. 2021 Jul 15;131(14):e147834.

doi: 10.1172/JCI147834.

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19

Gundula Povysil¹, Guillaume Butler-Laporte^{2

3}, Ning Shang⁴, Chen Wang⁴, Atlas Khan⁴, Manal Alaamery^{5

6}, Tomoko Nakanishi^{2

7

8}, Sirui Zhou², Vincenzo Forgetta², Robert Jm Eveleigh^{9

10}, Mathieu Bourgey^{9

10}, Naveed Aziz¹¹, Steven Jm Jones¹¹, Bartha Knoppers¹¹, Stephen W Scherer¹¹, Lisa J Strug¹¹, Pierre Lepage⁹, Jiannis Ragoussis^{7

9}, Guillaume Bourque^{7

10

9}, Jahad Alghamdi, Nora Aljawini¹², Nour Albes¹², Hani M Al-Afghani¹³, Bader Alghamdi⁵, Mansour S Almutairi⁵, Ebrahim Sabri Mahmoud¹⁴, Leen Abu-Safieh¹⁵, Hadeel El Bardisy¹⁵, Fawz S Al Harthi¹⁵, Abdulraheem Alshareef¹⁶, Bandar Ali Suliman¹⁶, Saleh A Alqahtani^{17

18}, Abdulaziz Almalik¹⁹, May M Alrashed²⁰, Salam Massadeh^{5

6}, Vincent Mooser⁷, Mark Lathrop^{7

11

9}, Mohamed Fawzy¹⁵, Yaseen M Arabi¹⁴, Hamdi Mbarek²¹, Chadi Saad²¹, Wadha Al-Muftah²¹, Junghyun Jung^{22

23}, Serghei Mangul²², Radja Badji²¹, Asma Al Thani²¹, Said I Ismail²¹, Ali G Gharavi^{1

4

24}, Malak S Abedalthagafi¹⁵, J Brent Richards^{2

3

8

25}, David B Goldstein^{1

26}, Krzysztof Kiryluk^{1

4}

Affiliations

¹ Institute for Genomic Medicine, Columbia University, New York, New York, USA.
² Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
³ Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montréal, Québec, Canada.
⁴ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.
⁵ Developmental Medicine Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
⁶ Saudi Human Genome Project at King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
⁷ Department of Human Genetics, McGill University, Montréal, Québec, Canada.
⁸ Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁹ Canadian Centre for Computational Genomics, McGill University, Montréal, Québec, Canada.
¹⁰ McGill Genome Center, McGill University, Montréal, Québec, Canada.
¹¹ Canadian COVID Genomics Network, HostSeq Project, Canada.
¹² KACST-BWH Centre of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
¹³ Laboratory Department, Security Forces Hospital, General Directorate of Medical Services, Ministry of Interior, Makkah, Saudi Arabia.
¹⁴ Ministry of the National Guard Health Affairs, King Abdullah International Medical Research Center and King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
¹⁵ Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
¹⁶ College of Applied Medical Sciences, Taibah University, Madina, Saudi Arabia.
¹⁷ Liver Transplant Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
¹⁸ Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA.
¹⁹ Life Science and Environmental Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
²⁰ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
²¹ Qatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar.
²² Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
²³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
²⁴ Center for Precision Medicine and Genomics, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.
²⁵ Department of Twin Research, King's College London, London, United Kingdom.
²⁶ Department of Genetics & Development, Columbia University, New York, New York, USA.

PMID: 34043590
PMCID: PMC8279578
DOI: 10.1172/JCI147834

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19

Gundula Povysil et al. J Clin Invest. 2021.

. 2021 Jul 15;131(14):e147834.

doi: 10.1172/JCI147834.

