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  1. Author Response

    Reviewer #3 (Public Review):

    This manuscript describes host genetic data of several cohorts of Kenyan children with culture proven bacteremia, severe malaria, and controls, and the association with bacteraemia. We know that many children with severe malaria actually have a bacterial co-infection. Because it is difficult to get the numbers needed for such GWAS studies, the authors plus up their numbers by lumping together bacteremia and severe malaria cases - the latter in a weighted manner for the continuum of malaria and bacteraemia. In the next step they validate their findings in a new cohort of 434 bacteraemia cases and present functional studies in monocytes. The methods used are interesting and the data are valid. Findings are important. I am not an expert in statistics, so I cannot judge the statistical methods in detail, but they seemed to be valid.

    Very many thanks.

    I have a few major points.

    1. Overview of cohorts - overview. A graphical overview of cohort could be helpful for the reader- including groups, comparisons, and time periods of collection.

    We have added a new Figure 2 setting out recruitment to the study over time.

    1. Overview of cohorts - phenotypes. The datasets used have been published previously with clinical phenotypes in more detail. Would it be possible to include a supplementary table providing these clinical phenotypes per group? In how many patients in the severe malaria group cultures were performed?

    We now provide additional clinical information in an extended Table 2. All children included in the study with severe malaria had a blood culture taken at admission (this is now stated in the footnotes to Table 2).

    1. The potential impact of the prevalence of Pf HRP2 gene deletions on the analysis is probably limited because the cohort was collected in the period 1995-2008; this should be mentioned.

    As you suggest, the relevance to our data is likely to be limited. We now discuss how this may limit translatability of PfHRP2-based models for similar studies in other settings (lines 345-350).

    1. BIRC6 is identified as risk factor for invasive bacterial infection. BIRC6 (or BRUCE) is rightfully discussed by the authors in detail. BIRC6/BRUCE indeed is a ubiquitin conjugating E2 enzyme and a well-established anti-apoptosis regulator. Interestingly, we identified UBE2U to be associated with outcome in invasive pneumococcal disease (Lees et al Nature Comm 2019). The author may well find a link here.

    Many thanks for highlighting this. This association is also interesting as the association is seen in the context of meningitis caused by pathogens not just limited to the pneumococcus. We have added this to our discussion (lines 327-330).

    1. The discussion could a presented a bit more balanced. 2/3 is now used to discuss the potential role of BIRC 6- this could be condensed while limitations of the study should also be discussed.

    We have added a section summarising our study’s limitations in the discussion (lines 331-350).

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  2. Evaluation Summary:

    The paper presents evidence that a genetic variant in the BIRC6 gene increases the risk of invasive bacterial infection. This paper will be of interest to researchers working in areas relating to invasive bacterial infections, malaria, sepsis, and immunogenetics. While this paper presents a hypothesis for the mechanism through which the risk variant acts, larger samples carrying the variant that increases risk, only present in African populations, are needed to further investigate potential mechanisms.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

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  3. Reviewer #1 (Public Review):

    By performing a genome-wide association study that exploits a previously developed probabilistic model to discriminate between 'true' severe malaria and invasive bacterial infection, Gilchrist et al. identify a variant in the gene BIRC6 that increases the risk of invasive bacterial disease across a diverse range of bacterial pathogens in Kenyan children. Although discovered in a fairly modest sample size, the association at rs183868412 replicates in an independent sample with a fairly large effect size (OR=2.77, 95% CI 1.49-5.12). It, therefore, seems likely that the association is a true positive and that the variant has a fairly large effect on risk of invasive bacterial infection.

    The risk variant, rs183868412:T, is present at frequencies of only around 1-3% in African populations (Table 5), and is absent from non-African samples. This makes investigation of potential mechanisms by which the variant exerts its influence on invasive bacterial disease difficult. Leveraging a study of 100 European ancestry and 100 African ancestry samples, the authors find evidence that rs183868412:T affects the splicing of BIRC6 in stimulated monocytes and that this may explain the association signal they found. However, due to the fact that rs183868412:T is at relatively low frequency in Africans and not present in European samples, it is hard to be completely confident in this analysis since it must hinge on only a handful of carriers of the rs183868412:T allele.

    The paper gives an example of how a probabilistic model for phenotypic classification can be used via weighting to increase power to discover genetic variants with effects on a specific (sub)phenotype. Further investigation of the discovered variant may be useful for understanding the biology of general susceptibility to invasive bacterial disease.

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  4. Reviewer #2 (Public Review):

    This is a thoughtful paper that infers likely bacteremia cases probabilistically amp amongst putative severe malaria cases and then uses them in a GWAS. Based on this approach it identifies a biologically interesting risk allele for bacteremia, which is found at low frequencies in African population which seems to increase risk uniformly amongst a variety of age groups and bacterial diseases.

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  5. Reviewer #3 (Public Review):

    This manuscript describes host genetic data of several cohorts of Kenyan children with culture proven bacteremia, severe malaria, and controls, and the association with bacteraemia. We know that many children with severe malaria actually have a bacterial co-infection. Because it is difficult to get the numbers needed for such GWAS studies, the authors plus up their numbers by lumping together bacteremia and severe malaria cases - the latter in a weighted manner for the continuum of malaria and bacteraemia. In the next step they validate their findings in a new cohort of 434 bacteraemia cases and present functional studies in monocytes. The methods used are interesting and the data are valid. Findings are important. I am not an expert in statistics, so I cannot judge the statistical methods in detail, but they seemed to be valid.

    I have a few major points.

    1. Overview of cohorts - overview. A graphical overview of cohort could be helpful for the reader- including groups, comparisons, and time periods of collection.
    2. Overview of cohorts - phenotypes. The datasets used have been published previously with clinical phenotypes in more detail. Would it be possible to include a supplementary table providing these clinical phenotypes per group? In how many patients in the severe malaria group cultures were performed?
    3. The potential impact of the prevalence of Pf HRP2 gene deletions on the analysis is probably limited because the cohort was collected in the period 1995-2008; this should be mentioned.
    4. BIRC6 is identified as risk factor for invasive bacterial infection. BIRC6 (or BRUCE) is rightfully discussed by the authors in detail. BIRC6/BRUCE indeed is a ubiquitin conjugating E2 enzyme and a well-established anti-apoptosis regulator. Interestingly, we identified UBE2U to be associated with outcome in invasive pneumococcal disease (Lees et al Nature Comm 2019). The author may well find a link here.
    5. The discussion could a presented a bit more balanced. 2/3 is now used to discuss the potential role of BIRC 6- this could be condensed while limitations of the study should also be discussed.

    Was this evaluation helpful?