Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries

A. Rouf Banday; Megan L. Stanifer; Oscar Florez-Vargas; Olusegun O. Onabajo; Brenen W. Papenberg; Muhammad A. Zahoor; Lisa Mirabello; Timothy J. Ring; Chia Han Lee; Paul S. Albert; Evangelos Andreakos; Evgeny Arons; Greg Barsh; Leslie G. Biesecker; David L. Boyle; Mark S. Brahier; Andrea Burnett-Hartman; Mary Carrington; Euijin Chang; Pyoeng Gyun Choe; Rex L. Chisholm; Leandro M. Colli; Clifton L. Dalgard; Carolynn M. Dude; Jeff Edberg; Nathan Erdmann; Heather S. Feigelson; Benedito A. Fonseca; Gary S. Firestein; Adam J. Gehring; Cuncai Guo; Michelle Ho; Steven Holland; Amy A. Hutchinson; Hogune Im; Les’Shon S. Irby; Michael G. Ison; Naima T. Joseph; Hong Bin Kim; Robert J. Kreitman; Bruce R. Korf; Steven M. Lipkin; Siham M. Mahgoub; Iman Mohammed; Guilherme L. Paschoalini; Jennifer A. Pacheco; Michael J. Peluso; Daniel J. Rader; David T. Redden; Marylyn D. Ritchie; Brooke Rosenblum; M. Elizabeth Ross; Hanaisa P.Sant Anna; Sharon A. Savage; Sudha Sharma; Eleni Siouti; Alicia K. Smith; Vasiliki Triantafyllia; Joselin M. Vargas; Jose D. Vargas; Anurag Verma; Vibha Vij; Duane R. Wesemann; Meredith Yeager; Xu Yu; Yu Zhang; Steeve Boulant; Stephen J. Chanock; Jordan J. Feld; Ludmila Prokunina-Olsson

doi:10.1038/s41588-022-01113-z

Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries

A. Rouf Banday, Megan L. Stanifer, Oscar Florez-Vargas, Olusegun O. Onabajo, Brenen W. Papenberg, Muhammad A. Zahoor, Lisa Mirabello, Timothy J. Ring, Chia Han Lee, Paul S. Albert, Evangelos Andreakos, Evgeny Arons, Greg Barsh, Leslie G. Biesecker, David L. Boyle, Mark S. Brahier, Andrea Burnett-Hartman, Mary Carrington, Euijin Chang, Pyoeng Gyun ChoeRex L. Chisholm, Leandro M. Colli, Clifton L. Dalgard, Carolynn M. Dude, Jeff Edberg, Nathan Erdmann, Heather S. Feigelson, Benedito A. Fonseca, Gary S. Firestein, Adam J. Gehring, Cuncai Guo, Michelle Ho, Steven Holland, Amy A. Hutchinson, Hogune Im, Les’Shon S. Irby, Michael G. Ison, Naima T. Joseph, Hong Bin Kim, Robert J. Kreitman, Bruce R. Korf, Steven M. Lipkin, Siham M. Mahgoub, Iman Mohammed, Guilherme L. Paschoalini, Jennifer A. Pacheco, Michael J. Peluso, Daniel J. Rader, David T. Redden, Marylyn D. Ritchie, Brooke Rosenblum, M. Elizabeth Ross, Hanaisa P.Sant Anna, Sharon A. Savage, Sudha Sharma, Eleni Siouti, Alicia K. Smith, Vasiliki Triantafyllia, Joselin M. Vargas, Jose D. Vargas, Anurag Verma, Vibha Vij, Duane R. Wesemann, Meredith Yeager, Xu Yu, Yu Zhang, Steeve Boulant, Stephen J. Chanock, Jordan J. Feld, Ludmila Prokunina-Olsson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

