Genome-wide association study of susceptibility to hospitalised respiratory infections

<ns3:p><ns3:bold>Background</ns3:bold>: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood.</ns3:p><ns3:p> <ns3:bold>Methods</ns3:bold>: 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.</ns3:p><ns3:p> <ns3:bold>Results</ns3:bold>: In the discovery analysis, we report 56 signals at <ns3:italic>P</ns3:italic>&lt;5<ns3:italic>×</ns3:italic>10<ns3:sup>-6</ns3:sup>, one of which was genome-wide significant (<ns3:italic>P</ns3:italic>&lt;5<ns3:italic>×</ns3:italic>10<ns3:sup>-8</ns3:sup>). The genome-wide significant signal was in an intron of <ns3:italic>PBX3</ns3:italic>, 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 <ns3:italic>PBX3</ns3:italic> in lung tissue, where the respiratory infection risk alleles were associated with decreased <ns3:italic>PBX3</ns3:italic> 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.</ns3:p><ns3:p> <ns3:bold>Conclusions</ns3:bold>: Our discovery analysis implicated <ns3:italic>PBX3</ns3:italic> as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the <ns3:italic>PBX3</ns3:italic> 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.</ns3:p>