Integrated Genomic Approaches to Elucidate the Genetic Basis of Brugada Syndrome in Taiwanese Patients

Brugada syndrome (BrS) is a rare cardiac arrhythmia with a complex and largely unexplained genetic basis. In this study, we analysed genomic data from 214 Taiwanese BrS cases and 1316 controls to uncover susceptibility loci using genome-wide association study (GWAS), copy number variation (CNV) analysis, and rare-variant association test (RVAT). Imputation with a population-specific Merged-TWN-panel yielded the highest accuracy across SNP categories. GWAS identified four genome-wide significant SNPs across three loci, including SCN10A, ZNF451, and RP11-510I5, with the ZNF451 locus showing a strong association (OR = 9.845, P = 6.8e-11). The total SNP-heritability for BrS was estimated at 0.18 (SE = 0.20), and SNPs located in the 3 risk loci regions accounted for 0.13 (SE = 0.02) of the phenotypic variance. Functional annotation revealed several regulatory non-coding SNPs, and gene-based analysis confirmed SCN10A as significant. Notably, ZNF451-AS1, a non-coding RNA gene overlapping the ZNF451 region, was identified via RVAT, suggesting that both common and rare variants at this locus contribute to BrS risk. CNV analysis further identified potential case-enriched regions, including a duplication involving HRAS. These findings underscore the importance of population-specific genomic resources and highlight ZNF451 as a key susceptibility locus, bridging both common and rare-variant contributions to BrS.