Rare coding variation and risk for myocardial infarction

描述（由申请人提供）：心肌梗死（MI）是美国死亡的主要原因，并且是遗传性的。目前，针对常见遗传变异的大型研究已经确定了30多个与心肌梗死风险相关的位点。尽管取得了成功，但这些常见变异只能解释心肌梗死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的假设，即不常见的遗传变异在心肌梗死等复杂疾病中起着重要作用。我们概述了几种方法来探索罕见遗传变异在心肌梗死风险中的作用。使用一组通过全外显子组测序（即基因组的所有蛋白质编码区）鉴定的罕见（小等位基因频率< 5%）编码变异，我们将检验罕见变异单独和集体导致心肌梗死风险的假设，并进一步证明这种知识可以改善基于人群的风险分层。为了验证这些假设，我们提出以下具体目标：在目标1中，我们将

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.