Genetic Architecture of Adiposity in Multiple Large Cohorts

多个大群体中肥胖的遗传结构

• 批准号: 8501439
• 负责人: Ingrid Bernadette Borecki
• 金额: $ 56万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2014-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501439
• 关键词: Address; African American; Age; Aging; American; Amish; Architecture; Atherosclerosis; Bioinformatics; Biological; Biological Factors; Body mass index; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Characteristics; Cohort Studies; Collaborations; Communities; Complex; Data; Data Aggregation; Data Set; Dependency; Detection; Development; Diabetes Mellitus; Environment; Environmental Risk Factor; Epidemic; Epidemiology; Ethnic group; European; Family; Family Study; Fatty Liver; Framingham Heart Study; Gene Expression; Genes; Genetic; Genetic Determinism; Genomics; Genotype; Health; Heart; High Density Lipoprotein Cholesterol; Human Genome; Individual; Insulin; International; Intervention; Investigation; LDL Cholesterol Lipoproteins; Leptin; Lipids; Liver diseases; Malignant Neoplasms; Meta-Analysis; Metabolic; Mining; Minor; Minority; Morbid Obesity; Morbidity - disease rate; Motivation; Obesity; Other Genetics; Pathway interactions; Phenotype; Play; Population; Predisposition; Race; Relative (related person); Research; Resources; Risk; Risk Factors; Role; Sample Size; Sampling; Scanning; Series; Signal Transduction; Single Nucleotide Polymorphism; Smoking; Staging; Systems Biology; Techniques; Testing; Triglycerides; Variant; Waist-Hip Ratio; Weight; Work; aging gene; base; cardiovascular risk factor; cohort; cost effective; density; experience; fasting glucose; gene discovery; gene environment interaction; genome wide association study; genome-wide; glucose metabolism; high risk; indexing; insight; insulin sensitivity; lipid metabolism; named group; novel; obesity risk; public health relevance; sex; success; therapeutic target; tool; trait; waist circumference; working group

DESCRIPTION (provided by applicant): Obesity continues to grow as a modern-day epidemic. Because obesity is a strong risk factor for numerous other metabolic derangements, diabetes, cardiovascular disease, fatty liver disease, various cancers, as well as a host of other morbidities, there is strong motivation to understand the genetic architecture of adiposity traits. Genomewide association scans (GWAS) aimed at adiposity traits recently have produced many findings, implicating numerous novel genes, owing to cooperation of large cohort and family studies in meta-analyses of tens of thousands of subjects. The international Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES- Reykjavik Study) was convened to promote the discovery of new genes involved in multiple complex traits using GWAS analysis. The Adiposity Working Group includes these cohorts plus the Family Heart Study (FamHS), the European Special Population Network consortium (EUROSPAN), and the Old Order Amish (OOA), together representing over 37,000 subjects. Data on ~8,200 African-Americans are available from the FamHS and the Candidate gene Association Resource (CARe) resource, which includes the Jackson Heart Study, the Cleveland Family Study, ARIC, CARDIA and MESA. These sample sizes enable detection of variants influencing as little as ~0.5% of trait variance. We propose to extend the meta-analysis approach of these cohorts to investigate body mass index (BMI, wt/ht2), waist circumference (WC), waist-hip ratio (WHR), obesity (BMI>30 kg/m2) and extreme obesity (BMI>40 kg/m2). We will address 4 major aims that go beyond primary gene discovery. We propose to contrast the genetic architecture for adiposity traits between European-Americans and African-Americans; to investigate a series of g x e interaction hypotheses, including sex, age, and smoking; to identify adiposity loci with pleiotropic effects on lipid and glucose metabolism traits to deconstruct the correlations among these risk factors; and to identify and test pathways with high impact on adiposity traits, investigating whether the predominant pathways differ by sex and race. For these aims, we will work with studies from the GIANT (Genetic Investigation of ANthropometric Traits) Consortium to augment power, together potentially including up to ~125,000 European- American subjects. We have a unique opportunity to investigate a number of issues using extant GWAS scans to elucidate the genetic architecture of obesity and related traits in two ethnic groups. Findings from these studies will be validated with additional genotyping and / or sequencing, as warranted. This work will stimulate the discovery of variants and pathways, and potentially extend our understanding of the genetic basis of obesity risk and suggest potential therapeutic targets.

描述（由申请人提供）：肥胖症继续随着现代流行而发展。由于肥胖是许多其他代谢危险，糖尿病，心血管疾病，脂肪肝病，各种癌症以及许多其他病因的强烈危险因素，因此了解肥胖性状的遗传结构有很大的动力。全基因组关联扫描（GWAS）最近针对肥胖性状，最近产生了许多发现，这暗示了许多新型基因，这是由于大型队列和家庭研究的合作和成千上万受试者的荟萃分析中的合作。国际基因组流行病学心脏和衰老研究的群体（CHAIL）联盟（社区动脉粥样硬化风险研究（ARIC），心血管健康研究（CHS），Framingham Heart研究（FHS）（FHS）（FHS），鹿特丹研究（RS），鹿特丹研究（RS），Gene/Gemementibility-Reperibility-reperibility-Reak recavik rey toik-Reak reykjavik rey reykjavik reyykjjavik rey toy toy toy toy toy toy toy toy toy toy toy toy toy toy toy toy toy toe toy toe to kuk Ju.使用GWAS分析涉及多个复杂性状的新基因。克利夫兰家庭研究，ARIC，Cardia和Mesa。肥胖（BMI> 40 kg/m2）。我们将解决超出主要基因发现的4个主要目标。我们建议将欧洲人与非裔美国人之间的肥胖特征的遗传结构与遗传结构进行对比；研究一系列的互动假设，包括性别，年龄和吸烟；确定对脂肪性作用对脂质和葡萄糖代谢特征的影响，以解构这些危险因素之间的相关性；并确定和测试对肥胖特征高影响的途径，研究主要途径是否因性别和种族而有所不同。对于这些目标，我们将研究巨型（人体测量特征的遗传研究）联盟的研究，以增强能力，其中可能包括大约125,000名欧美受试者。我们有一个独特的机会，可以使用现存的GWAS扫描来调查许多问题，以阐明两个种族中肥胖和相关特征的遗传结构。这些研究的结果将通过有必要的其他基因分型和 /或测序来验证。这项工作将刺激变异和途径的发现，并有可能扩展我们对肥胖风险遗传基础的理解，并提出潜在的治疗靶标。