A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene

被引:66
作者
Magusali, Naciye [1 ]
Graham, Andrew C. [1 ]
Piers, Thomas M. [2 ]
Panichnantakul, Pantila [1 ]
Yaman, Umran [1 ]
Shoai, Maryam [1 ,3 ]
Reynolds, Regina H. [3 ,4 ,5 ]
Botia, Juan A. [3 ,6 ]
Brookes, Keeley J. [7 ]
Guetta-Baranes, Tamar [8 ]
Bellou, Eftychia [9 ]
Bayram, Sevinc [10 ]
Sokolova, Dimitra [1 ]
Ryten, Mina [3 ,4 ,5 ]
Frigerio, Carlo Sala [1 ]
Escott-Price, Valentina [9 ]
Morgan, Kevin [8 ]
Pocock, Jennifer M. [2 ]
Hardy, John [1 ,3 ]
Salih, Dervis A. [1 ]
机构
[1] UCL, UK Dementia Res Inst, Gower St, London WC1E 6BT, England
[2] UCL, Queen Sq Inst Neurol, Dept Neuroinflammat, London WC1N 1PJ, England
[3] UCL, Dept Neurodegenerat Dis, Queen Sq Inst Neurol, London WC1N 1PJ, England
[4] UCL, NIHR Great Ormond St Hosp Biomed Res Ctr, London WC1N 1EH, England
[5] UCL, Great Ormond St Inst Child Hlth Genet & Genom Med, London WC1N 1EH, England
[6] Univ Murcia, Dept Informat & Commun Engn, Murcia 30100, Spain
[7] Nottingham Trent Univ, Sch Sci & Technol, Biosci, Nottingham NG8 11NS, England
[8] Univ Nottingham, Sch Life Sci, Genet, Life Sci Bldg,Univ Pk, Nottingham NG7 2RD, England
[9] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Dementia Res Inst, Cardiff CF24 4HQ, Wales
[10] Hitachi Rail Europe Ltd, London EC4M 7HX, England
基金
欧盟地平线“2020”; 英国医学研究理事会;
关键词
OAS1; Alzheimer's disease; COVID-19; microglia; interferon; RNASE-L; 2'; 5'-OLIGOADENYLATE SYNTHETASE; MULTIPLE-SCLEROSIS; MICROGLIA; EXPRESSION; ASSOCIATION; ACTIVATION; POLYMORPHISM; METAANALYSIS; IMMUNITY;
D O I
10.1093/brain/awab337
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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-alpha with IFN-gamma 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.
引用
收藏
页码:3727 / 3741
页数:15
相关论文
共 118 条
  • [1] Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response
    Alasoo, Kaur
    Rodrigues, Julia
    Mukhopadhyay, Subhankar
    Knights, Andrew J.
    Mann, Alice L.
    Kundu, Kousik
    Hale, Christine
    Dougan, Gordon
    Gaffney, Daniel J.
    [J]. NATURE GENETICS, 2018, 50 (03) : 424 - +
  • [2] [Anonymous], 2015, Nature, DOI DOI 10.1038/NATURE15393
  • [3] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans
    Ardlie, Kristin G.
    DeLuca, David S.
    Segre, Ayellet V.
    Sullivan, Timothy J.
    Young, Taylor R.
    Gelfand, Ellen T.
    Trowbridge, Casandra A.
    Maller, Julian B.
    Tukiainen, Taru
    Lek, Monkol
    Ward, Lucas D.
    Kheradpour, Pouya
    Iriarte, Benjamin
    Meng, Yan
    Palmer, Cameron D.
    Esko, Tonu
    Winckler, Wendy
    Hirschhorn, Joel N.
    Kellis, Manolis
    MacArthur, Daniel G.
    Getz, Gad
    Shabalin, Andrey A.
    Li, Gen
    Zhou, Yi-Hui
    Nobel, Andrew B.
    Rusyn, Ivan
    Wright, Fred A.
    Lappalainen, Tuuli
    Ferreira, Pedro G.
    Ongen, Halit
    Rivas, Manuel A.
    Battle, Alexis
    Mostafavi, Sara
    Monlong, Jean
    Sammeth, Michael
    Mele, Marta
    Reverter, Ferran
    Goldmann, Jakob M.
    Koller, Daphne
    Guigo, Roderic
    McCarthy, Mark I.