Authors

Affiliations

¹ Institute for Genomic Medicine, Columbia University, New York, New York, USA.
² Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
³ Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montréal, Québec, Canada.
⁴ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.
⁵ Developmental Medicine Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
⁶ Saudi Human Genome Project at King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
⁷ Department of Human Genetics, McGill University, Montréal, Québec, Canada.
⁸ Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁹ Canadian Centre for Computational Genomics, McGill University, Montréal, Québec, Canada.
¹⁰ McGill Genome Center, McGill University, Montréal, Québec, Canada.
¹¹ Canadian COVID Genomics Network, HostSeq Project, Canada.
¹² KACST-BWH Centre of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
¹³ Laboratory Department, Security Forces Hospital, General Directorate of Medical Services, Ministry of Interior, Makkah, Saudi Arabia.
¹⁴ Ministry of the National Guard Health Affairs, King Abdullah International Medical Research Center and King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
¹⁵ Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
¹⁶ College of Applied Medical Sciences, Taibah University, Madina, Saudi Arabia.
¹⁷ Liver Transplant Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
¹⁸ Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA.
¹⁹ Life Science and Environmental Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
²⁰ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
²¹ Qatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar.
²² Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
²³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
²⁴ Center for Precision Medicine and Genomics, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.
²⁵ Department of Twin Research, King's College London, London, United Kingdom.
²⁶ Department of Genetics & Development, Columbia University, New York, New York, USA.

PMID: 34043590
PMCID: PMC8279578
DOI: 10.1172/JCI147834

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.

Keywords: Genetic variation; Genetics; Infectious disease.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

**Figure 1. Power curves for a gene set–based collapsing test.**
Power calculations for the Columbia COVID-19 Biobank cohort of 480 severe cases and 9,589 population controls were performed using the samplesizeCMH R package for a dominant model at α = 0.05 and a range of odds ratios. Results are shown for the pLOF model and the model including pLOF and missense variants. Because power is influenced by the carrier frequency, we have adequate power to detect effect sizes as small as 1.5 for the model including missense variants compared with 5.5 for the pLOF-only model.

See this image and copyright information in PMC

Update of

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19.
Povysil G, Butler-Laporte G, Shang N, Weng C, Khan A, Alaamery M, Nakanishi T, Zhou S, Forgetta V, Eveleigh R, Bourgey M, Aziz N, Jones S, Knoppers B, Scherer S, Strug L, Lepage P, Ragoussis J, Bourque G, Alghamdi J, Aljawini N, Albes N, Al-Afghani HM, Alghamdi B, Almutair M, Mahmoud ES, Safie LA, Bardisy HE, Al Harthi FS, Alshareef A, Suliman BA, Alqahtani S, AlMalik A, Alrashed MM, Massadeh S, Mooser V, Lathrop M, Arabi Y, Mbarek H, Saad C, Al-Muftah W, Badji R, Al Thani A, Ismail SI, Gharavi AG, Abedalthagafi MS, Richards JB, Goldstein DB, Kiryluk K. Povysil G, et al. medRxiv [Preprint]. 2020 Dec 21:2020.12.18.20248226. doi: 10.1101/2020.12.18.20248226. medRxiv. 2020. Update in: J Clin Invest. 2021 Jul 15;131(14):147834. doi: 10.1172/JCI147834. PMID: 33398295 Free PMC article. Updated. Preprint.

Comment in

Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia.
Zhang Q, Cobat A, Bastard P, Notarangelo LD, Su HC, Abel L, Casanova JL; COVID Human Genetic Effort (CHGE). Zhang Q, et al. J Clin Invest. 2021 Aug 2;131(15):e152474. doi: 10.1172/JCI152474. J Clin Invest. 2021. PMID: 34166232 Free PMC article. No abstract available.

References

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1. doi: 10.1101/2021.03.10.21252820. The COVID-19 Host Genetics Initiative, Ganna A. Mapping the human genetic architecture of COVID-19 by worldwide meta-analysis [preprint]. Posted on medRxiv March 12, 2021. - DOI
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Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19

Affiliations

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical