Human Genetics and Phenotyping Core

项目总结 这一核心是该计划项目中所有实验的核心，并利用巴基斯坦基因组资源 (PGR)建立了最大的“人类基因敲除”生物库。具体地说，PGR利用了高杠杆 巴基斯坦的血缘水平，并在#年进行了全外显组和全基因组测序研究 80,000名参与者，并已确定了&gt；5000个基因的完整KO和&gt；18,000个杂合子KO 基因。PGR还发现了许多错义变体的罕见纯合子，其中许多现在已经成为 以功能丧失(LoF)或功能恢复(GoF)为特征。此外，PGR还招聘了45,000名 心肌梗死2,000例，超声心力衰竭2,000例，影像6,000例 确诊的中风--所有这些参与者都接受了Gwas基因分型和全外显子组测序 学习。将由核心提供的服务将包括：(I)针对四个项目的高优先级基因， KO/突变先证者及其近亲家庭成员的深层表型。这样的表型 研究将包括：详细的临床检查，心电图和超声心动图，评估 任何节律紊乱，通过Biotel贴片心脏监测器、运动负荷测试和详细的生化检查； (2)分析与心血管特征和结局(即心肌梗塞)有关的大规模基因组数据 梗塞、中风、心力衰竭、心电特征和其他危险因素)记录在PGR、UK Biobank和其他 以人口为基础的资源，最多有100万人参加。

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.