DDN gene downregulation in endometrium: a potential immune-mediated link between bipolar disorder and spontaneous abortion revealed by Mendelian randomization and bioinformatics

IF 2.6 Q2 MULTIDISCIPLINARY SCIENCES

Beni-Suef University Journal of Basic and Applied Sciences Pub Date : 2025-09-27 DOI:10.1186/s43088-025-00674-2

Jian Tang, Zhixin Xu, Lingling Yang, Qiong Zou

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引用次数: 0

Abstract

Background

Spontaneous abortion, affecting over 20% of pregnancies, presents significant physical and psychological burdens. While chromosomal aneuploidy and environmental factors contribute to its etiology, the role of maternal genetic and psychiatric factors remains underexplored. Emerging evidence links psychiatric disorders, particularly bipolar disorder, to increased spontaneous abortion risk, potentially via immune or neuroendocrine dysregulation. This research examines the causal link between bipolar disorder and spontaneous abortion using mendelian randomization (MR) and delves into molecular mechanisms via bioinformatics analysis.

Results

Initial MR analysis revealed no direct causal association between bipolar disorder and spontaneous abortion (odds ratio (OR) = 1.05, 95% Confidence Interval (CI): 0.99–1.12). However, single-nucleotide-polymorphism-level analysis identified rs1054442 as a potential mediator, linked to reduced expression of DDN, a gene implicated in neurodevelopment and immune modulation. Microarray data demonstrated significant downregulation of DDN in endometrial tissue from spontaneous abortion patients (logFold Change (logFC) = − 1.21, p = 0.004). Concurrently, immune checkpoint genes—CTLA4, IGSF8, ITPRIPL1, and TIGIT—exhibited altered expression patterns, suggesting disrupted immune tolerance at the maternal–fetal interface.

Conclusions

Although bipolar disorder does not directly elevate spontaneous abortion risk, genetic variants associated with the disorder may contribute to immune dysfunction via DDN dysregulation, indirectly predisposing to spontaneous abortion. These discoveries point to the potential influence of maternal immune modulation in the origins of spontaneous abortion and indicate therapeutic targets for those at risk. Further studies are needed to validate these mechanisms and explore clinical interventions targeting immune checkpoint pathways.

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子宫内膜DDN基因下调：孟德尔随机化和生物信息学揭示的双相情感障碍与自然流产之间潜在的免疫介导联系

自然流产影响了超过20%的妊娠，造成了严重的生理和心理负担。虽然染色体非整倍体和环境因素有助于其病因，但母体遗传和精神因素的作用仍未得到充分探讨。新出现的证据表明，精神疾病，特别是双相情感障碍，可能通过免疫或神经内分泌失调导致自然流产风险增加。本研究利用孟德尔随机化（MR）研究了双相情感障碍与自然流产之间的因果关系，并通过生物信息学分析深入研究了分子机制。结果初步MR分析显示双相情感障碍与自然流产之间无直接因果关系(优势比（OR) = 1.05, 95%可信区间（CI）： 0.99-1.12）。然而，单核苷酸多态性水平分析发现rs1054442是一个潜在的中介，与DDN（一种与神经发育和免疫调节有关的基因）的表达减少有关。微阵列数据显示，自然流产患者子宫内膜DDN显著下调（logFold Change (logFC) = - 1.21, p = 0.004）。同时，免疫检查点基因ctla4、IGSF8、ITPRIPL1和tigit表现出表达模式的改变，表明母胎界面的免疫耐受被破坏。结论双相情感障碍不直接增加自然流产风险，但其相关基因变异可能通过DDN失调导致免疫功能障碍，间接导致自然流产。这些发现指出了母体免疫调节在自然流产起源中的潜在影响，并指出了高危人群的治疗靶点。需要进一步的研究来验证这些机制，并探索针对免疫检查点途径的临床干预措施。

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

Beni-Suef University Journal of Basic and Applied Sciences MULTIDISCIPLINARY SCIENCES-

CiteScore

2.60

自引率

0.00%

发文量

期刊介绍： Beni-Suef University Journal of Basic and Applied Sciences (BJBAS) is a peer-reviewed, open-access journal. This journal welcomes submissions of original research, literature reviews, and editorials in its respected fields of fundamental science, applied science (with a particular focus on the fields of applied nanotechnology and biotechnology), medical sciences, pharmaceutical sciences, and engineering. The multidisciplinary aspects of the journal encourage global collaboration between researchers in multiple fields and provide cross-disciplinary dissemination of findings.