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

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.