Integrating single-cell transcriptomics and epigenetics in a multi-omics MR framework identifies PARK7 as a causal gene in streptococcal septicemia

Streptococcal septicemia is associated with high mortality and morbidity, yet the underlying epigenetic mechanisms, particularly those involving mitochondrial genes, remain poorly understood. This study employed a multi-omics Mendelian randomization (MR) framework to investigate the causal role of mitochondrial gene regulation in streptococcal septicemia, with an emphasis on epigenetic influences. We utilized genetic instruments—including cis-methylation quantitative trait loci (mQTLs), cis-expression QTLs (eQTLs), and cis-protein QTLs (pQTLs)—for 1,136 mitochondrial-related genes from MitoCarta3.0. These were analyzed for causal associations with streptococcal septicaemia (FinnGen R12: 3,239 cases, 439,048 controls). Epigenetic and transcriptomic data were integrated with MR analyses of 731 immune cell traits. Single-cell RNA sequencing (GSE175453: 4 sepsis patients, 5 controls) and bulk transcriptomic data (GSE57065: 28 septic shock patients, 25 controls) were used for validation. Additionally, single-cell eQTLs for PARK7 across 14 immune cell types were applied in MR to evaluate cell-type-specific causality. MR analyses identified 280 mQTLs, 79 eQTLs, and 29 pQTLs with causal links to streptococcal septicemia. Integrative multi-omics analysis revealed PARK7 as the only gene consistently implicated across epigenetic, transcriptomic, and proteomic levels. Epigenetic regulation via mQTLs was notably prominent. Single-cell RNA sequencing demonstrated significant PARK7 upregulation in T and NK cells from sepsis patients, corroborated by elevated PARK7 expression in septic shock patients across multiple timepoints. Temporal correlation analyses indicated that PARK7 levels inversely correlated with depleted CD8 + T cells, naive CD4 + T cells, and resting NK cells. Critically, sc-eQTL MR confirmed that genetically predicted PARK7 upregulation in two immune subsets—CD4 + KLRB1+ T cells and CD4 + KLRB1- T cells—causally increased septicemia risk. Our multi-omics genetic approach establishes PARK7 as a causal gene in streptococcal septicemia, mediated in part by epigenetic mechanisms. PARK7 upregulation in specific T and NK cell subsets contributes to susceptibility, linking mitochondrial epigenetic regulation to immune dysfunction and underscoring its potential as a therapeutic target.