NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene)

This study is part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Program. TOPMed is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole-genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program aims to uncover factors that increase or decrease the risk of disease, to identify subtypes of disease, and to develop more targeted and personalized treatments. Two genotype call sets derived from WGS are now available, Freeze 5b (GRCh38) and Freeze 8 (GRCh38), with largely overlapping sample sets. Information about how to identify other TOPMed WGS accessions for cross-study analysis, as well as descriptions of TOPMed methods of data acquisition, data processing and quality control, are provided in the accompanying documents, "TOPMed Whole Genome Sequencing Project - Freeze 5b, Phases 1 and 2" and "TOPMed Whole Genome Sequencing Project - Freeze 8, Phases 1-4". Please check the study list at the top of each of these methods documents to determine whether it applies to this study accession.

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;
2. Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes;
3. 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 Weblinks:
  • COPDGene
  • phs000179
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 10623
• Subject Sample Telemetry Report (SSTR)

COPD Cases:

Inclusion Criteria

• Age at Enrollment: 45 - 80 years
• Smoking history of ≥ 10 pack-years
• Diagnosis of COPD Stages 2, 3 and 4 by GOLD criteria (post-bronchodilator FEV1/FVC < 0.70 and FEV1 < 80% predicted)
• Non-Hispanic White or non-Hispanic African American

Exclusion Criteria

• Concomitant respiratory disorder other than asthma or COPD (such as, but not limited to, diffuse bronchiectasis, cystic fibrosis, or interstitial lung disease)
• Lung surgery with removal of a lobe or more (including lung volume reduction surgery or lung transplantation)
• Lung cancer, known or suspected
• Surgical or bronchoscopic lung volume reduction
• Pregnancy or suspected pregnancy
• Uncontrolled cancer, defined as ongoing radiation therapy, ongoing chemotherapy, narcotics for pain control, or known metastatic disease
• History of radiation therapy to the chest (other than for breast cancer)
• Use of antibiotics and/or systemic steroids (new prescription or increased dose) for a COPD exacerbation or respiratory infection within the last month
• Inability to use albuterol
• First or second degree relative (parent, brother, sister, daughter, son, aunt, uncle, nephew, niece, half-sibling, grandparent, grandchild) of a subject enrolled in COPDGene
• Subjects who indicate they are in more than one racial category
• Metal objects that may interfere with chest CT quantification including presence of a cardiac pacemaker, defibrillator, metal prosthetic heart valve, or metal shoulder prosthesis
• Subjects with affirmative answers to the following:
  • chest or abdominal surgery in the past three months
  • a heart attack in the last three months
  • detached retina or eye surgery in the past three months
  • hospitalization for any other heart problem in the past month
• Participation in the ECLIPSE study, Boston Early-Onset COPD Study, or International COPD Genetics Network (Selected replication cohorts)

Smokers without COPD:

Inclusion Criteria

• Age at Enrollment: 45 - 80 years
• History (current or former) of cigarette smoking ≥ 10 pack-years
• Post-bronchodilator FEV1/FVC ≥ 0.70 and FEV1 ≥ 80% predicted
• Non-Hispanic White or non-Hispanic African American

Exclusion Criteria

• Physician diagnosed respiratory disease other than COPD or asthma (based on subject report)
• Lung surgery with removal of a lobe or more (including lung volume reduction surgery and lung transplantation)
• Pregnancy or suspected pregnancy
• Lung cancer, known or suspected
• Uncontrolled cancer, defined as ongoing radiation therapy, ongoing chemotherapy, narcotics for pain control, or known metastatic disease
• History of radiation therapy to the chest
• Use of antibiotics (new prescription or increased dose) for a respiratory infection within the past month
• Use of systemic corticosteroids (new prescription or increased dose) for a respiratory process within the past month
• Inability to use albuterol
• First or second degree relative (parent, brother, sister, daughter, son, aunt, uncle, nephew, niece, half-sibling, grandparent, or grandchild) of a subject enrolled in COPDGene
• Subjects who indicate they are in more than one racial category
• Metal objects that may interfere with chest CT quantification including presence of a cardiac pacemaker, defibrillator, metal prosthetic heart valve, or metal shoulder prosthesis
• Subjects with affirmative answers to the following:
  • chest or abdominal surgery in the past three months
  • a heart attack in the last three months
  • detached retina or eye surgery in the past three months
  • hospitalization for any other heart problem in the past month
• Participation in the ECLIPSE study, Boston Early-Onset COPD Study, or International COPD Genetics Network (Selected replication cohorts)

Note that similar enrollment criteria were utilized for lifelong nonsmoking control subjects.

The COPDGene Study was funded by the NHLBI in October 2007 as two U01 grants-one to National Jewish Medical and Research Center (PI: James D. Crapo) and one to Brigham and Women's Hospital (PI: Edwin K. Silverman). After a pilot study in 2007, study recruitment began in February 2008 at 21 clinical centers throughout the United States. In 2012, the NHLBI funded longitudinal assessment of the COPDGene cohort and additional genetic analysis through paired R01 grants. In 2017, the COPDGene project was refunded as two U01 grants to support further longitudinal follow-up.

• Primary Phenotype: Pulmonary Disease, Chronic Obstructive
• Emphysema

• Principal Investigators
  • James D. Crapo. National Jewish Health, Denver, CO, USA.
  • Edwin K. Silverman. Brigham and Women's Hospital Boston, MA, USA.
• Institute
  • National Heart, Lung and Blood Institute, Bethesda, MD, USA.
• Funding Source
  • U01 HL089897. National Institutes of Health, Bethesda, MD, USA.
  • U01 HL089856. National Institutes of Health, Bethesda, MD, USA.