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  • Gaziano, LiamVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.;Univ Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England. (author)

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • 2021-04-09
  • Springer Nature,2021
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-454586
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-454586URI
  • https://doi.org/10.1038/s41591-021-01310-zDOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Large-scale Mendelian randomization and colocalization analyses using gene expression and soluble protein data for 1,263 actionable druggable genes, which encode protein targets for approved drugs or drugs in clinical development, identify IFNAR2 and ACE2 as the most promising therapeutic targets for early management of COVID-19. Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 x 10(-6); IFNAR2, P = 9.8 x 10(-11) and IL-10RB, P = 2.3 x 10(-14)) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

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  • Giambartolomei, ClaudiaIst Italiano Tecnol, Cent RNA Lab, Genoa, Italy.;Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. (author)
  • Pereira, Alexandre C.Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil.;Harvard Univ, Harvard Med Sch, Genet Dept, Boston, MA 02115 USA. (author)
  • Gaulton, AnnaEuropean Bioinformat Inst, European Mol Biol Lab, Chem Biol, Hinxton, England. (author)
  • Posner, Daniel C.VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Swanson, Sonja A.Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. (author)
  • Ho, Yuk-LamVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Iyengar, Sudha K.Louis Stokes Cleveland VA Med Ctr, Cleveland, OH USA.;Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA.;Cleveland VA, Louis Stoke, Cleveland, OH USA. (author)
  • Kosik, Nicole M.VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Vujkovic, MarijanaUniv Penn, Perelman Sch Med, Corporal Michael J Crescenz VA Med Ctr, Philadelphia, PA 19104 USA.;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. (author)
  • Gagnon, David R.VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.;Boston Univ, Sch Publ Hlth, Biostat, Boston, MA USA. (author)
  • Bento, A. PatriciaEuropean Bioinformat Inst, European Mol Biol Lab, Chem Biol, Hinxton, England. (author)
  • Barrio-Hernandez, InigoEuropean Bioinformat Inst, European Mol Biol Lab, Hinxton, England. (author)
  • Rönnblom, LarsUppsala universitet,Reumatologi(Swepub:uu)larsronn (author)
  • Högberg, Niclas,1979-Uppsala universitet,Institutionen för medicinska vetenskaper(Swepub:uu)nihog677 (author)
  • Lundtoft, ChristianUppsala universitet,Reumatologi(Swepub:uu)chrlu632 (author)
  • Langenberg, ClaudiaCharite Univ Med Berlin, Berlin Inst Hlth, Berlin, Germany.;Univ Cambridge, MRC Epidemiol Unit, Cambridge, England. (author)
  • Pietzner, MaikUniv Cambridge, MRC Epidemiol Unit, Cambridge, England. (author)
  • Valentine, DennisUCL, Inst Hlth Informat, London, England.;UCL, Hlth Data Res, London, England. (author)
  • Gustincich, StefanoIst Italiano Tecnol, Cent RNA Lab, Genoa, Italy. (author)
  • Tartaglia, Gian GaetanoIst Italiano Tecnol, Cent RNA Lab, Genoa, Italy. (author)
  • Allara, EliasUniv Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England. (author)
  • Surendran, PraveenUniv Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England.;Univ Cambridge, British Heart Fdn Ctr Res Excellence, Cambridge, England.;Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England.;Univ Cambridge, Cambridge, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. (author)
  • Burgess, StephenUniv Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, MRC Biostat Unit, Cambridge, England. (author)
  • Zhao, Jing HuaUniv Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England. (author)
  • Peters, James E.Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England.;Univ Cambridge, Cambridge, England.;Imperial Coll, Dept Immunol & Inflammat, Ctr Inflammatory Dis, London, England. (author)
  • Prins, Bram P.Univ Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England.;Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England.;Univ Cambridge, Cambridge, England. (author)
  • Angelantonio, Emanuele DiUniv Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England.;Univ Cambridge, British Heart Fdn Ctr Res Excellence, Cambridge, England.;Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England.;Univ Cambridge, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res, Blood & Transplant Res Unit Donor Hlth & Genom, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge, England.;Cambridge Univ Hosp, Cambridge, England. (author)
