Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.
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Gaziano L, Giambartolomei C, Pereira AC, Gaulton A, Posner DC, Swanson SA, Ho Y, 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 K, Sun YV, Joseph J, Leach AR, Edwards TL, Cho K, Gaziano JM, Butterworth AS, Casas JP, VA Million Veteran Program COVID-19 Science Initiative
Nat Med 27 (4) 668-676 [2021-04-09; online 2021-04-09]
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.
PubMed 33837377
DOI 10.1038/s41591-021-01310-z
Crossref 10.1038/s41591-021-01310-z
pii: 10.1038/s41591-021-01310-z
GTEx project v.8 data
CheMBL database used to identify 1,263 human proteins as ‘actionable’ (therapeutic targets of approved or clinical-stage drugs) for SARS-COV2
https://omicscience.org/apps/covidpgwas/
HGI COVID-19 hospitalization summary statistics
PhenoScanner results for searching proteins, traits and diseases