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

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Fältnamn	Indikatorer	Metadata
000		13141naa a2200961 4500
001		oai:DiVA.org:uu-454586
003		SwePub
008		210929s2021 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4545862 URI
024	7	a https://doi.org/10.1038/s41591-021-01310-z2 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Gaziano, Liamu 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.4 aut
245	1 0	a Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19
264		c 2021-04-09
264	1	b Springer Nature,c 2021
338		a print2 rdacarrier
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Medicinsk genetik0 (SwePub)301072 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medical Genetics0 (SwePub)301072 hsv//eng
700	1	a Giambartolomei, Claudiau 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.4 aut
700	1	a Pereira, Alexandre C.u Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil.;Harvard Univ, Harvard Med Sch, Genet Dept, Boston, MA 02115 USA.4 aut
700	1	a Gaulton, Annau European Bioinformat Inst, European Mol Biol Lab, Chem Biol, Hinxton, England.4 aut
700	1	a Posner, Daniel C.u VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Swanson, Sonja A.u Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.4 aut
700	1	a Ho, Yuk-Lamu VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Iyengar, Sudha K.u 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.4 aut
700	1	a Kosik, Nicole M.u VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Vujkovic, Marijanau Univ 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.4 aut
700	1	a Gagnon, David R.u VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.;Boston Univ, Sch Publ Hlth, Biostat, Boston, MA USA.4 aut
700	1	a Bento, A. Patriciau European Bioinformat Inst, European Mol Biol Lab, Chem Biol, Hinxton, England.4 aut
700	1	a Barrio-Hernandez, Inigou European Bioinformat Inst, European Mol Biol Lab, Hinxton, England.4 aut
700	1	a Rönnblom, Larsu Uppsala universitet,Reumatologi4 aut0 (Swepub:uu)larsronn
700	1	a Högberg, Niclas,d 1979-u Uppsala universitet,Institutionen för medicinska vetenskaper4 aut0 (Swepub:uu)nihog677
700	1	a Lundtoft, Christianu Uppsala universitet,Reumatologi4 aut0 (Swepub:uu)chrlu632
700	1	a Langenberg, Claudiau Charite Univ Med Berlin, Berlin Inst Hlth, Berlin, Germany.;Univ Cambridge, MRC Epidemiol Unit, Cambridge, England.4 aut
700	1	a Pietzner, Maiku Univ Cambridge, MRC Epidemiol Unit, Cambridge, England.4 aut
700	1	a Valentine, Dennisu UCL, Inst Hlth Informat, London, England.;UCL, Hlth Data Res, London, England.4 aut
700	1	a Gustincich, Stefanou Ist Italiano Tecnol, Cent RNA Lab, Genoa, Italy.4 aut
700	1	a Tartaglia, Gian Gaetanou Ist Italiano Tecnol, Cent RNA Lab, Genoa, Italy.4 aut
700	1	a Allara, Eliasu Univ Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England.4 aut
700	1	a Surendran, Praveenu 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, Dept Publ Hlth & Primary Care, Cambridge, England.4 aut
700	1	a Burgess, Stephenu Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, MRC Biostat Unit, Cambridge, England.4 aut
700	1	a Zhao, Jing Huau Univ Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England.4 aut
700	1	a Peters, James E.u Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England.;Univ Cambridge, Cambridge, England.;Imperial Coll, Dept Immunol & Inflammat, Ctr Inflammatory Dis, London, England.4 aut
700	1	a Prins, Bram P.u 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.4 aut
700	1	a Angelantonio, Emanuele Diu 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.4 aut
700	1	a Devineni, Poornimau VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Shi, Yunlingu VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Lynch, Kristine E.u 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.4 aut
700	1	a DuVall, Scott L.u 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.4 aut
700	1	a Garcon, Heleneu VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Thomann, Lauren O.u VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Zhou, Jin J.u Univ Arizona, Dept Epidemiol & Biostat, Tucson, AZ USA.;Phoenix VA Hlth Care Syst, Phoenix, AZ USA.4 aut
700	1	a Gorman, Bryan R.u VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Huffman, Jennifer E.u VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Ctr Populat Genom, Boston, MA USA.4 aut
700	1	a O'Donnell, Christopher J.u VA Boston Healthcare Syst, Cardiol, Boston, MA USA.;Harvard Med Sch, Brigham & Womens Hosp, Med, Boston, MA 02115 USA.4 aut
700	1	a Tsao, Philip S.u 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.4 aut
700	1	a Beckham, Jean C.u Durham VA Med Ctr, MIRECC, Durham, NC USA.;Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA.4 aut
700	1	a Pyarajan, Saijuu VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA.4 aut
700	1	a Muralidhar, Sumitrau US Dept Vet Affairs, Off Res & Dev, Washington, DC USA.4 aut
700	1	a Huang, Grant D.u US Dept Vet Affairs, Off Res & Dev, Washington, DC USA.4 aut
700	1	a Ramoni, Rachelu US Dept Vet Affairs, Off Res & Dev, Washington, DC USA.4 aut
700	1	a Beltrao, Pedrou European Bioinformat Inst, European Mol Biol Lab, Hinxton, England.4 aut
700	1	a Danesh, Johnu 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.4 aut
700	1	a Hung, Adriana M.u VA Tennessee Valley Healthcare Syst, Nashville, TN USA.;Vanderbilt Univ, Nephrol & Hypertens, 221 Kirkland Hall, Nashville, TN 37235 USA.4 aut
700	1	a Chang, Kyong-Miu Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA.;Corporal Michael J Crescenz VA Med Ctr, Philadelphia, PA USA.4 aut
700	1	a Sun, Yan V.u Atlanta VA Hlth Care Syst, Decatur, GA USA.;Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA.4 aut
700	1	a Joseph, Jacobu VA 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.4 aut
700	1	a Leach, Andrew R.u European Bioinformat Inst, European Mol Biol Lab, Chem Biol, Hinxton, England.4 aut
700	1	a Edwards, Todd L.u 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.4 aut
700	1	a Cho, Kellyu 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.4 aut
700	1	a Gaziano, J. Michaelu 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.4 aut
700	1	a Butterworth, Adam S.u 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.4 aut
700	1	a Casas, Juan P.u 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.4 aut
710	2	a 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.b 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.4 org
773	0	t Nature Medicined : Springer Natureg 27:4q 27:4x 1078-8956x 1546-170X
856	4	u https://www.nature.com/articles/s41591-021-01310-z.pdf
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-454586
856	4 8	u https://doi.org/10.1038/s41591-021-01310-z

