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Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk

Author

Listed:
  • Pingting Ying

    (Wuhan University
    Zhongnan Hospital of Wuhan University
    Renmin Hospital of Wuhan University)

  • Can Chen

    (Wuhan University
    Zhongnan Hospital of Wuhan University
    Renmin Hospital of Wuhan University)

  • Zequn Lu

    (Wuhan University
    Zhongnan Hospital of Wuhan University
    Renmin Hospital of Wuhan University)

  • Shuoni Chen

    (Wuhan University)

  • Ming Zhang

    (Wuhan University)

  • Yimin Cai

    (Wuhan University)

  • Fuwei Zhang

    (Wuhan University)

  • Jinyu Huang

    (Wuhan University)

  • Linyun Fan

    (Wuhan University)

  • Caibo Ning

    (Wuhan University)

  • Yanmin Li

    (Wuhan University)

  • Wenzhuo Wang

    (Wuhan University)

  • Hui Geng

    (Wuhan University)

  • Yizhuo Liu

    (Wuhan University)

  • Wen Tian

    (Wuhan University)

  • Zhiyong Yang

    (Zhongnan Hospital of Wuhan University)

  • Jiuyang Liu

    (Wuhan University)

  • Chaoqun Huang

    (Wuhan University)

  • Xiaojun Yang

    (Wuhan University)

  • Bin Xu

    (Wuhan University)

  • Heng Li

    (Huazhong University of Science and Technology)

  • Xu Zhu

    (Renmin Hospital of Wuhan University)

  • Ni Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bin Li

    (Wuhan University)

  • Yongchang Wei

    (Zhongnan Hospital of Wuhan University)

  • Ying Zhu

    (Wuhan University)

  • Jianbo Tian

    (Wuhan University
    Zhongnan Hospital of Wuhan University
    Renmin Hospital of Wuhan University)

  • Xiaoping Miao

    (Wuhan University
    Zhongnan Hospital of Wuhan University
    Renmin Hospital of Wuhan University
    Huazhong University of Sciences and Technology)

Abstract

Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05–1.16, P = 4.02 × 10−5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.

Suggested Citation

  • Pingting Ying & Can Chen & Zequn Lu & Shuoni Chen & Ming Zhang & Yimin Cai & Fuwei Zhang & Jinyu Huang & Linyun Fan & Caibo Ning & Yanmin Li & Wenzhuo Wang & Hui Geng & Yizhuo Liu & Wen Tian & Zhiyong, 2023. "Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41690-z
    DOI: 10.1038/s41467-023-41690-z
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