NGS in Large CAD Families: In-Depth Identification of Rare Risk Genomic Variants

大型 CAD 家族中的 NGS：深入鉴定罕见风险基因组变异

• 批准号: 8762112
• 负责人: QING Kenneth WANG
• 金额: $ 70.76万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762112
• 关键词: 17q11; 3q23; 3q28; 7p22; 7p22.2; Accounting; Affect; Architecture; Back; Binding Sites; Bioinformatics; Cause of Death; Chromatin; Chromosomes; Code; Complex; Coronary Arteriosclerosis; Data; Data Set; Development; Disease; Early treatment; Exons; Family; Family member; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomic DNA; Genomics; Goals; Haplotypes; Heritability; Human Genome; Individual; Introns; Lead; Maps; Molecular Genetics; Molecular Target; Mutation; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathway interactions; Patients; Polymorphic Microsatellite Marker; Population; Prevention; Proteins; Research; Resources; Risk; Sampling; Scanning; Single Nucleotide Polymorphism; Specific qualifier value; Susceptibility Gene; Technology; Variant; abstracting; base; cohort; disease-causing mutation; drug development; early onset; genetic linkage analysis; genetic pedigree; genome sequencing; genome wide association study; genome-wide; genome-wide linkage; high risk; histone modification; innovation; next generation sequencing; novel; programs; promoter; public health relevance; rare variant; risk variant; screening; segregation; trait

DESCRIPTION (provided by applicant): NGS in Large CAD Families: In-Depth Identification of Rare Risk Genomic Variants Abstract Coronary artery disease (CAD) is the leading cause of death worldwide. Genetic factors contribute significantly to the development of CAD. The long-term objective of this project is thus to identify novel genetic and molecular determinants/markers for CAD. To achieve this goal, we have spent more than 10 years of extensive efforts to identify and acquire data for 24 very large, multigenerational families (GeneQuest II, mean pedigree size=16). This has become a unique and highly valuable resource for discovering susceptibility genes and genomic variants that confer risk of CAD. We have completed a genome-wide linkage scan with 408 polymorphic markers that cover the entire human genome by every 10 cM in GeneQuest II families, and identified two highly significant CAD loci on chromosome 3q28 and 7p22.3 and four other significant loci. Back in the 90s, we also had established another well-characterized US cohort of 428 CAD families with familial, early onset CAD (GeneQuest, mean pedigree size=5). The same 3q28 CAD locus showed a highly significant linkage in GeneQuest, too. Whole genome next generation sequencing (NGS) has become an enabling technology to identify susceptibility genes for complex diseases. Thus, we propose to employ an innovative, integrated strategy that combines whole genome NGS and genome-wide linkage analysis in the 24 GeneQuest II families to identify genomic variants associated with CAD. All affected family members in the 24 GeneQuest II families will be subjected to whole genome NGS, and novel rare genomic variants will be identified. Private variants will be characterized by simple co- segregation with disease i families to determine whether they are disease-causing mutations. Other rare variants will be analyzed for association with CAD in the 24 large GeneQuest II families using family-based rare variant association studies that incorporate multiple variants in a gene or a functional region as well as haplotypes from multiple variants. Positive associations will be validated in the replication population (428 GeneQuest families). We prioritize rare variants in the following succeeding order: (1) Rare variants under linkage peaks; (2) Rare variants at or near CAD loci identified by GWAS; (3) Rare variants outside of linkage peaks or GWAS loci. Bioinformatics analysis and relevant functional/expression studies will be used to determine whether variants associated with CAD affect the function or expression of nearby genes. These studies should lead to identification of new genomic variants that confer risk of CAD and uncover novel genetic/molecular pathways for the pathogenesis of CAD.

描述（由申请人提供）：大型 CAD 家族中的 NGS：罕见风险基因组变异的深入鉴定 摘要 冠状动脉疾病 (CAD) 是全世界死亡的主要原因。遗传因素对 CAD 的发展有显着影响。因此，该项目的长期目标是确定 CAD 的新遗传和分子决定因素/标记。为了实现这一目标，我们花费了 10 多年的广泛努力来识别和获取 24 个非常大的多代家庭的数据（GeneQuest II，平均谱系大小 = 16）。这已成为发现导致 CAD 风险的易感基因和基因组变异的独特且非常有价值的资源。我们在 GeneQuest II 家族中完成了 408 个多态性标记的全基因组连锁扫描，每 10 cM 覆盖整个人类基因组，并鉴定了染色体 3q28 和 7p22.3 上的两个高度显着的 CAD 位点以及其他四个显着位点。早在 90 年代，我们还建立了另一个特征明确的美国队列，其中包含 428 个患有家族性早发 CAD 的 CAD 家族（GeneQuest，平均谱系大小 = 5）。同样的 3q28 CAD 基因座在 GeneQuest 中也显示出高度显着的连锁。全基因组下一代测序（NGS）已成为识别复杂疾病易感基因的支持技术。因此，我们建议采用创新的综合策略，将 24 个 GeneQuest II 家族中的全基因组 NGS 和全基因组连锁分析相结合，以识别与 CAD 相关的基因组变异。 24 个 GeneQuest II 家族中所有受影响的家族成员都将接受全基因组 NGS，并将鉴定新的罕见基因组变异。私人变异的特点是与疾病家族进行简单的共分离，以确定它们是否是致病突变。将使用基于家族的罕见变异关联研究来分析 24 个大型 GeneQuest II 家族中其他罕见变异与 CAD 的关联，这些研究纳入了基因或功能区域中的多个变异以及来自多个变异的单倍型。正相关性将在复制群体（428 个 GeneQuest 家族）中得到验证。我们按以下顺序对罕见变异进行优先排序：（1）连锁峰下的罕见变异； (2) GWAS 鉴定出的 CAD 基因座或其附近的罕见变异； (3) 连锁峰或 GWAS 位点之外的罕见变异。生物信息学分析和相关功能/表达研究将用于确定与 CAD 相关的变异是否影响附近基因的功能或表达。这些研究应该能够鉴定出导致 CAD 风险的新基因组变异，并揭示 CAD 发病机制的新遗传/分子途径。