Next Generation Association Studies of Adiposity in Samoans Enhanced by a Samoan-Specific Whole Genome Sequence Reference Panel

萨摩亚特有的全基因组序列参考面板增强了萨摩亚人肥胖的下一代关联研究

• 批准号: 10267489
• 负责人: Ryan Lee Minster
• 金额: $ 17.41万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267489
• 关键词: Adult; Affect; African; Asians; Biological; Biology; Child; Complex; Custom; Data; Disease; Drug Targeting; European; Genetic; Genetic Heterogeneity; Genetic study; Genomics; Genotype; Geography; Haplotypes; Health; Individual; Intervention; Investigation; Lead; Maps; Methodology; Obesity; Outcome; Pathway interactions; Pharmacology; Phenotype; Play; Polynesian; Population; Prevalence; Process; Quality Control; Recording of previous events; Regulation; Research; Role; SNP array; Samoan; Sampling; Scanning; Signal Transduction; Technology; Testing; Trans-Omics for Precision Medicine; Validation; Variant; Work; bead chip; biomarker panel; biomarker validation; cardiometabolism; drug development; follow-up; genetic architecture; genome sequencing; genome wide association study; genome-wide; genomic data; interest; next generation; programs; recruit; risk variant; trait; whole genome

SUMMARY In this project we will extend our genetic studies of adiposity and related cardiometabolic phenotypes that we began with a genome-wide association study of common variants in a discovery sample of 3,072 Samoans with follow-up validation in 2,512 additional Samoans. As part of the Trans-Omics for Precision Medicine Whole Genome Sequencing Project, 1,295 of the discovery sample Samoans are being sequenced, creating an opportunity to create an unprecedented genomic data set for over 5,000 well-phenotyped Samoans which we will use to explore the genetic architecture of adiposity and cardiometabolic traits. In our first aim we will create a set of Samoan-specific haplotypes from the whole genome sequencing data and will impute genotypes in the remainder of the discovery sample. We will then conduct association studies of our phenotypes and use the results to create custom content to be added to an Illumina HumanCore-24 BeadChip genotyping array. The genotyping array will be used in our second aim to take advantage of the replication sample, first by genotyping with the customized array, followed by imputation and then association testing in concert with the discovery sample. We will then validate the most promising variants by direct genotyping, with additional genotyping in 409 Samoan children to explore the effects of those SNPs on our phenotypes in younger individuals. Finally through active participation in the Whole Genome Sequencing Project we will explore the effects of our variants in other populations, as well as propose and lead other related investigations. By discovering and characterizing Samoan-specific variants that were not on our original SNP chip, we aim to fine-map known loci and are likely to discover and fine-map new association signals. By enabling us to explore our unique well-phenotyped Samoan sample with its unique population history, we are likely to discover risk variants that are undetectable in other, more outbred populations. Our discoveries will help us understand the basic biological underpinnings of obesity and downstream health outcomes as well as identify potential targets for pharmacological interventions.

总结 在这个项目中，我们将扩展我们对肥胖和相关心脏代谢表型的遗传研究， 我们首先对3,072名萨摩亚人的发现样本中的常见变异进行了全基因组关联研究 并在另外2,512名萨摩亚人中进行了后续验证。作为Trans-Omics for Precision Medicine的一部分， 全基因组测序项目，1,295个萨摩亚人的发现样本正在测序， 这是一个为5,000多名表现型良好的萨摩亚人创建前所未有的基因组数据集的机会， 我们将用它来探索肥胖和心脏代谢特征的遗传结构。 在我们的第一个目标中，我们将从全基因组测序数据中创建一组萨摩亚特有的单倍型 并将在发现样本的剩余部分中插补基因型。然后我们将进行关联研究 我们的表型，并使用结果来创建自定义内容添加到Illumina HumanCore-24 BeadChip基因分型阵列。 基因分型阵列将用于我们的第二个目标，以利用复制样本，首先通过 用定制的阵列进行基因分型，然后进行插补，然后与 发现样本 然后，我们将通过直接基因分型来验证最有希望的变体，并在409例患者中进行额外的基因分型。 萨摩亚儿童，以探索这些SNP对我们年轻个体表型的影响。 最后，通过积极参与全基因组测序项目，我们将探讨 我们在其他人群中的变异，以及提出和领导其他相关调查。 通过发现和表征原始SNP芯片上没有的萨摩亚特异性变体，我们的目标是 以精细定位已知的基因座，并有可能发现和精细定位新的关联信号。通过使我们能够 探索我们独特的表型良好的萨摩亚样本及其独特的人口历史，我们很可能会 发现在其他远系繁殖群体中检测不到的风险变异。我们的发现将帮助我们 了解肥胖和下游健康结果的基本生物学基础，并确定 药物干预的潜在目标。