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: 10018068
• 负责人: Danish Saleheen
• 金额: $ 60万
• 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/10018068
• 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 resource; 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.

项目总结/文摘