A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

Zhou, Sirui; Butler‐Laporte, Guillaume; Nakanishi, Teruyuki; Morrison, David R.; Afilalo, Jonathan; Afilalo, Marc; Laurent, Lætitia; Pietzner, Maik; Kerrison, Nicola D.; Zhao, Kaiqiong; Brunet-Ratnasingham, Elsa; Henry, Danielle; Kimchi, Nofar; Afrasiabi, Zaman; Rezk, Nardin; Bouab, Meriem; Petitjean, Louis; Guzman, Charlotte; Xue, Xiaoqing; Tselios, Chris; Vulesevic, Branka; Adeleye, Olumide; Abdullah, Tala; Almamlouk, Noor; Chen, Yiheng; Chassé, Michaël; Durand, Madéleine; Paterson, Clare; Normark, Johan; Frithiof, Robert; Lipcsey, Miklós; Hultström, Michael; Greenwood, Celia; Zeberg, Hugo; Langenberg, Claudia; Thysell, Elin; Pollak, Michael; Mooser, Vincent; Forgetta, Vincenzo; Kaufmann, Daniel E.; Richards, J. Brent

doi:10.1038/s41591-021-01281-1

Cited by 232 publications

(258 citation statements)

References 47 publications

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“…In the present study, we also found that genetically predicted higher OAS1 - an interferon-induced broad spectrum antiviral enzyme - was associated with lower risk of both susceptibility and severity of COVID-19, consistent with findings of a recent published report 58 . A large clinical trial of systemically-administered interferons failed to show any substantial therapeutic benefits for severe COVID-19 59 .…”

Section: Discussionsupporting

confidence: 93%

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

Karim

Shilts

Schwartzentruber

et al. 2021

Preprint

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The virus SARS-CoV-2 can exploit biological vulnerabilities in susceptible hosts that predispose to development of severe COVID-19. Previous reports have identified several host proteins related to the interferon response (e.g. OAS1), interleukin-6 signalling (IL-6R), and the coagulation cascade (linked via ABO) that were associated with risk of COVID-19. In the present study, we performed proteome-wide genetic colocalisation tests leveraging publicly available protein and COVID-19 datasets, to identify additional proteins that may contribute to COVID-19 risk. Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble FAS (colocalisation probability > 0.9, p = 1 x 10-4), implicating FAS-mediated apoptosis as a potential target for COVID-19 risk. We also undertook polygenic (pan) and cis-Mendelian randomisation analyses that showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal was associated with plasma concentrations of several proteins, with the strongest association observed with CD209 in several proteomic datasets. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.

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Section: Discussionsupporting

confidence: 93%

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

Karim

Shilts

Schwartzentruber

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…These data suggest that, while all three OAS genes play a critical role in cellular innate antiviral response 25 , differential expression of OAS1 is likely causally implicated in COVID-19 susceptibility. These findings are in agreement with previous studies showing that high plasma OAS1 levels are associated with reduced COVID-19 susceptibility and severity 26 .…”

Section: Loci Containing Associations Between Sars-cov2 Susceptibility and Eqtlssupporting

confidence: 94%

Insights into genetic factors contributing to variability in SARS-CoV-2 susceptibility and COVID-19 disease severity

D’Antonio

Arthur

Nguyen

et al. 2021

Preprint

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Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we applied colocalization to compare summary statistics for 16 GWASs from the COVID-19 Host Genetics Initiative to investigate similarities and differences in their genetic signals. We identified 9 loci associated with susceptibility (one with two independent GWAS signals; one with an ethnicity-specific signal), 14 associated with severity (one with two independent GWAS signals; two with ethnicity-specific signals) and one harboring two discrepant GWAS signals (one for susceptibility; one for severity). Utilizing colocalization we also identified 45 GTEx tissues that had eQTL(s) for 18 genes strongly associated with GWAS signals in eleven loci (1-4 genes per locus). Some of these genes showed tissue-specific altered expression and others showed altered expression in up to 41 different tissue types. Our study provides insights into the complex molecular mechanisms underlying inherited predispositions to COVID-19-disease phenotypes.

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“…The protective Neanderthal-derived haplotype confers ~23% reduced risk of becoming critically ill upon infection with SARS-CoV-2 3 . Supporting this, a recent Mendelian randomization study found that increased circulating levels of OAS1 were associated with reduced risk of very severe COVID-19, hospitalization for COVID-19 and susceptibility to this disease 8 . However, other evidence from a transcription-wide association study, suggested a stronger association with OAS3 levels 3 .…”

Section: Main Textmentioning

confidence: 77%

Alternative splicing of OAS1 alters the risk for severe COVID-19

Huffman

Butler‐Laporte

Khan

et al. 2021

Preprint

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A locus containing OAS1/2/3 has been identified as a risk locus for severe COVID-19 among Europeans ancestry individuals, with a protective haplotype of ∼75 kilobases derived from Neanderthals. Here, we show that among several potentially causal variants at this locus, a splice variant of OAS1 occurs in people of African ancestry independently of the Neanderthal haplotype and confers protection against COVID-19 of a magnitude similar to that seen in individuals without African ancestry.

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A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

Cited by 232 publications

References 47 publications

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

Insights into genetic factors contributing to variability in SARS-CoV-2 susceptibility and COVID-19 disease severity

Alternative splicing of OAS1 alters the risk for severe COVID-19

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