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<p>The roles of various immune cells and circulating inflammatory factors in neurodevelopmental disorders (NDDs) remain controversial. Therefore we employed a two-sample and bidirectional Mendelian randomization and mediation method to explore the causal relationships between immune cells, circulating inflammatory factors, and NDDs. All data were originated from Genome-Wide Association Study (GWAS) datasets. We found a significant positive causal relationship between 13 immune cells and autism spectrum disorder (ASD), including six CD8+ T cells, one CD3+ T cell, two CD20+ B cells, one CD38+  B cell, and two plasmacytoid DC. 9 inflammatory factors showed significant causal relationships with ASD: interleukins-7 (IL-7), interleukins-2 (IL-2), Interleukin-2 receptor subunit beta levels( IL-2β) and interleukins-18 receptor 1 levels (IL-18-R1) were negatively associated. In contrast, five inflammatory factors were positively associated, such as tumor necrosis factor-α (TNF-α). 14 immune cells exhibited significant causal relationships with attention deficit hyperactivity disorder (ADHD). CD3 on naive CD8br and CD4 on activated Treg were positively associated, while four CD27-expressing B cells were positively associated with ASD. Four CD40-expressing monocytes were negatively associated with ADHD. 7 inflammatory factors had significant causal relationships with ADHD: Fibroblast Growth Factor 23 levels (FGF-23), CD40L receptor levels, Glial Cell Line-Derived Neurotrophic Factor levels (GDNF), TNF-α were more important among these. Mediation analysis identified 12 mediating relationships, with three showing strong evidence: Natural killer cell receptor 2B4 levels (19.9%), FGF-23 (11%), and Eotaxin levels (− 5.95%). Strong causal relationships existed between immune cells, circulating inflammatory factors, and NDDs. Inflammatory factors mediated the pathways between immune cells and NDDs.</p>

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Identification of immune cells and circulating inflammatory factors associated with neurodevelopmental disorders by bidirectional Mendelian randomization and mediation analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月14日

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  • Zhiyue Liu,
  • Lihong Wang,
  • Lianhu Yu,
  • Yongheng Zhao,
  • Mengna Zhu,
  • Yu Wang,
  • Aihua Cao

摘要

The roles of various immune cells and circulating inflammatory factors in neurodevelopmental disorders (NDDs) remain controversial. Therefore we employed a two-sample and bidirectional Mendelian randomization and mediation method to explore the causal relationships between immune cells, circulating inflammatory factors, and NDDs. All data were originated from Genome-Wide Association Study (GWAS) datasets. We found a significant positive causal relationship between 13 immune cells and autism spectrum disorder (ASD), including six CD8+ T cells, one CD3+ T cell, two CD20+ B cells, one CD38+  B cell, and two plasmacytoid DC. 9 inflammatory factors showed significant causal relationships with ASD: interleukins-7 (IL-7), interleukins-2 (IL-2), Interleukin-2 receptor subunit beta levels( IL-2β) and interleukins-18 receptor 1 levels (IL-18-R1) were negatively associated. In contrast, five inflammatory factors were positively associated, such as tumor necrosis factor-α (TNF-α). 14 immune cells exhibited significant causal relationships with attention deficit hyperactivity disorder (ADHD). CD3 on naive CD8br and CD4 on activated Treg were positively associated, while four CD27-expressing B cells were positively associated with ASD. Four CD40-expressing monocytes were negatively associated with ADHD. 7 inflammatory factors had significant causal relationships with ADHD: Fibroblast Growth Factor 23 levels (FGF-23), CD40L receptor levels, Glial Cell Line-Derived Neurotrophic Factor levels (GDNF), TNF-α were more important among these. Mediation analysis identified 12 mediating relationships, with three showing strong evidence: Natural killer cell receptor 2B4 levels (19.9%), FGF-23 (11%), and Eotaxin levels (− 5.95%). Strong causal relationships existed between immune cells, circulating inflammatory factors, and NDDs. Inflammatory factors mediated the pathways between immune cells and NDDs.