| Title: | Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum |
| Journal: | Nature Genetics |
| Published: | 7 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40195560/ |
| DOI: | https://doi.org/10.1038/s41588-025-02140-2 |
Publication 14742
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Abstract
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.</p>
14 Keywords
- Adaptor Proteins, Signal Transducing
- Apoptosis Regulatory Proteins
- Carrier Proteins
- Connectin
- Exome Sequencing
- Female
- Gene Frequency
- Genetic Predisposition to Disease
- Genetic Variation
- Genome-Wide Association Study
- Heart Failure
- Humans
- Male
- Polymorphism, Single Nucleotide
35 Authors
- 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 Dilitikas
- Lily Hoffman-Andrews
- Renae L. Judy
- Atlas Khan
- Iftikhar J. Kullo
- Megan J. Puckelwartz
- Nosheen Reza
- Benjamin A. Satterfield
- Pankhuri Singhal
- 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
1 Application
| Application ID | Title |
|---|---|
| 32133 | Integration of multi-organ imaging phenotypes, clinical phenotypes, and genomic data |
Enabling scientific discoveries that improve human health