Convergence of coronary artery disease genes onto endothelial cell programs

Gavin R. Schnitzler, Helen Kang, Shi Fang, Ramcharan S. Angom, Vivian S. Lee-Kim, X. Rosa Ma, Ronghao Zhou, Tony Zeng, Katherine Guo, Martin S. Taylor, Shamsudheen K. Vellarikkal, Aurelie E. Barry, Oscar Sias-Garcia, Alex Bloemendal, Glen Munson, Philine Guckelberger, Tung H. Nguyen, Drew T. Bergman, Stephen Hinshaw, Nathan Cheng, Brian Cleary, Krishna Aragam, Eric S. Lander, Hilary K. Finucane, Debabrata Mukhopadhyay, Rajat M. Gupta () and Jesse M. Engreitz ()
Additional contact information
Gavin R. Schnitzler: Broad Institute of MIT and Harvard
Helen Kang: Stanford University School of Medicine
Shi Fang: Broad Institute of MIT and Harvard
Ramcharan S. Angom: Mayo Clinic College of Medicine and Science
Vivian S. Lee-Kim: Broad Institute of MIT and Harvard
X. Rosa Ma: Stanford University School of Medicine
Ronghao Zhou: Stanford University School of Medicine
Tony Zeng: Stanford University School of Medicine
Katherine Guo: Stanford University School of Medicine
Martin S. Taylor: Massachusetts General Hospital and Harvard Medical School
Shamsudheen K. Vellarikkal: Broad Institute of MIT and Harvard
Aurelie E. Barry: Broad Institute of MIT and Harvard
Oscar Sias-Garcia: Broad Institute of MIT and Harvard
Alex Bloemendal: Broad Institute of MIT and Harvard
Glen Munson: Broad Institute of MIT and Harvard
Philine Guckelberger: Broad Institute of MIT and Harvard
Tung H. Nguyen: Broad Institute of MIT and Harvard
Drew T. Bergman: Broad Institute of MIT and Harvard
Stephen Hinshaw: Stanford University School of Medicine
Nathan Cheng: Broad Institute of MIT and Harvard
Brian Cleary: Broad Institute of MIT and Harvard
Krishna Aragam: Broad Institute of MIT and Harvard
Eric S. Lander: Broad Institute of MIT and Harvard
Hilary K. Finucane: Broad Institute of MIT and Harvard
Debabrata Mukhopadhyay: Mayo Clinic College of Medicine and Science
Rajat M. Gupta: Broad Institute of MIT and Harvard
Jesse M. Engreitz: Broad Institute of MIT and Harvard

Nature, 2024, vol. 626, issue 8000, 799-807

Abstract: Abstract Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1–3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1–6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

Date: 2024
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DOI: 10.1038/s41586-024-07022-x

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