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: 9053995
• 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/9053995
• 关键词: 3q23; 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; Genomic DNA; Genomic Segment; Goals; Haplotypes; Heritability; Human Genome; Individual; Introns; Lead; Maps; Molecular Genetics; 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; genetic variant; genome sequencing; genome wide association study; genome-wide; genome-wide linkage; high risk; histone modification; innovation; molecular targeted therapies; next generation sequencing; novel; programs; promoter; public health relevance; rare variant; risk variant; screening; segregation; trait; whole genome

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）是全球死亡的主要原因。遗传因素对CAD的发展起着重要作用。因此，该项目的长期目标是确定CAD的新的遗传和分子决定因素/标记。为了实现这一目标，我们花了10年多的时间，为24个非常大的多代家庭（GeneQuest II，平均谱系大小=16）进行了广泛的努力，以确定和获取数据。这已成为发现赋予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。我们已经完成了一个全基因组的连锁扫描与408个多态性标记，覆盖整个人类基因组的每10 cM的GeneQuest II家庭，并确定了两个高度显着的CAD基因座染色体3q 28和7p22.3和其他四个显着的基因座。早在90年代，我们还建立了另一个具有良好特征的美国队列，其中包括428个家族性早发性CAD家族（GeneQuest，平均家系大小=5）。同样的3q 28 CAD位点在GeneQuest中也显示出高度显著的连锁。全基因组下一代测序（NGS）已成为鉴定复杂疾病易感基因的技术。因此，我们建议采用一种创新的综合策略，将全基因组NGS和全基因组连锁分析结合在24个GeneQuest II家族中，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将接受全基因组NGS，并将鉴定新的罕见基因组变异。私有变体将通过与疾病家族的简单共分离来表征，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分析24个大型GeneQuest II家族中其他罕见变异与CAD的关联性，该研究将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纳入其中。将在复制群体（428个GeneQuest家族）中验证阳性关联。我们按照以下顺序优先考虑罕见变异：（1）连锁峰下的罕见变异;（2）GWAS鉴定的CAD基因座处或附近的罕见变异;（3）连锁峰或GWAS基因座外的罕见变异。生物信息学分析和相关功能/表达研究将用于确定与CAD相关的变体是否影响附近基因的功能或表达。这些研究应导致识别新的基因组变异，赋予CAD的风险，并发现CAD发病机制的新的遗传/分子途径。