title: Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci.
abstract: Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations.
  
  
  
  We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls. The networks and top-ranked regulators according to these data-driven criteria were further queried against literature, experimental evidence, and drug information to evaluate their disease relevance and potential as drug targets. Our analysis uncovered several potential novel regulators of CAD such as LUM and STAT3, which possess properties suitable as drug targets. We also revealed molecular relations and potential mechanisms through which the top CAD loci operate. Furthermore, we found that multiple CAD-relevant biological processes such as extracellular matrix, inflammatory and immune pathways, complement and coagulation cascades, and lipid metabolism interact in the CAD networks.
  
  
  
  Our data-driven integrative genomics framework unraveled tissue-specific relations among the candidate genes of the CAD genome-wide association studies loci and prioritized novel network regulatory genes orchestrating biological processes relevant to CAD.
authors.affiliation: From the Department of Integrative Biology and Physiology, University of California, Los Angeles (Y.Z., Q.M., X.Y.); and Target Sciences Computational Biology (US), GSK, King of Prussia, PA (J.C., J.M.F., D.K.R.).
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the Department of Integrative Biology and Physiology, University of California, Los Angeles (Y.Z., Q.M., X.Y.); and Target Sciences Computational Biology (US), GSK, King of Prussia, PA (J.C., J.M.F., D.K.R.).
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Integrative Biology and Physiology, University of California, Los Angeles (Y.Z., Q.M., X.Y.); and Target Sciences Computational Biology (US), GSK, King of Prussia, PA (J.C., J.M.F., D.K.R.).
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Freudenberg
authors.affiliation: From the Department of Integrative Biology and Physiology, University of California, Los Angeles (Y.Z., Q.M., X.Y.); and Target Sciences Computational Biology (US), GSK, King of Prussia, PA (J.C., J.M.F., D.K.R.).
authors.forename: Qingying
authors.initials: Q
authors.lastname: Meng
authors.affiliation: From the Department of Integrative Biology and Physiology, University of California, Los Angeles (Y.Z., Q.M., X.Y.); and Target Sciences Computational Biology (US), GSK, King of Prussia, PA (J.C., J.M.F., D.K.R.). xyang123@ucla.edu deepak.k.rajpal@gsk.com.
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Rajpal
authors.affiliation: From the Department of Integrative Biology and Physiology, University of California, Los Angeles (Y.Z., Q.M., X.Y.); and Target Sciences Computational Biology (US), GSK, King of Prussia, PA (J.C., J.M.F., D.K.R.). xyang123@ucla.edu deepak.k.rajpal@gsk.com.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D016022:Case-Control Studies; D019295:Computational Biology; D003198:Computer Simulation; D003324:Coronary Artery Disease / Q000235:genetics*; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D006801:Humans; D000071234:Lumican / Q000235:genetics; D051379:Mice; D016571:Neural Networks, Computer; D010641:Phenotype; D060066:Protein Interaction Maps; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction
chemical_list: C000604306:LUM protein, human; D000071234:Lumican; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: coronary artery disease; gene expression; gene regulatory networks; genome-wide association study; genomics