Frequency of variants of unknown significance by ancestry groups in the All of Us Research Program cohort

我们所有人研究计划队列中不同祖先群体的未知意义变异的频率

• 批准号: 10659798
• 负责人: RICHARD A GIBBS
• 金额: $ 11.99万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659798
• 关键词: All of Us Research Program; Benign; Case-Control Studies; Classification; Clinical; Code; Control Groups; Data; Data Analyses; Data Set; Disease; Electronic Health Record; Environment; European; Frequencies; Future; Genes; Genetic; Genetic Variation; Genome; Genomic medicine; Goals; Health; Manuals; Manuscripts; Mutation; Neptune; Participant; Pathogenicity; Patients; Persons; Phenotype; Population; Prevalence; Reporting; Research Personnel; Rest; Surveys; Systematized Nomenclature of Medicine; Targeted Research; Testing; Thinness; Ursidae Family; Variant; Work; case control; clinically relevant; cohort; data resource; disparity reduction; falls; health disparity; high throughput screening; large datasets; phenotypic data; response; tool; variant of unknown significance

PROJECT SUMMARY Variants of uncertain significance (VUS) pose many problems in the delivery of genomic medicine, as they are hard to interpret for clinicians and confusing for patients. One important piece of evidence that can be used to reclassify VUS is case/control data; an enrichment of a particular variant in patients with a specific disease (generally already known to be related to the gene in which the variant occurs) is strong evidence for pathogenicity of that variant. The All of Us research program is assembling a cohort with unprecedented diversity that combines genetic data with electronic health records (EHR). This creates the opportunity to examine many VUS that have never been seen before, and explore the utility of the EHR data to build sets of AoU participants that fall into case and control groups. This project will thus inform variant classification, but also create a toolset for the researcher workbench that is currently missing: the ability to sift through and prioritize clinically-relevant variants. Additionally, data collected in this study will likely bear on health disparities. Previous studies have shown that pathogenic variants are distributed differently among groups with different ancestry backgrounds. The same is likely to be true for VUS, especially in understudied populations. Collecting data on VUS prevalence will allow the targeting of future efforts aimed at reducing these disparities.

项目摘要 重要性不确定的变异体（VUS）在基因组药物的递送中造成许多问题，因为它们是 临床医生很难解释，患者也很困惑。一个重要的证据可以用来 重新分类VUS是病例/对照数据;在患有特定疾病的患者中富集特定变体 （通常已经知道与发生变异的基因有关）是强有力的证据， 这种变异的致病性。我们所有人的研究计划正在聚集一批前所未有的 将遗传数据与电子健康记录（EHR）相结合。这就创造了一个机会， 检查许多以前从未见过的VUS，并探索EHR数据的实用性，以建立 AoU参与者分为病例组和对照组。因此，该项目将为变异分类提供信息，但 我还为研究人员工作台创建了一个目前缺少的工具集：筛选和 优先考虑临床相关的变体。此外，本研究中收集的数据可能会影响健康 差距。先前的研究表明，致病性变异在具有以下特征的群体中分布不同： 不同的祖先背景。VUS可能也是如此，特别是在研究不足的人群中。 收集关于疫苗接种和使用不足流行率的数据将有助于今后有针对性地开展旨在缩小这些差距的工作。

项目成果

FixItFelix: improving genomic analysis by fixing reference errors.

• DOI: 10.1186/s13059-023-02863-7
• 发表时间: 2023-02-21
• 期刊: Genome biology
• 影响因子: 12.3

The benefit of a complete reference genome for cancer structural variant analysis.

完整参考基因组对癌症结构变异分析的好处。

• DOI: 10.1101/2024.03.15.24304369
• 发表时间: 2024
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Paulin,LuisF;Fan,Jeremy;O'Neill,Kieran;Pleasance,Erin;Porter,VanessaL;Jones,StevenJM;Sedlazeck,FritzJ
• 通讯作者: Sedlazeck,FritzJ

Multiscale analysis of pangenomes enables improved representation of genomic diversity for repetitive and clinically relevant genes.

• DOI: 10.1038/s41592-023-01914-y
• 发表时间: 2023-08
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Chin, Chen-Shan;Behera, Sairam;Khalak, Asif;Sedlazeck, Fritz J.;Sudmant, Peter H.;Wagner, Justin;Zook, Justin M.
• 通讯作者: Zook, Justin M.

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

双等位基因 ACBD6 变异会导致神经发育综合征，并伴有进行性和复杂的运动障碍。

• DOI: 10.1093/brain/awad380
• 发表时间: 2024
• 期刊: Brain : a journal of neurology
• 作者: Kaiyrzhanov,Rauan;Rad,Aboulfazl;Lin,Sheng-Jia;Bertoli-Avella,Aida;Kallemeijn,WouterW;Godwin,Annie;Zaki,MahaS;Huang,Kevin;Lau,Tracy;Petree,Cassidy;Efthymiou,Stephanie;Karimiani,EhsanGhayoor;Hempel,Maja;Normand,ElizabethA;Rud
• 通讯作者: Rud

Towards accurate and reliable resolution of structural variants for clinical diagnosis.

• DOI: 10.1186/s13059-022-02636-8
• 发表时间: 2022-03-03
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Liu Z;Roberts R;Mercer TR;Xu J;Sedlazeck FJ;Tong W
• 通讯作者: Tong W