Abstract：
OBJECTIVE: 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.
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.
摘要：
目的：Brugada综合征（BrS）是一种遗传性心律失常，亚洲人比欧洲人的患病率更高，致死性心律失常事件更多。全基因组关联研究（GWAS）揭示了其主要在欧洲人群中的多基因结构。这项研究的目的是鉴定新的BrS相关基因座，并比较不同祖先的等位基因效应。
方法：在日本参与者中进行了GWAS，涉及940例和1634例控制，随后是日本和欧洲GWAS的交叉血统荟萃分析(总共3760例和11635例对照).新基因座的特征在于精细定位，基因表达，和剪接人类心脏中的数量性状关联。
结果：日本特异性GWAS在ZSCAN20附近发现了一个新基因座（P=1.0×10-8），交叉祖先荟萃分析确定了17个关联信号，包括六个新颖的基因座。17个导联变体的作用方向一致(94.1%;符号检验P=2.7×10-4),它们的等位基因效应在不同祖先之间高度相关(皮尔森的R=.91；P=2.9×10-7)。来自欧洲血统的BrSGWAS的遗传风险评分与日本人群的BrS风险显着相关[优势比2.12（95％置信区间1.94-2.31）；P=1.2×10-61]，暗示了祖先之间的共同遗传结构。功能表征显示，CAMK2D中的前导变体促进选择性剪接，导致钙调蛋白激酶II-δ的同工型开关，有利于促炎/促死亡途径。
结论：本研究表明新的易感基因位点与潜在的新的发病机制有关。尽管在临床表达和流行病学方面存在差异，BrS的多基因结构在祖先之间基本上共享。
方法：在日本参与者中进行了GWAS，涉及940例和1634例控制，随后是日本和欧洲GWAS的交叉血统荟萃分析(总共3760例和11635例对照).新基因座的特征在于精细定位，基因表达，和剪接人类心脏中的数量性状关联。
结果：日本特异性GWAS在ZSCAN20附近发现了一个新基因座（P=1.0×10-8），交叉祖先荟萃分析确定了17个关联信号，包括六个新颖的基因座。17个导联变体的作用方向一致(94.1%;符号检验P=2.7×10-4),它们的等位基因效应在不同祖先之间高度相关(皮尔森的R=.91；P=2.9×10-7)。来自欧洲血统的BrSGWAS的遗传风险评分与日本人群的BrS风险显着相关[优势比2.12（95％置信区间1.94-2.31）；P=1.2×10-61]，暗示了祖先之间的共同遗传结构。功能表征显示，CAMK2D中的前导变体促进选择性剪接，导致钙调蛋白激酶II-δ的同工型开关，有利于促炎/促死亡途径。
结论：本研究表明新的易感基因位点与潜在的新的发病机制有关。尽管在临床表达和流行病学方面存在差异，BrS的多基因结构在祖先之间基本上共享。
