Klasfeld Samantha J, Knutson Katherine A, Miller Melissa R, Fauman Eric B, Berghout Joanne, Moccia Rob, Kim Hye In
Internal Medicine Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA; Rare Disease Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Clinical Omics and Biomarker Statistics, Pfizer Research and Development, Cambridge, MA 02139, USA.
HGG Adv. 2025 May 22:100460. doi: 10.1016/j.xhgg.2025.100460.
Cardiomyopathy presents a significant medical burden due to frequent hospitalizations and invasive interventions. While cardiomyopathy is considered a rare monogenic disorder caused by rare pathogenic variants in a few genes, emerging evidence suggests that common genetic modifiers influence disease penetrance and clinical variability. Quantifying the interplay between common genetic modifiers and rare pathogenic variants is challenging due to the rarity of subjects with cardiomyopathy and pathogenic variant carriers. In this study, we utilized large-scale genetic and phenotypic data from the UK Biobank to refine the genetic architecture of hypertrophic and dilated cardiomyopathies. Using ClinVar annotations and variant effect prediction tools, we first identified known and predicted pathogenic variants and evaluated their association with disease risk, age of diagnosis, and quantitative cardiac phenotypes that reflect disease progression. We next examined the impact of polygenic risk scores on disease in the combined sets of known and predicted pathogenic variant carriers. Indeed, the polygenic risk scores were significantly associated with increased disease risk, with rare pathogenic variant carriers in the top 20% of polygenic risk having 5.7 and 2.3 times higher risk than those in the bottom 20% for hypertrophic and dilated cardiomyopathies, respectively. We observed stronger associations in the carrier sets that included predicted pathogenic variant carriers, suggesting improved statistical power. In summary, our study adds to the evidence that common genetic modifiers influence the cardiomyopathy disease risk among rare pathogenic variant carriers and illustrates the benefits and limitations of incorporating variant effect predictions to examine the polygenic influence in rare disease variant carriers.
由于频繁住院和侵入性干预，心肌病带来了巨大的医疗负担。虽然心肌病被认为是一种由少数基因中的罕见致病变异引起的罕见单基因疾病，但新出现的证据表明，常见的基因修饰因子会影响疾病的外显率和临床变异性。由于患有心肌病的受试者和致病变异携带者数量稀少，量化常见基因修饰因子和罕见致病变异之间的相互作用具有挑战性。在本研究中，我们利用英国生物银行的大规模基因和表型数据来完善肥厚型和扩张型心肌病的遗传结构。使用ClinVar注释和变异效应预测工具，我们首先识别已知和预测的致病变异，并评估它们与疾病风险、诊断年龄以及反映疾病进展的定量心脏表型的关联。接下来，我们在已知和预测的致病变异携带者组合集中研究多基因风险评分对疾病的影响。事实上，多基因风险评分与疾病风险增加显著相关，对于肥厚型和扩张型心肌病，多基因风险处于前20%的罕见致病变异携带者的风险分别是处于后20%者的5.7倍和2.3倍。我们在包括预测致病变异携带者的携带者组中观察到更强的关联，表明统计效力有所提高。总之，我们的研究进一步证明了常见基因修饰因子会影响罕见致病变异携带者中的心肌病疾病风险，并说明了纳入变异效应预测以研究罕见病变异携带者中多基因影响的益处和局限性。
