Highlight talk – Theme: Systems
Abstract
Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine.
Authors
Tom Michoel, The Roslin Institute, The University of Edinburgh, United Kingdom
Husain Talukdar, Karolinska Institute, Sweden
Hassan Foroughi Asl, Karolinska Institute, Sweden
Rajeev Jain, University of Tartu, Estonia
Raili Ermel, University of Tartu, Estonia
Arno Ruusalepp, University of Tartu, Estonia
Oscar Franzen, Icahn School of Medicine at Mount Sinai, United States
Brian Kidd, Icahn School of Medicine at Mount Sinai, United States
Ben Redhead, Icahn School of Medicine at Mount Sinai, United States
Chiara Giannarelli, Icahn School of Medicine at Mount Sinai, United States
Torbjorn Ivert, Karolinska Institute, Sweden
Joel Dudley, Icahn School of Medicine at Mount Sinai, United States
Mete Civelek, University of California Los Angeles, United States
Aldons Lusis, University of California Los Angeles, United States
Eric Schadt, Icahn School of Medicine at Mount Sinai, United States
Josefin Skogsberg, Karolinska Institute, Sweden
Johan Bjorkegren, Icahn School of Medicine at Mount Sinai, United States