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

14 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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10.1038/s41588-022-01113-z

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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

@article{7d72b1c81e30418db241a01682bfe828,

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 = "Funding Information: We are grateful to all the patients who donated their samples. We are also indebted to all the doctors and nurses who contributed to this study. Additionally, we thank L. McReynolds (CGB/DCEG/NCI) for clinical review of the samples; M. Machiela (ITEB/DCEG/NCI) for contributing to the data analysis plan, M. Yan (LTG/DCEG/NCI) for help with analyses, N. Cole (CGR/DCEG/NCI) for help with the acquisition of TCGA sliced BAM files, M. Dean (LTG/DCEG/NCI) for help with Oxford Nanopore sequencing; G. Vatsellas and A.G. Korovesi (Biomedical Research Foundation of the Academy of Athens) for technical assistance on DNA extraction and preparation; J.C. Sapp (NHGRI) for support and guidance in patient recruitment; M. Martin (BSP, Frederick National Laboratory for Cancer Research) for coordinating sample and data transfers; J. Li (Harvard Medical School) for cohort organization; L. Jin, J. Wu and R. Shevin in the UAB Center for Clinical and Translational Science for preparation of genomic DNA; and B. Ant{\^o}nio Lopes da Fonseca and F. Crivelenti Vilar (University of S{\~a}o Paulo, Brazil) for recruiting patients. The results are partially based on data generated by the TCGA Research Network. We used data provided by the Kaiser Permanente Research Bank (KPRB) from the KPRB collection, which includes the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH), funded by the National Institutes of Health (NIH; RC2 AG036607), the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation and the Kaiser Permanente Community Benefits Program. Access to data used in this study may be obtained by application to the KPRB at kp.org/researchbank/researchers. Research reported in this publication was supported by the Intramural Research Programs of the National Cancer Institute, Division of Cancer Epidemiology and Genetics and Center for Cancer Research, Frederick National Laboratory for Cancer Research, contract number HHSN261200800001E; National Center for Advancing Translational Science of the NIH under award number UL1TR003096 associated with the University of Alabama at Birmingham COVID-19 Enterprise Study IRB-20005127, NHGRI Intramural Research Program grants HG200388-07 and HG200359-12. Additional funding was provided by the state of Alabama through the Alabama Genomic Health Initiative (IRB F170303004). S.B. was supported by grants from Deutsche Forschungsgemeinschaft project numbers 415089553 (Heisenberg program), 240245660 (SFB1129) and 272983813 (TRR179) and from the state of Baden Wuerttemberg (AZ: 33.7533.-6-21/5/1) and the Bundesministerium Bildung und Forschung (01KI20198A). M.L.S. was supported by grants from the Bundesministerium Bildung und Forschung (01KI20239B) and Deutsche Forschungsgemeinschaft project 416072091. E.A. was supported by grants from the European Commission (IMMUNAID, 779295 and CURE, 767015) and the Hellenic Foundation for Research and Innovation INTERFLU (1574). H.B.K. was supported by grant no 02-2020-012 from the SNUBH Research Fund. Additional support was provided by the Emory Department of Gynecology and Obstetrics EmPOWR Initiative (IRB00101931) and a grant from the Emory Medical Care Foundation Grant (IRB00000312). M.E.R. and S.M.L. were supported by NIH grant NS105477 and the NYPH-Weill Cornell Medicine COVID-19 Biobank Fund (IRB 20-04021808). D.R.W. was supported by the Massachusetts Consortium on Pathogen Readiness and NIH grants AI165072 and AI139538. The pegIFN-λ1 clinical trial was supported by the Toronto COVID-19 Action Initiative (72059280), the Ontario Together COVID-19 Research Application (C-224-2428560-FELD) and the Canadian Institutes for Health Research (VR3-172648). Support for title page creation and format was provided by AuthorArranger (https://authorarranger.nci.nih.gov/), a tool developed at the NCI. