全基因组关联研究的元分析揭示了室上性心律失常的遗传机制。

IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation: Genomic and Precision Medicine Pub Date : 2024-06-01 Epub Date: 2024-05-28 DOI:10.1161/CIRCGEN.123.004320
Lu-Chen Weng, Shaan Khurshid, Amelia Weber Hall, Victor Nauffal, Valerie N Morrill, Yan V Sun, Joel T Rämö, Dominik Beer, Simon Lee, Girish Nadkarni, Renee Johnson, Laura Andreasen, Anne Clayton, Clive R Pullinger, Zachary T Yoneda, Daniel J Friedman, Matthew C Hyman, Renae L Judy, Allan C Skanes, Kate M Orland, Paloma Jordà, Timothy M Treu, Matthew T Oetjens, Rajesh Subbiah, Jacob P Hartmann, Heidi T May, John P Kane, Tariq Z Issa, Navid A Nafissi, Peter Leong-Sit, Marie-Pierre Dubé, Carolina Roselli, Seung Hoan Choi, Jean-Claude Tardif, Habib R Khan, Stacey Knight, Jesper H Svendsen, Bruce Walker, Richard Karlsson Linnér, J Michael Gaziano, Rafik Tadros, Diane Fatkin, Daniel J Rader, Svati H Shah, Dan M Roden, Gregory M Marcus, Ruth J F Loos, Scott M Damrauer, Christopher M Haggerty, Kelly Cho, Aarno Palotie, Morten S Olesen, Lee L Eckhardt, Jason D Roberts, Michael J Cutler, M Benjamin Shoemaker, Peter W F Wilson, Patrick T Ellinor, Steven A Lubitz
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引用次数: 0

摘要

背景:大量数据支持室上性心动过速具有遗传基础,但对这些心律失常的遗传决定因素和分子机制却知之甚少。我们试图确定与房室结性返流性心动过速(AVNRT)和房室附属通路或房室往复性心动过速(AVAPs/AVRT)相关的遗传位点:我们对全基因组关联研究进行了多巢荟萃分析,以确定 AVNRT(4 项研究)和 AVAP/AVRT (7 项研究)的遗传位点。我们通过分析相关变异与心脏基因表达之间的关系、进行全转录组分析以及检查先前的全基因组关联研究,评估了支持候选基因潜在因果效应的证据:分析对象包括 2384 个 AVNRT 病例和 106 489 个参照者,以及 2811 个 AVAP/AVRT 病例和 1 483 093 个参照者。我们为 AVNRT 确定了 2 个重要基因位点,这意味着 NKX2-5 和 TTN 是疾病易感基因。全转录组关联分析支持 NKX2-5 的预测心脏表达减少与 AVNRT 之间存在关联。我们确定了 AVAP/AVRT 的 3 个重要基因位点,其中涉及 SCN5A、SCN10A 和 TTN/CCDC141。以前曾报道过几个基因位点的变异与心脏表型有关,包括心房颤动、中风、布鲁加达综合征和心电图间期:我们的研究结果突出表明,与离子通道功能(AVAP/AVRT)以及心脏发育和肌纤维(AVAP/AVRT 和 AVNRT)相关的基因区域是室上性心动过速易感性的重要潜在影响因素。
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Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias.

Background: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).

Methods: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.

Results: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.

Conclusions: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.

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来源期刊
Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
9.20
自引率
5.40%
发文量
144
期刊介绍: Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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