Ishikawa, TaisukeTaisukeIshikawaMasuda, TatsuoTatsuoMasudaHachiya, TsuyoshiTsuyoshiHachiyaDina, ChristianChristianDinaSimonet, FlorianeFlorianeSimonetNagata, YukiYukiNagataTanck, Michael W TMichael W TTanckSonehara, KyutoKyutoSoneharaGlinge, CharlotteCharlotteGlingeTadros, RafikRafikTadrosKhongphatthanayothin, ApichaiApichaiKhongphatthanayothinTZU-PIN LUHiguchi, ChihiroChihiroHiguchiNakajima, TadashiTadashiNakajimaHayashi, KenshiKenshiHayashiAizawa, YoshiyasuYoshiyasuAizawaNakano, YukikoYukikoNakanoNogami, AkihikoAkihikoNogamiMorita, HiroshiHiroshiMoritaOhno, SeikoSeikoOhnoAiba, TakeshiTakeshiAibaKrijger Juárez, ChristianChristianKrijger JuárezMauleekoonphairoj, JohnJohnMauleekoonphairojPoovorawan, YongYongPoovorawanGourraud, Jean-BaptisteJean-BaptisteGourraudShimizu, WataruWataruShimizuProbst, VincentVincentProbstHorie, MinoruMinoruHorieWilde, Arthur A MArthur A MWildeRedon, RichardRichardRedonJYH-MING JIMMY JUANGNademanee, KoonlaweeKoonlaweeNademaneeBezzina, Connie RConnie RBezzinaBarc, JulienJulienBarcTanaka, ToshihiroToshihiroTanakaOkada, YukinoriYukinoriOkadaSchott, Jean-JacquesJean-JacquesSchottMakita, NaomasaNaomasaMakita2024-10-152024-10-152024-07-09https://scholars.lib.ntu.edu.tw/handle/123456789/722061Background 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.enSCN5ABrugada syndromeCross-ancestry meta-analysisGenetic risk scoreGenome-wide association studies[SDGs]SDG3journal article10.1093/eurheartj/ehae25138747976