Chronic Obstructive Pulmonary Disease
Whole Genome Sequence Analysis of Pulmonary Function and COPD in >16,000 Multi-ethnic Participants of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program Identifies New Associated Loci
| Submitted by | Manichaikul, Ani
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| Authors | Ani Manichaikul, Center for Public Health Genomics, University of Virginia
Xutong Zhao, Department of Biostatistics, University of Michigan Dandi Qiao, Department of Medicine, Brigham and Women’s Hospital Chaojie Yang, Center for Public Health Genomics, University of Virginia Jennifer N Nguyen, Center for Public Health Genomics, University of Virginia Phuwanat Sakornsakolpat, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Dmitry Prokopenko, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Elizabeth C Oelsner, Department of Medicine, Columbia University Pallavi Balte, Department of Medicine, Columbia University Bing Yu, Department of Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health Leslie Lange, Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine Anschutz Medical Campus Stephanie London, Epidemiology Branch, National Institute of Environmental Health Sciences Josée Dupuis, Department of Biostatistics, Boston University School of Public Health George O’Connor, Department of Medicine, Boston University School of Medicine Robert Reed, Department of Medicine, University of Maryland Brian Cade, Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women’s Hospital Sina Gharib, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington Michelle Daya, Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine Anschutz Medical Campus Bruce Psaty, Departments of Epidemiology and Medicine, University of Washington Susan Redline, Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women’s Hospital Kathleen Barnes, Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine Anschutz Medical Campus Stephen S Rich, Center for Public Health Genomics, University of Virginia Goncalo Abecasis, Department of Biostatistics, University of Michigan Edwin K Silverman, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School R Graham Barr, Department of Medicine, Columbia University Michael H Cho, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School On behalf of the TOPMed PFT, COPD and Lung Working Groups |
| Name and Date of Professional Meeting | American Society of Human Genetics (October 16-20, 2018)
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| Abstract Text |
Chronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States, is diagnosed by a decrease in lung function, namely forced expiratory volume in one second (FEV1) and its ratio to forced vital capacity (FEV1/FVC). Genome-wide association studies (GWAS) of lung function and COPD have already identified over 100 loci associated with one or more of these measures and conditions. We performed whole genome sequence (WGS) analysis of lung function traits (FEV1, FEV1/FVC and FVC) and COPD in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program to examine evidence for rare and/or common trait-associated variants that were not identified in previous GWAS. WGS had deep (~30X) coverage with joint-sample variant calling and comprehensive variant level quality control in >50,000 TOPMed samples (freeze 5b). Lung function measures and COPD were analyzed in a subset of 8,332 subjects from four population-based and two family-based studies, as well as 8,471 individuals from the COPD-ascertained COPDGene study. These samples included 4,232 moderate-to-severe COPD cases out of which 1,644 had severe COPD. We conducted analyses across all race/ethnic groups, in addition to stratified analyses in Whites (n=11,667) and African Americans (n=3,912) only. After removing variants with Minor Allele Count (MAC) < 30, single variant quantitative trait analysis of population- and family-based samples identified novel associations with FVC in Whites near GALR1 (minor allele frequency [MAF]=0.39; P=3x10-8) and with FEV1 in African Americans near LGALS8 (MAF=0.04; P=1.5x10-8). In combined analysis across population-based and COPD-ascertained samples, we identified novel loci for FEV1/FVC near ZNF462 (MAF=0.39; P=3.2x10-8) in pooled analysis of all race/ethnic groups, and for FEV1 near GALNT18 (MAF=0.30; P=4.3x10-8) and FVC near CMIP (MAF=0.13; P=1.3x10-8) in stratified analysis of African Americans. We further identified a novel association for moderate-to-severe COPD in pooled analysis of all race/ethnic groups near GRK7 (MAF=0.006; P=3.4x10-8). Replication of these findings will be needed. Our study thus identified multiple novel signals for lung function in African Americans and multi-ethnic samples, demonstrating the benefits of dense coverage across the genome by WGS.
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