Genetic variability associated with OAS1 expression in myeloid cells increases the risk of Alzheimer’s disease and severe COVID-19 outcomes

  1. Naciye Magusali
  2. Andrew C. Graham
  3. Thomas M. Piers
  4. Pantila Panichnantakul
  5. Umran Yaman
  6. Maryam Shoai
  7. Regina H. Reynolds
  8. Juan A. Botia
  9. Keeley J. Brookes
  10. Tamar Guetta-Baranes
  11. Eftychia Bellou
  12. Sevinc Bayram
  13. Dimitra Sokolova
  14. Mina Ryten
  15. Carlo Sala Frigerio
  16. Valentina Escott-Price
  17. Kevin Morgan
  18. Jennifer M. Pocock
  19. John Hardy
  20. Dervis A. Salih

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Abstract

Genome-wide association studies of late-onset Alzheimer’s disease (AD) have highlighted the importance of variants associated with genes expressed by the innate immune system in determining risk for AD. Recently, we and others have shown that genes associated with variants that confer risk for AD are significantly enriched in transcriptional networks expressed by amyloid-responsive microglia. This allowed us to predict new risk genes for AD, including the interferon-responsive oligoadenylate synthetase 1 ( OAS1 ). However, the function of OAS1 within microglia and its genetic pathway are not known. Using genotyping from 1,313 individuals with sporadic AD and 1,234 control individuals, we confirm that the OAS1 variant, rs1131454, is associated with increased risk for AD and decreased OAS1 expression. Moreover, we note that the same locus was recently associated with critical illness in response to COVID-19, linking variants that are associated with AD and a severe response to COVID-19. By analysing single-cell RNA-sequencing (scRNA-seq) data of isolated microglia from APP NL-G-F knock-in and wild-type C57BL/6J mice, we identify a transcriptional network that is significantly upregulated with age and amyloid deposition, and contains the mouse orthologue Oas1a , providing evidence that Oas1a plays an age-dependent function in the innate immune system. We identify a similar interferon-related transcriptional network containing OAS1 by analysing scRNA-seq data from human microglia isolated from individuals with AD. Finally, using human iPSC-derived microglial cells (h-iPSC-Mg), we see that OAS1 is required to limit the pro-inflammatory response of microglia. When stimulated with interferon-gamma (IFN-γ), we note that cells with lower OAS1 expression show an exaggerated pro-inflammatory response, with increased expression and secretion of TNF-α. Collectively, our data support a link between genetic risk for AD and susceptibility to critical illness with COVID-19 centred on OAS1 and interferon signalling, a finding with potential implications for future treatments of both AD and COVID-19, and the development of biomarkers to track disease progression.

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  1. ScreenIT

    SciScore for 10.1101/2021.03.16.435702: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableCell culture: Human iPSC-derived microglia cells (h-iPSC-Mg) were generated from the BIONi010-C human iPSC line (EBiSC), originating from a non-demented, normal male (15-19 years old).

    Table 2: Resources

    Antibodies
    SentencesResources
    Following four washes, wells were then incubated with horseradish peroxidase conjugated human TNF-α antibody for another 2 hr at RT.
    TNF-α
    suggested: None
    Software and Algorithms
    SentencesResources
    SNPs in the locus containing OAS1 associated with AD (Salih et al., 2018, 2019), and COVID (Pairo-Castineira et al., 2021), were illustrated with LocusZoom (Pruim et al.,
    LocusZoom
    suggested: (LOCUSZOOM, RRID:SCR_009257)
    Allele frequencies and LD between these SNPs were investigated using the 1000Genomes Phase 3 data (European populations, CEU and GBR; Auton et al., 2015), and LDlink (Machiela and Chanock, 2015; Myers et al., 2020), where the LD between SNPs was calculated with the LDpair tool (available at https://ldlink.nci.nih.gov/?tab=ldpair using data from European populations, CEU, TSI and GBR).
    https://ldlink.nci.nih.gov/
    suggested: (LDMatrix, RRID:SCR_017391)
    (RT-qPCR): Primers for genes of interest were designed using Primer-BLAST (NCBI) to test their specificity against the whole human transcriptome.
    Primer-BLAST
    suggested: (Primer-BLAST, RRID:SCR_003095)
    Gene expression analyses were performed by following the GeNorm method (Salih et al., 2012; Vandesompele et al., 2002).
    GeNorm
    suggested: (geNORM, RRID:SCR_006763)
    Statistical analyses for cell culture experiments: All statistical analyses were conducted on GraphPad Prism 9.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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.

    About SciScore

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