Improving Polygenic Prediction using Next-Generation Data Sets

使用下一代数据集改进多基因预测

• 批准号: 8632422
• 负责人: SHAMIL SUNYAEV
• 金额: $ 54.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632422
• 关键词: Accounting; Architecture; Binding; Chromatin; Code; Complex; Complex Genetic Trait; Computer software; Computing Methodologies; DNA; Data; Data Set; Development; Diagnostic; Disease; European; Explosion; Frequencies; Functional RNA; Future; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genotype; Goals; Height; Heritability; Human; Individual; Life; Linkage Disequilibrium; Lipids; Medical; Methods; Microarray Analysis; Modeling; Myocardial Infarction; Patient Selection; Patients; Pattern; Performance; Phenotype; Population; Population Genetics; Population Heterogeneity; Proteins; Publications; Risk; Sampling; Statistical Methods; Statistical Models; Study models; Testing; Therapeutic Intervention; Training; Variant; Work; base; case control; cell type; data acquisition; disorder risk; exome; exome sequencing; genetic variant; genome sequencing; genome wide association study; human disease; improved; interest; next generation; public health relevance; rare variant; simulation; trait; transcription factor

Understanding the relationship between genotype and phenotype is the central goal of genetics. Available heritability estimates for many human traits of medical relevance suggest that 30-80% of phenotypic variation is due to underlying genetic variation. The ability to predict phenotypes based on genotypes is the ultimate test of our understanding of complex trait genetics. Since the dawn of complex trait genetics in the early 20th century, progress has been limited by the availability of genetic data in well-phenotyped populations. Now, due to the extraordinary progress in technology, microarray genotyping datasets, exome sequencing datasets and targeted sequencing datasets are available for large clinically phenotyped populations, and functional data is becoming available. A future explosion of whole-genome sequencing data is also widely anticipated. This shifts the focus from data acquisition to data interpretation and development of computational and statistical methods for predicting phenotypes from genotypes and functional information. We propose to develop new methods for predicting phenotypes from genotypes and apply these methods to newly collected data on human complex traits of direct medical interest, including both quantitative and disease traits. Our work on phenotype prediction will be informative about the allelic architecture of complex traits and will provide guidance for future genetic studies. From a practical perspective, there is an ongoing debate on the potential of genetic diagnostics in identification of individuals at elevated risk for specific complex diseases early in life. If successful, genetic diagnostics may inform selection of patients for early therapeutic intervention. However, the practical utility of genetics in evaluating risk of complex diseases has not been proven and is widely debated. We will rigorously test the hypothesis of the utility of genotype-based phenotypic predictions. In Specific Aim 1 we will develop and test new statistical methods for predicting phenotypes from microarray genotyping data. We will investigate several model selection and shrinkage strategies. We will evaluate whether it is more efficient to estimate contributions of individual markers independently or to fit all markers simultaneously. In Specific Aim 2 we will improve polygenic prediction in populations of diverse ancestry. It is important that medical progress not be limited to European populations. Our methods will generate predictions across human populations, accounting for population differences in allele frequencies, rates of allelic variation and patterns of linkage disequilibrium. In Specific Aim 3 we will develop and test statistical methods for predicting phenotypes from sequencing data. Sequencing data provide a distinct set of statistical challenges because they contain low-frequency and rare allelic variants, and often the effects of individual rare variants cannot be estimated. In Specific Aim 4 we will incorporate functional data into methods for phenotype prediction. We will investigate whether incorporation of functional data can improve phenotype predictions from genetic data.

了解基因型和表型之间的关系是遗传学的中心目标。可用 对许多与医学相关的人类性状的遗传力估计表明，30 - 80%的表型变异 是由于潜在的遗传变异。根据基因型预测表型的能力是最终的考验 我们对复杂性状遗传学的理解。自20世纪初复杂性状遗传学出现以来， 世纪以来，进展一直受到表型良好人群遗传数据可用性的限制。现在由于 技术的非凡进步，微阵列基因分型数据集，外显子组测序数据集， 靶向测序数据集可用于大的临床表型人群，并且功能数据是 变得可用。全基因组测序数据的未来爆炸也被广泛预期。它会改变 从数据采集到数据解释，以及计算和统计方法的发展 用于从基因型和功能信息预测表型。我们建议开发新的方法， 从基因型中预测表型，并将这些方法应用于新收集的关于人类复杂 具有直接医学意义的性状，包括数量性状和疾病性状。我们在表型预测方面的工作 将提供有关复杂性状的等位基因结构的信息，并将为未来的遗传学研究提供指导。 问题研究从实践的角度来看，目前正在就遗传诊断在以下方面的潜力进行辩论： 识别生命早期患有特定复杂疾病的高风险个体。如果成功，遗传 诊断可以为选择早期治疗干预的患者提供信息。然而， 遗传学在评估复杂疾病风险方面的作用尚未得到证实，并受到广泛辩论。我们将严格 检验基于基因型的表型预测的实用性假设。 在具体目标1中，我们将开发和测试新的统计方法，用于预测微阵列表型 基因分型数据。我们将研究几种模型选择和收缩策略。我们将评估 独立估计单个标记的贡献或拟合所有标记是否更有效 同步在具体目标2中，我们将改进不同祖先群体中的多基因预测。它 重要的是，医学进步不仅限于欧洲人口。我们的方法将产生 在人群中的预测，占等位基因频率的人口差异， 等位基因变异和连锁不平衡模式。在具体目标3中，我们将开发和测试统计 从测序数据预测表型的方法。测序数据提供了一组独特的统计学特征， 挑战，因为它们含有低频率和罕见的等位基因变异，并且通常是个体罕见的影响， 变量无法估计。在具体目标4中，我们将把函数数据纳入方法中， 表型预测我们将调查是否纳入功能数据可以改善表型 基因数据的预测。