NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene)

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, and the only leading cause of death that is steadily increasing in frequency. This project established a racially diverse cohort that is sufficiently large and appropriately designed for genome-wide association analysis of COPD. A total of 10,720 subjects were recruited, including control smokers and nonsmokers, definite COPD cases (GOLD Stage 2 to 4), and subjects not included in either group (GOLD 1 and PRISm). This cohort is being used for cross-sectional analysis, and long-term longitudinal follow-up visits after five years and after ten years are also being performed. The primary focus of the study is to identify the genetic risk factors that determine susceptibility for COPD and COPD-related phenotypes. Detailed phenotyping of both cases and controls, including chest CT scan assessment of emphysema and airway disease, will allow identification of genetic determinants for the heterogeneous components of the COPD syndrome.

The aims for this study are:
1. Precise phenotypic characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, that will provide data to enable the broad COPD syndrome to be decomposed into clinically significant subtype; 1. Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes; 1. Distinct genetic determinants influence the development of emphysema and airway disease. The TOPMed analysis will include approximately 10,500 subjects with whole genome sequencing after quality control is completed.
Comprehensive phenotypic data for COPDGene subjects is available through dbGaP study [phs000179](study.cgi?study_id=phs000179).

慢性阻塞性肺疾病（Chronic obstructive pulmonary disease, COPD）是美国第四大死亡原因，也是唯一一种发病率持续攀升的主要致死病因。本项目构建了种族构成多元的研究队列，该队列规模充足、设计严谨，可用于慢阻肺的全基因组关联分析。本研究共招募受试者10720名，涵盖对照吸烟者、非吸烟者、确诊慢阻肺患者（GOLD 2至4期，GOLD即全球慢性阻塞性肺疾病倡议（Global Initiative for Chronic Obstructive Lung Disease, GOLD））以及未归入上述两组的受试者（GOLD 1期及隐匿性气道功能障碍（Preserved Ratio Impaired Spirometry, PRISm））。该队列目前已用于横断面分析，同时还在开展5年及10年后的长期纵向随访。本研究的核心目标是明确决定慢阻肺易感性及慢阻肺相关表型的遗传风险因素。对病例组与对照组均开展详细的表型分型，包括通过胸部CT评估肺气肿与气道疾病，此举将助力识别慢阻肺综合征异质性组分的遗传决定因素。

本研究的具体目标如下：
1. 借助计算机断层扫描、临床及生理学指标对慢阻肺受试者开展精准表型分型，所得数据可将宽泛的慢阻肺综合征拆解为具有临床意义的亚型；
2. 开展全基因组关联研究，识别慢阻肺易感性的遗传决定因素，以此深入解析临床相关的慢阻肺亚型；
3. 明确不同遗传决定因素对肺气肿与气道疾病发生发展的影响。质量控制完成后，精准医学跨组学计划（Trans-Omics for Precision Medicine, TOPMed）分析将纳入约10500名完成全基因组测序的受试者。

COPDGene队列受试者的综合表型数据可通过基因型与表型数据库（Database of Genotypes and Phenotypes, dbGaP）的研究条目[phs000179](study.cgi?study_id=phs000179)获取。