Structural and Nucleotide Variation as Genomic Risks for Venous Thrombosis: TOPMED and INVENT Collaboration

结构和核苷酸变异作为静脉血栓形成的基因组风险：TOPMED 和 INVENT 合作

• 批准号: 10441382
• 负责人: NATHAN D PANKRATZ
• 金额: $ 74.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441382
• 关键词: Adult; Affect; African ancestry; Algorithms; Atherosclerosis Risk in Communities; Biological; Biology; Blood coagulation; Candidate Disease Gene; Cardiovascular system; Characteristics; Clinical Trials Design; Coagulation Process; Collaborations; Collection; Complex; DNA; DNA Sequence; Data; Deep Vein Thrombosis; Ensure; Ethnic group; European; Event; Experimental Designs; Factor VIII; Fibrinogen; Genes; Genetic Determinism; Genomics; Genotype; Heritability; Heterozygote; Human Biology; Human Genome; Individual; International; Leadership; Leg; Lung; Maps; Measures; Methodology; Methods; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nucleic Acid Regulatory Sequences; Nucleotides; Participant; Pathway interactions; Persons; Phase; Phenotype; Population; Postphlebitic Syndrome; Pulmonary Embolism; Recurrence; Research; Resources; Risk; Sample Size; Single Nucleotide Polymorphism; Sleep; Structural Genes; Technology; Testing; Trans-Omics for Precision Medicine; Validation; Variant; Venous Thrombosis; base; case control; disorder prevention; experience; genome sequencing; genome-wide; genomic variation; human DNA; insertion/deletion mutation; loss of function mutation; mortality; multi-ethnic; novel; programs; risk variant; venous thromboembolism; whole genome; working group; Adult; Affect; African ancestry; Algorithms; Atherosclerosis Risk in Communities; Biological; Biology; Blood coagulation; Candidate Disease Gene; Cardiovascular system; Characteristics; Clinical Trials Design; Coagulation Process; Collaborations; Collection; Complex; DNA; DNA Sequence; Data; Deep Vein Thrombosis; Ensure; Ethnic group; European; Event; Experimental Designs; Factor VIII; Fibrinogen; Genes; Genetic Determinism; Genomics; Genotype; Heritability; Heterozygote; Human Biology; Human Genome; Individual; International; Leadership; Leg; Lung; Maps; Measures; Methodology; Methods; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nucleic Acid Regulatory Sequences; Nucleotides; Participant; Pathway interactions; Persons; Phase; Phenotype; Population; Postphlebitic Syndrome; Pulmonary Embolism; Recurrence; Research; Resources; Risk; Sample Size; Single Nucleotide Polymorphism; Sleep; Structural Genes; Technology; Testing; Trans-Omics for Precision Medicine; Validation; Variant; Venous Thrombosis; base; case control; disorder prevention; experience; genome sequencing; genome-wide; genomic variation; human DNA; insertion/deletion mutation; loss of function mutation; mortality; multi-ethnic; novel; programs; risk variant; venous thromboembolism; whole genome; working group

