Exome Sequencing to Identify CVD Risk Variants in Hispanics & African Americans

描述(申请人提供)：这项研究的目标是确定在西班牙裔美国人和非裔美国人中具有显著生物医学影响的低频率和罕见的编码变体。基于家系的连锁分析已经成为识别导致单基因疾病的基因的有力工具。直到最近，以家庭为基础的方法在复杂性状遗传学中的作用有限。在基因组广谱关联研究中，寻找与复杂性状相关的常见遗传变异是非常成功的。然而，现在人们普遍认识到，常见的变异往往只解释了种群中个体间变异的一小部分。例如，许多心血管疾病(CVD)、2型糖尿病和体重基因已经被发现，但这些基因加在一起只解释了10%或更少的遗传性。“遗漏的遗传性”有几个可能的来源。在胰岛素抵抗动脉粥样硬化家系研究(IRASFS)中，我们开发了一种强大而高效的基于家系的方法来识别低频(LF)或稀有变异，这些变异对复杂性状的表型变异有显著影响。这种方法已经在ADIPOQ(脂联素)基因的一个LF(1.1%MAF)编码变种的鉴定中得到了证实，在拉美裔美国人中，它可以将循环中的脂联素减少到正常水平的20%。这种突变解释了整个人群血浆脂联素变异的17%，并解释了连锁分析中的LOD得分8.2。基于这些努力，我们假设LF型和稀有变异型对心血管疾病危险因素的差异有重要作用。我们建议结合基于家族的连锁分析、整个外显子组测序和关联分析来确定在显著影响广泛的心血管疾病危险因素的新基因中具有大效应的LF/REARE变异。对IRASFS、西班牙裔和非裔美国人家庭的综合分析将被用于针对染色体区域，以详细评估外显子组序列数据。对在选定的染色体位置发现连锁的家系进行显著的编码变异评估。重要的是，这种方法能够快速询问各种心血管疾病风险表型，包括新的措施。从基于家族的方法中确定的变异将在整个IRASFS样本中进行相关性测试，并在多个西班牙裔(n=6880)和非裔美国人(n=15,180)DNA样本的荟萃分析中重复，以测试主要性状关联，并评估高效变异对亚临床和临床心血管疾病的影响。公共卫生相关性：这项研究的目标是确定在西班牙裔和非裔美国人中对心血管疾病风险具有显著生物医学影响的低频率和罕见的编码变体。这项研究将结合基于家族的分析和外显子组测序。

DESCRIPTION (provided by applicant): The goal of this study is to identify low frequency and rare coding variants that have significant biomedical impact in Hispanic Americans and African Americans. Family-based linkage analysis has been a powerful tool for identification of genes contributing to monogenic disorders. Until recently family-based approaches have been of limited utility in complex trait genetics. Searches for common genetic variants associated with complex traits have been highly successful in Genome Wide Association Studies (GWAS). It is now widely recognized, however, that common variations frequently explain only a small part of the inter-individual variation in populations. For example, numerous cardiovascular disease (CVD), type 2 diabetes, and body mass genes have been identified, but these genes collectively only explain 10% or less of the heritability. There are several possible sources for the "missing heritability". We have developed a powerful and highly efficient family-based method for identification of low frequency (LF) or rare variants which contribute significantly to phenotypic variation of complex traits in the Insulin Resistance Atherosclerosis Family Study (IRASFS). This method has been demonstrated with the identification of an LF (1.1% MAF) coding variant in the ADIPOQ (adiponectin) gene that reduces circulating adiponectin to <20% of normal in Hispanic Americans. This mutations accounts for 17% of the variance in plasma adiponectin in the entire population and accounts for the LOD score of 8.2 in linkage analysis. Based on these efforts, we hypothesize that LF and rare variants contribute substantially to the variance in CVD risk factors. We propose a combination of family-based linkage analyses, whole exome sequencing, and association analysis to identify LF/rare variants of large effect in novel genes that significantly influence a wide range of CVD risk factors. Comprehensive analysis of IRASFS Hispanic and African American families will be used to target chromosomal regions for detailed evaluation of exome sequence data. Families contributing to evidence of linkage at selected chromosomal locations will be assessed for significant coding variations. Importantly this approach enables the rapid interrogation of a wide range of CVD risk phenotypes including novel measures. Variants identified from the family-based approaches will be tested for association in the entire IRASFS sample and replicated in meta analysis of multiple Hispanic (n=6880) and African American (n=15,180) DNA samples to test the primary trait association and assess the influence of high effect variants on subclinical and clinical CVD. PUBLIC HEALTH RELEVANCE: The goal of this study is to identify low frequency and rare coding variants that have significant biomedical impact on cardiovascular disease risk in Hispanic and African Americans. The study will incorporate a combination of family-based analysis and exome sequencing.