Linking microbiome genetic variants with cardiovascular phenotypes in 50,000 individuals

将 50,000 名个体的微生物组遗传变异与心血管表型联系起来

• 批准号: 10516693
• 负责人: KATHERINE S. POLLARD
• 金额: $ 70.73万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516693
• 关键词: Accounting; Address; Algorithms; Alleles; Animal Model; Atherosclerosis; Bacterial Genes; Benchmarking; Biological Markers; Biology; Cardiovascular Diagnostic Techniques; Cardiovascular Diseases; Cardiovascular system; Cells; Code; Communities; Complex; Complex Mixtures; Copy Number Polymorphism; Country; DNA; Data; Data Set; Development; Diet; Disease; Drug Targeting; Ensure; Gene Dosage; Gene Family; Gene Frequency; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genotype; Goals; Haploidy; Health; Heart Diseases; Home; Human; Human Genetics; Human Microbiome; Human body; In Situ; Individual; Inflammation; Investigation; Israel; Label; Levocarnitine; Life Style; Linear Models; Link; Measurement; Measures; Mediating; Medical Records; Metabolic; Metagenomics; Methods; Microbe; Modeling; Outcome; Pan Genus; Pathway interactions; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Physiology; Population; Population Genetics; Prevention; Probiotics; Process; Research; Resolution; Running; Sampling; Shotgun Sequencing; Shotguns; Single Nucleotide Polymorphism; Statistical Models; Structure; Taxonomy; Testing; United States; Unmarried person; Variant; acute coronary syndrome; base; bioinformatics tool; cardiovascular disorder risk; cohort; computational platform; cost; design; drug metabolism; genetic approach; genetic variant; gut microbes; gut microbiome; heart function; host-microbe interactions; insight; metabolomics; metagenome; metagenomic sequencing; microbial; microbiome; microorganism; novel; open source; personalized medicine; population genetic structure; prebiotics; precision medicine; simulation; therapeutic target; tool; trait

PROJECT SUMMARY / ABSTRACT The human body is home to a complex community of microorganisms (“microbiome”) that differs in composition between people, with numerous correlates to cardiovascular disease (CVD). Any two people will harbor different strains of a given species, which can be more genetically different than a human and chimpanzee with <60% of their genes shared. Even within a single person, each microbiome species may be a complex mixture of strains with different genomes and functional capabilities. This striking within-species genetic diversity has functional consequences for CVD, because gene loss and gain modify how strains process our diet, metabolize drugs, and stimulate inflammation. Hence, a population genetic approach is essential for revealing causal links between the microbiome and CVD. We have compiled a deeply phenotyped cohort of ~50,000 individuals with metagenomic sequencing of their gut microbiomes. This dataset includes ~8,000 people with atherosclerosis, thousands with measurements of heart function and metabolic health, and hundreds with acute coronary syndrome. This cohort is a unique and ideal setting to perform a well-powered CVD metagenome-wide association study (MWAS). Several barriers must be overcome before MWAS can be deployed at this scale. First, we must reduce the infeasible computational cost of genotyping thousands of microbiome species across ~50,000 people. Second, to ensure that statistical tests for associations do not have high false positive rates we need statistical models that adjust for microbial population structure within and across hosts. The goal of this proposal is to create a research toolbox to address these challenges as well as to identify putative mechanistic links between microbiome and CVD. We will develop data structures and query algorithms for accelerated genotype estimation and mixed effects models for accurate association tests. All code and methods will be open source and designed to be easily extended to other microbiome cohorts. Applying these tools to our cohort, we aim to identify specific microbial genes and pathways responsible for known associations between microbes and CVD. We also expect to discover new associations that were missed because cohorts were too small or they were analyzed with methods that ignore differences in gene content across strains. These findings will be used to identify microbial biomarkers for CVD diagnosis and personalized treatments or to design microbiome targeted drugs, prebiotics, and probiotics to treat heart disease.

项目摘要 /摘要 人体是复杂的微生物社区（“微生物组”），与成分不同 在人们之间，与心血管疾病（CVD）有许多相关性。任何两个人都会有不同的 给定物种的菌株，这可能与人类和黑猩猩更普遍，<60％ 他们的基因分享。即使在一个人中，每个微生物组也可能是菌株的复杂混合物 具有不同的基因组和功能能力。这种罢工在物种内遗传多样性具有功能性 CVD的后果，因为基因流失和增益改变了菌株如何处理我们的饮食，代谢药物和 刺激炎症。因此，人口遗传学方法对于揭示因果关系至关重要 微生物组和CVD。 我们已经汇编了约50,000名元基因组测序的人的深层表型队列 微生物组。该数据集包括约8,000人患有动脉粥样硬化的人，成千上万的心脏测量 功能和代谢健康，数百种急性冠状动脉综合征。这个队列是一个独特而理想的 设置进行良好的CVD元基因组协会研究（MWAS）。 在此规模部署MWA之前，必须克服几个障碍。首先，我们必须减少 在约50,000人中为基因分型的数千种微生物组物种的计算成本不可行。第二， 为了确保关联的统计测试没有高误报率，我们需要统计模型 这可以调整宿主内部和跨宿主内部的微生物种群结构。该建议的目的是创建一个 研究工具箱，以应对这些挑战，并确定推定的机械联系 微生物组和CVD。我们将开发数据结构和查询算法，以加速基因型估计 以及用于准确关联测试的混合效应模型。所有代码和方法将是开源的，并设计 很容易扩展到其他微生物组队列。 将这些工具应用于我们的队列，我们​​旨在确定负责的特定微生物基因和途径 微生物与CVD之间的已知关联。我们还希望发现错过的新协会 因为队列太小，或者用忽略基因含量差异的方法对它们进行了分析 跨压力。这些发现将用于识别用于CVD诊断的微生物生物标志物和个性化的 治疗或设计微生物组靶向药物，益生元和益生菌治疗心脏病。