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

项目摘要： 这个项目的总体目标是评估新的策略，以确定有助于 常见、复杂的疾病，特别关注导致心血管疾病(CVD)的变异 风险通过起源的父母效应。心血管疾病是导致男性和女性死亡的主要原因，虽然 全基因组关联研究已经确定了一些与心血管疾病风险有很大关系的遗传基因。 目前仍不得而知。Gwas确定的风险等位基因对该性状的遗传力解释很少，而且有些 这种“缺失的遗传性”被归因于父母的起源效应。我建议弥合这一差距 通过表征亲本对基因表达和心血管相关表型的影响来了解 并计算哈特族CVD表型的起源遗传力。哈特利派是创始人之一 欧洲人后裔和我们的小组研究了大约1,400人的后裔 创始人和在13代人的谱系中彼此相关。哈特利人共同生活在 北部平原州和加拿大西部。拥有广泛的、记录良好的谱系和技术 在测序方面的进展，我们可以高精度地推测Hutterite基因，并鉴定亲本 从98个哈特人全基因组序列到我们样本中剩余的1400个个体的等位基因来源。 除了LCL和全血中的基因表达外，我们还记录了CVD相关表型 此样本的子集，包括对血脂(低密度脂蛋白-c、高密度脂蛋白-c、总胆固醇、甘油三酯和 Lp(A))、血压(收缩压和舒张压)、颈动脉中层厚度(CIMT)和超声心动图 这些指标包括左心室重量、左心房容量以及炎性细胞计数。使用 这一独特的人口资源，我们可以理清母亲遗传的等位基因和 CVD相关表型的父系遗传等位基因，并最终增加心血管疾病的风险。

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.