Researchers have identified the gene PARK7 as a causal factor in streptococcal septicemia, a life-threatening systemic inflammatory response syndrome caused by bacterial infection. This finding emerges from a comprehensive multi-omics Mendelian randomization framework that integrates single-cell transcriptomics and epigenetic data to dissect the genetic underpinnings of the disease. The study, published in Epigenetics & Chromatin, addresses a critical gap in understanding how mitochondrial gene regulation, specifically through epigenetic mechanisms, influences susceptibility to septicemia. By moving beyond correlation-based inferences typical of observational studies, the team provides genetic evidence that links specific immune cell dysfunctions to the pathogenesis of the condition.
The investigation was driven by the high mortality and morbidity associated with streptococcal septicemia, with conditions such as Group B Streptococcus sepsis exhibiting a 7% mortality rate. While previous genome-wide association studies have uncovered genetic susceptibility loci, they have often failed to pinpoint definitive causal genes due to linkage disequilibrium. The research team aimed to systematically investigate how mitochondrial genes and their epigenetic regulation contribute to septicemia, a systematic causal investigation that had previously been lacking in the field.
To address these questions, the researchers employed an integrated multi-omics Mendelian randomization framework with a specific emphasis on epigenetic regulation. They utilized genetic instruments, including cis-methylation quantitative trait loci, cis-expression QTLs, and cis-protein QTLs, for 1,136 mitochondrial-related genes from the MitoCarta3.0 database. These instruments were analyzed for causal associations with streptococcal septicemia using data from the FinnGen project, which included 3,239 cases and 439,048 controls. The approach allowed the team to infer causality by leveraging genetic variants as proxies for epigenetic, transcriptomic, and proteomic changes, thereby identifying key genes whose influence is consistent across multiple molecular levels.
The Mendelian randomization analyses revealed significant causal links between various genetic variants and streptococcal septicemia. Specifically, the study identified 280 statistically significant mQTL loci, 79 eQTLs, and 29 pQTLs with causal associations with the disease. Among the mQTLs, high methylation levels at 116 loci conferred a protective effect, whereas increased methylation at 164 loci was associated with elevated risk. The most significant MR association was observed for the methylation probe cg10385390, associated with the PARK7 gene, which exhibited an odds ratio of 0.74. This suggests that epigenetic silencing via hypermethylation at this specific site may reduce susceptibility to streptococcal septicemia by suppressing the expression of the PARK7 gene.
Integrative multi-omics analysis further revealed that PARK7 was the only gene consistently implicated across epigenetic, transcriptomic, and proteomic levels. This cross-omics convergence robustly addresses the limitation of conventional GWAS in pinpointing causal genes from linkage disequilibrium blocks. The consistent causal associations across mQTL, eQTL, and pQTL data provide strong genetic evidence for PARK7’s involvement. The direction of effects revealed a complex epigenetic regulatory paradigm where hypermethylation at the cg10385390 site was protective, likely through transcriptional repression, whereas other genetic instruments for increased PARK7 expression and protein levels consistently elevated disease risk. This indicates that fine-tuned epigenetic and transcriptional regulation of PARK7 is critical, with its overexpression being detrimental to the host.
To validate these genetic findings, the team analyzed single-cell RNA sequencing data from a public dataset comprising peripheral blood mononuclear cells from four sepsis patients and five healthy controls. Unsupervised clustering identified major immune cell lineages, including monocytes, T cells, B cells, and natural killer cells. Differential expression analysis revealed a significant upregulation of PARK7 specifically in T cells and NK cells from sepsis patients compared to healthy controls. No significant differences in PARK7 expression were observed in monocytes, B cells, platelets, or other progenitor cell types. This cell-type-specific expression pattern provides a plausible mechanistic link to the immune dysregulation observed in sepsis.
Further validation was conducted using bulk transcriptomic data from 28 septic shock patients and 25 healthy controls, sampled at 30 minutes, 24 hours, and 48 hours after shock onset. PARK7 transcript levels were significantly elevated in the blood of septic shock patients across all three time points compared to controls. An additional independent validation using a multi-center transcriptomic study of 392 human samples confirmed that PARK7 was among the genes showing significant upregulation in the sepsis group. These findings corroborate the genetic evidence and illustrate the sustained increase in PARK7 expression during the progression of septic shock.
The study also examined the dynamic changes in the immune landscape during sepsis progression. Analysis of immune cell composition revealed that septic shock patients exhibited significant decreases in CD8+ T cells, naive CD4+ T cells, and resting NK cells across all time points compared to healthy controls. Temporal correlation analyses indicated that PARK7 levels were significantly negatively correlated with the abundances of these depleted cell populations. This suggests that PARK7 may be involved in the lymphopenia and NK cell dysfunction that characterize sepsis immunopathology, linking mitochondrial epigenetic regulation to specific immune cell dysfunctions.
