%0 Journal Article
%T Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.
%A Ishikawa T
%A Masuda T
%A Hachiya T
%A Dina C
%A Simonet F
%A Nagata Y
%A Tanck MWT
%A Sonehara K
%A Glinge C
%A Tadros R
%A Khongphatthanayothin A
%A Lu TP
%A Higuchi C
%A Nakajima T
%A Hayashi K
%A Aizawa Y
%A Nakano Y
%A Nogami A
%A Morita H
%A Ohno S
%A Aiba T
%A Krijger Juárez C
%A Mauleekoonphairoj J
%A Poovorawan Y
%A Gourraud JB
%A Shimizu W
%A Probst V
%A Horie M
%A Wilde AAM
%A Redon R
%A Juang JJ
%A Nademanee K
%A Bezzina CR
%A Barc J
%A Tanaka T
%A Okada Y
%A Schott JJ
%A Makita N
%J Eur Heart J
%V 45
%N 26
%D 2024 Jul 9
%M 38747976
%F 35.855
%R 10.1093/eurheartj/ehae251
%X <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.