Journal Article

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

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

2025

Overview

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. Common-variant and rare-variant association analyses combining datasets from multiple populations yield insights into the genetic architecture of all-cause heart failure across the allele-frequency spectrum.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/39 / 38/43 / 38/91 / 45/43 / 631/208/205/2138 / 692/308/2056 / 692/699/75/230 / Adaptor Proteins, Signal Transducing - genetics / Agriculture / Alleles / Animal Genetics and Genomics / Anthropometry / Apoptosis Regulatory Proteins / Arrhythmia / Arteriosclerosis / Atherosclerosis / Biomedical and Life Sciences / Biomedicine / Blood pressure / Cancer Research / Cardiac arrhythmia / Cardiomyopathy / Carrier Proteins - genetics / Congestive heart failure / Connectin - genetics / Coronary vessels / Diabetes / Disease / Exome Sequencing / Failure / Female / Frequency spectrum / Gene frequency / Gene Frequency - genetics / Gene Function / Gene loci / Genetic diversity / Genetic factors / Genetic Predisposition to Disease / Genetic screening / Genetic Variation / Genome-Wide Association Study / Genomes / Heart failure / Heart Failure - genetics / Heritability / Human Genetics / Humans / Lipids / Male / Meta-analysis / Metabolism / Myosin Binding Protein C / Polygenic inheritance / Polymorphism, Single Nucleotide / Proteins / Renal function / Sequences / Whole genome sequencing