Abramowitz Sarah A, Hoffman-Andrews Lily, Zhang David, Judy Renae, Cappola Thomas P, Day Sharlene M, Reza Nosheen, Owens Anjali T, Damrauer Scott M, Levin Michael G
Department of Surgery, University of Pennsylvania Perelman School of Medicine.
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.
medRxiv. 2025 Jun 22:2025.06.20.25329138. doi: 10.1101/2025.06.20.25329138.
Polygenic background modifies variant penetrance in hypertrophic (HCM) and dilated (DCM) cardiomyopathy, diseases with opposing morphologic characteristics and inversely related genetic pathways. Whether polygenic susceptibility for one disease protects against monogenic risk for the other remains unexplored.
To characterize if polygenic background bidirectionally modifies pathogenicity of established rare variants associated with HCM and DCM.
Cross-sectional study.
The Penn Medicine BioBank (PMBB).
Volunteers enrolled in PMBB with available electronic health record and genotyping data.
Normalized polygenic scores (PGS) for HCM and DCM, as well as carrier status of pathogenic variants in established HCM or DCM genes.
HCM and DCM defined using electronic health record diagnosis and procedure code, as well as echocardiogram measurements derived from medical records.
This study included 49,434 PMBB participants. An increased HCM PGS was associated with significantly increased left ventricular ejection fraction (LVEF), decreased left ventricular internal diameter at end-diastole (LVIDd), and increased interventricular septal thickness (IVS) (p<0.001). An increased DCM PGS was significantly (p<0.001) associated with decreased LVEF and increased LVIDd, but was not associated with IVS. A one standard deviation increase in HCM PGS was associated with increased risk of HCM (OR 1.8; 95% CI 1.6-2.0; p=9.6×10) and decreased risk of DCM (OR 0.69; 95% CI 0.64-0.74; p=4.3×10). A one standard deviation increase in DCM PGS was associated with an increased risk of DCM (OR 1.6; 95% CI 1.5-1.7; p=1.7×10) and decreased risk of HCM (OR 0.69; 95% CI 0.63-0.76; p=3.0×10). Monogenic and polygenic risk terms had significant, independent effects when combined in models of disease status and echocardiographic measurements; the additional inclusion of either an HCM or DCM PGS improved the discrimination of models of HCM and DCM that included age, sex, and monogenic variant status (>95% probability of difference in AUROC).
HCM and DCM risk are markedly modified by polygenic background which exists on an overlapping spectrum. Consideration of polygenic background may offer clinical value through improving understanding and prediction of these inherited cardiomyopathies.
多基因背景会改变肥厚型心肌病（HCM）和扩张型心肌病（DCM）的变异外显率，这两种疾病具有相反的形态学特征和反向相关的遗传途径。一种疾病的多基因易感性是否能预防另一种疾病的单基因风险仍未得到探索。
确定多基因背景是否双向改变与HCM和DCM相关的已确定罕见变异的致病性。
横断面研究。
宾夕法尼亚大学医学生物样本库（PMBB）。
参加PMBB且有可用电子健康记录和基因分型数据的志愿者。
HCM和DCM的标准化多基因评分（PGS），以及已确定的HCM或DCM基因中致病变异的携带者状态。
使用电子健康记录诊断和程序代码以及从医疗记录中得出的超声心动图测量结果来定义HCM和DCM。
本研究纳入了49434名PMBB参与者。HCM PGS升高与左心室射血分数（LVEF）显著增加、舒张末期左心室内径（LVIDd）减小和室间隔厚度（IVS）增加相关（p<0.001）。DCM PGS升高与LVEF降低和LVIDd增加显著相关（p<0.001），但与IVS无关。HCM PGS每增加一个标准差与HCM风险增加相关（OR 1.8；95%CI 1.6 - 2.0；p = 9.6×10）和DCM风险降低相关（OR 0.69；95%CI 0.64 - 0.74；p = 4.3×10）。DCM PGS每增加一个标准差与DCM风险增加相关（OR 1.6；95%CI 1.5 - 1.7；p = 1.7×10）和HCM风险降低相关（OR 0.69；95%CI 0.63 - 0.76；p = 3.0×10）。在疾病状态和超声心动图测量模型中，单基因和多基因风险项联合时具有显著的独立效应；额外纳入HCM或DCM PGS可改善包含年龄、性别和单基因变异状态的HCM和DCM模型的判别能力（AUROC差异概率>95%）。
HCM和DCM风险受到存在于重叠谱上的多基因背景的显著影响。考虑多基因背景可能通过增进对这些遗传性心肌病的理解和预测而具有临床价值。
