Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10 –6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10 –8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.
|Number of pages||12|
|Publication status||Published - May 2022|
Bibliographical noteFunding Information:
FUNDING/SUPPORT: This work is supported by BREATHE , the Health Data Research Hub for Respiratory Health [ MC_PC_19004 ] in partnership with SAIL Databank. BREATHE is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK.
FUNDING/SUPPORT: This work is supported by BREATHE, the Health Data Research Hub for Respiratory Health [MC_PC_19004] in partnership with SAIL Databank. BREATHE is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK.Author contributions: C. J. A. L. G. and M. D. T. act as guarantors for the content of the manuscript. C. J. A. L. G. L. V. W. and M. D. T. contributed to the conception and design of the study. C. J. A. L. G. N. S. T. A. O. J. Liu, L. P. H. S. H. C. J. T. K. J. Luan, X. L. N. T. H. X. T. M. B. H. P. S. L. A. C. A. I. H. C. and M. O. undertook data analysis. C. J. A. L. G. N. S. R. P. S. A. B. M. O. G. T. D. A. M. E. R. B. L. C. S. C. I. Y. T. S. A. G. J. D. G. B. L. L. V. E. O. I. J. J. K. Q. D. D. S. Y. B. M. v. d. B. D. N. I. S. I. P. H. C. L. S. R. T. L. A. C. W. J. L.-S. P. B. A. G. C. P. H. C. H. A. L. B. B. K. S. M. H. C. L. V. W. and M. D. T. contributed to data acquisition and/or interpretation. C. J. A. L. G. L. V. W. and M. D. T. drafted the manuscript. All authors critically reviewed the manuscript before submission. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: C. J. held a Medical Research Council Clinical Research Training Fellowship (MR/P00167X/1). A. L. G. was funded by internal fellowships at the University of Leicester from the Wellcome Trust Institutional Strategic Support Fund (204801/Z/16/Z) and the BHF Accelerator Award (AA/18/3/34220). L. P. H. is funded by the NIH/NHLBI [5K23HL136851]. S. H. C. is funded by the NIH/NHLBI [1K01HL153941-01]. A. I. H. C. is supported by Mitacs Accelerate. C. H. was supported by a Medical Research Council Human Genetics Unit programme grant (U.MC_UU_00007/10). M. H. C. is supported by R01 HL137927, R01 HL089856, and R01 HL147148. L. V. W. holds a GSK/British Lung Foundation Chair in Respiratory Research. M. D. T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M. D. T. and L. V. W. have been supported by the MRC (MR/N011317/1). M. D. T. and I. P. H. hold NIHR Senior Investigator Awards. This research was partially supported by the NIHR Leicester Biomedical Research Centre and the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. C. J. and M. D. T. were involved in all stages of study development and delivery, and M. D. T. had full access to all data in the study and final responsibility for the decision to submit for publication. This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Please see e-Appendix 1 for additional study acknowledgments and funding statements. T. A. O. G. T. I. J. and K. S. are employees of deCODE Genetics/Amgen Inc. E. R. B. has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Novartis, Regeneron, and Sanofi Genzyme. E. R. B. has also served as a paid consultant for ALK-Abelló, AstraZeneca, GlaxoSmithKline (GSK), MedImmune, Novartis, Regeneron, Sanofi Genzyme, and TEVA. M. v. d. B. reports grants paid to the University from AstraZeneca, Teva, GSK, and Chiesi outside the submitted work. D. N. has been a Merck & Co. employee during this study and is now an employee at Biogen Inc. I. S. has received support from GSK and Boehringer Ingelheim. I. P. H. has funded research collaborations with GSK, Boehringer Ingelheim, and Orion. M. H. C. has received grant support from GSK and Bayer, and consulting and speaking fees from Genentech, Illumina, and AstraZeneca. L. V. W. receives funding from GSK for a collaborative research project outside of the submitted work. M. D. T. receives funding from GSK and Orion for collaborative research projects outside of the submitted work. Role of sponsors: The funders had no role in the design of the analyses or conduct of the study. Data sharing statement: Individual-level participant data are from UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access; accessed February 18, 2022). Summary-level genome-wide association statistics will be made publicly available via the EBI GWAS catalog on publication (https://www.ebi.ac.uk/gwas/; accessed February 18, 2022). Additional information: The e-Appendix, e-Figures, and e-Tables are available online under “Supplementary Data.”
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