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. We followed-up well-imputed top signals from the UK Biobank discovery analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts. 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: In the discovery 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 the 11 follow-up cohorts. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our discovery 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 when aggregating effect estimates across 11 independent cohorts. 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.
Highlights
Respiratory infections are a group of diseases characterised by infection and inflammation of the respiratory system
Discovery analysis in UK Biobank Cases were defined by the presence of one or more of the relevant hospitalised respiratory infection (HRI) ICD-10 codes (Table S1, Extended data12) in the linked Hospital Episode Statistics (HES) data over a 20-year period— from the inception of ICD-10 coding in the UK to the end of the period covered by the version of the HES data we analysed
In our UK Biobank discovery analysis, the strongest association signal was in an intron of the PBX3 gene, which encodes the pre-B-cell transcription factor 3 protein
Summary
Respiratory infections are a group of diseases characterised by infection and inflammation of the respiratory system. In 2016, over two million deaths worldwide were caused by lower respiratory tract infections, making this group of infectious diseases the sixth leading cause of death in individuals of all ages and the leading cause of death in very young children[3,4]. Environmental exposures, such as indoor air pollution and inhalation of tobacco smoke, are important risk factors for upper and lower respiratory tract infections[4]. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical article can be found at the end of the article
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