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

由宾夕法尼亚大学佩雷尔曼医学院Scottt组成的跨等位基因频谱心力衰竭的常见变异和罕见变异遗传结构 M. 经过不懈的努力，Damrauer研究小组取得了这一成果。这项最新研究成果于2025年4月7日发表在《自然遗传学》杂志上。

在这里，该小组报告了全因性心力衰竭的常见突变和罕见突变之间的相关研究，并讨论了不同类型的遗传突变如何影响遗传。在2358556个个人中，研究小组确定了176个具有全基因组意义的常见突变风险点，并将这些信号分为五个模块，基于与拟人特征/肥胖、血压/肾功能、动脉硬化/血脂、免疫活性和心率异常的多效性相关性。同时，研究人员在376334个人中确定了TTN、MYBPC3、在FLNC和BAG3主题外显子组的测序中，发现了心力衰竭与罕见的预测功能丧失变异之间的显著关系。

研究人员发现，罕见代码变异的总遗传负担高度集中在孟德尔心肌病基因的一小部分，而常见变异的遗传力在整个基因组中分布不均。最后，研究小组发现，共同变异的背景改变了TTN中罕见的致病性切断变异携带者心力衰竭的风险。简而言之，这些发现发现了代谢紊乱和心力衰竭之间的遗传关系，并强调了许多基因成分在临床基因检查中未捕获的心力衰竭。

研究人员表示，心力衰竭是一种复杂的特征，全世界有3000多万人受到环境和遗传因素的影响。

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.