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views and policies of the NIH or Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. Funding Information: We are grateful to all the patients who donated their samples. We are also indebted to all the doctors and nurses who contributed to this study. Additionally, we thank L. McReynolds (CGB/DCEG/NCI) for clinical review of the samples; M. Machiela (ITEB/DCEG/NCI) for contributing to the data analysis plan, M. Yan (LTG/DCEG/NCI) for help with analyses, N. Cole (CGR/DCEG/NCI) for help with the acquisition of TCGA sliced BAM files, M. Dean (LTG/DCEG/NCI) for help with Oxford Nanopore sequencing; G. Vatsellas and A.G. Korovesi (Biomedical Research Foundation of the Academy of Athens) for technical assistance on DNA extraction and preparation; J.C. Sapp (NHGRI) for support and guidance in patient recruitment; M. Martin (BSP, Frederick National Laboratory for Cancer Research) for coordinating sample and data transfers; J. Li (Harvard Medical School) for cohort organization; L. Jin, J. Wu and R. Shevin in the UAB Center for Clinical and Translational Science for preparation of genomic DNA; and B. Ant{\^o}nio Lopes da Fonseca and F. Crivelenti Vilar (University of S{\~a}o Paulo, Brazil) for recruiting patients. The results are partially based on data generated by the TCGA Research Network. We used data provided by the Kaiser Permanente Research Bank (KPRB) from the KPRB collection, which includes the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH), funded by the National Institutes of Health (NIH; RC2 AG036607), the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation and the Kaiser Permanente Community Benefits Program. Access to data used in this study may be obtained by application to the KPRB at kp.org/researchbank/researchers . Research reported in this publication was supported by the Intramural Research Programs of the National Cancer Institute, Division of Cancer Epidemiology and Genetics and Center for Cancer Research, Frederick National Laboratory for Cancer Research, contract number HHSN261200800001E; National Center for Advancing Translational Science of the NIH under award number UL1TR003096 associated with the University of Alabama at Birmingham COVID-19 Enterprise Study IRB-20005127, NHGRI Intramural Research Program grants HG200388-07 and HG200359-12. Additional funding was provided by the state of Alabama through the Alabama Genomic Health Initiative (IRB F170303004). S.B. was supported by grants from Deutsche Forschungsgemeinschaft project numbers 415089553 (Heisenberg program), 240245660 (SFB1129) and 272983813 (TRR179) and from the state of Baden Wuerttemberg (AZ: 33.7533.-6-21/5/1) and the Bundesministerium Bildung und Forschung (01KI20198A). M.L.S. was supported by grants from the Bundesministerium Bildung und Forschung (01KI20239B) and Deutsche Forschungsgemeinschaft project 416072091. E.A. was supported by grants from the European Commission (IMMUNAID, 779295 and CURE, 767015) and the Hellenic Foundation for Research and Innovation INTERFLU (1574). H.B.K. was supported by grant no 02-2020-012 from the SNUBH Research Fund. Additional support was provided by the Emory Department of Gynecology and Obstetrics EmPOWR Initiative (IRB00101931) and a grant from the Emory Medical Care Foundation Grant (IRB00000312). M.E.R. and S.M.L. were supported by NIH grant NS105477 and the NYPH-Weill Cornell Medicine COVID-19 Biobank Fund (IRB 20-04021808). D.R.W. was supported by the Massachusetts Consortium on Pathogen Readiness and NIH grants AI165072 and AI139538. The pegIFN-λ1 clinical trial was supported by the Toronto COVID-19 Action Initiative (72059280), the Ontario Together COVID-19 Research Application (C-224-2428560-FELD) and the Canadian Institutes for Health Research (VR3-172648). Support for title page creation and format was provided by AuthorArranger ( https://authorarranger.nci.nih.gov/ ), a tool developed at the NCI. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views and policies of the NIH or Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. 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",

