A Genome‐Wide Association Study Reveals Desmoglein‐2 Predominance in Japanese Arrhythmogenic Cardiomyopathy

ABSTRACT Background Rare pathogenic variations of desmosomal genes, particularly in plakophilin‐2 ( PKP2 ) and desmoglein‐2 ( DSG2 ), have been implicated in arrhythmogenic cardiomyopathy (ACM); however, their potential polygenic contribution remains unclear. Methods We performed a genome‐wide association study of 104 Japanese patients with ACM and 46 527 controls, adjusting for case–control imbalance. Results The strongest association was observed upstream of DSG2 (rs182626537, p = 2.3 × 10 −42 ), but the signal was abolished after excluding carriers of pathogenic DSG2 variants, suggesting a synthetic association driven by linkage disequilibrium. Conclusions These findings highlight a population‐specific genetic architecture of ACM, with DSG2 predominating in the Japanese population.