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: 10652342
• 负责人: NATHAN D PANKRATZ
• 金额: $ 72.07万
• 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/10652342
• 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; Dedications; Deep Vein Thrombosis; Ensure; Ethnic Population; European ancestry; 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; 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.

摘要

项目成果

Structural variation across 138,134 samples in the TOPMed consortium.

TOPMed 联盟中 138,134 个样本的结构变异。

• DOI: 10.21203/rs.3.rs-2515453/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Jun,Goo;English,AdamC;Metcalf,GingerA;Yang,Jianzhi;Chaisson,MarkJp;Pankratz,Nathan;Menon,VipinK;Salerno,WilliamJ;Krasheninina,Olga;Smith,AlbertV;Lane,JohnA;Blackwell,Tom;Kang,HyunMin;Salvi,Sejal;Meng,Qingchang;Shen,H
• 通讯作者: Shen,H