跨等位基因频率谱的心力衰竭的常见变异和罕见变异遗传结构，这一成果由宾夕法尼亚大学佩雷尔曼医学院Scott M. Damrauer研究组经过不懈努力而取得。2025年4月7日出版的《自然—遗传学》杂志发表了这一最新研究成果。

在这里，小组报告了全因性心力衰竭的常见变异和罕见变异关联研究，并研究了不同类别的遗传变异如何影响其遗传性。该研究组在2358556个个体中确定了176个具有全基因组意义的常见变异风险位点，并基于与拟人特征/肥胖、血压/肾功能、动脉粥样硬化/血脂、免疫活性和心律失常的多效性关联，将这些信号分为五大模块。同时，研究人员在376334个个体的TTN、MYBPC3、FLNC和BAG3主题外显子组测序中，发现了心力衰竭和罕见的预测功能丧失变异的显着关联。

研究人员发现，罕见编码变异的总负担遗传力高度集中在一小部分孟德尔心肌病基因中，而常见变异的遗传力在整个基因组中分布不均匀。最后，课题组人员发现共同变异背景改变了TTN中罕见致病性截断变异携带者的心力衰竭风险。总之，这些发现发现了代谢失调和心力衰竭之间的遗传联系，并强调了目前临床基因检测未捕获的心力衰竭的多基因成分。

研究人员表示，心力衰竭是一种复杂的特征，受环境和遗传因素的影响，全世界有超过3000万人受到影响。

附：英文原文

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

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

Issue&Volume: 2025-04-07

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.

DOI: 10.1038/s41588-025-02140-2

Source: https://www.nature.com/articles/s41588-025-02140-2