Instrumental variable and colocalization analyses identify endotrophin and HTRA1 as potential therapeutic targets for coronary artery disease
Paul C. Lee,
In-Hyuk Jung,
Shreeya Thussu,
Ved Patel,
Ryan Wagoner,
Kendall H. Burks,
Junedh Amrute,
Jared S. Elenbaas,
Chul Joo Kang,
Erica P. Young,
Philipp E. Scherer,
Nathan O. Stitziel
Affiliations
Paul C. Lee
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
In-Hyuk Jung
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Shreeya Thussu
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Ved Patel
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Ryan Wagoner
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Kendall H. Burks
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Junedh Amrute
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Jared S. Elenbaas
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Chul Joo Kang
McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO 63108, USA
Erica P. Young
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO 63108, USA
Philipp E. Scherer
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
Nathan O. Stitziel
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO 63108, USA; Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA; Corresponding author
Summary: Coronary artery disease (CAD) remains a leading cause of disease burden globally, and there is a persistent need for new therapeutic targets. Instrumental variable (IV) and genetic colocalization analyses can help identify novel therapeutic targets for human disease by nominating causal genes in genome-wide association study (GWAS) loci. We conducted cis-IV analyses for 20,125 genes and 1,746 plasma proteins with CAD using molecular trait quantitative trait loci variant (QTLs) data from three different studies. 19 proteins and 119 genes were significantly associated with CAD risk by IV analyses and demonstrated evidence of genetic colocalization. Notably, our analyses validated well-established targets such as PCSK9 and ANGPTL4 while also identifying HTRA1 and endotrophin (a cleavage product of COL6A3) as proteins whose levels are causally associated with CAD risk. Further experimental studies are needed to confirm the causal role of the genes and proteins identified through our multiomic cis-IV analyses on human disease.
