DOI: https://doi.org/10.1093/brain/awab337
PDF: https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awab337/40516064/awab337.pdf
Abstract
Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer’s disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known.
Using genotyping from 1313 individuals with sporadic Alzheimer’s disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer’s disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer’s disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer’s disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells.
Collectively, our data support a link between genetic risk for Alzheimer’s disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer’s disease and COVID-19, and development of biomarkers to track disease progression.
Funding
N.M. was supported by Alzheimer Nederland, the Erasmus+ Traineeship programme, and then a PhD studentship funded by Eli Lilly and Co. T.M.P. was supported by funding to J.M.P. and J.H. from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). R.H.R. was supported through the award of a Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration. J.A.B. is supported through the Science and Technology Agency, Séneca Foundation, CARM, Spain (research project 00007/COVI/20). The University of Nottingham Group is funded by ARUK and hosts the ARUK Consortium DNA Bank, with the members given in the Appendix below. J.H. is supported by the Dolby Foundation, and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. D.A.S. also received funding from the Alzheimer’s Research UK (ARUK) pump priming scheme via the UCL network. This work was funded by the UK DRI, which receives its funding from the DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and ARUK.
Competing interests
The authors report no competing interests.
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