Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19,medRxiv - Genetic and Genomic Medicine

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Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19
medRxiv - Genetic and Genomic Medicine Pub Date : 2020-12-21 , DOI: 10.1101/2020.12.18.20248226
Gundula Povysil ₁ , Guillaume Butler-Laporte _{2,

3} , Ning Shang ₄ , Chen Weng ₄ , Atlas Khan ₄ , Manal Alaamery _{5,

6,

7} , Tomoko Nakanishi _{2,

8,

9,

10} , Sirui Zhou ₂ , Vincenzo Forgetta ₂ , Robert Eveleigh _{11,

12} , Mathieu Bourgey _{11,

12} , Naveed Aziz ₁₃ , Steven Jones ₁₃ , Bartha Knoppers ₁₃ , Stephen Scherer ₁₃ , Lisa Strug ₁₃ , Pierre Lepage ₁₁ , Jiannis Ragoussis _{8,

11} , Guillaume Bourque _{8,

11,

12} , Jahad Alghamdi ₁₄ , Nora Aljawini _{5,

6,

7} , Nour Albes _{5,

6,

15} , Hani M Al-Afghani ₁₆ , Bader Alghamdi ₅ , Mansour Almutair ₅ , Ebrahim Sabri Mahmoud ₇ , Leen Abu Safie ₁₇ , Hadeel El Bardisy ₁₇ , Fawz S Al Harthi ₁₇ , Abdulraheem Alshareef ₁₆ , Bandar Ali Suliman ₁₈ , Saleh Alqahtani _{18,

19} , Abdulaziz AlMalik ₂₀ , May M Alrashed ₂₁ , Salam Massadeh _{5,

6,

7} , Vincent Mooser ₈ , Mark Lathrop _{8,

11,

13} , Yaseen Arabi _{7,

15} , Hamdi Mbarek ₂₂ , Chadi Saad ₂₂ , Wadha Al-Muftah ₂₂ , Radja Badji ₂₂ , Asma Al Thani ₂₂ , Said I Ismail ₂₂ , Ali G Gharavi _{1,

4,

23} , Malak S Abedalthagafi _{17,

20} , J Brent Richards _{2,

3,

8,

24} , David B Goldstein _{1,

25} , Krzysztof Kiryluk _{1,

4}

Affiliation

Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montréal, Québec, Canada.
Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University.
Developmental Medicine Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia.
KACST-BWH Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia.
King Abdulaziz City for Science and Technology (KACST)-Saudi Human Genome Satellite Lab at Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia.
Department of Human Genetics, McGill University, Montréal, Canada.
Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Research Fellow, Japan Society for the Promotion of Science, Japan.
Canadian Centre for Computational Genomics, McGill University, Montreal, Canada.
McGill Genome Center, McGill University, Montréal, Québec, Canada.
Canadian COVID Genomics Network, HostSeq Project, Canada.
Saudi Biobank, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
Intensive Care Department, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia.
Laboratory Department, Security Forces Hospital, General Directorate of Medical Services, Ministry of Interior, Clinical Laboratory Sciences, Taibah University, Madina, Saudi Arabia.
Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
The Liver Transplant Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
The Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, USA.
Life Science and Environmental Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
Qatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar.
Center for Precision Medicine and Genomics. Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.
Department of Twin Research, King's College London, London, UK.
Department of Genetics & Development, Columbia University, New York, New York, USA.

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.

中文翻译：

无法复制I型IFN免疫基因中罕见的功能丧失变异与严重COVID-19的关联

最近的一份报告发现，在依赖TLR3和IRF7的I型IFN途径中的13个候选基因中，罕见的预测功能丧失（pLOF）变异可解释高达3.5％的严重COVID-19病例。我们对四个独立的COVID-19生物库进行了1,934例COVID-19病例（713例重症和1,221例轻症）和15,251例血统匹配的人群对照全基因组或全基因组测序。然后，我们测试了这13个基因中的罕见pLOF变体是否与严重的COVID-19相关。在713例严重COVID-19病例中，我们在这些基因中仅发现了一个罕见的pLOF突变，与人群对照或轻度COVID-19病例相比，在严重病例中没有发现pLOF富集。我们没有证据表明拟议的13个候选基因中罕见的功能丧失变异与严重的COVID-19结果相关。

更新日期：2020-12-21

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