71 Scopus citations

Abstract

The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

Original language	English
Pages (from-to)	1103-1116
Number of pages	14
Journal	Nature Genetics
Volume	54
Issue number	8
DOIs	https://doi.org/10.1038/s41588-022-01113-z
State	Published - Aug 2022
Externally published	Yes

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Banday, A. R., Stanifer, M. L., Florez-Vargas, O., Onabajo, O. O., Papenberg, B. W., Zahoor, M. A., Mirabello, L., Ring, T. J., Lee, C. H., Albert, P. S., Andreakos, E., Arons, E., Barsh, G., Biesecker, L. G., Boyle, D. L., Brahier, M. S., Burnett-Hartman, A., Carrington, M., Chang, E., ... Prokunina-Olsson, L. (2022). Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries. Nature Genetics, 54(8), 1103-1116. https://doi.org/10.1038/s41588-022-01113-z

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title = "Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries",

abstract = "The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.",

author = "Banday, {A. Rouf} and Stanifer, {Megan L.} and Oscar Florez-Vargas and Onabajo, {Olusegun O.} and Papenberg, {Brenen W.} and Zahoor, {Muhammad A.} and Lisa Mirabello and Ring, {Timothy J.} and Lee, {Chia Han} and Albert, {Paul S.} and Evangelos Andreakos and Evgeny Arons and Greg Barsh and Biesecker, {Leslie G.} and Boyle, {David L.} and Brahier, {Mark S.} and Andrea Burnett-Hartman and Mary Carrington and Euijin Chang and Choe, {Pyoeng Gyun} and Chisholm, {Rex L.} and Colli, {Leandro M.} and Dalgard, {Clifton L.} and Dude, {Carolynn M.} and Jeff Edberg and Nathan Erdmann and Feigelson, {Heather S.} and Fonseca, {Benedito A.} and Firestein, {Gary S.} and Gehring, {Adam J.} and Cuncai Guo and Michelle Ho and Steven Holland and Hutchinson, {Amy A.} and Hogune Im and Irby, {Les{\textquoteright}Shon S.} and Ison, {Michael G.} and Joseph, {Naima T.} and Kim, {Hong Bin} and Kreitman, {Robert J.} and Korf, {Bruce R.} and Lipkin, {Steven M.} and Mahgoub, {Siham M.} and Iman Mohammed and Paschoalini, {Guilherme L.} and Pacheco, {Jennifer A.} and Peluso, {Michael J.} and Rader, {Daniel J.} and Redden, {David T.} and Ritchie, {Marylyn D.} and Brooke Rosenblum and Ross, {M. Elizabeth} and Anna, {Hanaisa P.Sant} and Savage, {Sharon A.} and Sudha Sharma and Eleni Siouti and Smith, {Alicia K.} and Vasiliki Triantafyllia and Vargas, {Joselin M.} and Vargas, {Jose D.} and Anurag Verma and Vibha Vij and Wesemann, {Duane R.} and Meredith Yeager and Xu Yu and Yu Zhang and Steeve Boulant and Chanock, {Stephen J.} and Feld, {Jordan J.} and Ludmila Prokunina-Olsson",

