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

摘要 在这个项目中，我们将扩展我们对肥胖症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 并对另外2512名萨摩亚人进行后续验证。作为精密医学的Trans-Omics的一部分 全基因组测序计划，正在对1,295个萨摩亚人的发现样本进行测序，创造出 为5000多名表型良好的萨摩亚人创建前所未有的基因组数据集的机会 我们将用来探索肥胖和心脏新陈代谢特征的遗传结构。 在我们的第一个目标中，我们将从整个基因组测序数据中创建一组萨摩亚人特有的单倍型 并将在发现样本的其余部分确定基因类型。然后，我们将进行关联研究 并使用结果创建要添加到Illumina HumanCore-24的自定义内容 珠芯片基因分型阵列。 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，然后进行归因，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异，并在409中进行额外的基因分型 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计划，我们将探索 我们在其他人群中的变异，以及提出和领导其他相关调查。 通过发现和鉴定原始SNP芯片上没有的萨摩亚人特有的变体，我们的目标是 以精细定位已知的基因座，并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，我们可能会 发现在其他更外交化的种群中无法检测到的风险变异。我们的发现将帮助我们 了解肥胖的基本生物学基础和下游健康结果，并确定 药物干预的潜在靶点。

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.