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

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.