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Genome-wide association study of susceptibility to hospitalised respiratory infections

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

Published on:

September 2, 2024

Abstract

: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. : 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. : From our Stage 1 analysis, we report 56 signals at <5×10 , one of which was genome-wide significant ( <5×10 ). The genome-wide significant signal was in an intron of , 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 in lung tissue, where the respiratory infection risk alleles were associated with decreased 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. : Our Stage 1 analysis implicated as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the 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.

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