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）已经确定了数百种与常见疾病和其他性状相关的风险变异，但在大多数情况下，仅解释了一小部分遗传性遗传力。这种“缺少遗传力”的根源是人类遗传学的关键问题。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上，使大部分遗传力仍然无法解释。我们将通过研究遗传含量如何通过段共享的遗传含量如何遗传遗传含量（IBD）或基因分型等位基因（IBS）（IBS）（跨基因组跨基因组或基因组跨基因组的基因组）来系统地解构遗传遗传能力，与人类特征的广泛范围的表型相似。我们将使用IBD来表征所有风险变体的集合，而IBS来表征由GWAS芯片对基因分型或标记的风险变体的子集。我们将探讨这样的观念，即“无关”个体之间的遗传相似性可以比近亲量化和理解遗传性遗传力的近亲之间的相似性更有用或更有用。通过基因组位置划分遗传力将使我们能够对各种人类特征的遗传结构得出结论，考虑到所有风险变异的集合和GWAS芯片捕获的风险变体的子集。我们将通过仿真来开发这些想法，并将其应用于包括70,000个样本的实际GWAS数据。我们将继续发布实施我们开发的方法的实用，公共可用的软件包。