Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes

Erping Long, Jinhu Yin, Ju Hye Shin, Yuyan Li, Bolun Li, Alexander Kane, Harsh Patel, Xinti Sun, Cong Wang, Thong Luong, Jun Xia, Younghun Han, Jinyoung Byun, Tongwu Zhang, Wei Zhao, Maria Teresa Landi, Nathaniel Rothman, Qing Lan, Yoon Soo Chang, Fulong Yu, Christopher I. Amos, Jianxin Shi, Jin Gu Lee (), Eun Young Kim () and Jiyeon Choi ()
Additional contact information
Erping Long: National Cancer Institute
Jinhu Yin: National Cancer Institute
Ju Hye Shin: Yonsei University College of Medicine
Yuyan Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Bolun Li: National Cancer Institute
Alexander Kane: National Cancer Institute
Harsh Patel: National Cancer Institute
Xinti Sun: Chinese Academy of Medical Sciences and Peking Union Medical College
Cong Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Thong Luong: National Cancer Institute
Jun Xia: Creighton University
Younghun Han: Baylor College of Medicine
Jinyoung Byun: Baylor College of Medicine
Tongwu Zhang: National Cancer Institute
Wei Zhao: National Cancer Institute
Maria Teresa Landi: National Cancer Institute
Nathaniel Rothman: National Cancer Institute
Qing Lan: National Cancer Institute
Yoon Soo Chang: Yonsei University College of Medicine
Fulong Yu: Guangzhou International Bio Island
Christopher I. Amos: Baylor College of Medicine
Jianxin Shi: National Cancer Institute
Jin Gu Lee: Yonsei University College of Medicine
Eun Young Kim: Yonsei University College of Medicine
Jiyeon Choi: National Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function.

Date: 2024
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DOI: 10.1038/s41467-024-52356-9

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