note = "Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2022",

month = aug,

doi = "10.1038/s41588-022-01113-z",

language = "English",

volume = "54",

pages = "1103--1116",

journal = "Nature Genetics",

issn = "1061-4036",

number = "8",

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Banday, AR, Stanifer, ML, Florez-Vargas, O, Onabajo, OO, Papenberg, BW, Zahoor, MA, Mirabello, L, Ring, TJ, Lee, CH, Albert, PS, Andreakos, E, Arons, E, Barsh, G, Biesecker, LG, Boyle, DL, Brahier, MS, Burnett-Hartman, A, Carrington, M, Chang, E, Choe, PG, Chisholm, RL, Colli, LM, Dalgard, CL, Dude, CM, Edberg, J, Erdmann, N, Feigelson, HS, Fonseca, BA, Firestein, GS, Gehring, AJ, Guo, C, Ho, M, Holland, S, Hutchinson, AA, Im, H, Irby, LSS, Ison, MG, Joseph, NT, Kim, HB, Kreitman, RJ, Korf, BR, Lipkin, SM, Mahgoub, SM, Mohammed, I, Paschoalini, GL, Pacheco, JA, Peluso, MJ, Rader, DJ, Redden, DT, Ritchie, MD, Rosenblum, B, Ross, ME, Anna, HPS, Savage, SA, Sharma, S, Siouti, E, Smith, AK, Triantafyllia, V, Vargas, JM, Vargas, JD, Verma, A, Vij, V, Wesemann, DR, Yeager, M, Yu, X, Zhang, Y, Boulant, S, Chanock, SJ, Feld, JJ & Prokunina-Olsson, L 2022, 'Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries', Nature Genetics, vol. 54, no. 8, pp. 1103-1116. https://doi.org/10.1038/s41588-022-01113-z

TY - JOUR

T1 - Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries

AU - Banday, A. Rouf

AU - Stanifer, Megan L.

AU - Florez-Vargas, Oscar

AU - Onabajo, Olusegun O.

AU - Papenberg, Brenen W.

AU - Zahoor, Muhammad A.

AU - Mirabello, Lisa

AU - Ring, Timothy J.

AU - Lee, Chia Han

AU - Albert, Paul S.

AU - Andreakos, Evangelos

AU - Arons, Evgeny

AU - Barsh, Greg

AU - Biesecker, Leslie G.

AU - Boyle, David L.

AU - Brahier, Mark S.

AU - Burnett-Hartman, Andrea

AU - Carrington, Mary

AU - Chang, Euijin

AU - Choe, Pyoeng Gyun

AU - Chisholm, Rex L.

AU - Colli, Leandro M.

AU - Dalgard, Clifton L.

AU - Dude, Carolynn M.

AU - Edberg, Jeff

AU - Erdmann, Nathan

AU - Feigelson, Heather S.

AU - Fonseca, Benedito A.

AU - Firestein, Gary S.

AU - Gehring, Adam J.

AU - Guo, Cuncai

AU - Ho, Michelle

AU - Holland, Steven

AU - Hutchinson, Amy A.

AU - Im, Hogune

AU - Irby, Les’Shon S.

AU - Ison, Michael G.

AU - Joseph, Naima T.

AU - Kim, Hong Bin

AU - Kreitman, Robert J.

AU - Korf, Bruce R.

AU - Lipkin, Steven M.

AU - Mahgoub, Siham M.

AU - Mohammed, Iman

AU - Paschoalini, Guilherme L.

AU - Pacheco, Jennifer A.

AU - Peluso, Michael J.

AU - Rader, Daniel J.

AU - Redden, David T.

AU - Ritchie, Marylyn D.

AU - Rosenblum, Brooke

AU - Ross, M. Elizabeth

AU - Anna, Hanaisa P.Sant

AU - Savage, Sharon A.

AU - Sharma, Sudha

AU - Siouti, Eleni

AU - Smith, Alicia K.

AU - Triantafyllia, Vasiliki

AU - Vargas, Joselin M.

AU - Vargas, Jose D.

AU - Verma, Anurag

AU - Vij, Vibha

AU - Wesemann, Duane R.

AU - Yeager, Meredith

AU - Yu, Xu

AU - Zhang, Yu

AU - Boulant, Steeve

AU - Chanock, Stephen J.

AU - Feld, Jordan J.

AU - Prokunina-Olsson, Ludmila

PY - 2022/8

Y1 - 2022/8

N2 - The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

AB - The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

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U2 - 10.1038/s41588-022-01113-z

DO - 10.1038/s41588-022-01113-z

M3 - Article

C2 - 35835913

AN - SCOPUS:85134324868

SN - 1061-4036

VL - 54

SP - 1103

EP - 1116

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries

Abstract

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