Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly.

扩张型心肌病 （DCM） 是一种心肌疾病，是导致发病率和死亡率的重要原因，但致病机制在很大程度上仍然难以捉摸。在这里，我们使用 9,365 个病例和 946,368 个对照对 DCM 进行了大规模的全基因组关联研究和多性状分析。我们确定了 70 个全基因组的重要基因座，这些基因座在独立样本中显示出广泛的复制，并映射到 63 个优先基因。组织、细胞类型和通路富集分析突出了心肌细胞和收缩装置在 DCM 发病机制中的核心作用。根据我们的全基因组关联研究构建的多基因风险评分可预测不同祖先群体的 DCM，根据罕见的致病性变异状态显示对 DCM 的不同贡献，并与各种临床环境中的收缩性心力衰竭相关。孟德尔随机化分析揭示了 DCM 的可操作潜在原因，包括更高的体重和更高的收缩压。我们的研究结果为更广泛地了解 DCM 和心肌功能的遗传结构和机制提供了见解。