跨组织全转录组关联研究揭示的脓毒症新易感基因

Tao Linfeng, Zhu Ning, Zhu Yue, Li Chao, Pan Yiyuan, Chen Yan, Liu Jun

Gusu School of Nanjing Medical University, Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou 215001, China.

Department of Breast and Thyroid Surgery, the Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou 215002, China.

Shock. 2025 Jul 23. doi: 10.1097/SHK.0000000000002652.

BACKGROUND

Sepsis, a life-threatening syndrome triggered by a dysregulated host response to infection, continues to impose a substantial global health burden. Advances in genomics and transcriptomics now enable systematic exploration of sepsis pathogenesis at the genetic level. The integration of genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) offers a powerful framework to identify causal genetic variants and delineate molecular mechanisms underlying sepsis susceptibility and clinical outcomes.

METHODS

A cross-tissue TWAS was implemented using UTMOST to integrate sepsis GWAS summary statistics with transcriptomic data from the Genotype-Tissue Expression version 8 (GTEx v8) project. Candidate genes were validated through complementary approaches: FUSION, FOCUS, and MAGMA. Tissue-specific and pathway enrichment analyses were applied to prioritize sepsis-associated genes and characterize their functional roles in disease-relevant biological processes. Bayesian colocalization and two-sample Mendelian randomization (MR) analyses were employed to infer putative causal relationships between prioritized genes and sepsis risk.

RESULTS

Four genes-ZCCHC4, PDGFB, C18orf54, and ATG4B-demonstrated significant associations with sepsis susceptibility in cross-tissue analyses. Two-sample MR provided evidence for causal effects of genetically regulated expression of these genes on sepsis risk. Bayesian colocalization identified shared causal variants between sepsis-associated loci and expression quantitative trait loci (eQTLs), implicating dysregulation of inflammatory and autophagy pathways in sepsis pathogenesis.

CONCLUSION

Our results highlight the efficacy of cross-tissue TWAS in mapping sepsis-associated loci and elucidating the genetic architecture underlying sepsis susceptibility. These prioritized loci constitute compelling targets for functional validation and represent actionable candidates for therapeutic intervention in sepsis.

背景

脓毒症是一种由宿主对感染的失调反应引发的危及生命的综合征，持续给全球健康带来沉重负担。基因组学和转录组学的进展使得在基因水平上系统探索脓毒症发病机制成为可能。全基因组关联研究（GWAS）和全转录组关联研究（TWAS）的整合提供了一个强大的框架，用于识别因果基因变异并描绘脓毒症易感性和临床结局背后的分子机制。

方法

使用UTMOST进行跨组织TWAS，将脓毒症GWAS汇总统计数据与来自基因型-组织表达版本8（GTEx v8）项目的转录组数据整合。通过互补方法对候选基因进行验证：FUSION、FOCUS和MAGMA。应用组织特异性和通路富集分析对脓毒症相关基因进行优先级排序，并表征它们在疾病相关生物学过程中的功能作用。采用贝叶斯共定位和双样本孟德尔随机化（MR）分析来推断优先级基因与脓毒症风险之间的假定因果关系。

结果

在跨组织分析中，四个基因——ZCCHC4、PDGFB、C18orf54和ATG4B——显示出与脓毒症易感性显著相关。双样本MR为这些基因的基因调控表达对脓毒症风险的因果效应提供了证据。贝叶斯共定位确定了脓毒症相关位点与表达数量性状位点（eQTL）之间的共享因果变异，提示炎症和自噬通路失调在脓毒症发病机制中的作用。