Genome-wide association study of susceptibility to hospitalised respiratory infections

Alexander T Williams; Nick Shrine; Hardeep Naghra-van Gijzel; Joanna C Betts; Jing Chen; Edith M Hessel; Catherine John; Richard Packer; Nicola F Reeve; Astrid J Yeo; Erik Abner; Bjørn Olav Åsvold; Juha Auvinen; Traci M Bartz; Yuki Bradford; Ben Brumpton; Archie Campbell; Michael H Cho; Su Chu; David R Crosslin; QiPing Feng; Tõnu Esko; Sina A Gharib; Caroline Hayward; Scott Hebbring; Kristian Hveem; Marjo-Riitta Järvelin; Gail P Jarvik; Sarah H Landis; Eric B Larson; Jiangyuan Liu; Ruth J F Loos; Yuan Luo; Arden Moscati; Hana Mullerova; Bahram Namjou; David J Porteous; Jennifer K Quint; Regeneron Genomics Center; Marylyn D Ritchie; Eeva Sliz; Ian B Stanaway; Laurent Thomas; James F Wilson; Ian P Hall; Louise V Wain; David Michalovich; Martin D Tobin

doi:10.12688/wellcomeopenres.17230.2

Genome-wide association study of susceptibility to hospitalised respiratory infections

Wellcome Open Res. 2023 Nov 21:6:290. doi: 10.12688/wellcomeopenres.17230.2. eCollection 2021.

Authors

Alexander T Williams¹, Nick Shrine¹, Hardeep Naghra-van Gijzel², Joanna C Betts², Jing Chen¹, Edith M Hessel², Catherine John¹, Richard Packer¹, Nicola F Reeve¹, Astrid J Yeo², Erik Abner³, Bjørn Olav Åsvold^{4

5

6}, Juha Auvinen⁷, Traci M Bartz^{8

9}, Yuki Bradford¹⁰, Ben Brumpton^{4

5

11}, Archie Campbell¹², Michael H Cho¹³, Su Chu¹³, David R Crosslin¹⁴, QiPing Feng¹⁵, Tõnu Esko³, Sina A Gharib^{9

16}, Caroline Hayward¹⁷, Scott Hebbring¹⁸, Kristian Hveem^{4

5}, Marjo-Riitta Järvelin^{19

20

21

22

23}, Gail P Jarvik¹⁴, Sarah H Landis²⁴, Eric B Larson^{14

25}, Jiangyuan Liu¹³, Ruth J F Loos²⁶, Yuan Luo²⁷, Arden Moscati²⁶, Hana Mullerova²⁴, Bahram Namjou²⁸, David J Porteous¹², Jennifer K Quint²⁹; Regeneron Genomics Center; Marylyn D Ritchie¹⁰, Eeva Sliz^{19

20

30}, Ian B Stanaway¹⁴, Laurent Thomas^{4

31

32

33}, James F Wilson^{17

34}, Ian P Hall³⁵, Louise V Wain^{1

36}, David Michalovich², Martin D Tobin^{1

36}

Affiliations

¹ Department of Population Health Sciences, University of Leicester, Leicester, UK.
² R&D, GSK, Stevenage, UK.
³ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Riia 23b, 51010, Estonia.
⁴ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁵ HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, Levanger, Norway.
⁶ Department of Endocrinology, Clinic of Medicine, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
⁷ Medical Research Center Oulu, Oulu University Hospital, Center for Life Course Health Research, University of Oulu, Oulu, Finland.
⁸ Department of Biostatistics, University of Washington, Seattle, Washington, USA.
⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁰ Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹¹ Clinic of Thoracic and Occupational Medicine, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
¹² Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹³ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁴ University of Washington, School of Medicine, Seattle, Washington, USA.
¹⁵ Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁶ Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁷ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹⁸ Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, Wisconsin, USA.
¹⁹ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
²⁰ Biocenter Oulu, University of Oulu, Oulu, Finland.
²¹ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
²² Department of Epidemiology and Biostatistics, School of Public Health, MRC Centre for Environment and Health, Imperial College London, London, UK.
²³ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.
²⁴ R&D, GSK, Stockley Park, UK.
²⁵ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
²⁶ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁷ Department of Preventive Medicine, Northwestern University, Chicago, Illinois, USA.
²⁸ Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
²⁹ National Heart and Lung Institute, Imperial College London, London, UK.
³⁰ Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
³¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
³² BioCore - Bioinformatics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway.
³³ Clinic of Laboratory Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
³⁴ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
³⁵ Division of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK.
³⁶ National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

Abstract

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank (Stage 1). We followed-up well-imputed top signals from our Stage 1 analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts (Stage 2). We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: From our Stage 1 analysis, we report 56 signals at P<5×10 ^-6, one of which was genome-wide significant ( P<5×10 ^-8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in Stage 2. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our Stage 1 analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate in the meta-analysis of Stages 1 and 2. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

Keywords: GWAS; Respiratory infections; UK Biobank; electronic medical records.

