Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk
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Published:2023-09-25
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Ying Pingting, Chen Can, Lu Zequn, Chen Shuoni, Zhang Ming, Cai YiminORCID, Zhang Fuwei, Huang Jinyu, Fan Linyun, Ning Caibo, Li Yanmin, Wang Wenzhuo, Geng Hui, Liu Yizhuo, Tian Wen, Yang Zhiyong, Liu Jiuyang, Huang Chaoqun, Yang Xiaojun, Xu Bin, Li Heng, Zhu Xu, Li NiORCID, Li Bin, Wei Yongchang, Zhu Ying, Tian JianboORCID, Miao XiaopingORCID
Abstract
AbstractGenome-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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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