Heritability of complex traits via IBD and IBS in related and unrelated individua

通过 IBD 和 IBS 在相关和无关个体中实现复杂性状的遗传力

• 批准号: 8444904
• 负责人: ALKES L PRICE
• 金额: $ 8.08万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-19 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444904
• 关键词: Address; Affect; Algorithms; Alleles; Architecture; Benchmarking; Chromosome Mapping; Collaborations; Complex; Computer software; Data; Data Set; Disease; Evaluation; Family; Family Study; Frequencies; Future; Genes; Genetic; Genetic Risk; Genome; Genomics; Genotype; Gold; Height; Heritability; Human; Human Genetics; Individual; Inequality; Inherited; Left; Linkage Disequilibrium; Location; Medical Genetics; Methods; Motivation; Non-Insulin-Dependent Diabetes Mellitus; Parents; Pattern; Phase; Population; Prevalence; Property; Publications; Relative (related person); Research; Research Design; Rheumatoid Arthritis; Sampling; Scanning; Signal Transduction; Source; Structure; Twin Studies; Variant; base; case control; disorder risk; genome wide association study; genome-wide; human disease; interest; public health relevance; risk variant; simulation; trait

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have identified hundreds of risk variants associated to common diseases and other traits, yet in most cases have explained only a small fraction of genetic heritability. The source of this "missing heritability" is a critical question in human genetics. Efforts to address this question have largely focused on the search for specific disease risk variants, leaving the bulk of heritability still unexplained. We will systematically deconstruct genetic heritability by investigating how genetic content shared either via segments inherited identical-by-descent (IBD) or genotyped alleles identical-by-state (IBS), either genome-wide or partitioned across the genome, corresponds to phenotypic similarity across a broad range of human traits. We will use IBD to characterize the set of all risk variants, and IBS to characterize the subset of risk variants genotyped or tagged by GWAS chips. We will explore the idea that genetic similarity between "unrelated" individuals can be as useful, or more useful, than similarity between close relatives in quantifying and understanding genetic heritability. Partitioning heritability by genomic location will enable us to draw conclusions about the genetic architecture of various human traits, considering both the set of all risk variants and the subset of risk variants captured by GWAS chips. We will develop these ideas via simulation and apply them to real GWAS data comprising 70,000 samples. We will continue to release practical, publicly available software packages implementing the methods that we develop.

描述（由申请人提供）： 全基因组关联研究（GWAS）已经识别出数百种与常见疾病和其他特征相关的风险变异，但在大多数情况下只能解释遗传性的一小部分。这种“遗传性缺失”的根源是人类遗传学中的一个关键问题。解决这个问题的努力主要集中在寻找特定的疾病风险变异，而大部分遗传性仍然无法解释。我们将系统地解构遗传性，通过研究通过血统相同（IBD）遗传的片段或状态相同（IBS）的基因型等位基因（IBS）共享的遗传内容（无论是全基因组还是跨基因组划分）与表型相似性相对应涵盖广泛的人类特征。我们将使用 IBD 来表征所有风险变异的集合，并使用 IBS 来表征由 GWAS 芯片进行基因分型或标记的风险变异子集。我们将探讨这样一个想法：在量化和理解遗传性方面，“不相关”个体之间的遗传相似性可能与近亲之间的相似性一样有用，甚至更有用。通过基因组位置划分遗传性将使我们能够得出有关各种人类性状的遗传结构的结论，同时考虑所有风险变异的集合和 GWAS 芯片捕获的风险变异的子集。我们将通过模拟开发这些想法，并将其应用于包含 70,000 个样本的真实 GWAS 数据。我们将继续发布实用的、公开可用的软件包来实施我们开发的方法。