A translational genomics approach identifies IL10RB as the top candidate gene target for COVID-19 susceptibility
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Abstract
Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes that reduce COVID-19 host susceptibility is a critical next step. Using a translational genomics approach that integrates COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX), and perturbagen signatures, we identified IL10RB as the top candidate gene target for COVID-19 host susceptibility. In a series of validation steps, we show that predicted GReX upregulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes and that in vitro IL10RB overexpression is associated with increased viral load and activation of disease-relevant molecular pathways.
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SciScore for 10.1101/2021.05.31.21254851: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: This study was approved by the Institutional Review Board (IRB) at the Icahn School of Medicine at Mount Sinai (20-0327).
Consent: Given the extraordinary challenges posed by the COVID-19 pandemic for obtaining informed consent, and in consideration of the public health crisis, a delayed consent model was applied.Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources IL10RB shRNA treatment for 96 hours in MCF7 cells) is assessed and ranked for its ability to reverse the trait-associated imputed transcriptomes using a … SciScore for 10.1101/2021.05.31.21254851: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: This study was approved by the Institutional Review Board (IRB) at the Icahn School of Medicine at Mount Sinai (20-0327).
Consent: Given the extraordinary challenges posed by the COVID-19 pandemic for obtaining informed consent, and in consideration of the public health crisis, a delayed consent model was applied.Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources IL10RB shRNA treatment for 96 hours in MCF7 cells) is assessed and ranked for its ability to reverse the trait-associated imputed transcriptomes using a previously published method16. MCF7suggested: NoneSoftware and Algorithms Sentences Resources The STAR aligner v2.5.2a33 was used to align reads to the GRCh38 genome (canonical chromosomes only) and Gencode v25 annotation. STARsuggested: (STAR, RRID:SCR_004463)Gencodesuggested: (GENCODE, RRID:SCR_014966)The module featureCounts34 from the Subread package v1.4.3-p135 was used to quantify genes. Subreadsuggested: (Subread, RRID:SCR_009803)RSeQC v2.6.136 and Picard v1.7737, were used to generate QC metrics. RSeQCsuggested: (RSeQC, RRID:SCR_005275)Picardsuggested: (Picard, RRID:SCR_006525)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This shRNA GReX antagonism approach identifies IL10RB (21q22.11) as the most promising gene target and overcomes traditional limitations of GWAS and TWAS analyses in identifying key genes within a gene cluster. Based on existing approaches, IL10RB would not have been the top candidate for further investigation. First, the index SNP for COVID-19 susceptibility in 21q22.11, rs1305072857, falls within an intronic region of IFNAR2 (less than 24kbp from IL10RB). In addition, integrating genotype-gene expression datasets cannot identify the most likely causal gene in this locus since the index SNP is associated with gene expression changes of both IFNAR2 and IL10RB57. Similarly, the genes can only be partially prioritized with targeted individual imputation (Figure 3A; IFNAR2 is not associated with COVID-19 death but is associated with COVID-19 severity) and cannot be prioritized on TWAS based on summary statistics (Figure 2A) even when considering splicing58 due to co-regulation59 (Supplementary Figure 10). IL10RB is, in part, prioritized because it has a more uniform imputed transcriptional dysregulation across tissues (predominant down-regulation; Figure 2A, Supplementary Figure 11). On the other hand, IFNAR2 is expected to be up-regulated in some tissues and down-regulated in others58 (Figure 2A, Supplementary Figure 11), e.g. there is a consistent, predicted, down-regulation in adipose tissue and an opposing up-regulation in muscle tissue (Supplementary Figure 12). Unfortunate...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04343976 Enrolling by invitation Pegylated Interferon Lambda Treatment for COVID-19 NCT04354259 Recruiting Interferon Lambda for Immediate Antiviral Therapy at Diagnos… NCT04534673 Recruiting Pegylated Interferon Lambda for Treatment of COVID-19 Infect… NCT04344600 Recruiting Peginterferon Lambda-1a for the Prevention and Treatment of … NCT02554019 Completed Proof-of-Concept Study With BT063 in Subjects With Systemic … Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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