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

描述（由申请人提供）：本研究的目的是识别在西班牙裔美国人和非洲裔美国人中具有显著生物医学影响的低频和罕见编码变异。基于家族的连锁分析已经成为鉴定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效用有限。在全基因组关联研究（GWAS）中，寻找与复杂性状相关的常见遗传变异已经非常成功。然而，现在人们普遍认识到，共同变异往往只能解释种群中个体间变异的一小部分。例如，已经确定了许多心血管疾病（CVD）、2型糖尿病和体重基因，但这些基因加起来只能解释10%或更少的遗传性。“缺失的遗传性”有几个可能的来源。在胰岛素抵抗动脉粥样硬化家族研究（IRASFS）中，我们开发了一种强大而高效的基于家族的方法来鉴定低频（LF）或罕见变异，这些变异对复杂性状的表型变异有重要影响。该方法已被证实，在西班牙裔美国人中，ADIPOQ（脂联素）基因中的LF （1.1% MAF）编码变异可将循环脂联素降低到正常水平的20%以下。该突变占整个人群血浆脂联素变异的17%，在连锁分析中LOD评分为8.2。基于这些努力，我们假设LF和罕见变异对CVD危险因素的差异有很大的贡献。我们建议将基于家族的连锁分析、全外显子组测序和关联分析相结合，以确定对心血管疾病危险因素有重大影响的新基因中的LF/罕见变异。对IRASFS西班牙裔和非洲裔美国家庭的综合分析将用于靶染色体区域，以详细评估外显子组序列数据。在选定的染色体位置提供连锁证据的家庭将被评估为显著的编码变异。重要的是，这种方法能够快速询问广泛的心血管疾病风险表型，包括新的措施。从基于家庭的方法中鉴定出的变异将在整个IRASFS样本中进行相关性测试，并在多个西班牙裔（n=6880）和非洲裔美国人（n=15,180） DNA样本的meta分析中进行重复，以测试主要性状相关性，并评估高效变异对亚临床和临床CVD的影响。

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.