The Identification and characterization of genetic variants underlying cardiovascular diseases

心血管疾病(CVD)，包括冠心病(CAD)和 先天性心脏病(CHD)是美国主要的死亡原因。 尽管遗传因素对心血管疾病有很大的贡献，但人们对其知之甚少 这些疾病的潜在遗传原因。我们已经开始了高吞吐量 脑血管病相关基因的测序和高通量体内鉴定 离群索居的亲属和血缘关系密切的后代。使用完整外显子 测序(WES)和最新的分析方法，从连锁到基因集 浓缩分析，我们已经确定了作为CAD基础的独立突变， 代谢综合征和多样化的冠心病。我们在疾病基因鉴定方面的成功是 部分原因是能够接触到世界各地独特的疾病人群，以及 耶鲁大学孟德尔基因组学中心。虽然我们设计了创造性的方法来 新的基因发现，我们实验室的鲜明特点是追求 疾病基因在体内的特性及其在识别新疾病中的成功 药物开发的途径和目标。我们已经建立了高吞吐量 实验室中鉴定的人类体外突变的功能表征技术 并通过使用新的基因编辑技术在体内进行。最近，我们已经开始 研究衰老、饮食和体力活动对疾病的表观遗传效应 在人和动物模型中的发病机制。最值得注意的是，我们又向前迈进了一步 并已发起与业界的合作努力，以筛选和 表征可以针对已识别的疾病途径的小分子，以便 挽救心血管和新陈代谢特征。我们高被引用的出版作品就是一个证明 对于我们在实验室中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.