IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-41690-z.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-41690-z
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-41690-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kaivalya Walavalkar & Bharath Saravanan & Anurag Kumar Singh & Ranveer Singh Jayani & Ashwin Nair & Umer Farooq & Zubairul Islam & Deepanshu Soota & Rajat Mann & Padubidri V. Shivaprasad & Matthew L. , 2020. "A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Joseph K. Pickrell & John C. Marioni & Athma A. Pai & Jacob F. Degner & Barbara E. Engelhardt & Everlyne Nkadori & Jean-Baptiste Veyrieras & Matthew Stephens & Yoav Gilad & Jonathan K. Pritchard, 2010. "Understanding mechanisms underlying human gene expression variation with RNA sequencing," Nature, Nature, vol. 464(7289), pages 768-772, April.
    3. Joseph Nasser & Drew T. Bergman & Charles P. Fulco & Philine Guckelberger & Benjamin R. Doughty & Tejal A. Patwardhan & Thouis R. Jones & Tung H. Nguyen & Jacob C. Ulirsch & Fritz Lekschas & Kristy Mu, 2021. "Genome-wide enhancer maps link risk variants to disease genes," Nature, Nature, vol. 593(7858), pages 238-243, May.
    4. Fredrick R. Schumacher & Stephanie L. Schmit & Shuo Jiao & Christopher K. Edlund & Hansong Wang & Ben Zhang & Li Hsu & Shu-Chen Huang & Christopher P. Fischer & John F. Harju & Gregory E. Idos & Flavi, 2015. "Genome-wide association study of colorectal cancer identifies six new susceptibility loci," Nature Communications, Nature, vol. 6(1), pages 1-7, November.
    5. Fredrick R. Schumacher & Stephanie L. Schmit & Shuo Jiao & Christopher K. Edlund & Hansong Wang & Ben Zhang & Li Hsu & Shu-Chen Huang & Christopher P. Fischer & John F. Harju & Gregory E. Idos & Flavi, 2015. "Correction: Corrigendum: Genome-wide association study of colorectal cancer identifies six new susceptibility loci," Nature Communications, Nature, vol. 6(1), pages 1-1, December.
    6. Anshul Kundaje & Wouter Meuleman & Jason Ernst & Misha Bilenky & Angela Yen & Alireza Heravi-Moussavi & Pouya Kheradpour & Zhizhuo Zhang & Jianrong Wang & Michael J. Ziller & Viren Amin & John W. Whit, 2015. "Integrative analysis of 111 reference human epigenomes," Nature, Nature, vol. 518(7539), pages 317-330, February.
    7. Carles A. Boix & Benjamin T. James & Yongjin P. Park & Wouter Meuleman & Manolis Kellis, 2021. "Regulatory genomic circuitry of human disease loci by integrative epigenomics," Nature, Nature, vol. 590(7845), pages 300-307, February.
    8. Song Wu & Scott Powers & Wei Zhu & Yusuf A. Hannun, 2016. "Substantial contribution of extrinsic risk factors to cancer development," Nature, Nature, vol. 529(7584), pages 43-47, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Samuel S. Kim & Buu Truong & Karthik Jagadeesh & Kushal K. Dey & Amber Z. Shen & Soumya Raychaudhuri & Manolis Kellis & Alkes L. Price, 2024. "Leveraging single-cell ATAC-seq and RNA-seq to identify disease-critical fetal and adult brain cell types," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Rikifumi Ohta & Yosuke Tanigawa & Yuta Suzuki & Manolis Kellis & Shinichi Morishita, 2024. "A polygenic score method boosted by non-additive models," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Guanghao Qi & Surya B. Chhetri & Debashree Ray & Diptavo Dutta & Alexis Battle & Samsiddhi Bhattacharjee & Nilanjan Chatterjee, 2024. "Genome-wide large-scale multi-trait analysis characterizes global patterns of pleiotropy and unique trait-specific variants," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Milton Pividori & Sumei Lu & Binglan Li & Chun Su & Matthew E. Johnson & Wei-Qi Wei & Qiping Feng & Bahram Namjou & Krzysztof Kiryluk & Iftikhar J. Kullo & Yuan Luo & Blair D. Sullivan & Benjamin F. V, 2023. "Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Alan Selewa & Kaixuan Luo & Michael Wasney & Linsin Smith & Xiaotong Sun & Chenwei