Identification of Pleiotropic loci for Asthma and Obesity

哮喘和肥胖的多效性基因座的鉴定

• 批准号: 9261052
• 负责人: Yasmmyn Salinas
• 金额: $ 4.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-16 至 2020-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261052
• 关键词: 18 year old; 20 year old; Adolescence; Adolescent; Adult; Adult asthma; Affect; Age; Architecture; Asthma; Biological; Biological Assay; Body mass index; Candidate Disease Gene; Child; Chronic; Chronic Disease; Comorbidity; Cross-Sectional Studies; Data; Detection; Development; Diagnosis; Disease; Family; Genetic; Genetic Predisposition to Disease; Genotype; Grant; Health; Health Care Costs; Height; Individual; Intervention; Knowledge; Link; Measurement; Measures; Mediating; Mediation; Methodology; Methods; Morbidity - disease rate; Norway; Obesity; Patient Self-Report; Performance; Phase; Phenotype; Phonation; Prevalence; Prevention; Public Health Schools; Questionnaires; Recruitment Activity; Reporting; Research Project Grants; Risk; Risk Factors; Sampling; Science; Series; Signal Transduction; Single Nucleotide Polymorphism; Surveys; Technology; Telephone; Twin Studies; Universities; Variant; Weight; Weight maintenance regimen; Work; analytical method; asthmatic; base; bead chip; cohort; disorder prevention; epidemiology study; exome sequencing; genetic variant; genome wide association study; genome-wide; inflammatory lung disease; obesity in children; obesity risk; phenotypic data; pleiotropism; population based; population stratification; screening; secondary analysis; study population; success

PROJECT SUMMARY Asthma and obesity are two of the most common chronic illnesses worldwide. Epidemiologic studies have consistently demonstrated the comorbidity of these conditions, with longitudinal reports suggesting that obesity is a risk factor for the development of asthma and vice versa. Asthma and obesity have strong genetic components, and twin studies suggest that a potential mechanism explaining the asthma-obesity association is shared genetic predisposition or genetic pleiotropy. However, to date, only a few studies have empirically sought to identify the posited pleiotropic variants. Those studies had limited success in identifying pleiotropic loci and had important methodological constraints, including the use of a candidate-gene approach. Specifically, the candidate-gene approach is limited by our current understanding of the genetic architectures of obesity and asthma and of the mechanistic overlaps between the two diseases. Therefore, our study will search for genetic variants that display pleiotropy for asthma and obesity using a hypothesis-free genome-wide association study approach. Two analytic methods will be employed: (1) a univariate pleiotropy-informed false discovery rate-based framework and (2) a multivariate approach called MultiPhen. Our discovery-phase analyses will utilize existing genotype and phenotype data from the third wave of the Nord-TrØndelag Health study (HUNT3). The HUNT3 analytic sample will consist of n=27,712 adults aged 20 years or older [11,285 obese and 1,119 asthmatic cases (of which 639 are both obese and asthmatic), and 15,947 non-asthmatic, normal weight controls]. Genome-wide significant pleiotropic loci identified in HUNT3 will be candidates for replication. Our replication-phase analyses will utilize existing phenotype and whole-exome sequencing data from Dr. Andrew DeWan's FAstGen Study. The FAstGen analytic sample will consist of n=384 adults aged 18 years or older [182 obese and 154 asthmatic cases (of which 81 are both obese and asthmatic) and 129 non- asthmatic, normal weight controls]. In secondary analyses, we will characterize the effects of the candidate pleiotropic loci via mediation analyses. We will also investigate whether the candidate pleiotropic loci are associated with asthma and obesity in children, using data from a subset of HUNT3 subjects who were originally recruited into the first wave of the adolescent component of HUNT (Young-HUNT1) and thus also have phenotype data from adolescence [n=1,202; ages 13-19 years]. Lastly, we will evaluate the performance of our two analytic methods, using replication of pleiotropic signals as a metric of the relative performance of the methods. This will be the first study to investigate pleiotropy for asthma and obesity on a genome-wide scale, using pleiotropy-informed methods and incorporating mediation analyses to characterize pleiotropic effects. Findings from this work will advance our understanding of the mechanistic links between asthma and obesity; provide the first comparison of the performance of our two pleiotropy detection methods using real- world data; and promote specific prevention and treatment efforts for obese asthmatics.

项目摘要 哮喘和肥胖是全球最常见的慢性疾病。流行病学研究已有 一贯证明了这些条件的合并症，并有纵向报告表明肥胖症 是哮喘发育的危险因素，反之亦然。哮喘和肥胖具有强大的遗传 组件和双研究研究表明，解释哮喘关联的潜在机制是 共有的遗传易感或遗传多效性。但是，迄今为止，只有少数研究在经验上 试图识别海报多效性变体。这些研究在鉴定多效性方面取得了有限的成功 基因座并具有重要的方法论限制，包括使用候选基因方法。 具体而言，候选 - 基因方法受到我们目前对遗传体系结构的理解的限制 肥胖和哮喘以及两种疾病之间的机械重叠。因此，我们的研究将 搜索使用不含假设的全基因组显示哮喘和肥胖的多效性的遗传变异 协会研究方法。将雇用两种分析方法：（1）单变量多效性伪造的false 基于发现率的框架和（2）一种称为Multiphen的多元方法。我们的发现阶段 分析将利用Nord-TrøndelagHealth第三波的现有基因型和表型数据 研究（Hunt3）。 HUNT3分析样本将包括20岁或20岁以上的27,712名成年人[11,285 肥胖和1,119例哮喘病例（其中639例肥胖和哮喘），15,947个非asthmattic 正常体重控制]。全基因组范围内的明显的多效性位于Hunt3中将是候选者 复制。我们的复制相分析将利用现有表型和全外观测序数据 来自Andrew Dewan博士的Fastgen研究。 FastGEN分析样本将包括n = 384岁的成年人18岁 年或以上[182肥胖和154例哮喘病例（其中81例都是肥胖和哮喘）和129个非 - 哮喘，正常体重控制]。在次要分析中，我们将表征候选人的影响 通过调解分析进行多效基因座。我们还将调查候选多效性基因座是否是 与儿童的哮喘和肥胖有关，使用来自Hunt3受试者的一部分数据 最初招募到亨特（Young-Hunt1）的青少年成分的第一波 具有来自青少年的表型数据[n = 1,202;年龄13-19岁]。最后，我们将评估性能 在我们的两种分析方法中，使用多效信号的复制作为相对性能的度量 方法。这将是第一项研究全基因组上哮喘和肥胖的多效性的研究 比例尺，使用多效性信息和编码中介分析以表征多效性的方法 效果。这项工作的发现将提高我们对哮喘与机械联系的理解 肥胖;使用REAL-提供我们两种多效性检测方法的性能的首次比较 世界数据；并促进肥胖哮喘患者的特定预防和治疗工作。