常见的基因修饰因子影响罕见致病变异携带者的心肌病易感性。

IF 3.3 Q2 GENETICS & HEREDITY
Samantha J Klasfeld, Katherine A Knutson, Melissa R Miller, Eric B Fauman, Joanne Berghout, Rob Moccia, Hye In Kim
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引用次数: 0

摘要

由于频繁的住院治疗和侵入性干预,心肌病带来了巨大的医疗负担。虽然心肌病被认为是一种罕见的单基因疾病,由少数基因的罕见致病变异引起,但新出现的证据表明,常见的遗传修饰因子会影响疾病的外显率和临床变异性。由于心肌病病例和致病变异携带者的罕见性,量化常见遗传修饰因子和罕见致病变异之间的相互作用具有挑战性。在这项研究中,我们利用来自英国生物银行的大规模遗传和表型数据来完善肥厚性和扩张性心肌病的遗传结构。使用ClinVar注释和变异效应预测工具,我们首先确定了已知和预测的致病变异,并评估了它们与疾病风险、诊断年龄和反映疾病进展的定量心脏表型的关系。接下来,我们在已知和预测的致病变异携带者组合中检查了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,多基因风险前20%的罕见致病变异携带者患肥厚性心肌病和扩张性心肌病的风险分别是后20%的5.7倍和2.3倍。我们观察到,包括预测致病变异携带者在内的携带者组的相关性更强,这表明统计能力有所提高。总之,我们的研究增加了常见遗传修饰因子影响罕见致病变异携带者心肌病疾病风险的证据,并说明了纳入变异效应预测以检查罕见疾病变异携带者多基因影响的益处和局限性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Common genetic modifiers influence cardiomyopathy susceptibility among the carriers of rare pathogenic variants.

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 cardiomyopathy cases 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% polygenic risk having 5.7- and 2.3-times higher risk than those in the bottom 20% for hypertrophic and dilated cardiomyopathy, 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.

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来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
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