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

VA Million Veteran Program COVID-19 Science Initiative; Liam Gaziano; Claudia Giambartolomei; Alexandre C. Pereira; Anna Gaulton; Daniel C. Posner; Sonja A. Swanson; Yuk Lam Ho; Sudha K. Iyengar; Nicole M. Kosik; Marijana Vujkovic; David R. Gagnon; A. Patrícia Bento; Inigo Barrio-Hernandez; Lars Rönnblom; Niklas Hagberg; Christian Lundtoft; Claudia Langenberg; Maik Pietzner; Dennis Valentine; Stefano Gustincich; Gian Gaetano Tartaglia; Elias Allara; Praveen Surendran; Stephen Burgess; Jing Hua Zhao; James E. Peters; Bram P. Prins; Emanuele Di Angelantonio; Poornima Devineni; Yunling Shi; Kristine E. Lynch; Scott L. DuVall; Helene Garcon; Lauren O. Thomann; Jin J. Zhou; Bryan R. Gorman; Jennifer E. Huffman; Christopher J. O’Donnell; Philip S. Tsao; Jean C. Beckham; Saiju Pyarajan; Sumitra Muralidhar; Grant D. Huang; Rachel Ramoni; Pedro Beltrao; John Danesh; Adriana M. Hung; Kyong Mi Chang; Yan V. Sun; Jacob Joseph

doi:10.1038/s41591-021-01310-z

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

VA Million Veteran Program COVID-19 Science Initiative, Liam Gaziano, Claudia Giambartolomei, Alexandre C. Pereira, Anna Gaulton, Daniel C. Posner, Sonja A. Swanson, Yuk Lam Ho, Sudha K. Iyengar, Nicole M. Kosik, Marijana Vujkovic, David R. Gagnon, A. Patrícia Bento, Inigo Barrio-Hernandez, Lars Rönnblom, Niklas Hagberg, Christian Lundtoft, Claudia Langenberg, Maik Pietzner, Dennis ValentineStefano Gustincich, Gian Gaetano Tartaglia, Elias Allara, Praveen Surendran, Stephen Burgess, Jing Hua Zhao, James E. Peters, Bram P. Prins, Emanuele Di Angelantonio, Poornima Devineni, Yunling Shi, Kristine E. Lynch, Scott L. DuVall, Helene Garcon, Lauren O. Thomann, Jin J. Zhou, Bryan R. Gorman, Jennifer E. Huffman, Christopher J. O’Donnell, Philip S. Tsao, Jean C. Beckham, Saiju Pyarajan, Sumitra Muralidhar, Grant D. Huang, Rachel Ramoni, Pedro Beltrao, John Danesh, Adriana M. Hung, Kyong Mi Chang, Yan V. Sun, Jacob Joseph

Epidemiology

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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 × 10⁻⁶; IFNAR2, P = 9.8 × 10⁻¹¹ and IL-10RB, P = 2.3 × 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.

Original language	English
Pages (from-to)	668-676
Number of pages	9
Journal	Nature Medicine
Volume	27
Issue number	4
DOIs	https://doi.org/10.1038/s41591-021-01310-z
Publication status	Published - 9 Apr 2021

Bibliographical note

Funding Information:
We are grateful to the Host Genetic Initiative for making their data publicly available (full acknowledgements can be found at https://www.covid19hg.org/acknowledgements/). This research is based on data from the MVP, Office of Research and Development, VA and was supported by award no. MVP035. This research was also supported by additional Department of Veterans Affairs awards grant no. MVP001. This publication does not represent the views of the Department of Veteran Affairs or the US Government. Full acknowledgements for the VA MVP COVID-19 Science Initiative can be found in Supplementary Methods. C.G. has received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 754490, MINDED project. A.G., P.B. and A.R.L. are funded by the Member States of the European Molecular Biology Laboratory. I.B.-H. received funding from Open Targets (grant agreement OTAR-044). The Fenland study59 is funded by the Medical Research Council (MC_UU_12015/1); we are grateful to all the volunteers and to the General Practitioners and practice staff for assistance with recruitment; we thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams; we further acknowledge support for genomics from the Medical Research Council (MC_PC_13046); proteomic measurements were supported and governed by a collaboration agreement between the University of Cambridge and Somalogic. J.E.P. is supported by UK Research and Innovation Fellowship at Health Data Research UK (MR/S004068/2). L.R., N.H. and C.L. are supported by the Swedish Research Council. E.A. was supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant no. 116074 and by the British Heart Foundation Programme grant RG/18/13/33946. We thank A. Wood for feedback on statistical analyses used in the paper. We thank the INTERVAL Study investigators, co-ordination team and the epidemiology field, data and laboratory teams, who were supported by core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014) (the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care) and the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). This work was also supported by Health Data Research UK, which is funded by the UK Medical Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the British Heart Foundation and Wellcome. J.D. holds a British Heart Foundation Professorship and an NIHR Senior Investigator Award.

