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

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 Yang, Jiuyang Liu, Chaoqun Huang, Xiaojun Yang, Bin Xu, Heng Li, Xu Zhu, Ni Li, Bin Li, Yongchang Wei, Ying Zhu, Jianbo Tian () and Xiaoping Miao ()
Additional contact information
Pingting Ying: Wuhan University
Can Chen: Wuhan University
Zequn Lu: 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
Xiaoping Miao: Wuhan University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41690-z

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