Genetic associations and architecture of asthma-chronic obstructive pulmonary disease overlap

Some individuals have characteristics of both asthma and COPD (asthma-COPD overlap, ACO), and evidence suggests they experience worse outcomes than those with either condition alone. Improved knowledge of the genetic architecture would contribute to understanding whether determinants of risk in this group differ from those in COPD or asthma. We conducted a genome-wide association study in 8,068 cases and 40,360 controls of European ancestry from UK Biobank (stage 1). After excluding variants only associated with asthma or COPD we selected 31 variants for further investigation in 12 additional cohorts (stage 2), and discovered eight novel signals for ACO in a meta-analysis of stage 1 and 2 studies. Our signals include an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function, and suggest a spectrum of shared and distinct genetic influences in asthma, COPD and ACO. A number of signals may represent loci that predispose to serious long-term consequences in people with asthma. ### Competing Interest Statement 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-Abello, AztraZeneca, Glaxo Smith Kline, MedImmune, Novartis, Regeneron, Sanofi Genzyme, and TEVA. M.v.d.B. reports grants paid to the University from Astra Zeneca, TEVA, GSK and Chiesi outside the submitted work. D.C.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. ### Funding Statement C.J. holds 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 NIH/NHLBI (5K23HL136851). S.H.C. is funded by NIH/NHLBI (1K01HL153941-01). A.I.H.C. is supported by MITACS accelerate. 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. The 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. The funders had no role in the design of the analyses. Please see the supplementary materials for additional study acknowledgements and funding statements. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The research was conducted using the UK Biobank resource (), under application 648. UK Biobank has Research Ethics Committee (REC) approval (11/NW/0382). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics are available from the authors on request and will be made available via public portals upon publication.