SYSTEMS BIOLOGY OF PTSD REVEALS MECHANISMS OF RISK AND DISEASE PROCESSES AT BRAIN MULTI-OMIC, BRAIN CELL TYPE, AND BLOOD LEVELS

IF 6.1 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology Pub Date : 2024-10-01 DOI:10.1016/j.euroneuro.2024.08.015

Nikolaos Daskalakis , Artemis Iatrou , Christos Chatzinakos , Aarti Jajoo , Clara Snijders , PGC PTSD Working Group , Charles Nemeroff , Joel Kleinman , Kerry Ressler

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引用次数: 0

Abstract

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.

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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

压力相关疾病源于遗传易感性和压力暴露的相互作用，通过整个生命周期的表观遗传修饰影响基因和蛋白质的表达。与神经畸形对照组相比，对创伤后应激障碍和精神障碍患者死后大脑的研究揭示了遗传重叠、性别差异、免疫和中间神经元信号参与等问题，但缺乏综合分析。为了填补这一空白，我们建立了一个大脑多组学、多区域数据库，其中包括创伤后应激障碍患者、MDD患者和NCs患者（77人/组，n = 231）。我们在转录组、甲基组和蛋白质组水平上分析了杏仁核中央核（CeA）、内侧前额叶皮层（mPFC）和海马齿状回（DG）的分子变化。我们的方法辅以单核 RNA 测序（snRNA-seq）、遗传学和血液蛋白质组学，旨在从全面的系统角度进行研究。我们的研究结果凸显了 mPFC 中主要的分子变化，其中差异表达基因 (DEG) 和外显子携带疾病信号。值得注意的是，甲基化改变集中在创伤后应激障碍的 DG 和 MDD 的 CeA。两个队列（n = 114）的重复分析支持了这一结果。我们观察到疾病之间存在一定程度的重叠，童年创伤和自杀是分子变异的驱动因素，而性别特异性在 MDD 中更为显著。通路分析将与疾病相关的分子特征与免疫机制、新陈代谢、线粒体功能和应激激素信号转导联系在一起，尽管在全局组学中的一致性较低。最主要的上游调节因子包括 IL1B、GR、STAT3 和 TNF。多组学因子和基因网络分析表明，潜在因子和模块与衰老、炎症、血管过程和应激有关。作为多组学的补充，我们在背外侧前脑功能区进行的snRNA-seq分析揭示了神经元和非神经元细胞类型中失调的通路和上游调控因子，包括与应激有关的基因。对英国生物库大型队列中的大脑多组学与血液蛋白质进行的研究显示了显著的相关性、重叠性和方向相似性，这意味着潜在的基于血液的生物标记物。创伤后应激障碍和多发性硬化症全基因组关联研究结果的精细图谱显示，风险与疾病过程在基因和通路水平上的重叠有限。最终，具有多组学、多区域或多性状关联的优先基因与通路/网络有牵连，表现出细胞类型特异性，显示出血液生物标记物的潜力，或与创伤后应激障碍和多发性硬化症的遗传风险有关。总之，我们的研究揭示了创伤后应激障碍和多发性抑郁症共有的和独特的大脑多组学分子失调，阐明了不同细胞类型的参与，为基于血液的生物标记物的开发铺平了道路。这些见解不仅牵涉到已确立的应激相关途径，还提供了潜在的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Neuropsychopharmacology 医学-精神病学

CiteScore

10.30

自引率

5.40%

发文量

730

审稿时长

41 days

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.