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

外显子组测序识别西班牙裔 CVD 风险变异

• 批准号: 8464763
• 负责人: DONALD W BOWDEN
• 金额: $ 111.45万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464763
• 关键词: Accounting; African American; American; Atherosclerosis; Blood Vessels; Calcified; Cardiovascular Diseases; Carotid Artery Plaques; Characteristics; Cholesterol; Clinical; Code; Complement; Complex; Complex Genetic Trait; DNA; DNA Resequencing; Data; Diabetes Mellitus; Disease; Distal; Ethnic Origin; European; Evaluation; Event; Family; Family Sizes; Family Study; Fatty acid glycerol esters; Frequencies; Future; Genes; Genomics; Goals; Haplotypes; Health; Heart; Hepatic; Heritability; Hispanic Americans; Hispanics; Individual; Inheritance Patterns; Insulin Resistance; Life; Lipids; Location; Measures; Meta-Analysis; Methods; Molecular Genetics; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pattern; Phenotype; Physiological; Plasma; Population; Risk Factors; Sample Size; Sampling; Sequence Analysis; Signal Transduction; Source; Testing; Thick; Variant; adiponectin; base; cardiovascular disorder risk; case control; clinically significant; design; disorder risk; ethnic difference; exome sequencing; experience; forest; genetic analysis; genetic association; genetic linkage analysis; genetic pedigree; genetic variant; genome wide association study; inflammatory marker; kindred; next generation; novel; response; risk variant; tool; trait

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.

描述（由申请人提供）：这项研究的目的是确定对西班牙裔美国人和非裔美国人具有重大生物医学影响的低频和稀有编码变体。基于家庭的连锁分析是鉴定有助于单基因疾病的基因的强大工具。直到最近，基于家庭的方法在复杂性状遗传学中的实用性一直有限。在基因组广泛的关联研究（GWAS）中，搜索与复杂性状相关的常见遗传变异已非常成功。然而，现在被广泛认识到，常见的变化经常仅解释人口间个体间差异的一小部分。例如，已经鉴定出许多心血管疾病（CVD），2型糖尿病和体重基因，但是这些基因共同解释了10％或更少的遗传力。 “缺少遗传力”有几种可能的来源。我们已经开发了一种强大且高效的基于家庭的方法来鉴定低频（LF）或稀有变体，该方法在胰岛素抵抗动脉粥样硬化家庭研究（IRASFS）中对复杂性状的表型变化产生了显着贡献。通过鉴定adipoq（脂联素）基因中的LF（1.1％MAF）编码变体的鉴定，该方法已证明，该方法将循环脂联素降低到西班牙裔美国人的正常<20％。该突变占整个人群血浆脂肪素方差的17％，在链接分析中，LOD得分为8.2。基于这些努力，我们假设LF和稀有变体对CVD风险因素的差异有很大贡献。我们提出了基于家庭的连锁分析，整个外显子组测序和关联分析的组合，以识别新型基因中的LF/稀有变体，这些变体显着影响广泛的CVD风险因素。对IRASFS西班牙裔和非裔美国家庭的全面分析将用于靶向染色体区域，以详细评估外显序序列数据。将评估有效的染色体位置上有联系的证据的家庭，以进行重大编码变化。重要的是，这种方法可以快速询问包括新措施在内的广泛的CVD风险表型。从基于家庭的方法中鉴定出的变体将在整个IRASFS样本中进行关联测试，并在对多个西班牙裔（n = 6880）和非裔美国人（n = 15,180）DNA样本的元分析中进行了复制，以测试主要特质和评估高效应变体对亚周期和临床CVD的影响。