Abstract Background: Lung cancer is one of the most prevalent and life-threatening cancers worldwide. Genetic factors contribute to lung cancer risk in smokers and non-smokers, and genome-wide association studies (GWAS) identified 50 genomic loci from diverse populations. Expression quantitative trait loci (eQTL) and splicing QTL (sQTL) analyses can reveal distinct genetic effects on gene- or transcript isoform-level regulation contributing to GWAS signals to identify target genes and elucidate etiology. However, current sQTL studies using short-read sequencing of bulk tissues fail to capture full-length and novel isoforms or cell-type-specific splicing events contributing to tumorigenesis.Methods: We present an isoform-level lung cell atlas from 129 never-smoking Korean women using single-cell long-read RNA-sequencing. Epithelial cells, where lung cancer originate, were enriched by FACS sorting. Isoform signatures of each lung cell type were identified by differential analysis. We mapped isoform-level QTLs (isoQTLs) using jaxQTL negative binomial model of pseudo-bulk counts. Colocalization and transcriptome-wide association study (TWAS) with GWAS were performed to prioritize susceptibility isoforms.Results: We identified 325,865 full-length isoforms from 360,133 lung cells, where 83% are novel isoforms not annotated in GENCODE v32. We identified isoform-level signatures of 37 lung cell types, where 67.2% of differential isoforms display larger differences than in gene levels. Isoform-QTLs (isoQTLs) identified unreported genes in bulk tissue-based sQTL studies attributed to cell-type-specific and unannotated isoforms. Compared to the barcode-matched short-read expression data, 46% of isoQTLs did not colocalize with eQTLs in the same cell type. Consistently, isoQTLs were distinctly enriched in the functional elements of splicing and post-transcriptional regulation. Colocalization of isoQTLs with lung cancer and trait GWAS signals nominated candidate isoforms, where 69% were previously unreported at the gene level. Moreover, 71% of GWAS-colocalized isoforms were independent from eQTLs, including PPIL6-207 for lung cancer. TWAS of ancestry-matched lung adenocarcinoma identified 12 isoforms from the sub-threshold GWAS regions, which include lineage or cell-type-specific genes.Conclusions: We established an isoform-level lung cell atlas using single-cell long-read sequencing and detected isoQTLs that are cell-type-specific and independent from eQTLs. This isoform-level resource advances our understanding of cell-type-specific isoform regulation and its contribution to lung cancer and diseases. Citation Format: Bolun Li, Thong Luong, Elelta Sisay, Jinhu Yin, Zixuan Zhang, Ju Hye Shin, Jinyoung Byun, Yoon Soo Chang, Maria Teresa Landi, Nat Rothman, Erping Long, Qing Lan, Christopher I. Amos, Tongwu Zhang, Jianxin Shi, Nicholas Mancuso, Haoyu Zhang, Jin Gu Lee, Eon Young Kim, Jiyeon Choi. Single-cell full-length transcriptome of lung cells reveals genetic effects on isoform regulation beyond eQTL abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5924.
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