Single-cell eQTL mapping reveals cell-type-specific genetic regulation in lung cancer
Genome-wide association studies (GWASs) have identified over 50 lung cancer risk loci; however, the precise cellular context of these genetic mechanisms remains unclear due to limitations in bulk tissue expression quantitative trait locus (eQTL) analyses. Here, we present the largest single-cell eQTL (sc-eQTL) atlas of human lung tissue to date, profiling 222 donors using multiplexed single-cell RNA sequencing (scRNA-seq). We identified 4,341 independent eQTLs across 17 cell types, with over 60% of sc-eQTLs and 51% of eGenes being cell-type specific, and fewer than 52% were detectable in paired bulk datasets. Integration with GWASs for non-small cell lung cancer highlighted epithelial and immune cells as key contributors to genetic susceptibility, identifying 28 candidate genes within known risk loci and 24 in novel regions. Notably, 47% of established non-small cell lung cancer (NSCLC) susceptibility loci exhibited cell-type-specific pleiotropic genetic regulation. This study provides a valuable resource of lung sc-eQTLs and illuminates how genetic variation modulates gene expression in a cell-type-specific fashion, contributing to lung cancer susceptibility.
Authors
- Hongbing Shen (ORCID: https://orcid.org/0000-0002-2581-5906)
- Hongxia Ma (ORCID: https://orcid.org/0000-0002-9821-6955)
- Lijun Bian (ORCID: https://orcid.org/0000-0002-2865-0721)
- Mengping Wang (ORCID: https://orcid.org/0000-0001-5655-9004)
- Jin Chen (ORCID: https://orcid.org/0000-0002-5557-2079)
- Chenying Jin
- Yuanlin Mou (ORCID: https://orcid.org/0000-0003-4117-9660)
- Chang Zhang (ORCID: https://orcid.org/0000-0003-0404-2446)
- Guangfu Jin (ORCID: https://orcid.org/0000-0003-0249-5337)
- Linnan Gong
- Shuying Miao (ORCID: https://orcid.org/0000-0001-7729-5343)
- Huimin Ma (ORCID: https://orcid.org/0000-0001-7361-6381)
- Yating Fu (ORCID: https://orcid.org/0009-0009-0278-4594)
- Erbao Zhang (ORCID: https://orcid.org/0000-0002-5752-7976)
- Xinyuan Ge (ORCID: https://orcid.org/0000-0002-3242-8912)
- Xiaoyang Ma (ORCID: https://orcid.org/0000-0002-8198-6785)
- Shihao Wu (ORCID: https://orcid.org/0000-0002-3360-1633)
- Gang Chen (ORCID: https://orcid.org/0000-0002-9989-2381)
- Cheng Zhang (ORCID: https://orcid.org/0000-0001-5317-8775)
- Meng Zhu (ORCID: https://orcid.org/0000-0001-5122-1733)
- Yi Wang (ORCID: https://orcid.org/0000-0001-8042-5970)
- Jiaying Cai
- Yong Dai (ORCID: https://orcid.org/0000-0003-1260-4234)
- Juncheng Dai (ORCID: https://orcid.org/0000-0002-4813-0168)
- Zhibin Hu
Institutions
- Nanjing Municipal Center for Disease Control And Prevention (CN)
- Nanjing Chest Hospital (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-12-11
- DOI
- https://doi.org/10.1016/j.xgen.2025.101100
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Government of Jiangsu Province
- National Science and Technology Major Project