Genome-wide enhancer maps link risk variants to disease genes

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 Mualim, Heini M. Natri, Elle M. Weeks, Glen Munson, Michael Kane, Helen Y. Kang, Ang Cui, John P. Ray, Thomas M. Eisenhaure, Ryan L. Collins, Kushal Dey, Hanspeter Pfister, Alkes L. Price, Charles B. Epstein, Anshul Kundaje, Ramnik J. Xavier, Mark J. Daly, Hailiang Huang, Hilary K. Finucane, Nir Hacohen, Eric S. Lander () and Jesse M. Engreitz ()
Additional contact information
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
Philine Guckelberger: Broad Institute of MIT and Harvard
Benjamin R. Doughty: Broad Institute of MIT and Harvard
Tejal A. Patwardhan: Broad Institute of MIT and Harvard
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
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
Ang Cui: Broad Institute of MIT and Harvard
John P. Ray: Broad Institute of MIT and Harvard
Thomas M. Eisenhaure: Broad Institute of MIT and Harvard
Ryan L. Collins: Broad Institute of MIT and Harvard
Kushal Dey: Harvard T. H. Chan School of Public Health
Hanspeter Pfister: Harvard University
Alkes L. Price: Broad Institute of MIT and Harvard
Charles B. Epstein: Broad Institute of MIT and Harvard
Anshul Kundaje: Stanford University School of Medicine
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Mark J. Daly: Broad Institute of MIT and Harvard
Hailiang Huang: Broad Institute of MIT and Harvard
Hilary K. Finucane: Broad Institute of MIT and Harvard
Nir Hacohen: Broad Institute of MIT and Harvard
Eric S. Lander: Broad Institute of MIT and Harvard
Jesse M. Engreitz: Broad Institute of MIT and Harvard

Nature, 2021, vol. 593, issue 7858, 238-243

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03446-x

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