Finally, the researchers applied single-cell eQTL data for PARK7 across 14 immune cell types in a follow-up Mendelian randomization analysis to evaluate cell-type-specific causality. This analysis confirmed that genetically predicted PARK7 upregulation in two specific immune subsets, CD4+ KLRB1+ T cells and CD4+ KLRB1- T cells, causally increased septicemia risk. This finding elevates the role of PARK7 from a general association to a cell-context-dependent causal driver. By extending the MR framework to single-cell resolution, the study demonstrates that the pathogenic mechanism of PARK7 is highly context-specific, providing novel genetic evidence for understanding its functions in sepsis immunopathology.
The study has several limitations that warrant consideration. The primary GWAS and QTL data are derived from European populations, which may limit the generalizability of the findings to other ethnic groups. Additionally, while Mendelian randomization strongly suggests causality, the exact molecular mechanisms by which PARK7 influences immune cell function and sepsis susceptibility remain to be fully elucidated through experimental studies. The opposing effects of different methylation sites on PARK7 represent a specific knowledge gap in understanding the context-dependent epigenetic regulation of this gene. Future research should focus on elucidating the precise role of PARK7 in T cell and NK cell biology during infection and evaluating its potential as a biomarker or therapeutic target.
The study design incorporated a protein-protein interaction network to contextualize the identified genetic signals. Researchers constructed a network comprising 224 nodes and 1,388 interactions using the STRING database to map functional relationships among proteins encoded by the significant QTLs. Within this network, the node with the highest degree centrality was SOD2, a gene previously linked to sepsis pathophysiology. Existing literature cited in the study indicates that SOD2, when carried by neutrophil-derived extracellular vesicles, can alleviate septic coagulopathy by scavenging endothelial reactive oxygen species. Additionally, prior research has shown that SOD2, when upregulated via the SIRT1/FOXO1a pathway, clears mitochondrial reactive oxygen species to mitigate sepsis-induced liver injury. This network analysis provided a broader functional landscape for the causal genes identified in the multi-omics framework.
Parallel Mendelian randomization analyses extended to 731 immune cell traits to identify specific cellular mediators of disease susceptibility. This investigation identified 34 immune cell types or states with significant causal effects on streptococcal septicemia. T-regulatory cells emerged as the most frequently implicated cell type, with 14 distinct Treg traits showing significant associations. This finding suggests a potentially important role for Tregs in the pathogenesis of the condition, aligning with the broader immune dysregulation observed in the transcriptomic data. The integration of these immune trait analyses with the gene-level MR results helped delineate the cellular context in which PARK7 exerts its effects.
The role of PARK7, also known as DJ-1, in sepsis is complex and context-dependent, as highlighted by the study’s discussion of prior literature. Elevated serum PARK7 levels have been associated with an increased risk of acute lung injury in patients with severe sepsis, suggesting its potential utility as a biomarker for adverse outcomes. Conversely, experimental studies in murine models indicate that PARK7 can protect against sepsis by interacting with p47phox to promote NADPH oxidase-dependent reactive oxygen species production, thereby modulating inflammation and improving survival. However, other research demonstrates that PARK7 deficiency can enhance bacterial clearance and reduce organ injury. These apparent discrepancies may be explained by the dualistic functions of PARK7 in different cell types, disease stages, or its differential epigenetic regulation, underscoring the need for context-specific investigations to fully understand its multifaceted role in sepsis pathogenesis.
The study’s methodological approach included specific statistical thresholds to ensure the robustness of the genetic instruments. For the primary two-sample Mendelian randomization analyses, a stringent genome-wide significance threshold of P < 5 × 10⁻⁸ was applied for selecting single-nucleotide polymorphisms associated with the exposure. To avoid confounding due to linkage disequilibrium, a clumping procedure with an r² threshold of less than 0.1 was performed. The inverse-variance weighted method served as the primary analytical approach, supplemented by MR-Egger regression, the weighted median method, and MR-PRESSO for bias assessment. Sensitivity analyses, including Cochran’s Q test for heterogeneity and the MR-Egger intercept test for horizontal pleiotropy, were conducted to validate the causal inferences. For the single-cell eQTL data, where conventional thresholds were not applicable, SNPs were selected based on a P < 0.05 threshold, r² < 0.3, and an F-statistic greater than 10.
Subject of Research: Multi-omics Mendelian randomization analysis of PARK7 in streptococcal septicemia
Article Title: Integrating single-cell transcriptomics and epigenetics in a multi-omics MR framework identifies PARK7 as a causal gene in streptococcal septicemia
Article References: Han, H., Huang, E., Liu, D., Zhang, Y., Zhou, S., Huang, L., & Du, X. (2026). Integrating single-cell transcriptomics and epigenetics in a multi-omics MR framework identifies PARK7 as a causal gene in streptococcal septicemia. Epigenetics & Chromatin, 19(1), Article 20. https://doi.org/10.1186/s13072-026-00673-2
Image Credits: AI Generated
DOI: 10.1186/s13072-026-00673-2
Keywords: PARK7, streptococcal septicemia, Mendelian randomization, epigenetics, single-cell transcriptomics, mitochondrial genes, immune dysfunction, DNA methylation, sepsis, genetic causality, Integrating, single-cell
News Source: Juliet Wilcox. (November 10, 2026). Multi-omics MR study identifies PARK7 as causal in sepsis. Scienmag.
