Lina Song, Miaoxin Pan, Yueping Li, Shasha Liu, Jialing Ma, Qianqian Su, Yutong Wu, Zifei Yang, Yintong Luo, Jingwei Feng, Ni Zhang, Wei Ping, Li Zhang, Yuan Lin, Chen Wu, Jiang Chang
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.