Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci

Taisuke Ishikawa, Tatsuo Masuda, Tsuyoshi Hachiya, Christian Dina, Floriane Simonet, Yuki Nagata, Michael W T Tanck, Kyuto Sonehara, Charlotte Glinge, Rafik Tadros, Apichai Khongphatthanayothin, Tzu-Pin Lu, Chihiro Higuchi, Tadashi Nakajima, Kenshi Hayashi, Yoshiyasu Aizawa, Yukiko Nakano, Akihiko Nogami, Hiroshi Morita, Seiko OhnoTakeshi Aiba, Christian Krijger Juárez, John Mauleekoonphairoj, Yong Poovorawan, Jean-Baptiste Gourraud, Wataru Shimizu, Vincent Probst, Minoru Horie, Arthur A M Wilde, Richard Redon, Jyh-Ming Jimmy Juang, Koonlawee Nademanee, Connie R Bezzina, Julien Barc, Toshihiro Tanaka, Yukinori Okada, Jean-Jacques Schott, Naomasa Makita*

*Corresponding author af dette arbejde
3 Citationer (Scopus)

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.

OriginalsprogEngelsk
TidsskriftEuropean Heart Journal
Vol/bind45
Udgave nummer26
Sider (fra-til)2320-2332
Antal sider13
ISSN0195-668X
DOI
StatusUdgivet - 9 jul. 2024

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