  • Devineni, PoornimaVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Shi, YunlingVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Lynch, Kristine E.VA Salt Lake City Hlth Care Syst, VA Informat & Comp Infrastruct, Salt Lake City, UT USA.;Univ Utah, Dept Internal Med, Epidemiol, Salt Lake City, UT 84112 USA. (author)
  • DuVall, Scott L.VA Salt Lake City Hlth Care Syst, VA Informat & Comp Infrastruct, Salt Lake City, UT USA.;Univ Utah, Dept Internal Med, Epidemiol, Salt Lake City, UT 84112 USA. (author)
  • Garcon, HeleneVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Thomann, Lauren O.VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Zhou, Jin J.Univ Arizona, Dept Epidemiol & Biostat, Tucson, AZ USA.;Phoenix VA Hlth Care Syst, Phoenix, AZ USA. (author)
  • Gorman, Bryan R.VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Huffman, Jennifer E.VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Ctr Populat Genom, Boston, MA USA. (author)
  • O'Donnell, Christopher J.VA Boston Healthcare Syst, Cardiol, Boston, MA USA.;Harvard Med Sch, Brigham & Womens Hosp, Med, Boston, MA 02115 USA. (author)
  • Tsao, Philip S.VA Palo Alto Hlth Care Syst, Epidemiol Res & Informat Ctr ERIC, Palo Alto, CA USA.;Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. (author)
  • Beckham, Jean C.Durham VA Med Ctr, MIRECC, Durham, NC USA.;Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. (author)
  • Pyarajan, SaijuVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA. (author)
  • Muralidhar, SumitraUS Dept Vet Affairs, Off Res & Dev, Washington, DC USA. (author)
  • Huang, Grant D.US Dept Vet Affairs, Off Res & Dev, Washington, DC USA. (author)
  • Ramoni, RachelUS Dept Vet Affairs, Off Res & Dev, Washington, DC USA. (author)
  • Beltrao, PedroEuropean Bioinformat Inst, European Mol Biol Lab, Hinxton, England. (author)
  • Danesh, JohnUniv Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England.;Univ Cambridge, British Heart Fdn Ctr Res Excellence, Cambridge, England.;Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England.;Univ Cambridge, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res, Blood & Transplant Res Unit Donor Hlth & Genom, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge, England.;Cambridge Univ Hosp, Cambridge, England. (author)
  • Hung, Adriana M.VA Tennessee Valley Healthcare Syst, Nashville, TN USA.;Vanderbilt Univ, Nephrol & Hypertens, 221 Kirkland Hall, Nashville, TN 37235 USA. (author)
  • Chang, Kyong-MiUniv Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA.;Corporal Michael J Crescenz VA Med Ctr, Philadelphia, PA USA. (author)
  • Sun, Yan V.Atlanta VA Hlth Care Syst, Decatur, GA USA.;Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. (author)
  • Joseph, JacobVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.;VA Boston Healthcare Syst, Med, Cardiovasc, Boston, MA USA.;Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. (author)
  • Leach, Andrew R.European Bioinformat Inst, European Mol Biol Lab, Chem Biol, Hinxton, England. (author)
  • Edwards, Todd L.Vanderbilt Univ, US Dept Vet Affairs, Tennessee Valley Healthcare Syst, 221 Kirkland Hall, Nashville, TN 37235 USA.;Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Med,Epidemiol, Nashville, TN USA. (author)
  • Cho, KellyVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.;Harvard Med Sch, Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. (author)
  • Gaziano, J. MichaelVA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.;Harvard Med Sch, Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. (author)
  • Butterworth, Adam S.Univ Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England.;Univ Cambridge, British Heart Fdn Ctr Res Excellence, Cambridge, England.;Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England.;Univ Cambridge, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res, Blood & Transplant Res Unit Donor Hlth & Genom, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge, England.;Cambridge Univ Hosp, Cambridge, England. (author)
  • Casas, Juan P.VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.;Harvard Med Sch, Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. (author)
  • VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.;Univ Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England.Ist Italiano Tecnol, Cent RNA Lab, Genoa, Italy.;Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. (creator_code:org_t)

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  • In:Nature Medicine: Springer Nature27:41078-89561546-170X

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