Leveraging consanguinity and homozygosity to identify novel recessive variants

利用血缘和纯合性来识别新的隐性变异

• 批准号: 9803204
• 负责人: Danish Saleheen
• 金额: $ 62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803204
• 关键词: Alleles; Asia; Biological Markers; Blood Pressure; Cholesterol; Complex; Consanguinity; Data; Disease; Disease susceptibility; Exhibits; Family; Frequencies; Genetic; Genetic Models; Genome; Genomic Segment; Genomics; Genotype; Height; Heritability; Human Genome; Human Inbreeding; Inbreeding; Individual; Life Style; Marriage; Marriage Pattern; Medical; Mental Depression; Methods; Modeling; Pakistan; Parents; Participant; Partner in relationship; Pattern; Phase; Phenotype; Population Genetics; Recording of previous events; Resources; Running; SNP array; Sampling; South Asian; Testing; Time; Variant; Work; blood lipid; cohort; expectation; fitness; genetic risk factor; genetic variant; genome wide association study; genome-wide; improved; novel; offspring; phenotypic data; purge; recessive genetic trait; theories; trait

PROJECT SUMMARY/ABSTRACT Genome-wide association studies (GWAS) traditionally assume an additive model of genetic inheritance, where the genetic effect of a heterozygous genotype is exactly intermediate to the genetic effects of the two homozygous genotypes. However, we know that many alleles act in either a dominant or recessive fashion. Detecting the phenotypic effects of rare, recessive variants is especially challenging, due to the scarcity of rare, homozygous genotypes. Here, we propose to use data from 96,000 individuals from the Pakistan Genomic Resource (PGR) to quantify the effects of rare, recessive variants on a wide range of phenotypic traits and common, complex diseases. Our study leverages the high rates of inbreeding within the PGR (which increases the frequency of rare, homozygous genotypes), as well as extensive lifestyle, family history and genetic data from all participants. The specific aims for our project are (1) Phase and impute variants into more than 96,000 PGR genomes using a reference panel that includes 6,200 high- coverage genome sequences from South Asia; (2) Test for associations between a wide range of phenotypes and genotype, using a combination of standard single-variant tests and novel homozygosity-mapping approaches; and (3) Infer historical models of consanguinity within the PGR, using the distributions of long runs of homozygosity (caused by consanguineous marriages) both within and between individuals.

项目概要/摘要 全基因组关联研究（GWAS）传统上假设一个加性模型 遗传，杂合基因型的遗传效应恰好是 两个纯合基因型的遗传效应的中间值。然而，我们知道 许多等位基因以显性或隐性方式起作用。检测表型 由于稀有、隐性变异的稀缺性，罕见、隐性变异的影响尤其具有挑战性。 纯合基因型。在这里，我们建议使用来自 96,000 名个人的数据 巴基斯坦基因组资源 (PGR) 量化罕见隐性变异对基因组的影响 广泛的表型特征和常见、复杂的疾病。我们的研究利用 PGR 内的高近交率（这增加了稀有、 纯合基因型），以及广泛的生活方式、家族史和遗传数据 所有参与者。我们项目的具体目标是 (1) 阶段并将变体归咎于 超过 96,000 个 PGR 基因组使用参考面板，其中包括 6,200 个高 覆盖南亚的基因组序列； (2) 测试广泛的关联性 表型和基因型的范围，使用标准单变体测试的组合 以及新颖的纯合性作图方法； (3) 推断历史模型 PGR 内的血缘关系，使用纯合性的长期分布（导致 通过近亲结婚）在个人内部和个人之间。