Using genetic variation to study biology of blood lipids & coronary heart disease

项目摘要/摘要 心血管疾病是全球主要的死亡原因，而血脂水平的升高是 最强的风险因素。R01提案的目标是继续发现和表征基因变异 和与血脂水平相关的基因，使用新方法、不同的队列和临床试验来确定 血脂和心血管疾病的新治疗目标和风险缓解框架。我们的研究 团队结合了心血管医学、统计遗传学、高通量遗传学和 基因组学，以及创新计算和统计方法的开发和应用。在目标1中，我们 将利用超过250万个多民族样本确定与血脂水平相关的遗传变异。在……里面 目标2，我们将对脂质相关等位基因和双向多表型进行表型范围的扫描 孟德尔随机化在约100万人中进行。在目标3中，我们将构建和评估多伦理多基因风险 流行病学研究和已完成的临床试验中的血脂水平得分。在目标4中，我们将创建一个网络- 基于计算引擎，既提供关联结果，又计算个人级别的多基因风险 分数，以促进跨研究分数的标准化。这项提案是对以前提案的更新。 全球脂质遗传联盟(GLGC)奖和建立的合作关系，并将允许 感谢财团的持续努力和协调。完成我们的目标将提供新的见解 有可能在心血管疾病的预防、治疗和诊断方面取得突破 并可作为其他大规模基因研究的模型。

PROJECT SUMMARY / ABSTRACT Cardiovascular disease is the leading cause of death worldwide and elevated blood lipid levels are the strongest risk factor. The goal of this R01 proposal is to continue discovering and characterize genetic variants and genes associated with blood lipid levels using new methods, diverse cohorts, and clinical trials to identify new therapeutic targets and risk mitigation frameworks for lipids and cardiovascular disease. Our research team combines strengths in cardiovascular medicine, statistical genetics, high-throughput genetics and genomics, and development and application of innovative computational and statistical methods. In Aim 1, we will determine genetic variants associated with lipid levels leveraging over 2.5 million multi-ethnic samples. In Aim 2, we will perform phenome-wide scans for lipid-associated alleles and bi-directional multi-phenotype Mendelian randomization in ~1 million individuals. In Aim 3, we will build and evaluate multi-ethic polygenic risk scores for lipid levels in epidemiologic studies and completed clinical trials. In Aim 4 we will create a web- based compute engine to both provide our association results and calculate individual-level polygenic risk scores to facilitate the standardization of scores across studies. This proposal is a renewal of the previous Global Lipids Genetics Consortium (GLGC) award and established collaborative relationships, and will allow for the continued effort and coordination of the consortium. Completion of our aims will provide new insights that have the potential to catalyze breakthroughs in prevention, treatment, and diagnosis of cardiovascular disease and may serve as a model for other large-scale genetic studies.