Wellcome Open Research (Nov 2023)
Genome-wide association study of susceptibility to hospitalised respiratory infections [version 2; peer review: 1 approved, 2 approved with reservations]
- Sina A. Gharib,
- Louise V. Wain,
- Tõnu Esko,
- Gail P. Jarvik,
- Scott Hebbring,
- Eric B. Larson,
- Sarah H. Landis,
- Ruth J.F. Loos,
- Jiangyuan Liu,
- Caroline Hayward,
- Arden Moscati,
- Yuan Luo,
- Bahram Namjou,
- Hana Mullerova,
- Marjo-Riitta Järvelin,
- Jennifer K. Quint,
- Eeva Sliz,
- Marylyn D. Ritchie,
- Laurent Thomas,
- Ian B. Stanaway,
- Kristian Hveem,
- David Michalovich,
- Ian P. Hall,
- James F. Wilson,
- Jing Chen,
- Alexander T. Williams,
- Martin D. Tobin,
- Joanna C. Betts,
- Hardeep Naghra-van Gijzel,
- Richard Packer,
- Edith M. Hessel,
- Astrid J. Yeo,
- Nicola F. Reeve,
- Bjørn Olav Åsvold,
- Erik Abner,
- Archie Campbell,
- Traci M. Bartz,
- Juha Auvinen,
- Catherine John,
- Ben Brumpton,
- Yuki Bradford,
- Su Chu,
- David J. Porteous,
- Nick Shrine,
- Michael H. Cho,
- QiPing Feng,
- David R. Crosslin
Affiliations
- Sina A. Gharib
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA
- Louise V. Wain
- ORCiD
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Tõnu Esko
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Riia 23b, 51010, Estonia
- Gail P. Jarvik
- University of Washington, School of Medicine, Seattle, Washington, USA
- Scott Hebbring
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, Wisconsin, USA
- Eric B. Larson
- University of Washington, School of Medicine, Seattle, Washington, USA
- Sarah H. Landis
- R&D, GSK, Stockley Park, UK
- Ruth J.F. Loos
- ORCiD
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Jiangyuan Liu
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Caroline Hayward
- ORCiD
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Arden Moscati
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Yuan Luo
- Department of Preventive Medicine, Northwestern University, Chicago, Illinois, USA
- Bahram Namjou
- Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Hana Mullerova
- ORCiD
- R&D, GSK, Stockley Park, UK
- Marjo-Riitta Järvelin
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
- Jennifer K. Quint
- ORCiD
- National Heart and Lung Institute, Imperial College London, London, UK
- Eeva Sliz
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
- Marylyn D. Ritchie
- Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Laurent Thomas
- ORCiD
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Ian B. Stanaway
- University of Washington, School of Medicine, Seattle, Washington, USA
- Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- David Michalovich
- R&D, GSK, Stevenage, UK
- Ian P. Hall
- ORCiD
- Division of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
- James F. Wilson
- ORCiD
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Jing Chen
- ORCiD
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Alexander T. Williams
- ORCiD
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Martin D. Tobin
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Joanna C. Betts
- R&D, GSK, Stevenage, UK
- Hardeep Naghra-van Gijzel
- R&D, GSK, Stevenage, UK
- Richard Packer
- ORCiD
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Edith M. Hessel
- R&D, GSK, Stevenage, UK
- Astrid J. Yeo
- ORCiD
- R&D, GSK, Stevenage, UK
- Nicola F. Reeve
- ORCiD
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Bjørn Olav Åsvold
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Erik Abner
- ORCiD
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Riia 23b, 51010, Estonia
- Archie Campbell
- ORCiD
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Traci M. Bartz
- Department of Biostatistics, University of Washington, Seattle, Washington, USA
- Juha Auvinen
- Medical Research Center Oulu, Oulu University Hospital, Center for Life Course Health Research, University of Oulu, Oulu, Finland
- Catherine John
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Ben Brumpton
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Yuki Bradford
- Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Su Chu
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
- David J. Porteous
- ORCiD
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Nick Shrine
- ORCiD
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Michael H. Cho
- ORCiD
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
- QiPing Feng
- ORCiD
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- David R. Crosslin
- University of Washington, School of Medicine, Seattle, Washington, USA
- Journal volume & issue
-
Vol. 6
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.
