Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

Harri Lempiäinen, Ingrid Brænne, Tom Michoel, Vinicius Tragante, Baiba Vilne, Tom R. Webb, Theodosios Kyriakou, Johannes Eichner, Lingyao Zeng, Christina Willenborg, Oscar Franzen, Arno Ruusalepp, Anuj Goel, Sander W. Van Der Laan, Claudia Biegert, Stephen Hamby, Husain A. Talukdar, Hassan Foroughi Asl, Martin Dichgans, Tobias DrekerMira Graettinger, Philip Gribbon, Thorsten Kessler, Rainer Malik, Matthias Prestel, Barbara Stiller, Christine Schofield, Gerard Pasterkamp, Hugh Watkins, Nilesh J. Samani, Timo Wittenberger, Jeanette Erdmann, Heribert Schunkert, Folkert W. Asselbergs, Johan L.M. Björkegren

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.

Original languageEnglish
Article number3434
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018
Externally publishedYes

Field of Science

  • 3.2 Clinical medicine
  • 3.1 Basic medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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