A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene.
2',5'-Oligoadenylate Synthetase
/ genetics
Adolescent
Aged
Aged, 80 and over
Alzheimer Disease
/ diagnosis
COVID-19
/ diagnosis
Cells, Cultured
Female
Gene Regulatory Networks
/ genetics
Genetic Linkage
/ genetics
Genetic Predisposition to Disease
/ epidemiology
Humans
Induced Pluripotent Stem Cells
/ physiology
Male
Middle Aged
Patient Acuity
Polymorphism, Single Nucleotide
/ genetics
Young Adult
OAS1
Alzheimer’s disease
COVID-19
interferon
microglia
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
31 12 2021
31 12 2021
Historique:
received:
22
04
2021
revised:
19
07
2021
accepted:
02
08
2021
pubmed:
8
10
2021
medline:
18
1
2022
entrez:
7
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34619763
pii: 6382473
doi: 10.1093/brain/awab337
pmc: PMC8500089
doi:
Substances chimiques
OAS1 protein, human
EC 2.7.7.-
2',5'-Oligoadenylate Synthetase
EC 2.7.7.84
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3727-3741Subventions
Organisme : Alzheimer Nederland
Organisme : Medical Research Council
ID : MR/K01417X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1001253
Pays : United Kingdom
Organisme : National Institute for Health Research University College London Hospitals Biomedical Research Centre
Organisme : Medical Research Council
ID : G0901254
Pays : United Kingdom
Organisme : European Federation of Pharmaceutical Industries and Associations
Organisme : Alzheimer's Society and ARUK
Organisme : Medical Research Council
ID : MR/L501542/1
Pays : United Kingdom
Organisme : UK Medical Research Council
Organisme : Parkinson's UK
ID : G-0907
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N008324/1
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-1307
Pays : United Kingdom
Organisme : The University of Nottingham Group
Organisme : Erasmus+ Traineeship programme
Organisme : Medical Research Council
ID : MR/J004758/1
Pays : United Kingdom
Organisme : European Union's Horizon 2020
Organisme : European Federation of Pharmaceutical Industries and Associations (EFPIA)
Organisme : Alzheimer's Research UK
Organisme : Science and Technology Agency
ID : 00007/COVI/20
Organisme : Medical Research Council
ID : G0701075
Pays : United Kingdom
Organisme : Innovative Medicines Initiative 2 Joint Undertaking
ID : 115976
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.
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