The contribution of exonic variants to cardiovascular disease risk in the Amish

描述（由申请人提供）：多种证据表明遗传风险因素在心血管疾病（CVD）发展中的重要性。最近的全基因组关联研究（GWAS）已经成功地确定了影响心血管疾病及其危险因素的常见变异，但这些变异只能解释总遗传风险的一小部分。罕见的功能性变异（如在基因组的编码或外显子区域中发现的变异）可能解释额外的遗传性。这项职业发展建议的总体目标是确定与亚临床CVD特征相关的外显子变异。我们将在旧秩序阿米什人（OOA）中进行这些研究，这是一个特别适合这种方法的人群，因为由于遗传漂变，在单个染色体上进入人群的罕见外显子变异可能存在于多个个体中，因此比在近亲繁殖的高加索人群中更容易发现。为了鉴定这些罕见的变异，我们将首先通过使用外显子组基因分型芯片鉴定OOA个体的外显子变异，然后通过测序数据鉴定。然后，我们将测试这些变异与亚临床心血管疾病特征的关联，并将我们的分析扩展到非阿米什受试者。在确定感兴趣的变异后，我们将进行基因型导向的参与者招募，以进一步表征变异携带者的亚临床CVD特征。该研究计划旨在补充我的培训目标，即接受以下方面的额外培训：1)心血管疾病流行病学；2)与下一代测序方法和混合模型开发相关的统计方法；3)以患者为导向的临床研究。这个K01申请将通过提供有保障的时间来学习有针对性的指导技能来促进我的职业发展，并将有助于我过渡到心血管疾病遗传流行病学领域的独立研究者。

DESCRIPTION (provided by applicant): Multiple lines of evidence point to the importance of genetic risk factors in the development of cardiovascular disease (CVD). Recent genome-wide association studies (GWAS) have been successful in identifying common variants influencing CVD and its risk factors, but these variants explain only a small portion of the total heritable rik. Rare, functional variants (like those found in the coding, or exonic, regions of the genome) may explain additional heritability. The overall objective of this career development proposal is to identify exonic variants associated with sub-clinical CVD traits. We will perform these studies in the Old Order Amish (OOA), a population that is uniquely suited for this approach because rare, exonic variants that entered the population on a single chromosome are likely to be present in multiple individuals due to genetic drift and therefore easier to find than in the outbred Caucasian populations. To identify these rare variants, we will identify exonic variants in OOA individuals first, through the use of an exome genotyping chip and second, by using sequencing data. We will then test these variants for association with sub-clinical CVD traits and extend our analysis to non-Amish subjects. After identifying variants of interest, we will conduct genotype-directed participant recruitment to further characterize sub-clinical CVD traits in variant carrier. This research plan was designed to complement my training objectives which are to receive additional training in: 1) cardiovascular disease epidemiology, 2) statistical methods relevant to next generation sequencing methodologies and mixed model development and 3) patient-oriented clinical research. This K01 application will promote my career development by providing protected time to learn the targeted mentored skills and will facilitate my transition ino an independent investigator in the field of cardiovascular disease genetic epidemiology.