A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease
Year: 2021
Type: article
Study design: Observational Study
Abstract: Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant ( P < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B ( GSDMB) splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, P = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 ( CCHCR1), a gene involved in regulating cell proliferation, were associated with COPD (both P < 0.0001). The SERPINA1 Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17–1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.
Authors: Matthew Moll, Victoria E. Jackson, Bing Yu, Megan L. Grove, Stephanie J. London, Sina A. Gharib, Traci M. Bartz, Colleen M. Sitlani, Josée Dupuis, George T. O’Connor, Hanfei Xu, Patricia A. Cassano, Bonnie Kaufmann Patchen, Woo Jin Kim, Jinkyeong Park, Kun Hee Kim, Buhm Han, R. Graham Barr, Ani Manichaikul, Jennifer N. Nguyen, Stephen S. Rich, Lies Lahousse, Natalie Terzikhan, Guy Brusselle, Phuwanat Sakornsakolpat, Jiangyuan Liu, Christopher J. Benway, Ian P. Hall, Martin D. Tobin, Louise V. Wain, Edwin K. Silverman, Michael H. Cho, Brian D. Hobbs
Institutions: Brigham and Women's Hospital, University of Leicester, The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, The University of Texas Health Science Center at Houston, National Institutes of Health, National Institute of Environmental Health Sciences, University of Washington, Boston University, Boston Medical Center, Cornell University, Weill Cornell Medicine, Kangwon National University, Dongguk University Ilsan Hospital, Asan Medical Center, University of Ulsan, Seoul National University, Columbia University Irving Medical Center, University of Virginia, Erasmus MC, Ghent University, Siriraj Hospital, Mahidol University, Queen's Medical Centre, Nottingham Biomedical Research Centre, Glenfield Hospital, National Institute for Health and Care Research, Harvard University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: AstraZeneca, GlaxoSmithKline, Wellcome Trust, National Institute for Health and Care Research, British Lung Foundation, National Institutes of Health, Genentech, NIHR Imperial Biomedical Research Centre, NIHR Leicester Biomedical Research Centre, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences
Awards: G2292322124, Identifying functional variants in COPD GWAS loci, G3217600862, Genetic and Functional Dissection of a Cluster of COPD GWAS Signals on Chromosome 4q, G3851224574, (2 of 2) Genetic Epidemiology of COPD, G485517832, (1 of 2) Genetic Epidemiology of COPD, G5790931794, Multi-omic Subtyping of Chronic Obstructive Pulmonary Disease, G5957994314, (1 of 2) Genetic Epidemiology of COPD, G7531143628, G7732978665, G8728689340, G9000218965, G9000228787, Genetic And Environmental Factors In Adult Respiratory and Cardiac Disease, G9000296006, NUTRITION TRAINING, COPD Susceptibility, Heterogeneity, and Progression: Proteomics and Genetics, Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers, SYSTEMS APPROACHES TO THE EPIDEMIOLOGY, GENETICS AND GENOMICS OF LUNG DISEASES, Genetic and Genomic Characterization of the Occurrence and Progression of Interstitial Lung Abnormalities
OpenAlex ID: W3157898909