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

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.