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By the author/editor: Gaziano, Liam; Giambartolomei, ...; Pereira, Alexand ...; Gaulton, Anna; Posner, Daniel C ...; Swanson, Sonja A ...; show more...; Ho, Yuk-Lam; Iyengar, Sudha K ...; Kosik, Nicole M.; Vujkovic, Marija ...; Gagnon, David R.; Bento, A. Patric ...; Barrio-Hernandez ...; Rönnblom, Lars; Högberg, Niclas, ...; Lundtoft, Christ ...; Langenberg, Clau ...; Pietzner, Maik; Valentine, Denni ...; Gustincich, Stef ...; Tartaglia, Gian ...; Allara, Elias; Surendran, Prave ...; Burgess, Stephen; Zhao, Jing Hua; Peters, James E.; Prins, Bram P.; Angelantonio, Em ...; Devineni, Poorni ...; Shi, Yunling; Lynch, Kristine ...; DuVall, Scott L.; Garcon, Helene; Thomann, Lauren ...; Zhou, Jin J.; Gorman, Bryan R.; Huffman, Jennife ...; O'Donnell, Chris ...; Tsao, Philip S.; Beckham, Jean C.; Pyarajan, Saiju; Muralidhar, Sumi ...; Huang, Grant D.; Ramoni, Rachel; Beltrao, Pedro; Danesh, John; Hung, Adriana M.; Chang, Kyong-Mi; Sun, Yan V.; Joseph, Jacob; Leach, Andrew R.; Edwards, Todd L.; Cho, Kelly; Gaziano, J. Mich ...; Butterworth, Ada ...; Casas, Juan P.; show less...

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