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<p>Left and right ventricular imaging measures are essential for heart failure diagnosis and prognostication, yet their genetic architecture remains underexplored. We conduct genome-wide association analyses of twenty left and right cardiovascular magnetic resonance phenotypes in 56,509 UK Biobank participants, including conventional measurements (e.g., volumes/ejection fraction) and novel parameters (left ventricular global function index and myocardial contraction fraction). We identify 200 loci associated with at least one phenotype (<i>P</i> &lt; 5×10<sup>-8</sup>); 58 being novel. A polygenic risk score for left ventricular global function index negative associates with heart failure in phenome-wide scan. Rare variant analysis reveals enrichment of deleterious variants across 13 genes (<i>P</i> &lt; 2.5×10<sup>-6</sup>). Colocalisation with heart failure implicates 23 shared loci and bioinformatic analysis prioritises genes including <i>HSPB7, CAMK2D, ALDH2, ENG</i>, and <i>YWHAE</i>. Druggability analysis highlights <i>PDE3A</i>, informing divergent effects of non-selective PDE3 inhibition. In this work, we expand our knowledge of cardiac ventricular genetics, suggesting potential heart failure therapeutic targets.</p>

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Genome-wide analysis of cardiac ventricular phenotypes reveals novel loci and therapeutic targets for heart failure

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月27日

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  • Hannah L. Nicholls,
  • Jose D. Vargas,
  • Mihir M. Sanghvi,
  • Hyo-Suk Ahn,
  • C. Anwar A. Chahal,
  • Mohammed Y. Khanji,
  • Steffen E. Petersen,
  • Patricia B. Munroe,
  • Nay Aung

摘要

Left and right ventricular imaging measures are essential for heart failure diagnosis and prognostication, yet their genetic architecture remains underexplored. We conduct genome-wide association analyses of twenty left and right cardiovascular magnetic resonance phenotypes in 56,509 UK Biobank participants, including conventional measurements (e.g., volumes/ejection fraction) and novel parameters (left ventricular global function index and myocardial contraction fraction). We identify 200 loci associated with at least one phenotype (P < 5×10-8); 58 being novel. A polygenic risk score for left ventricular global function index negative associates with heart failure in phenome-wide scan. Rare variant analysis reveals enrichment of deleterious variants across 13 genes (P < 2.5×10-6). Colocalisation with heart failure implicates 23 shared loci and bioinformatic analysis prioritises genes including HSPB7, CAMK2D, ALDH2, ENG, and YWHAE. Druggability analysis highlights PDE3A, informing divergent effects of non-selective PDE3 inhibition. In this work, we expand our knowledge of cardiac ventricular genetics, suggesting potential heart failure therapeutic targets.