The Identification and characterization of genetic variants underlying cardiovascular diseases

心血管疾病（CVD），包括冠状动脉疾病（CAD）和 先天性心脏病（CHD）是美国的主要死因。 尽管遗传因素对CVD有很大的影响，但人们对CVD的发病机制知之甚少。 这些疾病的潜在遗传原因。我们已经开始了高吞吐量 对CVD相关基因进行测序和高通量体内表征， 在近亲结合的后代中。使用全外显子组 测序（WES）和最先进的分析方法，从连锁到基因集 富集分析，我们已经确定了CAD的独立突变， 代谢综合征和多种CHD。我们在识别疾病基因方面的成功是 部分原因是可以接触到世界各地的独特疾病人群， 耶鲁大学孟德尔基因组学中心。虽然我们已经设计了创造性的方法， 新的基因发现，我们实验室的鲜明特色是在追求 体内疾病基因的表征及其在鉴定新疾病中的成功 药物开发的途径和目标。我们已经建立了高吞吐量 实验室技术，用于体外鉴定的人类突变的功能表征 以及通过采用新的基因编辑技术在体内进行。最近，我们开始 研究衰老、饮食和体力活动对疾病的表观遗传影响 在人类和动物模型中的发病机制。最值得注意的是， 并已与业界展开合作， 表征可靶向已确定疾病途径的小分子， 挽救心血管和代谢特征。我们被高度引用的已发表作品证明了 因为我们在实验室里产生的结果的质量和有希望的性质。

Cardiovascular disorders (CVD), including coronary artery disease (CAD) and congenital hear diseases (CHD) are the leading causes of death in the United States. Despite strong contribution of genetic factors to CVD, very little is known about the underlying genetic causes of these diseases. We have embarked on high throughput sequencing and high throughput in vivo characterization of genes underlying CVD in outlier kindreds and in offsprings of consanguineous unions. Using whole-exome sequencing (WES) and state of the art analytic approaches, from linkage to gene set enrichment analysis, we have identified independent mutations that underlie CAD, metabolic syndrome and diverse CHD. Our success in identification of disease genes is in part due to access to unique disease populations across the world and the support of Yale Center for Mendelian Genomics. While we have devised inventive approaches for novel gene discovery, the distinctive feature of our laboratory is in pursuing the characterization of disease genes in vivo and its success in identifying novel disease pathways and targets for drug development. We have established high throughput techniques in the lab for functional characterization of identified human mutations in vitro and in vivo by employing novel gene editing techniques. Most recently, we have begun to investigate the epigenetic effects of aging, diet and physical activity on disease pathogenesis in human and animal models. Most notably, we have taken a step further and have initiated collaborative efforts with the industry in order to screen and characterize small molecules that can target identified disease pathways in order to rescue cardiovascular and metabolic traits. Our highly cited published work is an attest for the quality and the promising nature of the results we generate in the lab.