Publication: A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease
Issued Date
2021-07-01
Resource Type
ISSN
15221504
10400605
10400605
Other identifier(s)
2-s2.0-85111160817
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
American Journal of Physiology - Lung Cellular and Molecular Physiology. Vol.321, No.1 (2021), L130-L143
Suggested Citation
Matthew Moll, Victoria E. Jackson, Bing Yu, Megan L. Grove, Stephanie J. London, Sina A. Gharib, Traci M. Bartz, Colleen M. Sitlani, Josee 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 A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease. American Journal of Physiology - Lung Cellular and Molecular Physiology. Vol.321, No.1 (2021), L130-L143. doi:10.1152/AJPLUNG.00009.2021 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/76115
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Title
A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease
Author(s)
Matthew Moll
Victoria E. Jackson
Bing Yu
Megan L. Grove
Stephanie J. London
Sina A. Gharib
Traci M. Bartz
Colleen M. Sitlani
Josee 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
Victoria E. Jackson
Bing Yu
Megan L. Grove
Stephanie J. London
Sina A. Gharib
Traci M. Bartz
Colleen M. Sitlani
Josee 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
Other Contributor(s)
Siriraj Hospital
Dongguk University Ilsan Hospital
Universiteit Gent
University of Leicester
Erasmus MC
University of Virginia School of Medicine
Queen's Medical Centre
National Institute of Environmental Health Sciences (NIEHS)
University of Washington School of Medicine
Columbia University Irving Medical Center
Walter and Eliza Hall Institute of Medical Research
University of Melbourne
School of Public Health
Brigham and Women's Hospital
University of Washington
University of Texas School of Public Health
Glenfield Hospital
Weill Cornell Medicine
Cornell University
University of Ulsan College of Medicine
Boston Medical Center
Harvard Medical School
Kangwon National University
Seoul National University College of Medicine
Dongguk University Ilsan Hospital
Universiteit Gent
University of Leicester
Erasmus MC
University of Virginia School of Medicine
Queen's Medical Centre
National Institute of Environmental Health Sciences (NIEHS)
University of Washington School of Medicine
Columbia University Irving Medical Center
Walter and Eliza Hall Institute of Medical Research
University of Melbourne
School of Public Health
Brigham and Women's Hospital
University of Washington
University of Texas School of Public Health
Glenfield Hospital
Weill Cornell Medicine
Cornell University
University of Ulsan College of Medicine
Boston Medical Center
Harvard Medical School
Kangwon National University
Seoul National University College of Medicine
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 a-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.