biostudies-literatureUnknownMoll TNIDDK NIH HHSNHLBI NIH HHSNational Institute for Health Research (NIHR)NHGRI NIH HHSMotor Neurone Disease AssociationWellcome TrustBiotechnology and Biological Sciences Research CouncilNIH HHSNew therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic, caused by the SARS-CoV-2 virus. Genome-wide association studies (GWAS) have identified risk loci, but some loci are associated with co-morbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins; EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. Lung-specific eQTLs were identified from GTEx (v7) for each of the 332 host proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed an asbioRxiv : the preprint server for biology2022.03.06.483172https://www.ebi.ac.uk/biostudies/studies/S-EPMC8923113biostudies-literatureLow expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication.PMC8923113216596/Z/19/ZCooper-Knock/Oct20/899-792203141/Z/16/ZP30 DK116074P50 HL083800R01 HL122939UM1 HG00944210077BB/S009566/1NF-SI-0617-10077S10 OD025212R01 HL101388Cooper-Knock JFerraiuolo LMoll TPeden AShaw PJAzzouz MZhang SOdon VFranklin JSouza CDSCollins MOGordon DKrogan NSnyder MPHarvey CGraves EMarshall JNGRehwinkel JfalseLow expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication.New therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic, caused by the SARS-CoV-2 virus. Genome-wide association studies (GWAS) have identified risk loci, but some loci are associated with co-morbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins; EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. Lung-specific eQTLs were identified from GTEx (v7) for each of the 332 host proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed an as2022-01-01T00:00:00Z2022 Mar2025-05-18T12:32:28.533Z2025-05-18T12:32:28.533ZS-EPMC89231133529129410.1101/2022.03.06.483172