Associated data

figshare/10.6084/m9.figshare.16622062

Grants and funding

This research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. ATW was supported by a BBSRC industrial CASE studentship between the University of Leicester and GlaxoSmithKline. AY, DM, IPH, JB, LVW and MDT lead a research collaboration between the Universities of Leicester and Nottingham, and GlaxoSmithKline. IPH has been partially supported by the NIHR Nottingham Biomedical Research Centre. LVW holds a GSK/British Lung Foundation Chair in Respiratory Research. MDT was supported by a Wellcome Trust Investigator Award [202849, https://doi.org/10.35802/202849] and an NIHR Senior Investigator Award (NIHR201371). LVW and MDT have been supported by the Medical Research Council (MRC) (MR/N011317/1). CJ holds a Medical Research Council Clinical Research Training Fellowship (MR/P00167X/1). This work was supported by BREATHE - The Health Data Research Hub for Respiratory Health [MC_PC_19004] in partnership with the SAIL Databank. BREATHE is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. This work used data provided by patients and collected by the NHS as part of their care and support. CH was supported by an MRC Human Genetics Unit programme grant ‘Quantitative traits in health and disease’ (U. MC_UU_00007/10). MHC was supported by NHLBI R01HL135142, R01HL137927, R01HL089856, R01HL147148. SC was supported by NHLBI K01HL153941. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200960009C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This phase of the eMERGE Network was initiated and funded by the NHGRI through the following grants: U01HG008657 (Kaiser Permanente Washington/University of Washington); U01HG008685 (Brigham and Women’s Hospital); U01HG008672 (Vanderbilt University Medical Center); U01HG008666 (Cincinnati Children’s Hospital Medical Center); U01HG006379 (Mayo Clinic); U01HG008679 (Geisinger Clinic); U01HG008680 (Columbia University Health Sciences); U01HG008684 (Children’s Hospital of Philadelphia); U01HG008673 (Northwestern University); U01HG008701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG008676 (Partners Healthcare/Broad Institute); U01HG008664 (Baylor College of Medicine); and U54MD007593 (Meharry Medical College). The work of Estonian Genome Center, University of Tartu has been supported by the European Regional Development Fund and grants no. GENTRANSMED (2014-2020.4.01.15-0012), MOBERA5 (Norface Network project no 462.16.107) and 2014-2020.4.01.16-0125. This study was also funded by the European Union through Horizon 2020 research and innovation programme under grant no. 810645 and through the European Regional Development Fund project no. MOBEC008 and Estonian Research Council Grants PRG1291 and PUT1660. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767, https://doi.org/10.35802/216767]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) [104036, https://doi.org/10.35802/104036]). The NFBC1966 follow-up studies were supported by the University of Oulu (Grants no. 65354, 24000692), Oulu University Hospital (Grants no. 2/97, 8/97, 24301140), National research funding via City of Oulu, Ministry of Health and Social Affairs (Grants no. 23/251/97, 160/97, 190/97), National Institute for Health and Welfare, Helsinki (Grant no. 54121), Regional Institute of Occupational Health, Oulu, Finland (Grants no. 50621, 54231), and ERDF European Regional Development Fund (Grant no. 539/2010 A31592). The research on NFBC1966 data has been supported in part by H2020-633595 DynaHealth, H2020-733206 LifeCycle, H2020-824989 EUCANCONNECT, H2020-873749 LongITools, H2020-848158 EarlyCause, the JPI HDHL, PREcisE project, and ZonMw the Netherlands no. P75416. The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), a Royal Society URF to J.F.W., the MRC Human Genetics Unit quinquennial programme “QTL in Health and Disease”, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). The Viking Health Study – Shetland (VIKING) was supported by the MRC Human Genetics Unit quinquennial programme grant “QTL in Health and Disease”. J.F.W. acknowledges support from the MRC Human Genetics Unit programme grant, “Quantitative traits in health and disease” (U. MC_UU_00007/10).