Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.
Journal
European heart journal
Journal Volume
45
Journal Issue
26
Start Page
2320-2332
ISSN
1522-9645
Date Issued
2024-07-09
Author(s)
Ishikawa, Taisuke
Masuda, Tatsuo
Hachiya, Tsuyoshi
Dina, Christian
Simonet, Floriane
Nagata, Yuki
Tanck, Michael W T
Sonehara, Kyuto
Glinge, Charlotte
Tadros, Rafik
Khongphatthanayothin, Apichai
Higuchi, Chihiro
Nakajima, Tadashi
Hayashi, Kenshi
Aizawa, Yoshiyasu
Nakano, Yukiko
Nogami, Akihiko
Morita, Hiroshi
Ohno, Seiko
Aiba, Takeshi
Krijger Juárez, Christian
Mauleekoonphairoj, John
Poovorawan, Yong
Gourraud, Jean-Baptiste
Shimizu, Wataru
Probst, Vincent
Horie, Minoru
Wilde, Arthur A M
Redon, Richard
Nademanee, Koonlawee
Bezzina, Connie R
Barc, Julien
Tanaka, Toshihiro
Okada, Yukinori
Schott, Jean-Jacques
Makita, Naomasa
Abstract
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.
Subjects
SCN5A
Brugada syndrome
Cross-ancestry meta-analysis
Genetic risk score
Genome-wide association studies
SDGs
Publisher
Oxford University Press
Type
journal article