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

Gundula Povysil; Guillaume Butler‐Laporte; Ning Shang; Chen Wang; Atlas Khan; Manal A. Alaamery; Tomoko Nakanishi; Sirui Zhou; Vincenzo Forgetta; Robert J. M. Eveleigh; Mathieu Bourgey; Naveed Aziz; Steven J.M. Jones; Bartha Maria Knoppers; Stephen W. Scherer; Lisa J. Strug; Pierre Lepage; Jiannis Ragoussis; Guillaume Bourque; Jahad Alghamdi; Nora Aljawini; Nour Albes; Hani M. Al-Afghani; Bader M. Alghamdi; Mansour S. Almutairi; Ebrahim Mahmoud; Leen Abu‐Safieh; Hadeel Elbardisy; Fawz S. Al Harthi; Abdulraheem Alshareef

doi:10.1172/jci147834

Genetic & Genomic MedicineJournal of Clinical InvestigationMay 27, 2021

Peer-reviewed journal article

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

Gundula Povysil iD, Guillaume Butler‐Laporte iD, Ning Shang iD, Chen Wang iD, Atlas Khan iD, Manal A. Alaamery iD, Tomoko Nakanishi iD, Sirui Zhou iD, Vincenzo Forgetta iD, Robert J. M. Eveleigh iD, Mathieu Bourgey iD, Naveed Aziz, Steven J.M. Jones iD, Bartha Maria Knoppers iD, Stephen W. Scherer iD, Lisa J. Strug iD, Pierre Lepage iD, Jiannis Ragoussis iD, Guillaume Bourque iD, Jahad Alghamdi iD, Nora Aljawini, Nour Albes, Hani M. Al-Afghani iD, Bader M. Alghamdi iD, Mansour S. Almutairi iD, , Krzysztof Kiryluk iD

Abstract

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.

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