炎症相关蛋白与重度抑郁症风险的遗传关联及药物靶点探索

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

作者信息

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

机构信息

Suzhou Medical College of Soochow University, Suzhou 215031, Jiangsu, China; Suzhou Guangji Hospital, Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China.

School of Systems Biology, George Mason University, Manassas, VA, USA.

出版信息

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jan 10;136:111165. doi: 10.1016/j.pnpbp.2024.111165. Epub 2024 Oct 9.

DOI:10.1016/j.pnpbp.2024.111165

PMID:39383931

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.

摘要

背景

在众多观察性研究中，循环炎症相关蛋白与重度抑郁症（MDD）有关联，但这种关系的确切因果方向仍不明确。本研究旨在调查炎症相关蛋白与患MDD风险之间的潜在因果联系。

方法

我们利用了一项针对14824名欧洲血统个体的91种循环炎症相关蛋白的全基因组关联研究（GWAS）的汇总数据。此外，我们纳入了一项关于MDD的大型GWAS的研究结果，该研究包括294322例病例和741438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，以逆方差加权（IVW）作为主要方法。我们用两种补充技术（MR-Egger和加权中位数方法）对其进行补充，以检测和解决潜在的多效性。此外，为了识别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分析发现，基因决定的半胱天冬酶8（优势比（OR）：0.97）、CD40（OR：0.96）、白细胞介素18（IL-18，OR：0.98）、信号淋巴细胞激活分子家族成员1（SLAMF1，OR：0.97）和尿激酶型纤溶酶原激活剂（uPA，OR：0.98）与MDD之间存在显著的因果关联。相反，反向MR分析表明MDD与CC趋化因子配体19（CCL19，OR：1.15）、肝细胞生长因子（HGF，OR：1.15）、IL-8（OR：1.10）、IL-18（OR：1.11）、白细胞介素20受体A（IL20RA，OR：1.12）、转化生长因子α（TGFA，OR：1.12）和肿瘤坏死因子超家族成员14（TNFSF14，OR：1.16）之间存在因果关联。值得注意的是，在IL-18与MDD之间观察到显著的双向因果联系。基因-药物分析确定CD40、HGF、IL-8、IL-18、SLAMF1和TGFA为潜在的治疗靶点。