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.

项目概要 意义不确定的变异 (VUS) 在基因组医学的实施中带来了许多问题，因为它们 临床医生难以解释，患者也感到困惑。一项重要的证据可以用来 重新分类 VUS 是病例/对照数据；患有特定疾病的患者中特定变异的富集 （通常已知与发生变异的基因有关）是强有力的证据 该变异体的致病性。 “我们所有人”研究计划正在组建一个前所未有的队列 将遗传数据与电子健康记录 (EHR) 相结合的多样性。这创造了机会 检查许多以前从未见过的 VUS，并探索 EHR 数据的实用性来构建数据集 AoU 参与者分为病例组和对照组。因此，该项目将告知变体分类，但是 还为研究人员工作台创建了目前缺少的工具集：筛选和分析的能力 优先考虑临床相关的变异。此外，本研究中收集的数据可能会对健康产生影响 差异。先前的研究表明，致病变异在不同群体之间的分布不同 不同的血统背景。 VUS 可能也是如此，尤其是在研究不足的人群中。 收集 VUS 患病率数据将有助于确定未来旨在减少这些差异的努力。

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