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Genome-wide enhancer maps link risk variants to disease genes

Author

Listed:
  • Joseph Nasser

    (Broad Institute of MIT and Harvard)

  • Drew T. Bergman

    (Broad Institute of MIT and Harvard)

  • Charles P. Fulco

    (Broad Institute of MIT and Harvard
    Bristol Myers Squibb)

  • Philine Guckelberger

    (Broad Institute of MIT and Harvard
    Freie Universität Berlin)

  • Benjamin R. Doughty

    (Broad Institute of MIT and Harvard
    Stanford University School of Medicine)

  • Tejal A. Patwardhan

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Thouis R. Jones

    (Broad Institute of MIT and Harvard)

  • Tung H. Nguyen

    (Broad Institute of MIT and Harvard)

  • Jacob C. Ulirsch

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Fritz Lekschas

    (Harvard University)

  • Kristy Mualim

    (Stanford University School of Medicine)

  • Heini M. Natri

    (Stanford University School of Medicine)

  • Elle M. Weeks

    (Broad Institute of MIT and Harvard)

  • Glen Munson

    (Broad Institute of MIT and Harvard)

  • Michael Kane

    (Broad Institute of MIT and Harvard)

  • Helen Y. Kang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Ang Cui

    (Broad Institute of MIT and Harvard
    Harvard-MIT Division of Health Sciences and Technology, MIT)

  • John P. Ray

    (Broad Institute of MIT and Harvard
    Systems Immunology, Benaroya Research Institute at Virginia Mason)

  • Thomas M. Eisenhaure

    (Broad Institute of MIT and Harvard)

  • Ryan L. Collins

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Kushal Dey

    (Harvard T. H. Chan School of Public Health)

  • Hanspeter Pfister

    (Harvard University)

  • Alkes L. Price

    (Broad Institute of MIT and Harvard
    Harvard T. H. Chan School of Public Health
    Harvard T. H. Chan School of Public Health)

  • Charles B. Epstein

    (Broad Institute of MIT and Harvard)

  • Anshul Kundaje

    (Stanford University School of Medicine
    Stanford University)

  • Ramnik J. Xavier

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital and Harvard Medical School)

  • Mark J. Daly

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School
    University of Helsinki)

  • Hailiang Huang

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Hilary K. Finucane

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Nir Hacohen

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Eric S. Lander

    (Broad Institute of MIT and Harvard
    Department of Biology, MIT
    Harvard Medical School
    Executive Office of the President, White House)

  • Jesse M. Engreitz

    (Broad Institute of MIT and Harvard
    Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer–gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:593:y:2021:i:7858:d:10.1038_s41586-021-03446-x
    DOI: 10.1038/s41586-021-03446-x
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    Cited by:

    1. Long Jin & Danyang Wang & Jiaman Zhang & Pengliang Liu & Yujie Wang & Yu Lin & Can Liu & Ziyin Han & Keren Long & Diyan Li & Yu Jiang & Guisen Li & Yu Zhang & Jingyi Bai & Xiaokai Li & Jing Li & Lu Lu, 2023. "Dynamic chromatin architecture of the porcine adipose tissues with weight gain and loss," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. 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.
    3. 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.
    4. Tian Zhou & Xinyi Zhu & Zhizhong Ye & Yong-Fei Wang & Chao Yao & Ning Xu & Mi Zhou & Jianyang Ma & Yuting Qin & Yiwei Shen & Yuanjia Tang & Zhihua Yin & Hong Xu & Yutong Zhang & Xiaoli Zang & Huihua D, 2022. "Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Arthur S. Lee & Lauren J. Ayers & Michael Kosicki & Wai-Man Chan & Lydia N. Fozo & Brandon M. Pratt & Thomas E. Collins & Boxun Zhao & Matthew F. Rose & Alba Sanchis-Juan & Jack M. Fu & Isaac Wong & X, 2024. "A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    6. Sourya Bhattacharyya & Ferhat Ay, 2024. "Identifying genetic variants associated with chromatin looping and genome function," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    7. 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.
    8. Ghislain Rocheleau & Shoa L. Clarke & Gaëlle Auguste & Natalie R. Hasbani & Alanna C. Morrison & Adam S. Heath & Lawrence F. Bielak & Kruthika R. Iyer & Erica P. Young & Nathan O. Stitziel & Goo Jun &, 2024. "Rare variant contribution to the heritability of coronary artery disease," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    9. Hannah Poisner & Annika Faucon & Nancy Cox & Alexander G. Bick, 2024. "Genetic determinants and phenotypic consequences of blood T-cell proportions in 207,000 diverse individuals," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    10. 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.
    11. 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.
    12. 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.
    13. Andrew R. Hamel & Wenjun Yan & John M. Rouhana & Aboozar Monovarfeshani & Xinyi Jiang & Puja A. Mehta & Jayshree Advani & Yuyang Luo & Qingnan Liang & Skanda Rajasundaram & Arushi Shrivastava & Kather, 2024. "Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    14. Chaitali Chakraborty & Itzel Nissen & Craig A. Vincent & Anna-Carin Hägglund & Andreas Hörnblad & Silvia Remeseiro, 2023. "Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    15. 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.

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