Rare coding variation and risk for myocardial infarction

描述(申请人提供)：心肌梗死(MI)是美国主要的死亡原因，是可遗传的。针对常见遗传变异的大型研究现已确定了30多个与心肌梗死风险相关的基因座。尽管取得了这一成功，但这些常见的变异只解释了MI遗传基础的一小部分。群体遗传学和候选基因研究支持这样一种假设，即较少见的遗传变异在复杂的疾病中发挥着重要作用，如心肌梗死。在这个提案中，我们概述了几种方法来探索罕见的遗传变异在心肌梗死风险中的作用。使用一组通过整个外显子组测序(即基因组的所有蛋白质编码区)识别的罕见(次要等位基因频率<5%)编码变异，我们将检验罕见变异单独和共同导致心肌梗死风险的假设，并进一步证明这一知识可以改善基于人群的风险分层。为了检验这些假设，我们提出了以下具体目标：在目标1中，我们将 在目标2中，我们将开发新的稀有变异分析方法，以识别共同与心肌梗死相关的稀有变异；在目标3中，我们将开发基于人群的心肌梗死风险分层的稀有变异方法。除了阐明罕见的编码变异在心肌梗塞风险中的作用外，这份为期五年的提案还概述了首席研究员在学术心血管医学领域的职业发展的综合战略。从逻辑上讲，这一策略建立在首席研究员以前的研究经验和临床培训的基础上。在获得生物信息学博士学位后，校长 研究人员完成了内科住院医师培训，目前正在完成心血管疾病研究员培训。这项提议现在侧重于通过在人类遗传学和基因组学、统计遗传学和风险建模方面获得更多知识和实际研究经验来扩展他的科学技能。职业发展目标将通过多方面的方法实现，包括Sekar Kathiresan博士(人类遗传学和基因组学)和Shamil Sunyaev博士(统计遗传学、风险建模)的指导、教学课程、科学调查以及科学交流和研究伦理方面的培训。这项工作将在一个独特的培训环境中进行，该培训环境由马萨诸塞州总医院、布里格姆妇女医院和布罗德研究所的互补经验组成。成功完成这项职业发展奖将使人们更好地了解心肌梗塞的遗传基础，使首席研究人员过渡到独立的内科科学家，并为他申请RO1级资金提供坚实的基础。

DESCRIPTION (provided by applicant): Myocardial infarction (MI) is the leading cause of death in the United States and is heritable. Large studies focusing on common genetic variation have now identified over 30 loci associated with risk for MI. Despite this success, these common variants explain only a small proportion of the genetic basis of MI. Population genetics and candidate gene studies support the hypothesis that less common genetic variation plays a significant role in complex disorders such as MI. In this proposal, we outline several methods to explore the role of rare genetic variation in risk for MI. Using a set of rare (minor allele frequecy < 5%) coding variants identified through whole exome sequencing (i.e. all protein coding regions of the genome), we will test the hypotheses that rare variants contribute to MI risk both individually and collectively and further that this knowledge can improve population-based risk stratification. To test these hypotheses, we propose the following specific aims: in Aim 1, we will genotype exome variants in a well-powered case/control study to identify rare variants that individually contribute to risk of MI; in Aim 2, we will develop novel computational methods for rare variant analysis to identify rare variants collectively associated with MI; and in Aim 3, we will develop a rare variant method for population-based MI risk stratification. In addition to elucidating the role of rare coding variation in risk for MI, this five-year proposal outlines a comprehensive strategy for the principal investigator's career development in academic cardiovascular medicine. This strategy logically builds on the principal investigator's previous research experience and clinical training. After obtaining a Ph.D. in Bioinformatics, the principal investigator completed residency training in Internal Medicine and is currently finishing fellowship training in Cardiovascular Disease. This proposal now focuses on expanding his scientific skills by attaining additional knowledge and practical research experience in human genetics and genomics, statistical genetics, and risk modeling. The career development goals will be achieved through a multi-faceted approach involving mentoring by Dr. Sekar Kathiresan (human genetics and genomics) and Dr. Shamil Sunyaev (statistical genetics, risk modeling), didactic coursework, scientific investigation, and training in scientific communication and research ethics. This work will take place in a unique training environment comprised of complementary experiences at Massachusetts General Hospital, Brigham and Women's Hospital, and the Broad Institute. Successful completion of this career development award will result in a better understanding of the genetic basis for MI, result in the principal investigator' transition to an independent physician-scientist, and provide a solid foundation from which he will apply for RO1-level funding.