Integrative single-cell eQTL and GWAS analyses identify cell-type-specific regulatory mechanisms underlying ESCC...

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Interpreting genetic risk variants in esophageal squamous cell carcinoma (ESCC) is challenging due to the need for cellular context.
• ESCC has a significant inherited component, necessitating a deeper understanding of its genetic underpinnings.

Purpose of the Study:

• To create a cell-type-resolved map of gene expression regulation in ESCC tissues.
• To identify specific cellular populations and genetic variants contributing to ESCC susceptibility.

Main Methods:

• Integration of single-cell RNA sequencing (scRNA-seq) with genotype data to generate a cell-type-resolved expression quantitative trait loci (sc-eQTL) map.
• Analysis of epithelial, immune, and stromal compartments within ESCC tissues.
• Integration with genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS).

Main Results:

• Most regulatory effects of genetic variants are cell-type-specific and missed by bulk analyses.
• ESCC risk variants are enriched in specific cell populations, particularly invasive epithelial cells.
• RPS3A is identified as a key susceptibility gene, with its expression linked to ESCC risk variants and malignant progression.

Conclusions:

• A cell-type-resolved regulatory framework is established for interpreting inherited susceptibility in ESCC.
• The study highlights the importance of cell-specific regulatory mechanisms in cancer genetics.
• RPS3A plays a role in ESCC pathogenesis through alternative splicing programs influenced by genetic variants.