificity, demonstrate blood biomarker potential, or are linked to genetic risk for PTSD and MDD.</div><div>In conclusion, our study unveils shared and unique brain multi-omic molecular dysregulations in PTSD and MDD, elucidating distinct cell-type involvement and paving the way for blood-based biomarker development. These insights not only implicate established stress-related pathways but also offer potential therapeutic avenues.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"SYSTEMS BIOLOGY OF PTSD REVEALS MECHANISMS OF RISK AND DISEASE PROCESSES AT BRAIN MULTI-OMIC, BRAIN CELL TYPE, AND BLOOD LEVELS\",\"authors\":\"Nikolaos Daskalakis , Artemis Iatrou , Christos Chatzinakos , Aarti Jajoo , Clara Snijders , PGC PTSD Working Group , Charles Nemeroff , Joel Kleinman , Kerry Ressler\",\"doi\":\"10.1016/j.euroneuro.2024.08.015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Stress-related disorders stem from the interplay of genetic susceptibility and stress exposure, shaping gene and protein expression through epigenetic modifications across the lifespan. Studies on postmortem brains of PTSD and MDD patients, compared to neurotypical controls, reveal genetic overlaps, sex disparities, and immune and interneuron signaling involvement, yet lack integrative analyses. To address this gap, we established a brain multi-omic, multi-region database comprising individuals with PTSD, MDD, and NCs (77/group, n = 231). We analyzed molecular changes across the central nucleus of the amygdala (CeA), medial prefrontal cortex (mPFC), and hippocampal dentate gyrus (DG) at transcriptomic, methylomic, and proteomic levels. Our approach is supplemented by single-nucleus RNA sequencing (snRNA-seq), genetics, and blood proteomics, aiming for a comprehensive systems perspective. Our findings highlight predominant molecular</div><div>changes in the mPFC, with differentially expressed genes (DEGs) and exons carrying disease signals. Notably, methylation alterations were concentrated in the DG for PTSD and CeA for MDD. Findings supported by replication analyses across two cohorts (n = 114). We observed a moderate overlap between disorders, with childhood trauma and suicide driving molecular variations, and sex-specificity was more notable in MDD. Pathway analyses link disease-associated molecular signatures to immune mechanisms, metabolism, mitochondria function, and stress hormone signaling, albeit with low concordance across omics. Top upstream regulators include IL1B, GR, STAT3, and TNF. Multi-omic factor and gene network analyses suggest latent factors and modules related to aging, inflammation, vascular processes, and stress.</div><div>Complementing multi-omics, our snRNA-seq in the dorsolateral PFC reveals dysregulated pathways and upstream regulators in neuronal and non-neuronal cell types, including stress-related genes. Examining brain multi-omics with blood proteins in the large UK Biobank cohort shows significant correlation, overlap, and directional similarity, implying potential blood-based biomarkers. Fine-mapping of PTSD and MDD genome-wide association study results reveals limited overlap between risk and disease processes at the gene and pathway level.</div><div>Ultimately, prioritized genes with multi-omic, multi-region, or multi-trait associations are implicated in pathways/networks, exhibit cell-type specificity, demonstrate blood biomarker potential, or are linked to genetic risk for PTSD and MDD.</div><div>In conclusion, our study unveils shared and unique brain multi-omic molecular dysregulations in PTSD and MDD, elucidating distinct cell-type involvement and paving the way for blood-based biomarker development. These insights not only implicate established stress-related pathways but also offer potential therapeutic avenues.</div></div>\",\"PeriodicalId\":12049,\"journal\":{\"name\":\"European Neuropsychopharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.1000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Neuropsychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0924977X24002141\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Neuropsychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0924977X24002141","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
SYSTEMS BIOLOGY OF PTSD REVEALS MECHANISMS OF RISK AND DISEASE PROCESSES AT BRAIN MULTI-OMIC, BRAIN CELL TYPE, AND BLOOD LEVELS
Stress-related disorders stem from the interplay of genetic susceptibility and stress exposure, shaping gene and protein expression through epigenetic modifications across the lifespan. Studies on postmortem brains of PTSD and MDD patients, compared to neurotypical controls, reveal genetic overlaps, sex disparities, and immune and interneuron signaling involvement, yet lack integrative analyses. To address this gap, we established a brain multi-omic, multi-region database comprising individuals with PTSD, MDD, and NCs (77/group, n = 231). We analyzed molecular changes across the central nucleus of the amygdala (CeA), medial prefrontal cortex (mPFC), and hippocampal dentate gyrus (DG) at transcriptomic, methylomic, and proteomic levels. Our approach is supplemented by single-nucleus RNA sequencing (snRNA-seq), genetics, and blood proteomics, aiming for a comprehensive systems perspective. Our findings highlight predominant molecular
changes in the mPFC, with differentially expressed genes (DEGs) and exons carrying disease signals. Notably, methylation alterations were concentrated in the DG for PTSD and CeA for MDD. Findings supported by replication analyses across two cohorts (n = 114). We observed a moderate overlap between disorders, with childhood trauma and suicide driving molecular variations, and sex-specificity was more notable in MDD. Pathway analyses link disease-associated molecular signatures to immune mechanisms, metabolism, mitochondria function, and stress hormone signaling, albeit with low concordance across omics. Top upstream regulators include IL1B, GR, STAT3, and TNF. Multi-omic factor and gene network analyses suggest latent factors and modules related to aging, inflammation, vascular processes, and stress.
Complementing multi-omics, our snRNA-seq in the dorsolateral PFC reveals dysregulated pathways and upstream regulators in neuronal and non-neuronal cell types, including stress-related genes. Examining brain multi-omics with blood proteins in the large UK Biobank cohort shows significant correlation, overlap, and directional similarity, implying potential blood-based biomarkers. Fine-mapping of PTSD and MDD genome-wide association study results reveals limited overlap between risk and disease processes at the gene and pathway level.
Ultimately, prioritized genes with multi-omic, multi-region, or multi-trait associations are implicated in pathways/networks, exhibit cell-type specificity, demonstrate blood biomarker potential, or are linked to genetic risk for PTSD and MDD.
In conclusion, our study unveils shared and unique brain multi-omic molecular dysregulations in PTSD and MDD, elucidating distinct cell-type involvement and paving the way for blood-based biomarker development. These insights not only implicate established stress-related pathways but also offer potential therapeutic avenues.
期刊介绍:
European Neuropsychopharmacology is the official publication of the European College of Neuropsychopharmacology (ECNP). In accordance with the mission of the College, the journal focuses on clinical and basic science contributions that advance our understanding of brain function and human behaviour and enable translation into improved treatments and enhanced public health impact in psychiatry. Recent years have been characterized by exciting advances in basic knowledge and available experimental techniques in neuroscience and genomics. However, clinical translation of these findings has not been as rapid. The journal aims to narrow this gap by promoting findings that are expected to have a major impact on both our understanding of the biological bases of mental disorders and the development and improvement of treatments, ideally paving the way for prevention and recovery.