Cardiovascular Research Center (L.-C.W.), The Broad Institute of MIT and Harvard, Cambridge.
Massachusetts General Hospital, Boston. Cardiovascular Disease Initiative (L.-C.W., S. Khurshid, V.N., V.N.M., J.T.R., C.R., S.H.C., P.T.E., S.A.L.), The Broad Institute of MIT and Harvard, Cambridge.
Circ Genom Precis Med. 2024 Jun;17(3):e004320. doi: 10.1161/CIRCGEN.123.004320. Epub 2024 May 28.
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).
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.
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 and as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate , , and . Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.
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.
大量数据支持室上性心动过速具有遗传基础，但这些心律失常的遗传决定因素和分子机制仍知之甚少。我们试图确定与房室结折返性心动过速（AVNRT）和房室旁路或房室折返性心动过速（AVAP/AVRT）相关的遗传基因座。
我们对全基因组关联研究进行了多祖先荟萃分析，以确定 AVNRT（4 项研究）和 AVAP/AVRT（7 项研究）的遗传基因座。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，评估候选基因潜在因果效应的证据。
分析包括 2384 例 AVNRT 病例和 106489 名对照者，以及 2811 例 AVAP/AVRT 病例和 1483093 名对照者。我们确定了 2 个与 AVNRT 相关的显著基因座，提示 和 是疾病易感基因。全转录组关联分析支持 与 AVNRT 之间存在相关性。我们确定了 3 个与 AVAP/AVRT 相关的显著基因座，提示 、 和 。在多个基因座的变异关联先前已被报道与心脏表型有关，包括心房颤动、中风、Brugada 综合征和心电图间期。
我们的研究结果突出了与离子通道功能（AVAP/AVRT）以及心脏发育和肌节（AVAP/AVRT 和 AVNRT）相关的基因区域，作为室上性心动过速易感性的重要潜在效应器。
