{Reference Type}: Journal Article
{Title}: Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.
{Author}: Ishikawa T;Masuda T;Hachiya T;Dina C;Simonet F;Nagata Y;Tanck MWT;Sonehara K;Glinge C;Tadros R;Khongphatthanayothin A;Lu TP;Higuchi C;Nakajima T;Hayashi K;Aizawa Y;Nakano Y;Nogami A;Morita H;Ohno S;Aiba T;Krijger Juárez C;Mauleekoonphairoj J;Poovorawan Y;Gourraud JB;Shimizu W;Probst V;Horie M;Wilde AAM;Redon R;Juang JJ;Nademanee K;Bezzina CR;Barc J;Tanaka T;Okada Y;Schott JJ;Makita N;
{Journal}: Eur Heart J
{Volume}: 45
{Issue}: 26
{Year}: 2024 Jul 9
{Factor}: 35.855
{DOI}: 10.1093/eurheartj/ehae251
{Abstract}: <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.