整合单细胞eQTL和GWAS分析识别ESCC易感性的细胞类型特异性调控机制
Integrative single-cell eQTL and GWAS analyses identify cell-type-specific regulatory mechanisms underlying ESCC susceptibility.
摘要(中文译文)
在相关细胞背景中解读遗传风险变异仍然是食管鳞状细胞癌（ESCC）这一具有显著遗传易感性的恶性肿瘤的核心挑战。我们将单细胞RNA测序与基因型数据整合，构建了覆盖ESCC组织中上皮、免疫和基质区室的细胞类型解析表达数量性状位点（sc-eQTL）图谱。大多数调控效应具有高度细胞类型特异性，且在批量转录组分析中大多无法检测到。与ESCC全基因组关联研究整合后发现，风险变异在特定细胞群体中显著富集，最突出的是在侵袭性上皮细胞中。细胞类型特异性转录组范围关联分析、孟德尔随机化和共定位分析将RPS3A优先确定为易感基因，其受遗传调控的表达与ESCC风险变异共定位，并在恶性进展过程中升高。精细定位识别出影响RPS3A表达的协同增强子-启动子变异，整合功能分析提示RPS3A参与可变剪接程序。这些结果建立了一个细胞类型解析的调控框架，用于解读ESCC中的遗传易感性。
Abstract
Interpreting genetic risk variants within their relevant cellular contexts remains a central challenge in esophageal squamous cell carcinoma (ESCC), a malignancy with a substantial inherited component. We integrate single-cell RNA sequencing with genotype data to generate a cell-type-resolved expression quantitative trait loci (sc-eQTL) map spanning epithelial, immune, and stromal compartments in ESCC tissues. Most regulatory effects are highly cell-type-specific and largely undetectable in bulk transcriptomic analyses. Integration with ESCC genome-wide association studies reveals significant enrichment of risk variants in defined cellular populations, most prominently within invasive epithelial cells. Cell-type-specific transcriptome-wide association, Mendelian randomization, and colocalization analyses prioritize RPS3A as a susceptibility gene whose genetically regulated expression colocalizes with ESCC risk variants and increases during malignant progression. Fine-mapping identifies cooperative enhancer-promoter variants influencing RPS3A expression, and integrative functional analyses implicate RPS3A in alternative splicing programs. These results establish a cell-type-resolved regulatory framework for interpreting inherited susceptibility in ESCC.
如何引用
AMA
Lina Song, Miaoxin Pan, Yueping Li, Shasha Liu, Jialing Ma, Qianqian Su, et al. Integrative single-cell eQTL and GWAS analyses identify cell-type-specific regulatory mechanisms underlying ESCC susceptibility.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117790.
APA
Lina Song, Miaoxin Pan, Yueping Li, Shasha Liu, Jialing Ma, Qianqian Su, et al (2026). Integrative single-cell eQTL and GWAS analyses identify cell-type-specific regulatory mechanisms underlying ESCC susceptibility.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117790
GB/T 7714
Lina Song, Miaoxin Pan, Yueping Li, Shasha Liu, Jialing Ma, Qianqian Su, et al. Integrative single-cell eQTL and GWAS analyses identify cell-type-specific regulatory mechanisms underlying ESCC susceptibility.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117790.
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