![]() The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children. In doing so, we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. Using these data, we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. We construct a joint dataset including 1445 bacteraemia cases and 1143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Here, we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with Plasmodium falciparum parasitaemia. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. Invasive bacterial disease is a major cause of morbidity and mortality in African children. Institute for Global Health Innovation, Department of Surgery and Cancer, Imperial College, United Kingdom.Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, United Kingdom.Division of Medicine, Imperial College, United Kingdom.The Jenner Institute, University of Oxford, United Kingdom. ![]() Wellcome Sanger Institute, United Kingdom.Institute of Computer Science, University of Tartu, Estonia. ![]()
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