    Dermitzakis, Emmanouil T.
    Gamazon, Eric R.
    Im, Hae Kyung
    Konkashbaev, Anuar
    Nicolae, Dan L.
    Cox, Nancy J.
    Flutre, Timothee
    Wen, Xiaoquan
    Stephens, Matthew
    [J]. SCIENCE, 2015, 348 (6235) : 648 - 660
  • [4] Neurologic Alterations Due to Respiratory Virus Infections
    Bohmwald, Karen
    Galvez, Nicolas M. S.
    Rios, Mariana
    Kalergis, Alexis M.
    [J]. FRONTIERS IN CELLULAR NEUROSCIENCE, 2018, 12
  • [5] Variation in antiviral 2′,5′-oligoadenylate synthetase (2′5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene
    Bonnevie-Nielsen, V
    Field, LL
    Lu, S
    Zheng, DJ
    Li, M
    Martensen, PM
    Nielsen, TB
    Beck-Nielsen, H
    Lau, YL
    Pociot, F
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2005, 76 (04) : 623 - 633
  • [6] An additional k-means clustering step improves the biological features of WGCNA gene co-expression networks
    Botia, Juan A.
    Vandrovcova, Jana
    Forabosco, Paola
    Guelfi, Sebastian
    D'Sa, Karishma
    Hardy, John
    Lewis, Cathryn M.
    Ryten, Mina
    Weale, Michael E.
    [J]. BMC SYSTEMS BIOLOGY, 2017, 11
  • [7] Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease
    Broce, Iris J.
    Tan, Chin Hong
    Fan, Chun Chieh
    Jansen, Iris
    Savage, Jeanne E.
    Witoelar, Aree
    Wen, Natalie
    Hess, Christopher P.
    Dillon, William P.
    Glastonbury, Christine M.
    Glymour, Maria
    Yokoyama, Jennifer S.
    Elahi, Fanny M.
    Rabinovici, Gil D.
    Miller, Bruce L.
    Mormino, Elizabeth C.
    Sperling, Reisa A.
    Bennett, David A.
    McEvoy, Linda K.
    Brewer, James B.
    Feldman, Howard H.
    Hyman, Bradley T.
    Pericak-Vance, Margaret
    Haines, Jonathan L.
    Farrer, Lindsay A.
    Mayeux, Richard
    Schellenberg, Gerard D.
    Yaffe, Kristine
    Sugrue, Leo P.
    Dale, Anders M.
    Posthuma, Danielle
    Andreassen, Ole A.
    Karch, Celeste M.
    Desikan, Rahul S.
    [J]. ACTA NEUROPATHOLOGICA, 2019, 137 (02) : 209 - 226
  • [8] Anosmia in COVID-19: Underlying Mechanisms and Assessment of an Olfactory Route to Brain Infection
    Butowt, Rafal
    von Bartheld, Christopher S.
    [J]. NEUROSCIENTIST, 2021, 27 (06) : 582 - 603
  • [9] Identification of a new susceptibility variant for multiple sclerosis in OAS1 by population genetics analysis
    Cagliani, Rachele
    Fumagalli, Matteo
    Guerini, Franca R.
    Riva, Stefania
    Galimberti, Daniela
    Comi, Giacomo P.
    Agliardi, Cristina
    Scarpini, Elio
    Pozzoli, Uberto
    Forni, Diego
    Caputo, Domenico
    Asselta, Rosanna
    Biasin, Mara
    Paraboschi, Elvezia M.
    Bresolin, Nereo
    Clerici, Mario
    Sironi, Manuela
    [J]. HUMAN GENETICS, 2012, 131 (01) : 87 - 97
  • [10] Clinical and immunological features of severe and moderate coronavirus disease 2019
    Chen, Guang
    Wu, Di
    Guo, Wei
    Cao, Yong
    Huang, Da
    Wang, Hongwu
    Wang, Tao
    Zhang, Xiaoyun
    Chen, Huilong
    Yu, Haijing
    Zhang, Xiaoping
    Zhang, Minxia
    Wu, Shiji
    Song, Jianxin
    Chen, Tao
    Han, Meifang
    Li, Shusheng
    Luo, Xiaoping
    Zhao, Jianping
    Ning, Qin
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2020, 130 (05) : 2620 - 2629