A Genome-wide Association Study for Early-Onset Myocardial Infarction

描述（由申请人提供）： 心肌梗塞（MI）是美国的主要死亡原因。Ml在独立于传统风险因素的家庭中聚集，并且当Ml在生命早期发生时，遗传性显著更大。因此，遗传的DNA变异在Ml中起因果作用，在早发性Ml中具有特别强的作用。然而，迄今为止，Ml（早期和晚期）的家族聚集在很大程度上仍然无法用已知的基因变体来解释。最近的证据表明，常见的遗传变异有助于常见疾病的风险。由于遗传学的最新进展，现在实际上可以在全基因组范围内搜索影响MI风险的常见DNA变体。在这种方法中，成功的关键决定因素包括：表型的选择，样本量，有效的研究设计，注意系统性偏倚的潜在来源，严格的分析，以及区分真阳性和假线索的验证。我们假设：（a）早发性MI是基因发现的特别有希望的靶点;（B）常见的DNA变异体影响早发性MI的风险;（c）许多这样的变异体不在“候选基因”或鉴定的连锁峰中;（d）影响通常是适度的并且先验较低，需要大的样本量;和（e）提供足够数量的SNP、样本大小和分析严谨性，可以通过与人群中疾病的关联来识别风险变体。 为了验证这些假设，我们提出了以下具体目标：（1）在两阶段设计的第一阶段，收集并整理1500例早发性MI病例和1500例匹配的无MI对照的550，000个SNP中的每一个的基因型数据;（2）利用目标1中收集的数据，系统分析SNPs与早发MI风险之间的关联，基于统计学证据的强度鉴定前0.1%;（3）在II期，在1748个早发性MI的额外病例和1743个对照中，对来自I期的前0.1%进行基因分型;联合分析I期和II期以鉴定与疾病相关的变体。 拟议的项目结合了前所未有的收集流行病学研究的早发性心肌梗死与独特的专业知识，在基因组学和统计/群体遗传学。我们的研究将彻底检验常见基因变异在早发性MI中发挥作用的假设。成功识别常见的基因变异和潜在的MI风险的新途径有可能改变美国主要死亡原因的理解，治疗和预防。

DESCRIPTION (provided by applicant): Myocardial infarction (Ml) is the leading cause of death in the US. Ml clusters in families independent of traditional risk factors and when Ml occurs early in life, heritability is substantially greater. Thus, inherited DNA variation plays a causal role in Ml, with a particularly strong role in early-onset Ml. To date, however, the familial aggregation of Ml (early and late) remains largely unexplained by known gene variants. Recent evidence shows that common genetic variants contribute to risk of common diseases. Due to recent progress in genetics, it is now practical to search genome-wide for common DNA variants influencing Ml risk. In such an approach, critical determinants of success include: the choice of phenotype, sample size, an efficient study design, attention to potential sources of systematic bias, rigorous analysis, and validation to distinguish true positives from false leads. We hypothesize that: (a) that early-onset Ml is a particularly promising target for gene discovery;(b) that common DNA variants influence risk of early-onset Ml;(c) that many such variants are not in "candidate genes" or identified linkage peaks; (d) that effects will often be modest and priors low, requiring large sample sizes; and (e) provided adequate numbers of SNPs, sample size and analytical rigor, that risk variants can be recognized by association with disease in the population. To test these hypotheses, we propose the following specific aims: (1) In Stage I of a two-stage design, collect and curate genotype data for each of 550,000 SNPs in each of 1500 cases with early-onset Ml and 1500 matched controls without Ml; (2) Using data collected in Aim 1, systematically analyze associations between SNPs and risk of early-onset Ml, identifying the top 0.1% based on strength of statistical evidence; (3) In Stage II, genotype the top 0.1% from Stage I in 1748 additional cases of early-onset Ml and 1743 controls; jointly analyze Stages I and II to identify variants associated with disease. The proposed project combines an unprecedented collection of epidemiologic studies of early-onset Ml with unique expertise in genomics and statistical/population genetics. Our study will thoroughly test the hypothesis that common gene variants play a role in early-onset Ml. Successfully identifying common gene variants and novel pathways underlying risk of Ml has the potential to transform understanding, treatment, and prevention of the leading cause of death in the U.S. (End of Abstract)