A multi-omics and mediation-based genetic screening approach identifies STX4 as a key link between epigenetic regulation, immune cells, and childhood asthma
Jun 13, 2025Clinical epigenetics
Genetic and molecular analysis finds STX4 connects gene regulation, immune cells, and childhood asthma
STX4 is identified as a strong candidate gene for childhood asthma through comprehensive genetic analysis.
(MR) analyses confirmed STX4's causal role in childhood asthma susceptibility.
Colocalization analysis indicated shared causal variants between STX4 expression and asthma risk signals.
Protein quantitative trait loci (pQTL) analysis validated that STX4's effects are present at the protein level.
DNA methylation analysis identified key sites where higher methylation reduces the risk of childhood asthma.
Immune cell mediation analysis showed STX4's influence on asthma risk through CD4+ and CD8+ T cell subsets.
Linkage disequilibrium score regression (LDSC) revealed a significant genetic correlation between STX4 and childhood asthma.
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BACKGROUND: Childhood asthma presents a multifaceted immune-driven pathology shaped by genetic, epigenetic, and immune regulatory interactions. Despite extensive genome-wide analyses pinpointing multiple susceptibility loci, the precise functional contributors to asthma pathogenesis remain elusive. This study employs a comprehensive multi-omics framework and (MR) analysis to systematically identify and validate key genetic determinants implicated in childhood asthma.
METHODS: A genome-wide screening of over 19,000 human genes was performed to identify -regulated genes associated with childhood asthma. Two-sample MR was conducted to assess causality, followed by Summary-based Mendelian Randomization (SMR) to validate findings in independent datasets. Colocalization analysis determined whether gene expression and asthma GWAS signals share a common causal variant. Protein quantitative trait loci (pQTL) analysis further validated gene associations at the protein level. DNA methylation quantitative trait loci (mQTL) MR and mediation analysis explored epigenetic regulatory mechanisms, while linkage disequilibrium score regression (LDSC) quantified genome-wide genetic correlations. Immune cell mediation analysis examined potential immune-driven effects, and Phenome-Wide Association Study (PheWAS) evaluated pleiotropy and therapeutic safety.
RESULTS: Following systematic screening, STX4 emerged as a strong candidate gene for childhood asthma. MR and SMR analyses confirmed its causal role, while colocalization analysis provided robust genetic evidence supporting STX4's regulatory influence on childhood asthma susceptibility. pQTL validation confirmed that STX4's effects extend to the protein level, strengthening its biological relevance. DNA methylation analysis revealed key CpG (Cytosine-phosphate-Guanine) sites regulating STX4 expression, with higher methylation levels reducing childhood asthma risk. Immune cell mediation analysis demonstrated that STX4 influences childhood asthma risk via CD4+ and CD8+ T cell subsets. LDSC analysis reinforced a significant genetic correlation between STX4 and childhood asthma, while PheWAS detected no major pleiotropy, suggesting that STX4 is a specific and promising therapeutic target.
CONCLUSIONS: This study systematically identifies and validates STX4 as a key genetic regulator in childhood asthma by integrating large-scale genetic, epigenetic, and immune regulatory data. These findings provide strong evidence for STX4's role in childhood asthma pathogenesis, highlighting STX4 as a potential target for future precision therapies in childhood asthma.
Key numbers
0.55
Genetic correlation
LDSC analysis results for STX4 and childhood asthma.
15,695
15,695 genes
Total genes evaluated for causal effects on childhood asthma risk.
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