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.
| Original language | English |
|---|---|
| Pages (from-to) | L130-L143 |
| Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
| Volume | 321 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 7 Jul 2021 |
Bibliographical note
Funding Information:This work was supported by Grant T32HL007427 (to M.M.); NIH Grants K08HL136928 and R01 HL089856 (to B.D.H.); NIH Grants R01HL137927 and R01HL135142 (to M.H.C.); NIH Grants R01 HL137927, R01 HL147148, R01 HL133135, and P01 HL114501 (to E.K.S.); Wellcome Trust Investigator Award WT202849/Z/16/Z (to M.D.T); and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Grant ZO1 ES43012 to (S.J.L.). The research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health. L.V.W. holds a GSK/British Lung Foundation Chair in Respiratory Research (C17-1). I.P.H. holds an NIHR Senior Investigator Award.
Funding Information:
E.K.S. received grant support from GlaxoSmithKline and Bayer. M.H.C. has received grant support from GlaxoSmithKline and Bayer, consulting fees from Genentech and AstraZeneca, and speaking fees from Illumina. M.D.T. receives grant support from GlaxoSmithKline and Orion. L.V.W. received grant support from GlaxoSmithKline and Orion. I.P.H. has received grant support from GlaxoSmithKline and Orion. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.
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