Protein interaction networks in the vasculature prioritize genes and pathways underlying coronary artery disease

Qiuyu Martin Zhu; Yu-Han H Hsu; Frederik H Lassen; Bryan T MacDonald; Stephanie Stead; Edyta Malolepsza; April Kim; Taibo Li; Taiji Mizoguchi; Monica Schenone; Gaelen Guzman; Benjamin Tanenbaum; Nadine Fornelos; Steven A Carr; Rajat M Gupta; Patrick T Ellinor; Kasper Lage

doi:10.1038/s42003-023-05705-1

Protein interaction networks in the vasculature prioritize genes and pathways underlying coronary artery disease

Commun Biol. 2024 Jan 12;7(1):87. doi: 10.1038/s42003-023-05705-1.

Authors

Qiuyu Martin Zhu^#^{1

2

3}, Yu-Han H Hsu^#^{4

5

6}, Frederik H Lassen^#^{4

6

7}, Bryan T MacDonald¹, Stephanie Stead¹, Edyta Malolepsza⁸, April Kim^{4

6}, Taibo Li^{4

6}, Taiji Mizoguchi^{1

2}, Monica Schenone⁹, Gaelen Guzman⁹, Benjamin Tanenbaum⁹, Nadine Fornelos^{4

5

6}, Steven A Carr⁹, Rajat M Gupta¹⁰, Patrick T Ellinor^{11

12}, Kasper Lage^{13

14

15

16}

Affiliations

¹ Cardiovascular Disease Initiative & Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁷ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁸ Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Divisions of Cardiovascular Medicine and Genetics, Brigham and Women's Hospital, Boston, MA, USA.
¹¹ Cardiovascular Disease Initiative & Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ellinor@mgh.harvard.edu.
¹² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.
¹³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. klage@broadinstitute.org.
¹⁴ Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA. klage@broadinstitute.org.
¹⁵ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. klage@broadinstitute.org.
¹⁶ Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. klage@broadinstitute.org.

^# Contributed equally.

Abstract

Population-based association studies have identified many genetic risk loci for coronary artery disease (CAD), but it is often unclear how genes within these loci are linked to CAD. Here, we perform interaction proteomics for 11 CAD-risk genes to map their protein-protein interactions (PPIs) in human vascular cells and elucidate their roles in CAD. The resulting PPI networks contain interactions that are outside of known biology in the vasculature and are enriched for genes involved in immunity-related and arterial-wall-specific mechanisms. Several PPI networks derived from smooth muscle cells are significantly enriched for genetic variants associated with CAD and related vascular phenotypes. Furthermore, the networks identify 61 genes that are found in genetic loci associated with risk of CAD, prioritizing them as the causal candidates within these loci. These findings indicate that the PPI networks we have generated are a rich resource for guiding future research into the molecular pathogenesis of CAD.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Coronary Artery Disease* / genetics
Gene Regulatory Networks
Genetic Loci
Humans
Protein Interaction Maps
Proteomics

Abstract

Publication types

MeSH terms

Grants and funding