Genome-wide association study of susceptibility to hospitalised respiratory infections
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Published:2023-11-21
Issue:
Volume:6
Page:290
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ISSN:2398-502X
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Container-title:Wellcome Open Research
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language:en
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Short-container-title:Wellcome Open Res
Author:
Williams Alexander T.ORCID, Shrine NickORCID, Naghra-van Gijzel Hardeep, Betts Joanna C., Chen JingORCID, Hessel Edith M., John Catherine, Packer RichardORCID, Reeve Nicola F.ORCID, Yeo Astrid J.ORCID, Abner ErikORCID, Åsvold Bjørn Olav, Auvinen Juha, Bartz Traci M., Bradford Yuki, Brumpton Ben, Campbell ArchieORCID, Cho Michael H.ORCID, Chu Su, Crosslin David R., Feng QiPingORCID, Esko Tõnu, Gharib Sina A., Hayward CarolineORCID, Hebbring Scott, Hveem Kristian, Jarvelin Marjo-Riitta, Jarvik Gail P., Landis Sarah H., Larson Eric B., Liu Jiangyuan, Loos Ruth J.F.ORCID, Luo Yuan, Moscati Arden, Mullerova HanaORCID, Namjou Bahram, Porteous David J.ORCID, Quint Jennifer K.ORCID, Ritchie Marylyn D., Sliz Eeva, Stanaway Ian B., Thomas LaurentORCID, Wilson James F.ORCID, Hall Ian P.ORCID, Wain Louise V.ORCID, Michalovich David, Tobin Martin D.,
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.
Funder
NIHR Nottingham Biomedical Research Centre NIHR Leicester Biomedical Research Centre European Regional Development Fund Scottish Funding Council Arthritis Research UK National Institute of Diabetes and Digestive and Kidney Diseases National Human Genome Research Institute Medical Research Council National Heart, Lung, and Blood Institute Biotechnology and Biological Sciences Research Council National Center for Advancing Translational Sciences Horizon 2020 National Institute on Aging National Institute of Neurological Disorders and Stroke Chief Scientist Office of the Scottish Government Health Directorates EUROSPAN project National Institute for Health and Welfare Regional Institute of Occupational Health Wellcome Trust Estonian Research Council Oulu University Hospital University of Oulu City of Oulu Ministry of Health and Social Affairs
Publisher
F1000 Research Ltd
Subject
General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
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