Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

NIAID-USUHS COVID Study Group; COVID Human Genetic Effort; COVIDeF Study Group; French COVID Cohort Study Group; CoV-Contact Cohort; COVID Clinicians; COVID-STORM Clinicians; Amsterdam UMC Covid-19 Biobank; Orchestra Working Group; Daniela Matuozzo; Estelle Talouarn; Astrid Marchal; Peng Zhang; Jeremy Manry; Yoann Seeleuthner; Yu Zhang; Alexandre Bolze; Matthieu Chaldebas; Baptiste Milisavljevic; Adrian Gervais; Paul Bastard; Takaki Asano; Lucy Bizien; Federica Barzaghi; Hassan Abolhassani; Ahmad Abou Tayoun; Alessandro Aiuti; Ilad Alavi Darazam; Luis M. Allende; Rebeca Alonso-Arias; Andrés Augusto Arias; Gokhan Aytekin; Peter Bergman; Simone Bondesan; Yenan T. Bryceson; Ingrid G. Bustos; Oscar Cabrera-Marante; Sheila Carcel; Paola Carrera; Giorgio Casari; Khalil Chaïbi; Roger Colobran; Antonio Condino-Neto; Laura E. Covill; Ottavia M. Delmonte; Loubna El Zein; Carlos Flores; Peter K. Gregersen; Marta Gut; Filomeen Haerynck; Rabih Halwani; Selda Hancerli; Lennart Hammarström; Nevin Hatipoğlu; Adem Karbuz; Sevgi Keles; Christèle Kyheng; Rafael Leon-Lopez; Jose Luis Franco; Davood Mansouri; Javier Martinez-Picado; Ozge Metin Akcan; Isabelle Migeotte; Pierre Emmanuel Morange; Guillaume Morelle; Andrea Martin-Nalda; Giuseppe Novelli; Antonio Novelli; Figen Palabiyik; Qiang Pan-Hammarström; Rebeca Pérez de Diego; Laura Planas-Serra; Daniel E. Pleguezuelo; Carolina Prando; Aurora Pujol; Luis Felipe Reyes; Jacques G. Rivière; Carlos Rodriguez-Gallego; Julian Rojas; Patrizia Rovere-Querini; Agatha Schlüter; Mohammad Shahrooei; Ali Sobh; Pere Soler-Palacin; Yacine Tandjaoui-Lambiotte; Imran Tipu; Cristina Tresoldi; Jesus Troya; Diederik van de Beek; Mayana Zatz; Pawel Zawadzki; Saleh Zaid Al-Muhsen; Mohammed Faraj Alosaimi; Fahad M. Alsohime; Hagit Baris-Feldman; Manish J. Butte; Stefan N. Constantinescu; Megan A. Cooper; Clifton L. Dalgard; Jacques Fellay; James R. Heath; Yu Lung Lau; Richard P. Lifton; Tom Maniatis; Trine H. Mogensen; Horst von Bernuth; Alban Lermine; Michel Vidaud; Anne Boland; Jean François Deleuze; Robert Nussbaum; Amanda Kahn-Kirby; France Mentre; Sarah Tubiana; Guy Gorochov; Florence Tubach; Pierre Hausfater; Saleh Al-Muhsen; Fahd Al-Mulla; Mark S. Anderson; Evangelos Andreakos; Andrés A. Arias; Hagit Baris Feldman; Alexandre Belot; Catherine M. Biggs; Dusan Bogunovic; Anastasiia Bondarenko; Ahmed A. Bousfiha; Petter Brodin; Carlos D. Bustamante; Samya Chakravorty; John Christodoulou; Murkesh Desai; Beth A. Drolet; Jamila El Baghdadi; Sara Espinosa-Padilla; José Luis Franco; Antoine Froidure; David Hagin; Sarah E. Henrickson; Elena W.Y. Hsieh; Eystein Husebye; Kohsuke Imai; Yuval Itan; Erich D. Jarvis; Timokratis Karamitros; Kai Kisand; Cheng Lung Ku; Yun Ling; Carrie L. Lucas; László Maródi; Joshua D. Milner; Kristina Mironska; Tomohiro Morio; Lisa F.P. Ng; Cliona O’Farrelly; Satoshi Okada; Anna M. Planas; Lluis Quintana-Murci; Laurent Renia; Igor Resnick; Carlos Rodríguez-Gallego; Vanessa Sancho-Shimizu; Anna Sediva; Mikko R.J. Seppänen; Anna Shcherbina; Ondrej Slaby; Andrew L. Snow; Pere Soler-Palacín; András N. Spaan; Ivan Tancevski; Stuart G. Tangye; Sathishkumar Ramaswamy; Stuart E. Turvey; Furkan Uddin; Mohammed J. Uddin; Donald C. Vinh; Jean Laurent Casanova; Jean Laurent Casanova; Yannick Vacher; Anne Gysembergh-Houal; Lauren Demerville; Abla Chachoua; Sebastien Abad; Radhiya Abassi; Abdelrafie Abdellaoui; Abdelkrim Abdelmalek; Hendy Abdoul; Helene Abergel; Fariza Abeud; Sophie Abgrall; Noemie Abisror; Marylise Adechian; Nordine Aderdour; Hakeem Farid Admane; Frederic Adnet; Sara Afritt; Helene Agostini; Claire Aguilar; Sophie Agut; Tommaso Francesco Aiello; Marc Ait Kaci; Hafid Ait Oufella; Gokula Ajeenthiravasan; Virginie Alauzy; Fanny Alby-Laurent; Lucie Allard; Marie Alexandra Alyanakian; Blanca Amador Borrero

