Genetic Architecture of Adiposity in Multiple Large Cohorts

描述（由申请人提供）：肥胖作为一种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一个强大的风险因素，因此有强烈的动机去了解肥胖特征的遗传结构。最近，针对肥胖特征的全基因组关联扫描（GWAS）产生了许多发现，暗示了许多新基因，这是由于在数万受试者的荟萃分析中进行的大型队列和家庭研究的合作。基因组流行病学心脏和衰老研究国际队列（CHARGE）联盟(社区动脉粥样硬化风险研究（ARIC），心血管健康研究（CHS），弗雷明汉心脏研究（FHS），鹿特丹研究（RS）和年龄，基因/环境易感-雷克雅未克研究（AGES-雷克雅未克研究）召集，以促进使用GWAS分析发现涉及多种复杂性状的新基因。肥胖工作组包括这些队列以及家庭心脏研究（FamHS），欧洲特殊人口网络联盟（EUROSPAN）和旧秩序阿米什人（OOA），总共代表了37,000多名受试者。大约8200名非洲裔美国人的数据可以从FamHS和候选基因协会资源（CARe）资源中获得，其中包括杰克逊心脏研究、克利夫兰家庭研究、ARIC、CARDIA和MESA。这些样本量使检测到的变异影响小至约0.5%的性状方差。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/ht2）、腰围（WC）、腰臀比（WHR）、肥胖（BMI>30 kg/m2）和极度肥胖（BMI>40 kg/m2）。我们将讨论除发现原始基因之外的4个主要目标。我们建议对比欧裔美国人和非裔美国人肥胖特征的遗传结构；研究一系列的gx - e相互作用假设，包括性别、年龄和吸烟；寻找多效性影响脂糖代谢特征的肥胖基因座，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有高影响的途径，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（人体特征遗传调查）联盟的研究合作，以增加力量，总共可能包括多达125,000名欧美受试者。我们有一个独特的机会，利用现有的GWAS扫描来研究一些问题，以阐明肥胖的遗传结构和两个民族的相关特征。根据需要，这些研究的结果将通过额外的基因分型和/或测序进行验证。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. PUBLIC HEALTH RELEVANCE: Obesity continues to grow as a modern-day epidemic. Because obesity is a strong risk factor for numerous conditions such as diabetes, cardiovascular disease, fatty liver disease, various cancers, as well as a host of other problems, there is strong motivation to understand the genetic architecture of adiposity traits. Understanding the biological and environmental factors that predispose individuals towards obesity can help us to identify people at high risk for interventions and suggest new therapies to keep them within healthy weight range. New techniques aimed searching the human genome to find adiposity genes recently have produced many new findings, however, they are only a piece of the puzzle. The data suggest that there are many more genes to be found, and that environmental factors may play a role in how genes are expressed. We propose to extend studies of already-collected data on genome-wide association scans (GWAS), basing our work on 8 studies of European-Americans (EA), totaling over 37,000 subjects, and a large dataset of African-Americans (AA), totaling over 16,700 subjects. We will collaborate with another group of studies for these projects, which means we could potentially be analyzing up to 125,000 subjects. Because of this, we expect that our study has great power for discovery of new genes for adiposity and obesity. Specifically, we will study the differences and similarities of the genes associated with adiposity and obesity in EA and AA; we will search for genes whose effects depend of any of sex, age, or smoking; we will test whether genes that influence obesity also have effects on lipid profiles and glucose metabolism; and finally, we will identify biological pathways that may play a part in the development of obesity and test whether those pathways are similar of different by sex and race. We expect that this work will generate many new discoveries and provide important new information regarding the genetic underpinnings of obesity.