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.
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Data availability
GTEx project v.8 data are available at https://gtexportal.org/home/. CheMBL database data are available at https://www.ebi.ac.uk/chembl/. Fenland-SomaLogic protein GWAS data are available at https://omicscience.org/apps/covidpgwas/. HGI COVID-19 hospitalization summary statistics are available at https://www.covid19hg.org/. PhenoScanner results are available at http://www.phenoscanner.medschl.cam.ac.uk/.
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Acknowledgements
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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J.P.C., A.S.B. and J.M.G. conceived the study design. A.G., A.P.B. and A.R.L. defined the actionable genome and identified and curated drug information relating to SARS-CoV-2; P.B. and I.B.-H. provided biological annotation relating to SARS-CoV-2; C.G. performed stepwise conditional analysis on GTEx raw data; D.P. tested associations for COVID-19 in MVP; L.G. and J.H.Z. performed meta-analysis of HGI and MVP; L.G. performed MR analysis; L.G. and C.G. performed colocalization analyses; L.G. and B.P.P. performed conditional analysis on Olink proteins; L.G. and E.A. performed phenome-wide scans; A.C.P. performed pathway enrichment analysis; J.N.D., A.S.B. and J.E.P. provided INTERVAL data; several authors were involved in the curation of MVP data; L.G., C.G., A.C.P., A.G., D.P., A.S.B. and J.P.C. wrote the manuscript. J.P.C. oversaw all analyses. All authors critically reviewed the manuscript.
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Extended data
Extended Data Fig. 1 Regional association plots for rs2266590 and rs2239573 for plasma IL-10RB, IL10RB gene expression, and COVID-19 hospitalization.
This region was investigated further using IL-10RB pQTL data because it was available on an independent proteomic platform (Olink) and results using eQTL instruments for IL10RB passed our Mendelian randomization P value threshold (0.05 Bonferroni-corrected for 1,263 actionable druggable genes) and colocalization threshold (PP.H4 > 0.8). a, rs2266590 as pQTL for plasma IL-10RB measured by Olink in 4,998 INTERVAL participants. b, rs2266590 as an eQTL for IL10RB expression tibial artery tissue (N = 584). c, rs2266590 in COVID-19 hospitalization. d, rs2239573 as pQTL for plasma IL-10RB (after adjusting for rs2266590) measured by Olink in 4,998 INTERVAL participants. e, rs2239573 as an eQTL for IL10RB expression in whole blood (N = 670). f, rs2239573 in COVID-19 hospitalization. a colocalizes with b (PP.H4 = 0.97), and d colocalizes with e (PP.H4 = 1.00). The two variants highlighted in this figure (rs2266590 and rs2239573), which are associated with gene expression and plasma protein levels of IL-10RB, are not associated with COVID-19 hospitalization (P = 0.85 for rs2266590, P = 0.66 for rs2239573).
Extended Data Fig. 2 Enrichment analysis of peak eQTLs for IFNAR2-IL10RB and ACE2 regions.
Results obtained from association analysis using all 49 tissues from GTEx V8 contrasted against variant genotypes in an additive model. Dotplot of over-representation analysis using all significant (p < 0.05) differentially expressed (DE) genes (476 for rs13050728; 1,397 for rs4830976) for a, rs13050728, peak eQTL in the IFNAR2-IL10RB region and b, rs4830976, peak eQTL in the ACE2 region. Count = number of DE genes part of the enriched pathway. Gene ratio is the rate of DE genes represented in each pathway.
Extended Data Fig. 3 Regional association plots for cis-variants associated with ACE2 gene expression or ACE2 plasma protein levels, and their association with COVID-19 hospitalization.
a, rs4830976 as an eQTL for ACE2 expression in brain frontal cortex tissue (N = 175). b, rs4830976 in COVID-19 hospitalization (N = 1,377,758). c, rs5935998 as the primary pQTL for plasma ACE2 measured by Oink in 4,998 INTERVAL participants d, rs5935998 in COVID-19 hospitalization e, rs4646156 as the secondary pQTL (that is after adjusting for rs5935998) for plasma ACE2 measured by Oink in 4,998 INTERVAL participants. f, rs4646156 in COVID-19 hospitalization. a colocalizes with b (PP.H4 = 0.95), but c does not colocalize with d (PP.H4 = 0.49) and e does not colocalize with f (PP.H4 = 0.08).
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Supplementary Information
Supplementary Figs. 1 and 2, Supplementary Methods and VA Million Veteran Program COVID-19 Science Initiative members and their affiliations.
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Supplementary Tables 1–16
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Gaziano, L., Giambartolomei, C., Pereira, A.C. et al. Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19. Nat Med 27, 668–676 (2021). https://doi.org/10.1038/s41591-021-01310-z
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DOI: https://doi.org/10.1038/s41591-021-01310-z
