Integrative omics pipeline to identify novel COPD genes and pathways

用于识别新的 COPD 基因和通路的综合组学管道

• 批准号: 9294462
• 负责人: Jarrett MORROW
• 金额: $ 18.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294462
• 关键词: Affect; Bayesian Method; Bioinformatics; Biological; Biology; Biomedical Research; Biotechnology; Chronic; Chronic Obstructive Airway Disease; Communities; Complex; Consensus; Custom; DNA; DNA Methylation; Data; Data Analyses; Data Set; Development; Disease; Disease susceptibility; Electrical Engineering; Engineering; Environment; Environmental Epidemiology; Epigenetic Process; Etiology; Foundations; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic study; Genomics; Genotype; Goals; Hospitals; Hybridization Array; Inflammation; Institutes; Knowledge; Lead; Link; Lung diseases; Mediating; Mediation; Mediator of activation protein; Medicine; Mentors; Mentorship; Methods; Methylation; Morbidity - disease rate; Network-based; Noise; Obstruction; Output; Pathogenesis; Pathogenicity; Pathway interactions; Pharmacogenetics; Predisposition; Process; Regulator Genes; Research; Research Activity; Research Project Grants; Risk Factors; Scientist; Signal Transduction; Single Nucleotide Polymorphism; Site; Source; Structure of parenchyma of lung; Susceptibility Gene; System; Testing; Tissue Sample; Tissues; Training; Variant; Woman; base; career development; case control; cigarette smoking; epigenomics; evidence base; experience; genetic epidemiology; genetic variant; genome wide association study; genome-wide; genomic data; lectures; method development; mortality; multiple omics; novel; personalized medicine; phenotypic data; programs; respiratory; skills; software development; statistics; tool

Abstract Although cigarette smoking is the major risk factor, multiple studies have demonstrated a genetic component to chronic obstructive pulmonary disease (COPD) susceptibility. Genome Wide Association Studies (GWAS) have identified Single Nucleotide Polymorphisms (SNPs) that have a significant association with COPD. Beyond the informative top findings, many GWAS results are below the genome-wide threshold for significance and are typically ignored. The central hypothesis of this study is that sub-threshold GWAS SNPs confer susceptibility to COPD. We will develop a publicly available ensemble analysis tool to elucidate susceptibility factors from prior GWAS using genomic, epigenomic and genetic data in lung tissue. This integrative omics method will aggregate the gene expression effects from all potentially relevant SNPs by extracting the additional genetic and genomic signals contained in the sub-threshold results, from the biological and technical noise. The electrical engineering background of the applicant provides a valuable perspective for the extraction of the signals from noise, as well as experience in the creation of solutions from custom-tailored building blocks. His M.S. degrees in Biotechnology and Bioinformatics provide a foundation for biomedical research that has been centered on COPD, in particular the analysis of multidimensional omics and phenotype data. Training and mentorship within the Channing Division of Network Medicine (CDNM) at Brigham and Women’s Hospital will impart the necessary knowledge in lung disease biology, statistics, network methods and software development to succeed in this study and move toward independence. The CDNM has a well-established research program in respiratory, environmental and genetic epidemiology, pharmacogenetics and genomics, statistical genetics, bioinformatics, epigenetics and network medicine. This environment provides access to multiple didactic activities, within the Division and through neighboring institutes, such as seminars and lectures that will facilitate the applicant's training. The applicant will attain new skills to develop new methods and adapt existing ones to serve as components in the proposed pipeline. In this study, we will aggregate the effects of sub-threshold GWAS to implicate genes in the etiology of disease using the Bayesian method Sherlock, and adapt Sherlock for use with DNA methylation data. We will construct networks using omics data, and develop methods to observe edge perturbations associated with the genotypes of sub-threshold GWAS SNPs to highlight their regulatory influence. We will create between-network links based on causal evidence and identify gene expression regions influenced by epigenetic mediation. The network-based evidence from these aims will highlight gene communities affecting COPD susceptibility, which may inform the development of future personalized therapies. Through the proposed career development and mentored research activities, the applicant will progress towards the goal of becoming an independent bioinformatics scientist, with computational and statistics expertise, trained in the study of complex lung disease.

摘要 虽然吸烟是主要的危险因素，但多项研究表明， 慢性阻塞性肺疾病（COPD）易感性。全基因组关联研究（GWAS） 已经鉴定出与COPD有显著关联的单核苷酸多态性（SNP）。 除了信息量最大的发现之外，许多GWAS结果低于全基因组的显著性阈值 并且通常被忽略。这项研究的中心假设是，亚阈值GWAS SNP赋予了 对COPD的易感性。我们将开发一个公开可用的系综分析工具来阐明易感性 使用肺组织中的基因组、表观基因组和遗传数据从先前的GWAS中提取因子。这种整合组学 该方法将通过从所有潜在相关的SNP中提取基因表达效应， 来自生物和技术分析的亚阈值结果中包含的额外遗传和基因组信号 噪声申请人的电气工程背景为提取提供了有价值的视角 从噪音信号，以及在创建解决方案的经验，从定制的建筑 个街区.他的多发性硬化症。生物技术和生物信息学学位为生物医学研究提供了基础 以COPD为中心，特别是多维组学和表型数据的分析。 在布里格姆和妇女大学的网络医学（CDNM）的钱宁分部内进行培训和指导 医院将传授肺病生物学、统计学、网络方法和软件方面的必要知识 发展，在这项研究中取得成功，走向独立。CDNM有一个完善的 呼吸、环境和遗传流行病学、药物遗传学和基因组学研究计划， 统计遗传学、生物信息学、表观遗传学和网络医学。此环境提供访问 多种教学活动，在司内和通过邻近的机构，如研讨会和 讲座，这将有助于申请人的培训。申请人将获得新的技能，以开发新的方法 并调整现有的项目，作为拟议管道的组成部分。在这项研究中，我们将汇总 使用贝叶斯方法的亚阈值GWAS对疾病病因学基因的影响 夏洛克，并改编夏洛克用于DNA甲基化数据。我们将使用组学数据构建网络， 并开发方法来观察与亚阈值GWAS基因型相关的边缘扰动 SNPs以突出其监管影响。我们将根据因果证据创建网络间链接 并鉴定受表观遗传介导影响的基因表达区域。基于网络的证据来自 这些目标将突出影响COPD易感性的基因群落，这可能会为COPD的发展提供信息。 未来的个性化治疗。通过拟议的职业发展和辅导研究活动， 申请人将朝着成为一名独立的生物信息学科学家的目标前进， 计算和统计专业知识，在复杂的肺部疾病的研究培训。