PDF(Pubmed)
Abstract：
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■大量数据支持室上性心动过速的遗传基础，但对这些心律失常的遗传决定因素和分子机制了解甚少。我们试图确定与房室结折返性心动过速（AVNRT）和房室辅助途径或房室往复性心动过速（AVAP/AVRT）相关的遗传基因座。
■我们进行了全基因组关联研究的多血统荟萃分析，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，评估了支持候选基因潜在因果效应的证据。进行全转录组分析，并检查先前的全基因组关联研究。
■分析包括2384例AVNRT病例和106489例参考，和2811个AVAP/AVRT案例和1,483093个参考。我们确定了2个明显的AVNRT位点，这表明NKX2-5和TTN是疾病易感基因。全转录组关联分析支持预测的NKX2-5心脏表达降低与AVNRT之间的关联。我们确定了AVAP/AVRT的3个重要基因座，这牵涉到SCN5A，SCN10A,和TTN/CCDC141。先前已经报道了心脏表型的几个基因座的变异关联，包括心房颤动,中风,Brugada综合征,和心电图间隔。
■我们的发现突出了与离子通道功能（AVAP/AVRT）相关的基因区域，以及心脏发育和肌节（AVAP/AVRT和AVNRT）是室上性心动过速易感性的重要潜在效应因子。
■我们进行了全基因组关联研究的多血统荟萃分析，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，评估了支持候选基因潜在因果效应的证据。进行全转录组分析，并检查先前的全基因组关联研究。
■分析包括2384例AVNRT病例和106489例参考，和2811个AVAP/AVRT案例和1,483093个参考。我们确定了2个明显的AVNRT位点，这表明NKX2-5和TTN是疾病易感基因。全转录组关联分析支持预测的NKX2-5心脏表达降低与AVNRT之间的关联。我们确定了AVAP/AVRT的3个重要基因座，这牵涉到SCN5A，SCN10A,和TTN/CCDC141。先前已经报道了心脏表型的几个基因座的变异关联，包括心房颤动,中风,Brugada综合征,和心电图间隔。
■我们的发现突出了与离子通道功能（AVAP/AVRT）相关的基因区域，以及心脏发育和肌节（AVAP/AVRT和AVNRT）是室上性心动过速易感性的重要潜在效应因子。
