Genetic mechanisms of critical illness in COVID-19

Pairo-Castineira, Erola; Clohisey, Sara; Klarić, Lucija; Bretherick, Andrew D.; Rawlik, Konrad; Pasko, Dorota; Walker, Susan; Parkinson, Nick; Fourman, Max Head; Russell, Clark D; Furniss, James J; Richmond, Anne; Gountouna, Viktoria-Eleni; Wrobel, Nicola; Harrison, David A; Wang, Bo; Wu, Yang; Meynert, Alison; Griffiths, Fiona; Oosthuyzen, Wilna; Kousathanas, Athanasios; Moutsianas, Loukas; Yang, Zhijian; Zhai, Ranran; Zheng, Chenqing; Grimes, Graeme R.; Beale, Rupert; Millar, Jonathan; Shih, Barbara; Keating, Seán; Zechner, Marie; Haley, Chris; Porteous, David J.; Hayward, Caroline; Yang, Jian; Knight, Julian C.; Summers, Charlotte; Shankar-Hari, Manu; Klenerman, Paul; Turtle, Lance; Ho, Antonia; Moore, Shona C.; Hinds, C. J.; Horby, Peter; Nichol, Alistair; Maslove, David; Ling, Lowell; McAuley, Daniel F.; Montgomery, Hugh; Walsh, Timothy; Pereira, Alexandre C.; Renieri, Alessandra; Shen, Xia; Ponting, Chris P.; Fawkes, Angie; Tenesa, Albert; Caulfield, Mark; Scott, Richard; Rowan, Kathy; Murphy, Lee; Openshaw, Peter; Semple, Malcolm G; Law, Andy; Vitart, Véronique; Wilson, James F.; Baillie, J Kenneth

doi:10.1038/s41586-020-03065-y

Cited by 1,062 publications

(1,095 citation statements)

References 93 publications

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“…This indicates the necessity of expanding GWAS to more comprehensively explore the polygenic architecture for COVID-19 clinical outcome. In addition to FURIN and components of the immune system, variants in ACE2, TMPRSS2, and BSG harbor genetic variants that are significantly enriched in COVID-19 patients and are predicted to influence susceptibility to SARS-CoV-2 infection (Benetti et al, 2020;Pairo-Castineira et al, 2020;Russo et al, 2020). Such discoveries could help to generate hypotheses for drug repurposing, identify individuals at unusually high or low risk, and contribute to the global knowledge of the biology of SARS-CoV-2 infection and disease.…”

Section: Discussionmentioning

confidence: 99%

Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

Dobrindt¹,

Hoagland²,

Seah³

et al. 2021

Stem Cell Reports

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The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant inter-individual variability. In addition to showing more disease in males, the elderly, and individuals with underlying comorbidities, SARS-CoV-2 can seemingly render healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants impact vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR-engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single nucleotide polymorphism (rs4702), common in the population, and located in the 3’UTR of the protease FURIN, impacts alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can impact viral infection, and thus contribute to clinical heterogeneity in COVID-19. Ongoing genetic studies will help to identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs.

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Section: Discussionmentioning

confidence: 99%

Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

Dobrindt¹,

Hoagland²,

Seah³

et al. 2021

Stem Cell Reports

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“…Genomic analysis of critically ill COVID-19 patients revealed deficiency or alterations in type I interferon signaling (21)(22)(23). Imbalanced cytokine and interferon responses in COVID-19 patients were described (27,70,71).…”

Section: Profiling Inducible Transcription Factors Of Type I Interfermentioning

confidence: 99%

Profiling transcription factor sub-networks in type I interferon signaling and in response to SARS-CoV-2 infection

