A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene
| Autor: | Umran Yaman, Jennifer M. Pocock, Tamar Guetta-Baranes, Mina Ryten, John Hardy, Juan A. Botía, Valentina Escott-Price, Dimitra Sokolova, Eftychia Bellou, Naciye Magusali, Maryam Shoai, Thomas M. Piers, Andrew Graham, Regina H. Reynolds, Dervis A. Salih, Carlo Sala Frigerio, Keeley J. Brookes, Pantila Panichnantakul, Kevin Morgan, Sevinc Bayram |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Adolescent Genetic Linkage Induced Pluripotent Stem Cells Locus (genetics) Single-nucleotide polymorphism Disease Polymorphism Single Nucleotide Young Adult Alzheimer Disease Interferon 2' 5'-Oligoadenylate Synthetase Humans Medicine Gene Regulatory Networks Genetic Predisposition to Disease Induced pluripotent stem cell Gene Genotyping Cells Cultured Aged Aged 80 and over Microglia business.industry Patient Acuity COVID-19 Middle Aged medicine.anatomical_structure Immunology Female Neurology (clinical) business medicine.drug |
| ISSN: | 0006-8950 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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