Genetic association and drug target exploration of inflammation-related proteins with risk of major depressive disorder

IF 5.3 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry Pub Date : 2024-10-09 DOI:10.1016/j.pnpbp.2024.111165

Wenxi Sun , Hongbao Cao , Dongming Liu , Ancha Baranova , Fuquan Zhang , Xiaobin Zhang

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引用次数: 0

Abstract

Background

In numerous observational studies, circulating inflammation-related proteins have been linked with major depressive disorder (MDD), yet the precise causal direction of this relationship remains unclear. This study aims to investigate the potential causal link between inflammation-related proteins and the risk of developing MDD.

Methods

We utilized summary data from a genome-wide association study (GWAS) of 91 circulating inflammation-associated proteins in 14,824 individuals of European descent. Additionally, we incorporated findings from a substantial GWAS on MDD, which included 294,322 cases and 741,438 controls. Our analysis employed a two-sample bidirectional Mendelian randomization (MR) approach, with inverse variance weighting (IVW) as the primary method. We augmented this with two supplementary techniques (MR-Egger and weighted median approaches) to detect and address potential pleiotropy. Furthermore, to identify and evaluate possible drug targets, we conducted a thorough search within the Drug-Gene Interaction Database (DGIdb).

Results

Analysis using MR unveiled significant and causative associations between genetically determined CASP-8 (odds ratio (OR): 0.97), CD40 (OR: 0.96), IL-18 (OR: 0.98), SLAMF1 (OR: 0.97), and uPA (OR: 0.98) with MDD. Conversely, reverse MR analysis indicated causal associations between MDD and CCL19 (OR: 1.15), HGF (OR: 1.15), IL-8 (OR: 1.10), IL-18 (OR: 1.11), IL20RA (OR: 1.12), TGFA (OR: 1.12) and TNFSF14 (OR: 1.16). Notably, a significant bidirectional causal link was observed between IL-18 and MDD. Gene-drug analysis identified CD40, HGF, IL-8, IL-18, SLAMF1, and TGFA as potential therapeutic targets.

Conclusions

We've pinpointed causal links between inflammation-related proteins and MDD, offering compelling and innovative evidence to enhance our understanding of the inflammatory mechanisms involved in MDD and to investigate potential targets for anti-MDD medications.

查看原文本刊更多论文

与重度抑郁症风险有关的炎症相关蛋白的遗传关联和药物靶点探索。

背景：在许多观察性研究中，循环炎症相关蛋白与重度抑郁症（MDD）有关，但这种关系的确切因果方向仍不清楚。本研究旨在调查炎症相关蛋白与罹患重度抑郁症风险之间的潜在因果关系：我们利用全基因组关联研究（GWAS）的汇总数据，对 14,824 名欧洲后裔的 91 种循环炎症相关蛋白进行了研究。此外，我们还纳入了一项关于 MDD 的大型全基因组关联研究的结果，其中包括 294,322 例病例和 741,438 例对照。我们的分析采用了双样本双向孟德尔随机化（MR）方法，以反向方差加权（IVW）为主要方法。我们还采用了两种辅助技术（MR-Egger 法和加权中值法）来检测和解决潜在的多效性问题。此外，为了确定和评估可能的药物靶点，我们在药物基因相互作用数据库（DGIdb）中进行了全面搜索：结果：使用MR分析揭示了基因决定的CASP-8（几率比（OR）：0.97）、CD40（OR：0.96）、IL-18（OR：0.98）、SLAMF1（OR：0.97）和uPA（OR：0.98）与MDD之间的显著因果关系。相反，反向 MR 分析表明 MDD 与 CCL19（OR：1.15）、HGF（OR：1.15）、IL-8（OR：1.10）、IL-18（OR：1.11）、IL20RA（OR：1.12）、TGFA（OR：1.12）和 TNFSF14（OR：1.16）之间存在因果关系。值得注意的是，IL-18 与 MDD 之间存在明显的双向因果关系。基因药物分析发现，CD40、HGF、IL-8、IL-18、SLAMF1 和 TGFA 是潜在的治疗靶点：我们发现了炎症相关蛋白与 MDD 之间的因果关系，为我们进一步了解 MDD 所涉及的炎症机制和研究抗 MDD 药物的潜在靶点提供了令人信服的创新证据。

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

Progress in Neuro-Psychopharmacology & Biological Psychiatry 医学-精神病学

CiteScore

12.00

自引率

1.80%

发文量

153

审稿时长

56 days

期刊介绍： Progress in Neuro-Psychopharmacology & Biological Psychiatry is an international and multidisciplinary journal which aims to ensure the rapid publication of authoritative reviews and research papers dealing with experimental and clinical aspects of neuro-psychopharmacology and biological psychiatry. Issues of the journal are regularly devoted wholly in or in part to a topical subject. Progress in Neuro-Psychopharmacology & Biological Psychiatry does not publish work on the actions of biological extracts unless the pharmacological active molecular substrate and/or specific receptor binding properties of the extract compounds are elucidated.