Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19

Povysil, Gundula; Butler-Laporte, Guillaume; Shang, Ning; Weng, Chen; Khan, Atlas; Alaamery, Manal; Nakanishi, Tomoko; Zhou, Sirui; Forgetta, Vincenzo; Eveleigh, Robert; Bourgey, Mathieu; Aziz, Naveed; Jones, Steven; Knoppers, Bartha; Scherer, Stephen; Strug, Lisa; Lepage, Pierre; Ragoussis, Jiannis; Bourque, Guillaume; Alghamdi, Jahad; Aljawini, Nora; Albes, Nour; Al-Afghani, Hani M.; Alghamdi, Bader; Almutair, Mansour; Mahmoud, Ebrahim Sabri; Safie, Leen Abu; Bardisy, Hadeel El; Al Harthi, Fawz S.; Alshareef, Abdulraheem; Suliman, Bandar Ali; Alqahtani, Saleh; AlMalik, Abdulaziz; Alrashed, May M.; Massadeh, Salam; Mooser, Vincent; Lathrop, Mark; Arabi, Yaseen; Mbarek, Hamdi; Saad, Chadi; Al-Muftah, Wadha; Badji, Radja; Al Thani, Asma; Ismail, Said I.; Gharavi, Ali G.; Abedalthagafi, Malak S.; Richards, J Brent; Goldstein, David B.; Kiryluk, Krzysztof

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.