University of Leicester
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A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease

journal contribution
posted on 2021-09-20, 14:59 authored by 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 Wain, Edwin K Silverman, Michael H Cho, Brian D Hobbs
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.



American Journal of Physiology: Lung Cellular and Molecular Physiology, Volume 321, Issue 1, July 2021, Pages L130-L143

Author affiliation

Department of Health Sciences, University of Leicester


  • AM (Accepted Manuscript)

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American Journal of Physiology: Lung Cellular and Molecular Physiology






L130 - L143


American Physiological Society





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United States