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：对罕见风险基因组变异的深入识别抽象冠状动脉疾病（CAD）是全球死亡的主要原因。遗传因素对CAD的发展产生了显着贡献。因此，该项目的长期目标是确定CAD的新型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年以上的大量努力来识别和获取24个非常大的多代家族的数据（Genequest II，平均谱系大小= 16）。这已成为发现赋予CAD风险的敏感性基因和基因组变体的独特且高度宝贵的资源。我们已经使用408个多态性标记完成了全基因组的连锁扫描，这些标记在Genequest II家族中每10 cm覆盖整个人类基因组，并在3q28和7p22.3染色体上确定了两个非常重要的CAD基因座和其他四个重要的基因座。早在90年代，我们还建立了另一个具有家族性，早期发作CAD（Genequest，平均谱系尺寸= 5）的428个CAD家族的特征良好的美国队列。相同的3q28 CAD基因座在Genequest中也显示出高度显着的联系。整个基因组下一代测序（NGS）已成为一种识别复杂疾病的易感基因的能力。因此，我们建议采用一种创新的综合策略，将整个基因组NG和全基因组链接分析结合在一起，以识别与CAD相关的基因组变异。 24个Genequest II家族中的所有受影响的家庭成员都将受到整个基因组NG的影响，并将确定新颖的稀有基因组变异。私人变体的特征是与疾病I家族的简单隔离，以确定它们是否是引起疾病的突变。使用基于家庭的稀有变体关联研究，将对在24个大型Genequest II家族中分析其他罕见变体与CAD的关联，该研究纳入了基因或功能区域中的多种变体以及来自多个变体的单倍型。积极关联将在复制人群（428个Genequest家族）中得到验证。我们在以下后续顺序中优先考虑稀有变体：（1）连锁峰下的稀有变体； （2）GWAS确定的CAD基因座或附近的罕见变体； （3）在连锁峰或GWAS基因座之外的稀有变体。生物信息学分析和相关的功能/表达研究将用于确定与CAD相关的变体是否影响附近基因的功能或表达。这些研究应导致鉴定出新的基因组变异体，这些变体赋予CAD的风险，并发现新型的CAD发病机理的遗传/分子途径。