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: 8660319
• 负责人: DONALD W BOWDEN
• 金额: $ 116.18万
• 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/8660319
• 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; Jackson Heart Study; 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; rare variant; 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）：本研究的目标是识别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罕见编码变异。基于家族的连锁分析已成为鉴定导致单基因疾病的基因的有力工具。直到最近，基于家族的方法在复杂性状遗传学中的效用仍然有限。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非常成功。然而，现在人们普遍认识到，共同的变异常常只能解释人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被识别，但这些基因加起来只能解释 10% 或更少的遗传性。 “遗传性缺失”有几个可能的来源。我们开发了一种强大且高效的基于家族的方法，用于识别低频 (LF) 或罕见变异，这些变异对胰岛素抵抗动脉粥样硬化家族研究 (IRASFS) 中复杂性状的表型变异有显着贡献。该方法已通过 ADIPOQ（脂联素）基因中 LF (1.1% MAF) 编码变体的鉴定得到证实，该变体可将西班牙裔美国人的循环脂联素降低至正常值的 20% 以下。该突变导致整个人群血浆脂联素变异的 ​​17%，并导致连锁分析中 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影响。我们建议结合基于家族的连锁分析、全外显子组测序和关联分析来识别对多种 CVD 危险因素产生显着影响的新基因中具有大效应的 LF/罕见变异。 IRASFS 西班牙裔和非裔美国人家庭的综合分析将用于定位染色体区域，以对外显子组序列数据进行详细评估。将评估在选定的染色体位置上提供连锁证据的家族是否存在显着的编码变异。重要的是，这种方法能够快速询问各种 CVD 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 样本中进行关联测试，并在多个西班牙裔 (n=6880) 和非裔美国人 (n=15,180) DNA 样本的荟萃分析中进行复制，以测试主要性状关联并评估高效变异对亚临床和临床CVD的影响。