常见和罕见基因变异对缓慢性心律失常发生的影响。

The impact of common and rare genetic variants on bradyarrhythmia development.

作者信息

Weng Lu-Chen, Rämö Joel T, Jurgens Sean J, Khurshid Shaan, Chaffin Mark, Hall Amelia Weber, Morrill Valerie N, Wang Xin, Nauffal Victor, Sun Yan V, Beer Dominik, Lee Simon, Nadkarni Girish N, Duong ThuyVy, Wang Biqi, Czuba Tomasz, Austin Thomas R, Yoneda Zachary T, Friedman Daniel J, Clayton Anne, Hyman Matthew C, Judy Renae L, Skanes Allan C, Orland Kate M, Treu Timothy M, Oetjens Matthew T, Alonso Alvaro, Soliman Elsayed Z, Lin Honghuang, Lunetta Kathryn L, van der Pals Jesper, Issa Tariq Z, Nafissi Navid A, May Heidi T, Leong-Sit Peter, Roselli Carolina, Choi Seung Hoan, Khan Habib R, Knight Stacey, Karlsson Linnér Richard, Bezzina Connie R, Ripatti Samuli, Heckbert Susan R, Gaziano J Michael, Loos Ruth J F, Psaty Bruce M, Smith J Gustav, Benjamin Emelia J, Arking Dan E, Rader Daniel J, Shah Svati H, Roden Dan M, Damrauer Scott M, Eckhardt Lee L, Roberts Jason D, Cutler Michael J, Shoemaker M Benjamin, Haggerty Christopher M, Cho Kelly, Palotie Aarno, Wilson Peter W F, Ellinor Patrick T, Lubitz Steven A

机构信息

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

出版信息

Nat Genet. 2025 Jan;57(1):53-64. doi: 10.1038/s41588-024-01978-2. Epub 2025 Jan 2.

DOI:10.1038/s41588-024-01978-2

PMID:39747593

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11735381/

Abstract

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

摘要

为了拓宽我们对缓慢性心律失常和传导疾病的理解，我们对多达130万人进行了常见变异全基因组关联分析，并对46万人进行了罕见变异负担测试，以研究窦房结功能障碍（SND）、远端传导疾病（DCD）和起搏器（PM）植入情况。我们分别确定了13个、31个和21个与SND、DCD和PM相关的常见变异位点。四个知名位点（SCN5A/SCN10A、CCDC141、TBX20和CAMK2D）在SND和DCD中共有，而其他位点则对SND或DCD更具特异性。SND和DCD显示出中等程度的遗传相关性（r = 0.63）。心肌细胞表达的基因对DCD遗传度的贡献显著。罕见变异分析表明，LMNA与所有缓慢性心律失常表型相关，SMAD6和SCN5A与DCD相关，TTN、MYBPC3和SCN5A与PM相关。这些结果表明，多种遗传途径（如离子通道功能、心脏发育程序、肌节结构和细胞内稳态）的变异似乎对缓慢性心律失常的发生发展至关重要。