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.
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