Genetic Architecture of Adiposity in Multiple Large Cohorts

描述（由申请人提供）：肥胖症作为现代流行病继续增长。由于肥胖是许多其他代谢紊乱，糖尿病，心血管疾病，脂肪肝疾病，各种癌症以及许多其他疾病的强烈风险因素，因此有强烈的动机来了解肥胖性状的遗传结构。近年来，针对肥胖性状的全基因组关联扫描（GWAS）在对数万名受试者进行的荟萃分析中，由于大队列和家族研究的合作，产生了许多发现，涉及许多新基因。国际基因组流行病学心脏和衰老研究队列（CHARGE）联盟（社区动脉粥样硬化风险研究（ARIC）、心血管健康研究（CHS）、心脏病研究（FHS）、鹿特丹研究（RS）和年龄，基因/环境易感性-雷克雅未克研究（AGES-雷克雅未克研究）的召开是为了促进使用GWAS分析发现涉及多个复杂性状的新基因。肥胖工作组包括这些队列加上家庭心脏研究（FamHS），欧洲特殊人群网络联盟（EUROSPAN）和旧秩序阿米什人（OOA），共代表37，000多名受试者。约8,200名非洲裔美国人的数据可从FamHS和候选基因关联资源（CARe）资源获得，其中包括杰克逊心脏研究、克利夫兰家族研究、ARIC、CARDIA和梅萨。这些样本量使得能够检测影响小至~0.5%的性状方差的变体。我们建议扩展这些队列的荟萃分析方法，以调查体重指数（BMI，wt/ht 2），腰围（WC），腰臀比（WHR），肥胖（BMI>30 kg/m2）和极端肥胖（BMI>40 kg/m2）。我们将讨论超越主要基因发现的4个主要目标。本研究拟对欧美人和非裔美国人肥胖特征的遗传结构进行对比，探讨一系列的g x e相互作用假说，包括性别、年龄和吸烟情况，确定对脂糖代谢特征具有多效性的肥胖基因位点，以解构这些危险因素之间的相关性，并对肥胖基因位点的遗传结构进行分析。并确定和测试对肥胖特征具有高度影响的途径，调查主要途径是否因性别和种族而异。为了实现这些目标，我们将与GIANT（人体测量性状遗传调查）联盟的研究合作，以增加效力，可能包括多达125，000名欧美受试者。我们有一个独特的机会来调查一些问题，使用现存的GWAS扫描，以阐明两个种族群体的肥胖和相关性状的遗传结构。根据需要，将通过额外的基因分型和/或测序对这些研究的结果进行验证。这项工作将刺激变异和途径的发现，并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点。

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.