Background and Aims Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. Methods A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. Results The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10−8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10−4), and their allelic effects were highly correlated across ancestries (Pearson’s R = .91; P = 2.9 × 10−7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94–2.31); P = 1.2 × 10−61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. Conclusions This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

中文翻译：

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日本和欧洲的布鲁格达综合征：一项全基因组关联研究揭示了共享的遗传结构和新的风险位点


背景和目标 布鲁格达综合征 (BrS) 是一种遗传性心律失常，亚洲人比欧洲人患病率更高，致命性心律失常事件也更多。全基因组关联研究（GWAS）揭示了其多基因结构主要存在于欧洲人群中。本研究的目的是确定新的 BrS 相关位点并比较不同祖先的等位基因效应。方法对日本参与者进行 GWAS，涉及 940 例病例和 1634 名对照，然后对日本和欧洲 GWAS（总共 3760 例病例和 11 635 名对照）进行跨血统荟萃分析。这些新基因座的特征在于人类心脏中的精细定位、基因表达和剪接数量性状关联。结果 日本特有的 GWAS 在 ZSCAN20 附近识别出 1 个新位点（P = 1.0 × 10−8），跨祖先荟萃分析识别出 17 个关联信号，其中包括 6 个新位点。 17 个先导变异的效应方向是一致的（94.1%；符号检验 P = 2.7 × 10−4），并且它们的等位基因效应在不同祖先之间高度相关（Pearson's R = .91；P = 2.9 × 10−7） 。来自欧洲血统 BrS GWAS 的遗传风险评分与日本人群中 BrS 的风险显着相关 [比值比 2.12（95% 置信区间 1.94–2.31）； P = 1.2 × 10−61]，表明跨祖先具有共享的遗传结构。功能表征表明，CAMK2D 中的一个先导变体促进选择性剪接，导致钙调蛋白激酶 II-δ 的异构体转换，有利于促炎症/促死亡途径。结论 本研究表明新的易​​感位点暗示 BrS 潜在的新发病机制。 尽管临床表现和流行病学存在差异，但 BrS 的多基因结构在不同祖先之间基本上是共享的。