Genetic Epidemiology of GERD in COPD

项目摘要 该NIH F31申请的目的是为PI Ava Wilson获得指导研究的支持， 她的博士培训中的职业发展活动，将加强她成为一个独立的潜力 肺部领域的研究科学家该项目的目标是发展遗传流行病学方面的技能， 生物信息学，统计遗传学和肺病学，这将使她能够估计遗传的共同遗传性， 慢性阻塞性肺疾病（COPD）和胃食管反流病（GERD）（目的1）。GERD 是COPD中的一种常见合并症，两种疾病都是可遗传的（COPD的遗传遗传力估计值 而GERD高达38%和43%），然而，GERD和COPD的协同遗传度尚未研究。 全基因组关联研究（GWAS）已经确定了与GERD和COPD相关的遗传变异 然而，对于GERD和COPD共病个体而言，缺乏深入的基因组分析。填补 针对这一空白，PI将进行分析，以确定与流行GERD相关的基因组变异和区域 并进行中介分析，以确定多效性在多大程度上有助于共病 GERD和COPD（目标2A和2B）。GERD和COPD之间的相互作用长期以来被认为是 作为GERD一部分的过量胃酸可加重COPD，并且COPD的症状如咳嗽可 为GERD做出贡献。全基因组的遗传力建模、基因组分析和因果中介建模 来自TOPMed、All of Us和英国生物库队列的具有深度表型的测序（WGS）和GWAS数据 将使用最先进的云计算环境进行数据处理。核心假设是 重叠的遗传和/或分子途径导致COPD和GERD的共同病因， 尚未被充分探索。PI研究的长期目标是了解GERD的病因如何 和COPD重叠，为新的干预措施提供机会，并促进药物再利用。UAB是 全国公认的健康科学研究和培训计划，特别是在基因组学和 肺部疾病PI的拟议培训计划由其项目导师Merry-Lynn博士赞助 麦克唐纳和赫曼特·蒂瓦里。培训计划中包括帮助PI在以下方面发展的经验 主要领域：1）在肺部领域进行严格的研究，包括发展COPD和GERD的专业知识 流行病学、科学诚信原则和负责任的研究行为，以及 肺和胃肠道疾病; 2）遗传流行病学，包括先进的方法， 结果的解释; 3）先进的生物统计分析和统计遗传学; 4）职业和专业 5）接触分子生物学和遗传学，以补充“组学 research.培训计划的总体目标是为PI提供一个坚实的基础， 调查COPD和其他肺部疾病中GERD的遗传流行病学。

PROJECT SUMMARY The purpose of this NIH F31 application is to obtain support for the PI, Ava Wilson, for mentored research and career development activities within her PhD training that will strengthen her potential to become an independent research scientist in the pulmonary field. The project goal is to develop skills in genetic epidemiology, bioinformatics, statistical genetics, and pulmonology that will allow her to estimate the genetic co-heritability of Chronic Obstructive Pulmonary Disease (COPD) and Gastroesophageal Reflux Disease (GERD) (Aim 1). GERD is a prevalent comorbidity in COPD and both conditions are heritable (estimates of genetic heritability for COPD and GERD as high as 38% and 43%), however, the co-heritability of GERD and COPD has not been investigated. Genome-wide association studies (GWAS) have identified genetic variants associated with GERD and COPD individually, however, there exists a paucity of in-depth genomic analyses of comorbid GERD and COPD. To fill this gap, the PI will perform analyses to identify genomic variants and regions associated with prevalent GERD in COPD and conduct mediation analysis to determine the extent to which pleiotropy contributes to comorbid GERD and COPD (Aims 2A and 2B). The interaction between GERD and COPD has long been recognized as excess gastric acid as part of GERD can exacerbate COPD and symptoms of COPD such as cough can contribute to GERD. Heritability modeling, genomic analyses and causal mediation modeling of whole genome sequencing (WGS) and GWAS data from TOPMed, All of Us, and the UK Biobank cohorts with deep phenotype data will be performed using state-of-the-art cloud computing environments. The central hypothesis is overlapping genetic and/or molecular pathways contribute to a shared etiology in COPD and GERD, which has not been fully explored. The long-term objective of the PI’s research is to understand how the etiology of GERD and COPD overlap to provide opportunities for novel interventions and to facilitate drug repurposing. UAB is nationally recognized for its health science research and training programs, specifically in genomics and pulmonary disease. The proposed training plan for the PI is sponsored by her project mentors, Drs. Merry-Lynn McDonald and Hemant Tiwari. Included in the training plan are experiences to help the PI develop in the following major areas: 1) rigorous research in the pulmonary field, including developing expertise in COPD and GERD epidemiology, principles of scientific integrity and responsible conduct of research, and scientific expertise in pulmonary and gastrointestinal diseases; 2) genetic epidemiology, including advanced methodology, and interpretation of results; 3) advanced biostatistical analyses and statistical genetics; 4) career and professional development, and data presentation; and 5) exposure to molecular biology and genetics to complement ‘omics research. The overall goal of the training plan is to provide the PI with a solid foundation for continuing to investigate the genetic epidemiology of GERD in COPD and additional pulmonary diseases.