Epistasis regulates genetic control of cardiac hypertrophy.

Journal: Nature cardiovascular research
Published Date: Jun 5, 2025

Abstract

Although genetic variant effects often interact nonadditively, strategies to uncover epistasis remain in their infancy. Here we develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy, using deep learning-derived left ventricular mass estimates from 29,661 UK Biobank cardiac magnetic resonance images. We report epistatic variants near CCDC141, IGF1R, TTN and TNKS, identifying loci deemed insignificant in genome-wide association studies. Functional genomic and integrative enrichment analyses reveal that genes mapped from these loci share biological process gene ontologies and myogenic regulatory factors. Transcriptomic network analyses using 313 human hearts demonstrate strong co-expression correlations among these genes in healthy hearts, with significantly reduced connectivity in failing hearts. To assess causality, RNA silencing in human induced pluripotent stem cell-derived cardiomyocytes, combined with novel microfluidic single-cell morphology analysis, confirms that cardiomyocyte hypertrophy is nonadditively modifiable by interactions between CCDC141, TTN and IGF1R. Our results expand the scope of cardiac genetic regulation to epistasis.

Authors

  • Qianru Wang
    Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Tiffany M Tang
    Department of Statistics, University of California, Berkeley, Berkeley, CA, USA.
  • Michelle Youlton
    Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Chad S Weldy
    Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Ana M Kenney
    Department of Statistics, University of California, Berkeley, Berkeley, CA, USA.
  • Omer Ronen
    Statistics Department, University of California, Berkeley, CA 94720.
  • J Weston Hughes
    Department of Computer Science, Stanford University, Palo Alto, CA 94025.
  • Elizabeth T Chin
    Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Shirley C Sutton
    Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Abhineet Agarwal
    Statistics Department, University of California, Berkeley, CA 94720.
  • Xiao Li
    Department of Inner Mongolia Clinical Medicine College, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.
  • Merle Behr
    Department of Statistics, University of California, Berkeley, CA 94720.
  • Karl Kumbier
    Statistics Department, University of California, Berkeley, CA, USA.
  • Christine S Moravec
    Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • W H Wilson Tang
    Robert and Suzanne Tomsich Department of Cardiovascular Medicine Sydell and Arnold Miller Family Heart and Vascular Institute Cleveland Clinic Cleveland OH.
  • Kenneth B Margulies
    Cardiovascular Research Institute, University of Pennsylvania, Philadelphia, PA, United States of America.
  • Thomas P Cappola
    Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
  • Atul J Butte
    Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA.
  • Rima Arnaout
  • James B Brown
    Molecular Ecosystems Biology Department, Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States.
  • James R Priest
    Department of Pediatrics, Stanford University, Stanford, CA, 94304, USA.
  • Victoria N Parikh
    Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Bin Yu
    Department of Anesthesiology, Peking University First Hospital, Ningxia Women's and Children's Hospital, Yinchuan, China.
  • Euan A Ashley
    Department of Genetics, Stanford University, Stanford, California, United States of America.

Keywords

External Resources

Popular Topics
Recent Journals