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Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer

Author

Listed:
  • Congcong Chen

    (Nanjing Medical University
    Nanjing Medical University)

  • Yang Li

    (Nanjing Medical University)

  • Yayun Gu

    (Nanjing Medical University)

  • Qiqi Zhai

    (Nanjing Medical University)

  • Songwei Guo

    (Nanjing Medical University)

  • Jun Xiang

    (Nanjing Medical University)

  • Yuan Xie

    (Nanjing Medical University)

  • Mingxing An

    (Nanjing Medical University)

  • Chenmeijie Li

    (Nanjing Medical University)

  • Na Qin

    (Nanjing Medical University
    Nanjing Medical University)

  • Yanan Shi

    (Nanjing Medical University)

  • Liu Yang

    (Nanjing Medical University)

  • Jun Zhou

    (Nanjing Medical University)

  • Xianfeng Xu

    (Nanjing Medical University)

  • Ziye Xu

    (Nanjing Medical University)

  • Kai Wang

    (Nanjing Medical University)

  • Meng Zhu

    (Nanjing Medical University
    Nanjing Medical University)

  • Yue Jiang

    (Nanjing Medical University
    Nanjing Medical University)

  • Yuanlin He

    (Nanjing Medical University
    Nanjing Medical University)

  • Jing Xu

    (The First Affiliated Hospital of Nanjing Medical University)

  • Rong Yin

    (Nanjing Medical University Affiliated Cancer Hospital)

  • Liang Chen

    (The First Affiliated Hospital of Nanjing Medical University)

  • Lin Xu

    (Nanjing Medical University Affiliated Cancer Hospital)

  • Juncheng Dai

    (Nanjing Medical University
    Nanjing Medical University)

  • Guangfu Jin

    (Nanjing Medical University
    Nanjing Medical University)

  • Zhibin Hu

    (Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University)

  • Cheng Wang

    (Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University)

  • Hongxia Ma

    (Nanjing Medical University
    Nanjing Medical University
    Chinese Academy of Medical Sciences)

  • Hongbing Shen

    (Nanjing Medical University
    Nanjing Medical University
    Chinese Academy of Medical Sciences)

Abstract

Genome-wide association studies have identified thousands of genetic variants associated with non-small cell lung cancer (NSCLC), however, it is still challenging to determine the causal variants and to improve disease risk prediction. Here, we applied massively parallel reporter assays to perform NSCLC variant-to-function mapping at scale. A total of 1249 candidate variants were evaluated, and 30 potential causal variants within 12 loci were identified. Accordingly, we proposed three genetic architectures underlying NSCLC susceptibility: multiple causal variants in a single haplotype block (e.g. 4q22.1), multiple causal variants in multiple haplotype blocks (e.g. 5p15.33), and a single causal variant (e.g. 20q11.23). We developed a modified polygenic risk score using the potential causal variants from Chinese populations, improving the performance of risk prediction in 450,821 Europeans from the UK Biobank. Our findings not only augment the understanding of the genetic architecture underlying NSCLC susceptibility but also provide strategy to advance NSCLC risk stratification.

Suggested Citation

  • Congcong Chen & Yang Li & Yayun Gu & Qiqi Zhai & Songwei Guo & Jun Xiang & Yuan Xie & Mingxing An & Chenmeijie Li & Na Qin & Yanan Shi & Liu Yang & Jun Zhou & Xianfeng Xu & Ziye Xu & Kai Wang & Meng Z, 2025. "Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56725-w
    DOI: 10.1038/s41467-025-56725-w
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