Single-cell full-length transcriptome of human lung reveals genetic effects on isoform regulation beyond gene-level expression
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Genetic regulation of splicing uniquely contributes to trait-associated genome-wide association studies (GWAS) signals. However, quantitative trait loci (QTL) analysis using short-read sequencing of bulk tissues fails to capture full-length and cell-type-specific isoforms. Here, we present an isoform-level lung cell atlas from 129 never-smoking Korean women using single-cell long-read RNA-sequencing, identifying abundant unannotated and cell-type-specific isoforms. Isoform-level signatures of 37 lung cell types display a larger difference and therefore improve cell-type classification compared to gene-level expression. Notably, isoform-QTLs (isoQTLs) detect unannotated and/or cell-type-specific isoforms with independent genetic regulation from expression-QTL (eQTL), supported by enriched splicing functional elements. IsoQTLs nominate susceptibility isoforms from previously unexplained lung function and cancer GWAS loci, via eQTL-independent signals. We highlight a potentially functional novel variant of PPIL6 in multiciliated cells underlying lung cancer risk through alternative splicing. This isoform-level resource advances our understanding of cell-type-specific isoform regulation and its contribution to lung traits and diseases.
Authors: Bolun Li, Thong Luong, Elelta Sisay, Jinhu Yin, Zixuan Eleanor Zhang, Maryam Vaziripour, Ju Hye Shin, Yongmei Zhao, Bao Tran, Jinyoung Byun, Yafang Li, Chia Han Lee, Maura O’Neill, Thorkell Andresson, Yoon Soo Chang, Steven Gazal, Maria Teresa Landi, Nathaniel Rothman, Erping Long, Qing Lan, Christopher I Amos, Anny Xiaobo Zhou, Tongwu Zhang, Jin Gu Lee, Jianxin Shi, Nicholas Mancuso, Jun Xia, Haoyu Zhang, Eun Young Kim, Jiyeon Choi
Institutions: National Institutes of Health, Division of Cancer Epidemiology and Genetics, University of Pennsylvania, Yonsei University, Yonsei University Health System, Frederick National Laboratory for Cancer Research, University of New Mexico, National Cancer Institute, Center for Cancer Research, University of Southern California, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, University of Virginia
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7143370142