近日，美国麻省理工学院和哈佛大学的布罗德研究所Patrick T. Ellinor教授及其团队探明了超过50000病例的测序确定了房颤风险的编码和结构变异。相关论文于2025年3月6日发表于国际顶尖学术期刊《自然—遗传学》杂志上。

该课题组研究人员荟萃分析了来自36项研究的基因组和外显子组测序数据，其中包括52416例AF病例和277762例对照。在罕见编码变异的负荷试验中，课题组发现AF与MYBPC3、LMNA、PKP2、FAM189A2和KDM5B基因之间存在新的关联。课题组研究人员进一步确定了由于CTNNA3缺失和GATA4重复导致的AF与罕见结构变异之间的关联。

该课题组人员在来自MyCode、deCODE和UK Biobank的独立样本中广泛复制了他们的发现。最后，小组发现CRISPR敲除干细胞源性心房心肌细胞中的KDM5B可导致心房稳态和传导相关基因的动作电位持续时间缩短和广泛的转录组失调。他们的研究结果强调了罕见的编码和结构变异对房颤的贡献，包括房颤和心肌病之间的遗传联系，并扩大了他们对这种常见心律失常的罕见变异结构的理解。

研究人员表示，心房颤动（AF）是一种普遍和病态的心律异常与强遗传成分。

附：英文原文

Title: Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

Author: Choi, Seung Hoan, Jurgens, Sean J., Xiao, Ling, Hill, Matthew C., Haggerty, Christopher M., Sveinbjrnsson, Garar, Morrill, Valerie N., Marston, Nicholas A., Weng, Lu-Chen, Pirruccello, James P., Arnar, David O., Gudbjartsson, Daniel Fannar, Mantineo, Helene, von Falkenhausen, Aenne S., Natale, Andrea, Tveit, Arnljot, Geelhoed, Bastiaan, Roselli, Carolina, Van Wagoner, David R., Darbar, Dawood, Haase, Doreen, Soliman, Elsayed Z., Davogustto, Giovanni E., Jun, Goo, Calkins, Hugh, Anderson, Jeffrey L., Brody, Jennifer A., Halford, Jennifer L., Barnard, John, Hokanson, John E., Smith, Jonathan D., Bis, Joshua C., Young, Kendra, Johnson, Linda S. B., Risch, Lorenz, Gula, Lorne J., Kwee, Lydia Coulter, Chaffin, Mark D., Khne, Michael, Preuss, Michael, Gupta, Namrata, Nafissi, Navid A., Smith, Nicholas L., Nilsson, Peter M., van der Harst, Pim, Wells, Quinn S., Judy, Renae L., Schnabel, Renate B., Johnson, Renee, Smit, Roelof A. J., Gabriel, Stacey, Knight, Stacey, Furukawa, Tetsushi, Blackwell, Thomas W., Nauffal, Victor, Wang, Xin, Min, Yuan-I, Yoneda, Zachary T., Laksman, Zachary W. M., Bezzina, Connie R., Alonso, Alvaro, Psaty, Bruce M.

Issue&Volume: 2025-03-06

Abstract: Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.

DOI: 10.1038/s41588-025-02074-9

Source: https://www.nature.com/articles/s41588-025-02074-9