Genome-wide analysis in 756,646 individuals provides first genetic evidence that <i>ACE2</i> expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

Horowitz, Julie; Kosmicki, Jack A.; Damask, Amy; Sharma, Deepika; Roberts, Genevieve H.L.; Justice, Anne E.; Banerjee, Nilanjana; Coignet, Marie V.; Yadav, Ashish; Leader, Joseph B.; Marcketta, Anthony; Park, D. S.; Lanche, Rouel; Maxwell, Evan K.; Knight, Spencer C.; Bai, Xiaodong; Guturu, Harendra; Sun, Dylan; Baltzell, Asher K. Haug; Kury, Fabrício S. P.; Backman, Joshua; Girshick, Ahna R.; Ó'Dúshláine, Colm; McCurdy, Shannon R.; Partha, Raghavendran; Mansfield, Adam; Turissini, David A.; Li, A. H.; Zhang, M.; Mbatchou, Joelle; Watanabe, Kyoko; Gurski, Lauren; McCarthy, Shane; Kang, Hyun Min; Dobbyn, Lee; Stahl, Eli A.; Verma, Anurag; Sirugo, Giorgio; Ritchie, Marylyn D.; Jones, Marcus B.; Balasubramanian, Suganthi; Siminovitch, Katherine A.; Salerno, William; Shuldiner, Alan R.; Rader, Daniel J.; Mirshahi, Tooraj; Locke, Adam E.; Marchini, Jonathan; Overton, John D.; Carey, David J.; Habegger, Lukas; Cantor, Michael; Rand, Kristin A.; Hong, Eurie L.; Reid, Jeffrey G.; Ball, Catherine A.; Baras, Aris; Abecasis, Gonçalo R.; Ferreira, Manuel A. R.

doi:10.1101/2020.12.14.20248176

Cited by 42 publications

(29 citation statements)

References 75 publications

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“…Furthermore, we exploited this mechanistic insight and treated animals with rmsACE2 inhalation and observed a substantial protection of BALB/c and C57BL/6 mice from developing mCOVID-19 . A recently published genome-wide association study across more than 50 000 COVID-19 patients and more than 700 000 non-infected individuals revealed a rare variant that was associated with down-regulated ACE2 expression and reduced risk of COVID-19 (Horowitz et al , 2021), providing additional evidence for the importance of ACE2 for SARS-CoV-2 infection in humans. The principal effectiveness of recombinant human soluble (rhs) ACE2 towards SARS-CoV-2 was demonstrated earlier in organoids, as it slowed viral replication in this setting (Monteil et al , 2020).…”

Section: Discussionmentioning

confidence: 99%

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Gawish

Starkl

Pimenov

et al. 2021

Preprint

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Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modelling revealed how Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNγ and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

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Section: Discussionmentioning

confidence: 99%

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Gawish

Starkl

Pimenov

et al. 2021

Preprint

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“…Horowitz et al showed that a high genetic burden from seven common genetic variants that modulate COVID-19 susceptibility and severity was strongly associated with increased risk of hospitalization and severe disease among COVID-19 cases, especially among individuals with few known risk factors. Using genetics to identify individuals at highest risk of adverse outcomes may therefore help prioritize individuals for immunization by (mRNA) vaccines or for treatment with monoclonal antibody treatments when they are still in short supply [27].…”

Section: Individual and Clinical Decision Makingmentioning

confidence: 99%

Implementation and implications for polygenic risk scores in healthcare

et al. 2021

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Increasing amounts of genetic data have led to the development of polygenic risk scores (PRSs) for a variety of diseases. These scores, built from the summary statistics of genome-wide association studies (GWASs), are able to stratify individuals based on their genetic risk of developing various common diseases and could potentially be used to optimize the use of screening and preventative treatments and improve personalized care for patients. Many challenges are yet to be overcome, including PRS validation, healthcare professional and patient education, and healthcare systems integration. Ethical challenges are also present in how this information is used and the current lack of diverse populations with PRSs available. In this review, we discuss the topics above and cover the nature of PRSs, visualization schemes, and how PRSs can be improved. With these tools on the horizon for multiple diseases, scientists, clinicians, health systems, regulatory bodies, and the public should discuss the uses, benefits, and potential risks of PRSs.

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“…Factors contributing to disease severity include anthropometric factors (e.g., age, gender, BMI), comorbidities (e.g., hypertension, diabetes) and unhealthy habits (e.g., smoking) [3]. Host genetics studies in COVID-19 have reported genomic variations associated with disease severity in chromosomes 1 (1q22.1), 2 (2p21.1), 3 (3p21.1-3), 6 (6p21.1), 8 (8q24.13), 9 (9q34.1-2), 12 (12q24.1-2), 17 (17q21.3), 19 (19p13.1-3) and 21 (21q21-q22) as well as in specific loci that have been manually selected [4][5][6][7][8]. The COVID Host Genetics Initiative has set up one of the largest communities that are currently generating, sharing and analyzing data to learn the genetic determinants of COVID-19 susceptibility, severity and outcomes.…”

Section: Impact Of Human Genome On Covid-19mentioning

confidence: 99%

Implementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System

Dopazo

Maya-Miles

García

et al. 2021

JPM

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The COVID-19 pandemic represents an unprecedented opportunity to exploit the advantages of personalized medicine for the prevention, diagnosis, treatment, surveillance and management of a new challenge in public health. COVID-19 infection is highly variable, ranging from asymptomatic infections to severe, life-threatening manifestations. Personalized medicine can play a key role in elucidating individual susceptibility to the infection as well as inter-individual variability in clinical course, prognosis and response to treatment. Integrating personalized medicine into clinical practice can also transform health care by enabling the design of preventive and therapeutic strategies tailored to individual profiles, improving the detection of outbreaks or defining transmission patterns at an increasingly local level. SARS-CoV2 genome sequencing, together with the assessment of specific patient genetic variants, will support clinical decision-makers and ultimately better ways to fight this disease. Additionally, it would facilitate a better stratification and selection of patients for clinical trials, thus increasing the likelihood of obtaining positive results. Lastly, defining a national strategy to implement in clinical practice all available tools of personalized medicine in COVID-19 could be challenging but linked to a positive transformation of the health care system. In this review, we provide an update of the achievements, promises, and challenges of personalized medicine in the fight against COVID-19 from susceptibility to natural history and response to therapy, as well as from surveillance to control measures and vaccination. We also discuss strategies to facilitate the adoption of this new paradigm for medical and public health measures during and after the pandemic in health care systems.

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Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

Cited by 42 publications

References 75 publications

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Implementation and implications for polygenic risk scores in healthcare

Implementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System

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