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<p>Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in <i>TTN</i>, <i>MYBPC3</i>, <i>FLNC</i> and <i>BAG3</i> using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in <i>TTN</i>. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing.</p>

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Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum

  • 期刊论文

  • 发表日期：

    2025年4月7日

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  • David S. M. Lee,
  • Kathleen M. Cardone,
  • David Y. Zhang,
  • Noah L. Tsao,
  • Sarah Abramowitz,
  • Pranav Sharma,
  • John S. DePaolo,
  • Mitchell Conery,
  • Krishna G. Aragam,
  • Kiran Biddinger,
  • Ozan Dikilitas,
  • Lily Hoffman-Andrews,
  • Renae L. Judy,
  • Atlas Khan,
  • Iftikhar J. Kullo,
  • Megan J. Puckelwartz,
  • Nosheen Reza,
  • Benjamin A. Satterfield,
  • Pankhuri Singhal,
  • Giorgio Sirugo,
  • Anurag Verma,
  • Shefali S. Verma,
  • Theodore Drivas,
  • Zoltan Arany,
  • Thomas P. Cappola,
  • Eric D. Carruth,
  • Sharlene M. Day,
  • Ron Do,
  • Christopher M. Haggerty,
  • Jacob Joseph,
  • Elizabeth M. McNally,
  • Girish Nadkarni,
  • Anjali T. Owens,
  • Daniel J. Rader,
  • Marylyn D. Ritchie,
  • Yan V. Sun,
  • Benjamin F. Voight,
  • Michael G. Levin,
  • Scott M. Damrauer

摘要

Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing.