TY - JOUR
T1 - Brugada syndrome in Japan and Europe
T2 - a genome-wide association study reveals shared genetic architecture and new risk loci
AU - Ishikawa, Taisuke
AU - Masuda, Tatsuo
AU - Hachiya, Tsuyoshi
AU - Dina, Christian
AU - Simonet, Floriane
AU - Nagata, Yuki
AU - Tanck, Michael W T
AU - Sonehara, Kyuto
AU - Glinge, Charlotte
AU - Tadros, Rafik
AU - Khongphatthanayothin, Apichai
AU - Lu, Tzu-Pin
AU - Higuchi, Chihiro
AU - Nakajima, Tadashi
AU - Hayashi, Kenshi
AU - Aizawa, Yoshiyasu
AU - Nakano, Yukiko
AU - Nogami, Akihiko
AU - Morita, Hiroshi
AU - Ohno, Seiko
AU - Aiba, Takeshi
AU - Juárez, Christian Krijger
AU - Mauleekoonphairoj, John
AU - Poovorawan, Yong
AU - Gourraud, Jean-Baptiste
AU - Shimizu, Wataru
AU - Probst, Vincent
AU - Horie, Minoru
AU - Wilde, Arthur A M
AU - Redon, Richard
AU - Juang, Jyh-Ming Jimmy
AU - Nademanee, Koonlawee
AU - Bezzina, Connie R
AU - Barc, Julien
AU - Tanaka, Toshihiro
AU - Okada, Yukinori
AU - Schott, Jean-Jacques
AU - Makita, Naomasa
N1 - © The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].
PY - 2024/7/9
Y1 - 2024/7/9
N2 - 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.
AB - 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.
KW - Adult
KW - Asian People/genetics
KW - Brugada Syndrome/genetics
KW - Case-Control Studies
KW - Europe/epidemiology
KW - Female
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study
KW - Humans
KW - Japan/epidemiology
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide/genetics
KW - White People/genetics
UR - http://www.scopus.com/inward/record.url?scp=85198549725&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehae251
DO - 10.1093/eurheartj/ehae251
M3 - Journal article
C2 - 38747976
SN - 0195-668X
VL - 45
SP - 2320
EP - 2332
JO - European Heart Journal
JF - European Heart Journal
IS - 26
ER -