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A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene.
Magusali, Naciye; Graham, Andrew C; Piers, Thomas M; Panichnantakul, Pantila; Yaman, Umran; Shoai, Maryam; Reynolds, Regina H; Botia, Juan A; Brookes, Keeley J; Guetta-Baranes, Tamar; Bellou, Eftychia; Bayram, Sevinc; Sokolova, Dimitra; Ryten, Mina; Sala Frigerio, Carlo; Escott-Price, Valentina; Morgan, Kevin; Pocock, Jennifer M; Hardy, John; Salih, Dervis A.
  • Magusali N; UK Dementia Research Institute at UCL, Gower Street, London WC1E 6BT, UK.
  • Graham AC; UK Dementia Research Institute at UCL, Gower Street, London WC1E 6BT, UK.
  • Piers TM; Department of Neuroinflammation, Queen Square Institute of Neurology, UCL, London WC1N 1PJ, UK.
  • Panichnantakul P; UK Dementia Research Institute at UCL, Gower Street, London WC1E 6BT, UK.
  • Yaman U; UK Dementia Research Institute at UCL, Gower Street, London WC1E 6BT, UK.
  • Shoai M; UK Dementia Research Institute at UCL, Gower Street, London WC1E 6BT, UK.
  • Reynolds RH; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, UCL, London WC1N 1PJ, UK.
  • Botia JA; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, UCL, London WC1N 1PJ, UK.
  • Brookes KJ; NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London WC1N 1EH, UK.
  • Guetta-Baranes T; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, UCL, London WC1N 1EH, UK.
  • Bellou E; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, UCL, London WC1N 1PJ, UK.
  • Bayram S; Department of Information and Communications Engineering, Universidad de Murcia, 30100 Murcia, Spain.
  • Sokolova D; Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham NG8 11NS, UK.
  • Ryten M; Genetics, School of Life Sciences, Life Sciences Building, University Park, University of Nottingham, Nottingham NG7 2RD, UK.
  • Sala Frigerio C; Dementia Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff CF24 4HQ, UK.
  • Escott-Price V; Hitachi Rail Europe Ltd, New Ludgate, London EC4M 7HX, UK.
  • Morgan K; UK Dementia Research Institute at UCL, Gower Street, London WC1E 6BT, UK.
  • Pocock JM; Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, UCL, London WC1N 1PJ, UK.
  • Hardy J; NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London WC1N 1EH, UK.
  • Salih DA; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, UCL, London WC1N 1EH, UK.
Brain ; 144(12): 3727-3741, 2021 12 31.
Article in English | MEDLINE | ID: covidwho-1455243
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: 2',5'-Oligoadenylate Synthetase / Genetic Predisposition to Disease / Alzheimer Disease / Patient Acuity / COVID-19 / Genetic Linkage Type of study: Diagnostic study / Etiology study / Prognostic study / Risk factors Topics: Long Covid / Variants Limits: Adolescent / Adult / Aged / Female / Humans / Male / Middle aged / Young adult Language: English Journal: Brain Year: 2021 Document Type: Article Affiliation country: Brain

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Full text: Available Collection: International databases Database: MEDLINE Main subject: 2',5'-Oligoadenylate Synthetase / Genetic Predisposition to Disease / Alzheimer Disease / Patient Acuity / COVID-19 / Genetic Linkage Type of study: Diagnostic study / Etiology study / Prognostic study / Risk factors Topics: Long Covid / Variants Limits: Adolescent / Adult / Aged / Female / Humans / Male / Middle aged / Young adult Language: English Journal: Brain Year: 2021 Document Type: Article Affiliation country: Brain