Tang & Heather Eckart & Ivan P. Moskowitz & Anindita Basu & Xin He & Sebastian Pott, 2023. "Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Wendiao Zhang & Ming Zhang & Zhenhong Xu & Hongye Yan & Huimin Wang & Jiamei Jiang & Juan Wan & Beisha Tang & Chunyu Liu & Chao Chen & Qingtuan Meng, 2023. "Human forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Tiago C. Silva & Juan I. Young & Lanyu Zhang & Lissette Gomez & Michael A. Schmidt & Achintya Varma & X. Steven Chen & Eden R. Martin & Lily Wang, 2022. "Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Haoxi Chai & Harianto Tjong & Peng Li & Wei Liao & Ping Wang & Chee Hong Wong & Chew Yee Ngan & Warren J. Leonard & Chia-Lin Wei & Yijun Ruan, 2023. "ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Zhangyuan Pan & Yuelin Yao & Hongwei Yin & Zexi Cai & Ying Wang & Lijing Bai & Colin Kern & Michelle Halstead & Ganrea Chanthavixay & Nares Trakooljul & Klaus Wimmers & Goutam Sahana & Guosheng Su & M, 2021. "Pig genome functional annotation enhances the biological interpretation of complex traits and human disease," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    10. Palwende Romuald Boua & Jean-Tristan Brandenburg & Ananyo Choudhury & Hermann Sorgho & Engelbert A. Nonterah & Godfred Agongo & Gershim Asiki & Lisa Micklesfield & Solomon Choma & Francesc Xavier Góme, 2022. "Genetic associations with carotid intima-media thickness link to atherosclerosis with sex-specific effects in sub-Saharan Africans," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    11. Pascal Schlosser & Adrienne Tin & Pamela R. Matias-Garcia & Chris H. L. Thio & Roby Joehanes & Hongbo Liu & Antoine Weihs & Zhi Yu & Anselm Hoppmann & Franziska Grundner-Culemann & Josine L. Min & Ade, 2021. "Meta-analyses identify DNA methylation associated with kidney function and damage," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    12. Jingni He & Wanqing Wen & Alicia Beeghly & Zhishan Chen & Chen Cao & Xiao-Ou Shu & Wei Zheng & Quan Long & Xingyi Guo, 2022. "Integrating transcription factor occupancy with transcriptome-wide association analysis identifies susceptibility genes in human cancers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    13. Kosmidis, Kosmas & Hütt, Marc-Thorsten, 2023. "DNA visibility graphs," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 626(C).
    14. Nicoló Fusi & Oliver Stegle & Neil D Lawrence, 2012. "Joint Modelling of Confounding Factors and Prominent Genetic Regulators Provides Increased Accuracy in Genetical Genomics Studies," PLOS Computational Biology, Public Library of Science, vol. 8(1), pages 1-9, January.
    15. Bin Wang, 2020. "A Zipf-plot based normalization method for high-throughput RNA-seq data," PLOS ONE, Public Library of Science, vol. 15(4), pages 1-15, April.
    16. Andrew D. Grotzinger & Travis T. Mallard & Zhaowen Liu & Jakob Seidlitz & Tian Ge & Jordan W. Smoller, 2023. "Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    17. Andrew D. Grotzinger & Javier de la Fuente & Gail Davies & Michel G. Nivard & Elliot M. Tucker-Drob, 2022. "Transcriptome-wide and stratified genomic structural equation modeling identify neurobiological pathways shared across diverse cognitive traits," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    18. Joyce J. Thompson & Daniel J. Lee & Apratim Mitra & Sarah Frail & Ryan K. Dale & Pedro P. Rocha, 2022. "Extensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    19. Zhuoran Xu & Quan Li & Luigi Marchionni & Kai Wang, 2023. "PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    20. Guanghao Qi & Benjamin J. Strober & Joshua M. Popp & Rebecca Keener & Hongkai Ji & Alexis Battle, 2023. "Single-cell allele-specific expression analysis reveals dynamic and cell-type-specific regulatory effects," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41690-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.