A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease
| Autor: | Josée Dupuis, Victoria E. Jackson, Hanfei Xu, Brian D. Hobbs, Edwin K. Silverman, Michael H. Cho, Megan L. Grove, Jennifer N. Nguyen, Jiangyuan Liu, George T. O'Connor, Natalie Terzikhan, Ani Manichaikul, Patricia A. Cassano, Colleen M. Sitlani, Buhm Han, Ian P. Hall, Bing Yu, Sina A. Gharib, Lies Lahousse, Louise V. Wain, Traci M. Bartz, Christopher J. Benway, R. Graham Barr, Phuwanat Sakornsakolpat, Guy Brusselle, Stephanie J. London, Kun Hee Kim, Martin D. Tobin, Matthew Moll, Jinkyeong Park, Woo Jin Kim, Bonnie K Patchen, Stephen S. Rich |
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| Přispěvatelé: | Epidemiology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Nonsynonymous substitution Pulmonary and Respiratory Medicine EXPRESSION Genetic Markers Physiology Genome-wide association study Biology Polymorphism Single Nucleotide chronic obstructive pulmonary disease GENETIC ASSOCIATION 03 medical and health sciences Pulmonary Disease Chronic Obstructive 0302 clinical medicine DESIGN Meta-Analysis as Topic Physiology (medical) Medicine and Health Sciences genomics COPD Humans Exome Genetic Predisposition to Disease exon Allele GENOME-WIDE ASSOCIATION Genotyping Genetic association Genetics ZINC-FINGER PROTEIN Odds ratio Cell Biology GENOTYPE Minor allele frequency LUNG-FUNCTION functional 030104 developmental biology 030228 respiratory system ATHEROSCLEROSIS Gene Expression Regulation SMOKING exome Genome-Wide Association Study Research Article |
| Zdroj: | Am J Physiol Lung Cell Mol Physiol AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY American Journal of Physiology-Lung Cellular and Molecular Physiology, 321(1), L130-L143. American Physiological Society |
| ISSN: | 1522-1504 1040-0605 1107-8928 |
| DOI: | 10.1152/AJPLUNG.00009.2021 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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