Allele Specific and Parent of Origin Effects on Gene Expression and Cardiovascular Disease Associated Traits

等位基因特异性和亲本对基因表达和心血管疾病相关性状的影响

• 批准号: 9192024
• 负责人: Sahar Victoria Mozaffari
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-12-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192024
• 关键词: Accounting; Address; Affect; Alleles; Allelic Imbalance; Architecture; Blood Pressure; Canada; Cardiovascular Diseases; Carotid Arteries; Cause of Death; Cell Count; Cholesterol; Chromosomes; Complex; Data; Diploidy; Disease; European; Evolution; Fathers; Founder Generation; Gene Expression; Gene Expression Regulation; Gene Frequency; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genotype; Goals; Haplotypes; Heart Atrium; Heritability; High Density Lipoproteins; High-Throughput RNA Sequencing; Human; Individual; Inflammatory; Inherited; Knowledge; Left; Left Ventricular Mass; Life; Light; Lipids; Lipoprotein (a); Low-Density Lipoproteins; Maps; Measurement; Measures; Methods; Minor; Modeling; Molecular Mechanisms of Action; Mothers; Nucleic Acid Regulatory Sequences; Parents; Pathogenesis; Phenotype; Play; Population; Predisposition; Quantitative Trait Loci; Reading; Resources; Role; Sampling; Site; Susceptibility Gene; Testing; Thick; Transcript; Triglycerides; Variant; Whole Blood; Woman; base; cardiovascular disorder risk; disease phenotype; disease-causing mutation; genetic pedigree; genome sequencing; genome wide association study; genome-wide; hutterite; imprint; insight; interest; lymphoblastoid cell line; men; northern plains; novel; novel strategies; programs; risk variant; trait; transcriptome; transcriptome sequencing; whole genome

PROJECT ABSTRACT: The overall goal of this project is to evaluate novel strategies for identifying genetic variation that contributes to common, complex diseases, with a specific focus on variants that contribute to cardiovascular disease (CVD) risk through parent of origin effects. CVD is the leading cause of death among men and women, and while genome wide association studies (GWAS) have identified some genetic loci that contribute to CVD risk, a lot still remains unknown. The risk alleles identified by GWAS explain little of the heritability of the trait and some of this “missing heritability” has been attributed to parent of origin effects. I propose to bridge this gap of knowledge by characterizing parent of origin effects on gene expression and on CVD associated phenotypes and calculate parent of origin heritability for CVD phenotypes in the Hutterites. The Hutterites are a founder population of European descent and our group studies a group of ~1400 individuals who descend from 64 founders and are related to each other in a 13 generation pedigree. The Hutterites live communally in the northern plains states and western Canada. With an extended and well recorded pedigree and technological advances in sequencing, we can impute Hutterite genotypes with high accuracy and identify the parent of origin of alleles from 98 Hutterite whole genome sequences to the remaining >1400 individuals in our sample. In addition to gene expression in LCLs and whole blood, we recorded CVD-association phenotypes for a subset of this sample that include measurements of lipids (LDL-c, HDL-c, total cholesterol, triglycerides, and Lp(a)), blood pressure (systolic and diastolic), carotid artery media thickness (CIMT), and echocardiographic traits (left ventricular mass, left atrial volume, among many others), as well as inflammatory cell counts. With this unique population resource, we can disentangle the contribution of maternally inherited alleles and paternally inherited alleles to CVD-associated phenotypes and ultimately to risk for cardiovascular disease.

项目摘要： 该项目的总体目标是评估新的策略，以确定有助于 常见的复杂疾病，特别关注导致心血管疾病（CVD）的变体 通过父母效应的风险。 CVD是男女死亡的主要原因，而 基因组广泛的关联研究（GWAS）已经确定了一些有助于CVD风险的遗传局部 仍然未知。 GWAS确定的风险等位基因几乎没有说明特征的遗传力和一些特征的遗传力 这种“缺失的遗传力”归因于起源效应的父母。我建议弥合这一差距 通过表征原点对基因表达和CVD相关表型的知识的知识 并计算出Hutter石中CVD表型的来源遗传力。哈特人是创始人 欧洲血统的人口和我们的小组研究一组约1400个人，他们从64岁起 创始人并以13代人的血统相互关联。 hutter人共同生活在 北方计划州和加拿大西部。具有延长且记录良好的血统和技术 测序的进步，我们可以以高精度将Hutterite基因型归咎于 等位基因从98个Hutter石全基因组序列到我们样本中其余> 1400个个体的起源。 除了LCL和全血中的基因表达外，我们还记录了A 该样品的子集，其中包括脂质的测量（LDL-C，HDL-C，总胆固醇，甘油三酸酯和 LP（A）），血压（收缩压和舒张压），颈动脉培养基厚度（CIMT）和超声心动图 特征（左心室质量，左心房体积，等等）以及炎症细胞计数。和 这种独特的人口资源，我们可以解开主要继承等位基因的贡献 图案遗传了与CVD相关的表型的等位基因，并最终冒着心血管疾病的风险。