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: 10064846
• 负责人: Mariza de ANDRADE
• 金额: $ 77.3万
• 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/10064846
• 关键词: Adult; Affect; African; 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; 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; Structure; 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; 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.

摘要 静脉血栓栓塞症（VTE）是一种遗传性疾病，包括深静脉血栓形成和肺栓塞。 栓塞并与显著的发病率和死亡率相关。基因组的发现可以是第一步， 更好地了解人类生物学，并且已经确定VTE具有重要的遗传决定因素。 随着技术和样本规模的进步，支持新关联的证据越来越多。初始 探索构成人类基因组的31亿个核苷酸中罕见和不寻常的变异。 使用全基因组测序（WGS）的基因组为罕见的，潜在的破坏性的 已知VTE风险基因座中的单核苷酸变异（SNV）。此外，WGS可用于完全表征 结构变异体（SV）。我们的初步数据来自社区动脉粥样硬化风险 一项使用TOPMed WGS数据的研究揭示了已知与风险相关的多个基因中罕见的SV缺失 对于VTE，包括影响纤维蛋白原结构基因（FGB）的缺失，该基因与2倍 VTE风险增加。对与VTE相关的SV进行系统的和不可知的全基因组搜索， 如果没有专门的资源，例如本报告所建议的资源， 应用程序.该提案是TOPMed职业技术教育工作组领导层、 TOPMed结构变异工作组和国际静脉血栓防治网络 （INVENT）Consortium.以下具体目标旨在发现新的基因组变异（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例对照。 目标1：在TOPM和INVENT参与者中，使用新颖的方法来生成高质量和更多的 准确的SV调用比SV调用算法目前可用于WGS和现有的阵列数据。的 新的呼叫将被过滤，策划，并将可用于目标2。SV呼叫也将在 TOPM被工作组应用于其他心血管、肺和睡眠表型。目标2：行为 SV与VTE的关联分析。发现：使用Aim 1中衍生的SV调用进行基于基因的， 在多达32，545例VTE病例和170，000例对照中进行了节段性关联分析。验证和复制： 将使用定量PCR验证基于基因的具有遗传学意义的关联结果的SV， 将在未使用的人群/研究中的多达13，655例VTE病例和210，000例对照中重复 发现阶段。目的3：进行SNV基因型与VTE的关联分析。发现：使用SNV 来自WGS和WGS插补数据（包括插入和缺失）的数据，进行聚合-变异 对MAF <0.05的SNV的基因和调控区进行分析，以确定其与多达32，454例VTE的相关性 使用负荷测试和序列核关联测试（SKAT）对170，000例病例和170，000例对照进行分析。我们也 我建议采用联合收割机SV和SNV数据分析复合杂合子的功能缺失 突变及其与静脉血栓栓塞的关联。复制：重要关联将如目标2中所述进行复制。