Cardiomyopathy Genomes Project

心肌病基因组计划

• 批准号: 10615197
• 负责人: Elizabeth M McNally
• 金额: $ 57.53万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615197
• 关键词: Adult; Age of Onset; Cardiac; Cardiomyopathies; Cell model; Chromatin; Classification; Clinical; Clinical Data; Code; Complement; Complex; Coupled; DNA; DNA Sequence Alteration; Data; Data Set; Development; Diagnosis; Dilated Cardiomyopathy; Disease; Drosophila genus; Enhancers; Epigenetic Process; Exhibits; Exons; Family; Funding; Gene Expression; Gene Mutation; General Population; Genes; Genetic; Genetic Variation; Genome; Genomics; Heart; Heart Abnormalities; Heart failure; Heritability; Human; Hypertrophic Cardiomyopathy; Impairment; Individual; Investigation; Link; Mitochondria; Mitochondrial Membrane Protein; Morphology; Mus; Mutation; Nucleic Acid Regulatory Sequences; Orthologous Gene; Outcome; Outer Mitochondrial Membrane; Pathogenesis; Pathway interactions; Penetrance; Performance; Persons; Phenotype; Play; Primary Myocardial Diseases; Risk; Role; Sampling; Severity of illness; Shapes; Single Nucleotide Polymorphism; Testing; Untranslated RNA; Variant; autosome; biobank; candidate identification; clinical prognosis; cohort; data resource; driver mutation; genetic testing; genetic variant; genome sequencing; genomic signature; heart dimension/size; heart function; induced pluripotent stem cell derived cardiomyocytes; inherited cardiomyopathy; loss of function; member; model organism; novel; transcriptome sequencing; whole genome

PROJECT SUMMARY Cardiomyopathy is highly heritable, and cardiomyopathies are classified based on heart morphology with two major forms being dilated and hypertrophic cardiomyopathy (DCM and HCM, respectively). In adult familial cardiomyopathy, the most common form of inheritance is autosomal dominant with variable expressivity and penetrance. Genetic testing now samples >80 genes and identifies a primary mutation in approximately half the cases. With the same single mutation, there is considerable phenotypic variability. This is well seen in families, where all members share the same primary mutation but with differing age of onset and expression. The “missing heritability” for cardiomyopathy may be due to multiple factors, undiscovered primary or “driver” gene mutations and/or an oligogenic genetic mechanism involving the interplay between driver variants and the genomic context in which they are expressed. The genomic context for cardiomyopathy includes genetic modifiers, which are not restricted to coding regions of the genome and likely includes noncoding genetic variation. Genetic modifiers are defined as genetic variants that alter the phenotypic expression of a primary mutation, and identifying these pathways is useful for clinical prognosis and to identify potential pathways around which therapy can be developed. Historically, cardiomyopathy genetic investigations have been restricted to a small fraction of the genome with limited information on the larger genomic signature of heart failure. Whole genome sequencing (WGS) provides a more comprehensive picture of genomic context, including both rare and common variation, that shapes the manifestation of driver variant(s) extending beyond the coding region. In the prior funding interval, we generated and analyzed WGS data coupled with clinical cardiac phenotype information from >300 individuals with cardiomyopathy. As a complement, we also now have WGS data from >1000 individuals from Northwestern's NUgene Biobank, and these data are linked to clinical data. Analysis of the cardiomyopathy genomes reveals variants in genes regulating cardiac energetics and mitochondrial function as modifiers of HCM and DCM, as we will study this through mechanistic approaches in model organisms and human cell models. We now propose to decipher complex cardiomyopathy genetics by integrating WGS information, epigenetic signatures, and gene expression data. Defining genetic modifiers for cardiomyopathy is expected to provide novel pathways contributing to heart failure.

项目摘要 心肌病是高度遗传的，心肌病是根据心形态分类的 主要形式被扩张和肥厚的心肌病（分别为DCM和HCM）。在成人家庭 心肌病，最常见的遗传形式是常染色体显性，具有可变的表达性和 外观。基因测试现在样品> 80个基因，并鉴定出大约一半的主要突变 案件。具有相同的单个突变，存在相当大的表型变异性。这在 家庭，所有成员共享相同的主要突变，但具有不同的发作和表达年龄。 心肌病的“缺失遗传力”可能是由于多种因素，未被发现的主要或“驾驶员” 基因突变和/或寡聚遗传机制涉及驱动器变体之间的相互作用 它们表达的基因组环境。心肌病的基因组环境包括遗传 修饰符不限于基因组的编码区域，可能包括非编码遗传 变化。遗传修饰剂被定义为遗传变异，改变了原发性的表型表达 突变和识别这些途径对于临床预后很有用，并确定潜在的途径 可以开发疗法。从历史上看，心肌病基因研究已经 仅限于基因组的一小部分，其心脏较大基因组特征的信息有限 失败。整个基因组测序（WGS）提供了基因组环境的更全面的图景， 包括稀有和常见变化，塑造驱动器变体的表现延伸超出 编码区域。在先前的资金间隔中，我们生成和分析了WGS数据，并结合了临床 来自> 300名心肌病个体的心脏表型信息。作为一个完整的，我们现在也 从西北的Nugene Biobank中获得来自> 1000个人的WGS数据，这些数据与 临床数据。心肌病基因组的分析揭示了调节心脏能量学的基因的变异 线粒体功能作为HCM和DCM的修饰符，因为我们将通过机械进行研究 模型生物和人类细胞模型的方法。我们现在建议破译复合物 通过整合WGS信息，表观遗传学特征和基因表达数据，心肌病遗传学。 定义心肌病的遗传修饰符有望提供有助于心脏的新型途径 失败。