Transcriptomic profiles in major depressive disorder: the role of immunometabolic and cell-cycle-related pathways in depression with different levels of inflammation

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Psychiatry Pub Date : 2024-09-13 DOI:10.1038/s41380-024-02736-w
Luca Sforzini, Moira Marizzoni, Chiara Bottanelli, Veronika Kunšteková, Valentina Zonca, Samantha Saleri, Melisa Kose, Giulia Lombardo, Nicole Mariani, Maria A. Nettis, Naghmeh Nikkheslat, Courtney Worrell, Zuzanna Zajkowska, Linda Pointon, Philip J. Cowen, Jonathan Cavanagh, Neil A. Harrison, Marco A. Riva, Valeria Mondelli, Edward T. Bullmore, Annamaria Cattaneo, Carmine M. Pariante
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Abstract

Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression. We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls. We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 ‘not inflamed’ (CRP < 1 mg/L), n = 31 with ‘elevated CRP’ (1–3 mg/L), and n = 35 with ‘low-grade inflammation’ (>3 mg/L). We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1–3 group showed stronger immune activation than the CRP > 3 group. The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this ‘non-inflamed’ depressed group. We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response. In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders. The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual’s trajectory toward immunometabolic depression and/or treatment-non-responsive depression. The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD.

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重度抑郁症的转录组特征:免疫代谢和细胞周期相关通路在不同炎症水平的抑郁症中的作用
转录组特征是重度抑郁障碍(MDD)及其不同表型(如免疫代谢性抑郁)所涉及的分子机制和通路的重要指标。我们对来自病例对照观察性研究 "抑郁中的生物标记物"(BIOmarkers in DEPression,BIODEP)的 139 人(其中 105 人患有 MDD,34 人为对照组)进行了全转录组和通路分析。我们根据血清高敏 C 反应蛋白(CRP)测量的炎症水平将 MDD 患者分为 39 例 "无炎症"(CRP 为 1 毫克/升)、31 例 "CRP 升高"(1-3 毫克/升)和 35 例 "低度炎症"(3 毫克/升)。我们使用 Illumina NextSeq 550 进行了全血 RNA 测序,并使用 R 统计软件包 Deseq2 进行了统计分析(RUV 校正),随后使用 Ingenuity Pathway Analysis 进行了通路分析。尽管令人惊讶的是,CRP 1-3 组比 CRP 3 组显示出更强的免疫激活,但 CRP 1> 1 mg/L 组的免疫代谢通路被激活。在 CRP < 1 组与对照组的比较中发现的主要途径与细胞周期有关,这可能对这一 "非炎症 "抑郁组的免疫代谢异常具有保护作用。我们根据抗抑郁药的暴露和反应进一步划分了 MDD 参与者(n = 47 名无反应者、n = 37 名有反应者和 n = 22 名未用药者),并确定了有反应者(尤其是相对于无反应者)的特定免疫调节和神经保护通路,这可能与治疗反应有关。在进一步的亚组分析中,我们发现应答者的特定转录谱与 CRP 水平无关,而且在 CRP < 1 mg/L 的 MDD 患者中,细胞周期相关通路的抑制仅存在于目前抑郁的患者中,而不存在于应答者中。本研究展示了与 MDD 和不同(基于 CRP 和基于治疗的)MDD 表型相关的免疫代谢和细胞周期相关转录组通路,同时揭示了可预防或促进个体走向免疫代谢抑郁症和/或治疗无应答抑郁症的潜在分子机制。对这些机制的认识和整合将促进 MDD 的精准医疗方法。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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