2021

Preprint

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Type I interferons (IFN α/β) play a central role in innate immunity to respiratory viruses, including coronaviruses. Genetic defects in type I interferon signaling were reported in a significant proportion of critically ill CoOVID-19 patients. Extensive studies on interferon-induced intracellular signal transduction pathways led to the elucidation of the Jak-Stat pathway. Furthermore, advances in gene expression profiling by microarrays have revealed that type I interferon rapidly induced multiple transcription factor mRNA levels. In this study, transcription factor profiling in the transcriptome was used to gain novel insights into the role of inducible transcription factors in response to type I interferon signaling in immune cells and in lung epithelial cells after SARS-CoV-2 infection. Modeling the interferon-inducible transcription factor mRNA data in terms of distinct sub-networks based on biological functions such as antiviral response, immune modulation, and cell growth revealed enrichment of specific transcription factors in mouse and human immune cells. The evolutionarily conserved core type I interferon gene expression consists of the inducible transcriptional factor mRNA of the antiviral response sub-network and enriched in granulocytes. Analysis of the type I interferon-inducible transcription factor sub-networks as distinct protein-protein interaction pathways revealed insights into the role of critical hubs in signaling. Interrogation of multiple microarray datasets revealed that SARS-CoV-2 induced high levels of IFN-beta and interferon-inducible transcription factor mRNA in human lung epithelial cells. Transcription factor mRNA of the three major sub-networks regulating antiviral, immune modulation, and cell growth were differentially regulated in human lung epithelial cell lines after SARS-CoV-2 infection and in the tissue samples of COVID-19 patients. A subset of type I interferon-inducible transcription factors and inflammatory mediators were specifically enriched in the lungs and neutrophils of Covid-19 patients. The emerging complex picture of type I IFN transcriptional regulation consists of a rapid transcriptional switch mediated by the Jak-Stat cascade and a graded output of the inducible transcription factor activation that enables temporal regulation of gene expression.

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“…This initiative has specifically contributed to several published genome-wide association studies by releasing global metaanalyses immediately and publicly for all to use, including an early study of more than 1,600 cases of severe COVID-19 with respiratory failure from Italy and Spain, 6 which provided the first evidence of a 3p21.31 gene cluster and the ABO locus in patients with COVID-19 with respiratory failure, and a larger study from the United Kingdom of 2,200 patients admitted to the intensive care unit, 7 which implicated several new genes including TYK2, DPP9, and the OAS1/2/3 gene cluster. By the end of 2020, 48 groups around the world had contributed genetic association results to the COVID-19 Host Genetics Initiative and results publicly released in January 2021 provide the largest view of both severity and susceptibility, with more than 14,000 hospitalized cases and nearly 50,000 polymerase chain reaction (PCR)-positive cases overall included.…”

Section: The Covid-19 Host Genetics Initiative: a Worldwide Pandemic mentioning

confidence: 99%

The intersection of genetics and COVID-19 in 2021: preview of the 2021 Rodney Howell Symposium

Rasmussen

Abul‐Husn

Casanova

et al. 2021

Genetics in Medicine

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Coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first identified in late 2019 in China, has spread quickly throughout the world, resulting in significant morbidity and mortality. As of 21 January 2021, over 96 million cases and over 2 million deaths have occurred globally, with over 24 million cases and over 400,000 deaths in the United States alone (https://coronavirus.jhu.edu/). In addition to the direct effects of COVID-19 on illnesses and deaths, interventions to decrease transmission of SARS-CoV-2 have had devastating effects on preventive health services, education of children, economies of many countries, and biomedical research outside of COVID-19, among others. The recent availability of safe and effective COVID-19 vaccines is encouraging; however, it is expected that herd immunity and a return to normal life are several months away. Genetics in Medicine has organized the Rodney Howell Symposium for the upcoming 2021 American College of Medical Genetics and Genomics Meeting (April 2021), co-chaired by Drs. Robert Steiner and Michael Murray, to highlight some areas where the COVID-19 pandemic and the human genetics community have intersected. The pandemic year of 2020 has left a pervasive mark on all human communities, and the human genetics and genomics community is no different; this is made apparent by the breadth of topics covered by this expert group. The following are brief summaries of five presentations to be discussed at the Symposium on 16 April entitled "2021 COVID-19 State of the Science."

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Genetic mechanisms of critical illness in COVID-19

Cited by 1,062 publications

References 93 publications

Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

Profiling transcription factor sub-networks in type I interferon signaling and in response to SARS-CoV-2 infection

The intersection of genetics and COVID-19 in 2021: preview of the 2021 Rodney Howell Symposium

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