}

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

N1 - Funding Information: We are grateful to all the patients who donated their samples. We are also indebted to all the doctors and nurses who contributed to this study. Additionally, we thank L. McReynolds (CGB/DCEG/NCI) for clinical review of the samples; M. Machiela (ITEB/DCEG/NCI) for contributing to the data analysis plan, M. Yan (LTG/DCEG/NCI) for help with analyses, N. Cole (CGR/DCEG/NCI) for help with the acquisition of TCGA sliced BAM files, M. Dean (LTG/DCEG/NCI) for help with Oxford Nanopore sequencing; G. Vatsellas and A.G. Korovesi (Biomedical Research Foundation of the Academy of Athens) for technical assistance on DNA extraction and preparation; J.C. Sapp (NHGRI) for support and guidance in patient recruitment; M. Martin (BSP, Frederick National Laboratory for Cancer Research) for coordinating sample and data transfers; J. Li (Harvard Medical School) for cohort organization; L. Jin, J. Wu and R. Shevin in the UAB Center for Clinical and Translational Science for preparation of genomic DNA; and B. Antônio Lopes da Fonseca and F. Crivelenti Vilar (University of São Paulo, Brazil) for recruiting patients. The results are partially based on data generated by the TCGA Research Network. We used data provided by the Kaiser Permanente Research Bank (KPRB) from the KPRB collection, which includes the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH), funded by the National Institutes of Health (NIH; RC2 AG036607), the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation and the Kaiser Permanente Community Benefits Program. Access to data used in this study may be obtained by application to the KPRB at kp.org/researchbank/researchers. Research reported in this publication was supported by the Intramural Research Programs of the National Cancer Institute, Division of Cancer Epidemiology and Genetics and Center for Cancer Research, Frederick National Laboratory for Cancer Research, contract number HHSN261200800001E; National Center for Advancing Translational Science of the NIH under award number UL1TR003096 associated with the University of Alabama at Birmingham COVID-19 Enterprise Study IRB-20005127, NHGRI Intramural Research Program grants HG200388-07 and HG200359-12. Additional funding was provided by the state of Alabama through the Alabama Genomic Health Initiative (IRB F170303004). S.B. was supported by grants from Deutsche Forschungsgemeinschaft project numbers 415089553 (Heisenberg program), 240245660 (SFB1129) and 272983813 (TRR179) and from the state of Baden Wuerttemberg (AZ: 33.7533.-6-21/5/1) and the Bundesministerium Bildung und Forschung (01KI20198A). M.L.S. was supported by grants from the Bundesministerium Bildung und Forschung (01KI20239B) and Deutsche Forschungsgemeinschaft project 416072091. E.A. was supported by grants from the European Commission (IMMUNAID, 779295 and CURE, 767015) and the Hellenic Foundation for Research and Innovation INTERFLU (1574). H.B.K. was supported by grant no 02-2020-012 from the SNUBH Research Fund. Additional support was provided by the Emory Department of Gynecology and Obstetrics EmPOWR Initiative (IRB00101931) and a grant from the Emory Medical Care Foundation Grant (IRB00000312). M.E.R. and S.M.L. were supported by NIH grant NS105477 and the NYPH-Weill Cornell Medicine COVID-19 Biobank Fund (IRB 20-04021808). D.R.W. was supported by the Massachusetts Consortium on Pathogen Readiness and NIH grants AI165072 and AI139538. The pegIFN-λ1 clinical trial was supported by the Toronto COVID-19 Action Initiative (72059280), the Ontario Together COVID-19 Research Application (C-224-2428560-FELD) and the Canadian Institutes for Health Research (VR3-172648). Support for title page creation and format was provided by AuthorArranger (https://authorarranger.nci.nih.gov/), a tool developed at the NCI. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views and policies of the NIH or Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. Funding Information: We are grateful to all the patients who donated their samples. We are also indebted to all the doctors and nurses who contributed to this study. Additionally, we thank L. McReynolds (CGB/DCEG/NCI) for clinical review of the samples; M. Machiela (ITEB/DCEG/NCI) for contributing to the data analysis plan, M. Yan (LTG/DCEG/NCI) for help with analyses, N. Cole (CGR/DCEG/NCI) for help with the acquisition of TCGA sliced BAM files, M. Dean (LTG/DCEG/NCI) for help with Oxford Nanopore sequencing; G. Vatsellas and A.G. Korovesi (Biomedical Research Foundation of the Academy of Athens) for technical assistance on DNA extraction and preparation; J.C. Sapp (NHGRI) for support and guidance in patient recruitment; M. Martin (BSP, Frederick National Laboratory for Cancer Research) for coordinating sample and data transfers; J. Li (Harvard Medical School) for cohort organization; L. Jin, J. Wu and R. Shevin in the UAB Center for Clinical and Translational Science for preparation of genomic DNA; and B. Antônio Lopes da Fonseca and F. Crivelenti Vilar (University of São Paulo, Brazil) for recruiting patients. The results are partially based on data generated by the TCGA Research Network. We used data provided by the Kaiser Permanente Research Bank (KPRB) from the KPRB collection, which includes the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH), funded by the National Institutes of Health (NIH; RC2 AG036607), the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation and the Kaiser Permanente Community Benefits Program. Access to data used in this study may be obtained by application to the KPRB at kp.org/researchbank/researchers . Research reported in this publication was supported by the Intramural Research Programs of the National Cancer Institute, Division of Cancer Epidemiology and Genetics and Center for Cancer Research, Frederick National Laboratory for Cancer Research, contract number HHSN261200800001E; National Center for Advancing Translational Science of the NIH under award number UL1TR003096 associated with the University of Alabama at Birmingham COVID-19 Enterprise Study IRB-20005127, NHGRI Intramural Research Program grants HG200388-07 and HG200359-12. Additional funding was provided by the state of Alabama through the Alabama Genomic Health Initiative (IRB F170303004). S.B. was supported by grants from Deutsche Forschungsgemeinschaft project numbers 415089553 (Heisenberg program), 240245660 (SFB1129) and 272983813 (TRR179) and from the state of Baden Wuerttemberg (AZ: 33.7533.-6-21/5/1) and the Bundesministerium Bildung und Forschung (01KI20198A). M.L.S. was supported by grants from the Bundesministerium Bildung und Forschung (01KI20239B) and Deutsche Forschungsgemeinschaft project 416072091. E.A. was supported by grants from the European Commission (IMMUNAID, 779295 and CURE, 767015) and the Hellenic Foundation for Research and Innovation INTERFLU (1574). H.B.K. was supported by grant no 02-2020-012 from the SNUBH Research Fund. Additional support was provided by the Emory Department of Gynecology and Obstetrics EmPOWR Initiative (IRB00101931) and a grant from the Emory Medical Care Foundation Grant (IRB00000312). M.E.R. and S.M.L. were supported by NIH grant NS105477 and the NYPH-Weill Cornell Medicine COVID-19 Biobank Fund (IRB 20-04021808). D.R.W. was supported by the Massachusetts Consortium on Pathogen Readiness and NIH grants AI165072 and AI139538. The pegIFN-λ1 clinical trial was supported by the Toronto COVID-19 Action Initiative (72059280), the Ontario Together COVID-19 Research Application (C-224-2428560-FELD) and the Canadian Institutes for Health Research (VR3-172648). Support for title page creation and format was provided by AuthorArranger ( https://authorarranger.nci.nih.gov/ ), a tool developed at the NCI. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views and policies of the NIH or Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. Publisher Copyright: © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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.

UR - http://www.scopus.com/inward/record.url?scp=85134324868&partnerID=8YFLogxK

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

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