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

Author

Listed:
  • Erping Long

    (National Cancer Institute
    Chinese Academy of Medical Sciences and Peking Union Medical College)

  • 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)

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.

Suggested Citation

  • 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 & Ma, 2024. "Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52356-9
    DOI: 10.1038/s41467-024-52356-9
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