ABSTRACT Venous thromboembolism (VTE) is a heritable condition that includes deep vein thrombosis and pulmonary embolism and is associated with marked morbidity and mortality. Genomic discovery can be a first step to better understand human biology and it is well established that VTE has important genetic determinants. Evidence supporting new associations has grown with advances in technology and sample size. Initial exploration of rare and uncommon variation across the 3.1 billion nucleotides that constitute the human genome using whole-genome sequencing (WGS) is providing interesting results for rare, potentially-damaging single nucleotide variants (SNVs) in known VTE risk loci. Further, WGS can be used to fully characterizing structural variants (SVs) genome-wide. Our preliminary data from the Atherosclerosis Risk in Communities study using TOPMed WGS data reveals rare SV deletions in multiple genes known to be associated with risk for VTE, including a deletion affecting a fibrinogen structural gene (FGB) that is associated with a 2-fold increase in VTE risk. A systematic and agnostic genome-wide search for SVs associated with VTE has not been conducted and will not be possible without dedicated resources, such as those proposed in this application. This proposal is a collaboration between leadership within the TOPMed VTE Working Group, the TOPMed Structural Variation Working Group, and the International Network Against Venous Thrombosis (INVENT) Consortium. The following specific aims seek to uncover novel genomic variation (SVs and SNVs) contributing to VTE risk using data from 17 studies that include 46,200 VTE cases and over 380,000 controls. Aim 1: In TOPMed and INVENT participants, use novel methodology to generate high-quality and more accurate SV calls than the SV calling algorithms currently available for both WGS and existing array data. The new calls will be filtered, curated, and will be available for Aim 2. The SV call will also be shared within TOPMed and applied by working groups to other cardiovascular, lung, and sleep phenotypes. Aim 2: Conduct association analyses of SVs with VTE. Discovery: Using SV calls derived in Aim 1 to conduct gene-based, segmental association analyses in up to 32,545 VTE cases and 170,000 controls. Validation and Replication: SVs from statistically-significant gene-based association findings will be validated using quantitative PCR and will be replicated in up to 13,655 VTE cases and 210,000 controls in populations/studies not used in the discovery phase. Aim 3: Conduct association analyses of SNV genotypes with VTE. Discovery: Using SNV data derived from WGS and WGS-imputed data (including insertions and deletions), conduct aggregate-variant analyses of genes and regulatory regions for SNVs with MAF <0.05 for association with VTE in up to 32,454 cases and 170,000 controls using burden tests and the Sequence Kernel Association Test (SKAT). We also propose analyses that combine SV and SNV data to analyze compound heterozygotes for loss-of-function mutations and their association with VTE. Replication: Significant associations will be replicated as in Aim 2.

抽象的 静脉血栓栓塞（VTE）是一种可遗传的疾病，包括深静脉血栓形成和肺部 栓塞，与明显的发病率和死亡率有关。基因组发现可能是 更好地了解人类的生物学，并且可以很好地确定VTE具有重要的遗传决定因素。 支持新协会的证据随着技术和样本量的进步增长。最初的 构成人类的31亿个核苷酸中罕见和罕见变化的探索 使用全基因组测序（WGS）的基因组为罕见，潜在破坏的结果提供了有趣的结果 已知VTE风险基因座中的单核苷酸变体（SNV）。此外，WGS可用于充分表征 结构变体（SVS）全基因组。我们来自社区动脉粥样硬化风险的初步数据 使用顶级WGS数据的研究揭示了已知与风险相关的多个基因的罕见SV缺失 对于VTE，包括影响纤维蛋白原结构基因（FGB）的缺失，与2倍有关 增加VTE风险。对与VTE相关的SVS的系统和不可知论的全基因组搜索尚未 已经进行了，没有专门的资源，例如在此中提出的资源将是不可能的 应用。该建议是最佳VTE工作组中领导的合作 顶级结构变化工作组和国际反静脉血栓形成网络 （发明）财团。以下特定目的旨在发现新颖的基因组变异（SV和SNV） 使用来自17项研究的数据，包括46,200例VTE病例和超过380,000个对照，从而导致VTE风险。 目的1：在最高的和发明参与者中，使用新颖的方法来产生高质量以及更多 准确的SV调用比当前可用于WGS和现有数组数据的SV调用算法。这 新调用将被过滤，策划，并将用于AIM 2。SV调用也将在内共享 工作组最高并应用于其他心血管，肺和睡眠表型。目标2：行为 SVS与VTE的关联分析。发现：使用AIM 1中得出的SV调用来进行基于基因的基于基因的调用， 分段关联分析多达32,545例VTE病例和170,000个对照。验证和复制： 将使用定量PCR和 在不使用的人群/研究中，将在多达13,655例VTE病例和210,000个对照中复制 发现阶段。 AIM 3：对SNV基因型与VTE进行关联分析。发现：使用SNV 从WGS和WGS输入数据（包括插入和删除）中得出的数据，进行聚合变化 MAF <0.05的SNV的基因和调节区域的分析，可与VTE相关联32,454 使用负担测试和序列内核协会测试（SKAT）的病例和170,000个对照。我们也是 提出的分析将SV和SNV数据结合在一起，以分析化合物杂合子的功能丧失 突变及其与VTE的关联。复制：重大关联将如AIM 2所述复制。