Key result
Upstream DSG2 genetic variation is strongly linked to arrhythmogenic cardiomyopathy via linkage disequilibrium.
Why the study?
The potential polygenic contribution of desmosomal gene variations, especially PKP2 and DSG2, to arrhythmogenic cardiomyopathy remains unclear.
Case-Control (n=46,631)
p-value: p=2.3 × 10^-42
In the Japanese population, the genetic architecture of arrhythmogenic cardiomyopathy is predominated by DSG2 variants.
Supports DSG2 prioritization in Japanese ACM testing; extends population-specific genetic architecture insights.
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.
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Ishikawa et al. (2026) conducted a case-control in Arrhythmogenic cardiomyopathy (n=46,631). Genetic variations (DSG2 variants) vs. Controls was evaluated on Association with arrhythmogenic cardiomyopathy (p=2.3 × 10^-42). Genetic variation upstream of DSG2 was strongly associated with arrhythmogenic cardiomyopathy in Japanese patients (p = 2.3 × 10^-42), driven by linkage disequilibrium with pathogenic variants.
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