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© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19Final published version, 8.92 MBLicence: CC BY

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VA Million Veteran Program COVID-19 Science Initiative, Gaziano, L., Giambartolomei, C., Pereira, A. C., Gaulton, A., Posner, D. C., Swanson, S. A., Ho, Y. L., Iyengar, S. K., Kosik, N. M., Vujkovic, M., Gagnon, D. R., Bento, A. P., Barrio-Hernandez, I., Rönnblom, L., Hagberg, N., Lundtoft, C., Langenberg, C., Pietzner, M., ... Joseph, J. (2021). Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19. Nature Medicine, 27(4), 668-676. https://doi.org/10.1038/s41591-021-01310-z

@article{c9a83a015d6844a5bc727ede15d09571,

title = "Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19",

abstract = "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 × 10−6; IFNAR2, P = 9.8 × 10−11 and IL-10RB, P = 2.3 × 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.",

author = "{VA Million Veteran Program COVID-19 Science Initiative} and Liam Gaziano and Claudia Giambartolomei and Pereira, {Alexandre C.} and Anna Gaulton and Posner, {Daniel C.} and Swanson, {Sonja A.} and Ho, {Yuk Lam} and Iyengar, {Sudha K.} and Kosik, {Nicole M.} and Marijana Vujkovic and Gagnon, {David R.} and Bento, {A. Patr{\'i}cia} and Inigo Barrio-Hernandez and Lars R{\"o}nnblom and Niklas Hagberg and Christian Lundtoft and Claudia Langenberg and Maik Pietzner and Dennis Valentine and Stefano Gustincich and Tartaglia, {Gian Gaetano} and Elias Allara and Praveen Surendran and Stephen Burgess and Zhao, {Jing Hua} and Peters, {James E.} and Prins, {Bram P.} and Angelantonio, {Emanuele Di} and Poornima Devineni and Yunling Shi and Lynch, {Kristine E.} and DuVall, {Scott L.} and Helene Garcon and Thomann, {Lauren O.} and Zhou, {Jin J.} and Gorman, {Bryan R.} and Huffman, {Jennifer E.} and O{\textquoteright}Donnell, {Christopher J.} and Tsao, {Philip S.} and Beckham, {Jean C.} and Saiju Pyarajan and Sumitra Muralidhar and Huang, {Grant D.} and Rachel Ramoni and Pedro Beltrao and John Danesh and Hung, {Adriana M.} and Chang, {Kyong Mi} and Sun, {Yan V.} and Jacob Joseph",

note = "Funding Information: We are grateful to the Host Genetic Initiative for making their data publicly available (full acknowledgements can be found at https://www.covid19hg.org/acknowledgements/). This research is based on data from the MVP, Office of Research and Development, VA and was supported by award no. MVP035. This research was also supported by additional Department of Veterans Affairs awards grant no. MVP001. This publication does not represent the views of the Department of Veteran Affairs or the US Government. Full acknowledgements for the VA MVP COVID-19 Science Initiative can be found in Supplementary Methods. C.G. has received funding from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Program under the Marie Sk{\l}odowska-Curie grant agreement no. 754490, MINDED project. A.G., P.B. and A.R.L. are funded by the Member States of the European Molecular Biology Laboratory. I.B.-H. received funding from Open Targets (grant agreement OTAR-044). The Fenland study59 is funded by the Medical Research Council (MC_UU_12015/1); we are grateful to all the volunteers and to the General Practitioners and practice staff for assistance with recruitment; we thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams; we further acknowledge support for genomics from the Medical Research Council (MC_PC_13046); proteomic measurements were supported and governed by a collaboration agreement between the University of Cambridge and Somalogic. J.E.P. is supported by UK Research and Innovation Fellowship at Health Data Research UK (MR/S004068/2). L.R., N.H. and C.L. are supported by the Swedish Research Council. E.A. was supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant no. 116074 and by the British Heart Foundation Programme grant RG/18/13/33946. We thank A. Wood for feedback on statistical analyses used in the paper. We thank the INTERVAL Study investigators, co-ordination team and the epidemiology field, data and laboratory teams, who were supported by core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014) (the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care) and the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). This work was also supported by Health Data Research UK, which is funded by the UK Medical Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the British Heart Foundation and Wellcome. J.D. holds a British Heart Foundation Professorship and an NIHR Senior Investigator Award. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = apr,

day = "9",

doi = "10.1038/s41591-021-01310-z",

language = "English",

volume = "27",

pages = "668--676",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

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VA Million Veteran Program COVID-19 Science Initiative, Gaziano, L, Giambartolomei, C, Pereira, AC, Gaulton, A, Posner, DC, Swanson, SA, Ho, YL, Iyengar, SK, Kosik, NM, Vujkovic, M, Gagnon, DR, Bento, AP, Barrio-Hernandez, I, Rönnblom, L, Hagberg, N, Lundtoft, C, Langenberg, C, Pietzner, M, Valentine, D, Gustincich, S, Tartaglia, GG, Allara, E, Surendran, P, Burgess, S, Zhao, JH, Peters, JE, Prins, BP, Angelantonio, ED, Devineni, P, Shi, Y, Lynch, KE, DuVall, SL, Garcon, H, Thomann, LO, Zhou, JJ, Gorman, BR, Huffman, JE, O’Donnell, CJ, Tsao, PS, Beckham, JC, Pyarajan, S, Muralidhar, S, Huang, GD, Ramoni, R, Beltrao, P, Danesh, J, Hung, AM, Chang, KM, Sun, YV & Joseph, J 2021, 'Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19', Nature Medicine, vol. 27, no. 4, pp. 668-676. https://doi.org/10.1038/s41591-021-01310-z

