Whole genome sequences in ethnically diverse individuals with functional assays and genome editing to characterize the biology of plasma lipids

通过功能测定和基因组编辑对不同种族个体的全基因组序列进行分析，以表征血浆脂质的生物学特征

• 批准号: 10630871
• 负责人: Pradeep Natarajan
• 金额: $ 53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630871
• 关键词: Algorithms; Alleles; Architecture; Bioinformatics; Biological; Biological Assay; Biological Markers; Biology; CRISPR/Cas technology; Cardiometabolic Disease; Cardiovascular Diagnostic Techniques; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cellular Assay; Cholesterol; Clinical; Code; Complement; Complex; Coronary heart disease; Data; Diagnosis; Diagnostic; Discrimination; Ethnic Origin; European ancestry; Evaluation; Familial Hypercholesterolemia; Gene Expression Profile; Gene Frequency; Generations; Genes; Genetic; Genetic Code; Genetic Complementation Test; Genetic Determinism; Genetic Transcription; Genome; Genomics; Genotype; Goals; Hepatocyte; Heritability; High Density Lipoprotein Cholesterol; Human; In Vitro; Individual; Inherited; Knowledge; LDL Cholesterol Lipoproteins; Leadership; Lipids; Medical Genetics; Medicine; Methodology; Modeling; Molecular Profiling; National Heart, Lung, and Blood Institute; Nature; Open Reading Frames; Phenotype; Plasma; Population; Positioning Attribute; Prevalence; Prevention; Preventive care; Reporter; Research; Research Personnel; Risk; Risk Factors; Sample Size; Sequence Analysis; Technology; Testing; Therapeutic; Trans-Omics for Precision Medicine; Triglycerides; Untranslated RNA; Variant; Whole Blood; Work; cardiometabolism; cohort; ethnic difference; ethnic diversity; exome sequencing; functional genomics; genetic analysis; genetic testing; genetic variant; genome editing; genome sequencing; genomic variation; heart disease risk; hypercholesterolemia; improved; in silico; in vitro Assay; in vivo; innovation; insight; method development; new technology; novel; phenotypic data; pleiotropism; premature; prevent; programs; public health relevance; rare variant; risk prediction; success; therapeutic target; trait; transcriptomics; whole genome

PROJECT SUMMARY / ABSTRACT Coronary heart disease is the leading cause of death worldwide. Characterizing the inherited basis of plasma lipids, the strongest risk factor for coronary heart disease, has led to key biological and clinical insights. Large- scale deep-coverage whole genome sequencing is now feasible and offers the opportunity to characterize full genomic variation within a given individual. For any one individual, however, the interpretation of genomic variation is limited by 1) ethnic-specific impacts, and 2) prediction of functional impact, particularly for rare, non-coding variants. The goal of this R01 proposal is to fully characterize the inherited basis of plasma lipids through a novel `trans-omics' approach – complementing whole genome sequencing with novel statistical genetics and functional genomics. In Aim 1, we will discover novel genomic variation from ~100,000 ethnically- diverse individuals and associate with plasma lipids. We will complementarily use data-driven bioinformatic approaches to identify novel genetic regions. In Aim 2, we will improve the genomic diagnosis of familial hypercholesterolemia, characterized by severe hypercholesterolemia and marked increased risk for premature coronary heart disease. We will incorporate ethnicity, functional annotations, and pleiotropy to develop a novel polygenic model for familial hypercholesterolemia. We will jointly model the monogenic and polygenic components for risk of familial hypercholesterolemia. In Aim 3, we identify functional rare non-coding hypercholesterolemia variants with cell-based massively parallel reporter assays and CRISPR-based methods. We will further use these insights to improve power for discovering novel genes from whole genome sequence analysis. This work leverages data being generated within the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We have extensive expertise in whole genome sequence analysis, statistical genetics, functional genomics, and cardiovascular medicine. This proposal includes methodological, computational, and experimental innovations, and builds on established collaborative relationships between investigators with complementary strengths. Completion of our aims will yield novel insights to inform prevention, diagnosis, and treatments for coronary heart disease. Furthermore, we will demonstrate broad framework for trans-omics analysis to identify causally relevant genomic variants for both research and clinical genetic applications.

项目概要/摘要 冠心病是全世界死亡的主要原因，是血浆遗传基础的特征。 血脂是冠心病最严重的危险因素，它带来了重要的生物学和临床见解。 大规模深度覆盖全基因组测序现已成为可能，并提供了表征完整基因组的机会 然而，对于任何一个个体，基因组的解释都是不同的。 变异受到以下因素的限制：1) 特定种族的影响，2) 功能影响的预测，特别是对于罕见的、 R01 提案的目标是全面表征血浆脂质的遗传基础。 通过一种新颖的“跨组学”方法——用新颖的统计方法补充全基因组测序 在目标 1 中，我们将发现约 100,000 个种族的新基因组变异。 我们将互补地使用数据驱动的生物信息学。 在目标 2 中，我们将改进家族的基因组诊断。 高胆固醇血症，以严重高胆固醇血症为特征，早产风险显着增加 我们将结合种族、功能注释和多效性来开发一种新型药物。 家族性高胆固醇血症的多基因模型我们将联合建立单基因和多基因模型。 在目标 3 中，我们确定了功能性罕见非编码。 高胆固醇血症变异体采用基于细胞的大规模并行报告基因检测和基于 CRISPR 的方法。 我们将进一步利用这些见解来提高从全基因组序列中发现新基因的能力 这项工作利用 NHLBI Trans-Omics for Precision Medicine 生成的数据。 (TOPMed) 计划我们在全基因组序列分析、统计遗传学、 该提案包括方法学、计算和心血管医学。 实验创新，并建立在研究人员与 完成我们的目标将产生新的见解，为预防、诊断和治疗提供信息。 此外，我们将展示跨组学的广泛框架。 分析以确定因果相关的基因组变异，用于研究和临床遗传应用。

项目成果

Polygenic Scores to Assess Atherosclerotic Cardiovascular Disease Risk: Clinical Perspectives and Basic Implications.

评估动脉粥样硬化性心血管疾病风险的多基因评分：临床观点和基本意义。

• 发表时间: 2020
• 影响因子: 20.1
• 作者: Aragam, Krishna G;Natarajan, Pradeep
• 通讯作者: Natarajan, Pradeep

Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration: Protective Missense Variant on Lipoprotein(a) Concentration-Brief Report.

全基因组关联研究和脂蛋白（a）浓度保护性错义变异的鉴定：脂蛋白（a）浓度保护性错义变异简要报告。

• 发表时间: 2021
• 作者: Said, M Abdullah;Yeung, Ming Wai;van de Vegte, Yordi J;Benjamins, Jan Walter;Dullaart, Robin P F;Ruotsalainen, Sanni;Ripatti, Samuli;Natarajan, Pradeep;Juarez;Verweij, Niek;van der Harst, P
• 通讯作者: van der Harst, P