Human Genetics and Phenotyping Core

人类遗传学和表型核心

• 批准号: 10628912
• 负责人: Danish Saleheen
• 金额: $ 30.15万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628912
• 关键词: Adult; Alleles; Anthropometry; Biochemical; Biological; Biological Assay; Biological Markers; Birth; Calcium Channel; Callback; Cardiac; Cardiovascular system; Characteristics; Complex; Consanguinity; Diet; Disease; Disease Outcome; Echocardiography; Electrocardiogram; Embryo; Exercise stress test; Family member; General Population; Genes; Genetic; Genetic Engineering; Genetic Variation; Genotype; Glycosylated hemoglobin A; Heart; Heart Diseases; Heart failure; Heterozygote; Homozygote; Human; Human Biology; Human Genetics; Image; Individual; Knock-out; Life; Life Style; Lipids; Mediating; Medical History; Metabolic; Missense Mutation; Monitor; Mutation; Myocardial Infarction; Outcome; Pakistan; Participant; Pathway interactions; Persons; Phenotype; Physical activity; Physiology; Protein Truncation; RNA Splicing; Resources; Risk Factors; Services; Single base substitution; Site; Stroke; Structure; Tobacco use; Trans-Omics for Precision Medicine; Variant; biobank; clinical examination; consanguineous family; exome; exome sequencing; experimental study; gain of function; gene function; genome resource; genome sequencing; genome wide association study; genomic data; in vivo; in vivo Model; insight; large datasets; large scale data; loss of function; loss of function mutation; metabolomics; mutant; new therapeutic target; novel; offspring; pleiotropism; population based; proband; programs; protein function; recruit; reverse genetics; trait; whole genome

PROJECT SUMMARY This core is central for all experiments in this program project and capitalizes on the Pakistan Genomic Resource (PGR) that has established the largest biobank of “Human Knockouts”. Specifically, PGR has leveraged high levels of consanguinity in Pakistan and has conducted whole-exome and whole-genome sequencing studies in 80,000 participants and has already identified complete KOs for >5000 genes and heterozygous KOs for >18,000 genes. PGR has also found rare homozygotes for many missense variants, many of which have now been characterized to be loss of function (LoF) or gain of function (GoF). Moreover, PGR has also recruited > 45,000 cases with myocardial infarction, > 20,000 cases with echo-confirmed heart failure, > 6,000 cases with imaging confirmed stroke – all of these participants have undergone genotyping for GWAS and whole-exome sequencing studies. Services that will be provided by the core will include: (i) for high priority genes across the four projects, deep phenotyping of KOs / mutant probands and their consanguineous family members. Such phenotyping studies will include: detailed clinical exams, electrocardiograms (ECGs) and echocardiograms, assessment of any rhythm disorders through Biotel patch heart monitors, exercise stress test, and detailed biochemical exams; (ii) analyses of large-scale genomic data in relation to cardiovascular traits and outcomes (i.e., myocardial infarction, stroke, heart failure, ECG traits and other risk factors) recorded in PGR, UKBiobank and other population-based resources in up to 1 million participants.

项目摘要 该核心是该计划项目中所有实验的核心，并利用了巴基斯坦基因组资源 (PGR)建立了世界上最大的“人类基因库”具体来说，PGR的杠杆率很高 在巴基斯坦进行了全外显子组和全基因组测序研究， 80，000名参与者，并且已经确定了>5000个基因的完全科斯和> 18，000个基因的杂合科斯 基因. PCR还发现了许多错义变体的罕见纯合子，其中许多现在已经被发现。 其特征在于功能丧失（LoF）或功能获得（GoF）。此外，PGR还招募了> 45 000人 心肌梗死例，超声心动图证实的心力衰竭> 20，000例，影像学检查> 6，000例 确诊的卒中-所有这些参与者都进行了GWAS基因分型和全外显子组测序 问题研究核心将提供的服务包括：（i）对于四个项目中的高优先级基因， 对科斯/突变先证者及其近亲家族成员进行深度表型分型。这种表型 研究将包括：详细的临床检查、心电图（ECG）和超声心动图、 通过Biotel贴片心脏监测仪、运动负荷试验和详细的生化检查发现任何心律紊乱; (ii)分析与心血管特征和结果相关的大规模基因组数据（即，心肌 梗死、中风、心力衰竭、ECG特征和其他风险因素）记录在PGR、UKBiobank和其他 以人口为基础的资源，多达100万参与者。