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

Eur Heart J. 2024 Jul 9;45(26):2320-2332. doi: 10.1093/eurheartj/ehae251.

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.

Keywords: SCN5A; Brugada syndrome; Cross-ancestry meta-analysis; Genetic risk score; Genome-wide association studies.

Publication types

  • Meta-Analysis

MeSH terms

  • Adult
  • Asian People / genetics
  • Brugada Syndrome* / genetics
  • Case-Control Studies
  • Europe / epidemiology
  • Female
  • Genetic Predisposition to Disease* / genetics
  • Genome-Wide Association Study*
  • Humans
  • Japan / epidemiology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • White People / genetics