TY - JOUR

T1 - Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

AU - VA Million Veteran Program COVID-19 Science Initiative

AU - Gaziano, Liam

AU - Giambartolomei, Claudia

AU - Pereira, Alexandre C.

AU - Gaulton, Anna

AU - Posner, Daniel C.

AU - Swanson, Sonja A.

AU - Ho, Yuk Lam

AU - Iyengar, Sudha K.

AU - Kosik, Nicole M.

AU - Vujkovic, Marijana

AU - Gagnon, David R.

AU - Bento, A. Patrícia

AU - Barrio-Hernandez, Inigo

AU - Rönnblom, Lars

AU - Hagberg, Niklas

AU - Lundtoft, Christian

AU - Langenberg, Claudia

AU - Pietzner, Maik

AU - Valentine, Dennis

AU - Gustincich, Stefano

AU - Tartaglia, Gian Gaetano

AU - Allara, Elias

AU - Surendran, Praveen

AU - Burgess, Stephen

AU - Zhao, Jing Hua

AU - Peters, James E.

AU - Prins, Bram P.

AU - Angelantonio, Emanuele Di

AU - Devineni, Poornima

AU - Shi, Yunling

AU - Lynch, Kristine E.

AU - DuVall, Scott L.

AU - Garcon, Helene

AU - Thomann, Lauren O.

AU - Zhou, Jin J.

AU - Gorman, Bryan R.

AU - Huffman, Jennifer E.

AU - O’Donnell, Christopher J.

AU - Tsao, Philip S.

AU - Beckham, Jean C.

AU - Pyarajan, Saiju

AU - Muralidhar, Sumitra

AU - Huang, Grant D.

AU - Ramoni, Rachel

AU - Beltrao, Pedro

AU - Danesh, John

AU - Hung, Adriana M.

AU - Chang, Kyong Mi

AU - Sun, Yan V.

AU - Joseph, Jacob

N1 - Funding Information: We are grateful to the Host Genetic Initiative for making their data publicly available (full acknowledgements can be found at https://www.covid19hg.org/acknowledgements/). This research is based on data from the MVP, Office of Research and Development, VA and was supported by award no. MVP035. This research was also supported by additional Department of Veterans Affairs awards grant no. MVP001. This publication does not represent the views of the Department of Veteran Affairs or the US Government. Full acknowledgements for the VA MVP COVID-19 Science Initiative can be found in Supplementary Methods. C.G. has received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 754490, MINDED project. A.G., P.B. and A.R.L. are funded by the Member States of the European Molecular Biology Laboratory. I.B.-H. received funding from Open Targets (grant agreement OTAR-044). The Fenland study59 is funded by the Medical Research Council (MC_UU_12015/1); we are grateful to all the volunteers and to the General Practitioners and practice staff for assistance with recruitment; we thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams; we further acknowledge support for genomics from the Medical Research Council (MC_PC_13046); proteomic measurements were supported and governed by a collaboration agreement between the University of Cambridge and Somalogic. J.E.P. is supported by UK Research and Innovation Fellowship at Health Data Research UK (MR/S004068/2). L.R., N.H. and C.L. are supported by the Swedish Research Council. E.A. was supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant no. 116074 and by the British Heart Foundation Programme grant RG/18/13/33946. We thank A. Wood for feedback on statistical analyses used in the paper. We thank the INTERVAL Study investigators, co-ordination team and the epidemiology field, data and laboratory teams, who were supported by core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014) (the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care) and the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). This work was also supported by Health Data Research UK, which is funded by the UK Medical Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the British Heart Foundation and Wellcome. J.D. holds a British Heart Foundation Professorship and an NIHR Senior Investigator Award. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2021/4/9

Y1 - 2021/4/9

N2 - 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 × 10−6; IFNAR2, P = 9.8 × 10−11 and IL-10RB, P = 2.3 × 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.

AB - 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 × 10−6; IFNAR2, P = 9.8 × 10−11 and IL-10RB, P = 2.3 × 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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U2 - 10.1038/s41591-021-01310-z

DO - 10.1038/s41591-021-01310-z

M3 - Article

C2 - 33837377

AN - SCOPUS:85104295826

SN - 1078-8956

VL - 27

SP - 668

EP - 676

JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -

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

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