Mitochondria-Related Pathogenic Genes in Paediatric Asthma: A Multi-Omics Mendelian Randomization Study

Area of Science:

• Genetics and Genomics
• Systems Biology
• Respiratory Medicine

Background:

• Mitochondrial dysfunction is linked to asthma, but causal genetic factors in children are not well understood.
• Identifying specific mitochondrial-related genes involved in paediatric asthma is crucial for understanding disease mechanisms.

Purpose of the Study:

• To investigate the causal roles of mitochondrial-related genes in paediatric asthma using a multi-omics approach.
• To identify specific genes and regulatory pathways implicated in the pathogenesis of childhood asthma.

Main Methods:

• A multi-omics Mendelian randomization study integrating genome-wide association study (GWAS) data with methylation, expression, and protein quantitative trait loci (mQTLs, eQTLs, pQTLs).
• Utilized Summary-data-based Mendelian Randomization (SMR) and HEIDI testing, followed by colocalization analysis for causal inference.
• Validated findings in independent cohorts and explored tissue specificity using the Genotype-Tissue Expression (GTEx) database; conducted functional enrichment and protein-protein interaction (PPI) network analyses.

Main Results:

• Identified 80 methylation sites, 26 gene expressions, and three proteins significantly associated with paediatric asthma.
• Confirmed causal evidence for 10 methylation sites (7 genes), the STX17 eQTL, and the UNG pQTL through colocalization analysis.
• Multi-omics integration highlighted ALAS1 and TXNRD1, with DNA methylation potentially regulating their expression, converging on mitochondrial metabolic pathways. Seven hub genes were identified.

Conclusions:

• Provides multi-omics evidence for a causal role of mitochondrial-related genes, specifically ALAS1 and TXNRD1, in paediatric asthma.
• Suggests DNA methylation as a potential regulatory mechanism for ALAS1 and TXNRD1 expression in asthma pathogenesis.
• Offers novel insights into childhood asthma mechanisms and identifies potential therapeutic targets.