Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19
Gundula Povysil, Guillaume Butler‐Laporte, Ning Shang, Chen Wang, Atlas Khan, Manal Alaamery, Tomoko Nakanishi, Sirui Zhou, Vincenzo Forgetta, Robert 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 Al-Afghani, Bader Alghamdi, Mansour Almutairi, Ebrahim Mahmoud, Leen Abu‐Safieh, Hadeel El Bardisy, Fawz S. Al Harthi, Abdulraheem Alshareef, Bandar A. Suliman, Saleh A. Alqahtani, Abdulaziz Almalik, May Alrashed, Salam Massadeh, Vincent Mooser, Mark Lathrop, Fawzy Mohamed, Yaseen M. Arabi, Hamdi Mbarek, Chadi Saad, Wadha Al‐Muftah, Junghyun Jung, Serghei Mangul, Radja Badji, Asma Al Thani, Said I. Ismail, Ali G. Gharavi, Malak Abedalthagafi, J. Brent Richards, David B. Goldstein, Krzysztof Kiryluk
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 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 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 found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.