doi:10.1186/s13073-023-01173-8

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

NIAID-USUHS COVID Study Group, COVID Human Genetic Effort, COVIDeF Study Group, French COVID Cohort Study Group, CoV-Contact Cohort, COVID Clinicians, COVID-STORM Clinicians, Amsterdam UMC Covid-19 Biobank, Orchestra Working Group, Daniela Matuozzo, Estelle Talouarn, Astrid Marchal, Peng Zhang, Jeremy Manry, Yoann Seeleuthner, Yu Zhang, Alexandre Bolze, Matthieu Chaldebas, Baptiste Milisavljevic, Adrian GervaisPaul Bastard, Takaki Asano, Lucy Bizien, Federica Barzaghi, Hassan Abolhassani, Ahmad Abou Tayoun, Alessandro Aiuti, Ilad Alavi Darazam, Luis M. Allende, Rebeca Alonso-Arias, Andrés Augusto Arias, Gokhan Aytekin, Peter Bergman, Simone Bondesan, Yenan T. Bryceson, Ingrid G. Bustos, Oscar Cabrera-Marante, Sheila Carcel, Paola Carrera, Giorgio Casari, Khalil Chaïbi, Roger Colobran, Antonio Condino-Neto, Laura E. Covill, Ottavia M. Delmonte, Loubna El Zein, Carlos Flores, Peter K. Gregersen, Marta Gut, Filomeen Haerynck, Rabih Halwani, Selda Hancerli, Lennart Hammarström, Nevin Hatipoğlu, Adem Karbuz, Sevgi Keles, Christèle Kyheng, Rafael Leon-Lopez, Jose Luis Franco, Davood Mansouri, Javier Martinez-Picado, Ozge Metin Akcan, Isabelle Migeotte, Pierre Emmanuel Morange, Guillaume Morelle, Andrea Martin-Nalda, Giuseppe Novelli, Antonio Novelli, Figen Palabiyik, Qiang Pan-Hammarström, Rebeca Pérez de Diego, Laura Planas-Serra, Daniel E. Pleguezuelo, Carolina Prando, Aurora Pujol, Luis Felipe Reyes, Jacques G. Rivière, Carlos Rodriguez-Gallego, Julian Rojas, Patrizia Rovere-Querini, Agatha Schlüter, Mohammad Shahrooei, Ali Sobh, Pere Soler-Palacin, Yacine Tandjaoui-Lambiotte, Imran Tipu, Cristina Tresoldi, Jesus Troya, Diederik van de Beek, Mayana Zatz, Pawel Zawadzki, Saleh Zaid Al-Muhsen, Mohammed Faraj Alosaimi, Fahad M. Alsohime, Hagit Baris-Feldman, Manish J. Butte, Stefan N. Constantinescu, Megan A. Cooper, Clifton L. Dalgard, Jacques Fellay, James R. Heath, Yu Lung Lau, Richard P. Lifton, Tom Maniatis, Trine H. Mogensen, Horst von Bernuth, Alban Lermine, Michel Vidaud, Anne Boland, Jean François Deleuze, Robert Nussbaum, Amanda Kahn-Kirby, France Mentre, Sarah Tubiana, Guy Gorochov, Florence Tubach, Pierre Hausfater, Saleh Al-Muhsen, Fahd Al-Mulla, Mark S. Anderson, Evangelos Andreakos, Andrés A. Arias, Hagit Baris Feldman, Alexandre Belot, Catherine M. Biggs, Dusan Bogunovic, Anastasiia Bondarenko, Ahmed A. Bousfiha, Petter Brodin, Carlos D. Bustamante, Samya Chakravorty, John Christodoulou, Murkesh Desai, Beth A. Drolet, Jamila El Baghdadi, Sara Espinosa-Padilla, José Luis Franco, Antoine Froidure, David Hagin, Sarah E. Henrickson, Elena W.Y. Hsieh, Eystein Husebye, Kohsuke Imai, Yuval Itan, Erich D. Jarvis, Timokratis Karamitros, Kai Kisand, Cheng Lung Ku, Yun Ling, Carrie L. Lucas, László Maródi, Joshua D. Milner, Kristina Mironska, Tomohiro Morio, Lisa F.P. Ng, Cliona O’Farrelly, Satoshi Okada, Anna M. Planas, Lluis Quintana-Murci, Laurent Renia, Igor Resnick, Carlos Rodríguez-Gallego, Vanessa Sancho-Shimizu, Anna Sediva, Mikko R.J. Seppänen, Anna Shcherbina, Ondrej Slaby, Andrew L. Snow, Pere Soler-Palacín, András N. Spaan, Ivan Tancevski, Stuart G. Tangye, Sathishkumar Ramaswamy, Stuart E. Turvey, Furkan Uddin, Mohammed J. Uddin, Donald C. Vinh, Jean Laurent Casanova, Jean Laurent Casanova, Yannick Vacher, Anne Gysembergh-Houal, Lauren Demerville, Abla Chachoua, Sebastien Abad, Radhiya Abassi, Abdelrafie Abdellaoui, Abdelkrim Abdelmalek, Hendy Abdoul, Helene Abergel, Fariza Abeud, Sophie Abgrall, Noemie Abisror, Marylise Adechian, Nordine Aderdour, Hakeem Farid Admane, Frederic Adnet, Sara Afritt, Helene Agostini, Claire Aguilar, Sophie Agut, Tommaso Francesco Aiello, Marc Ait Kaci, Hafid Ait Oufella, Gokula Ajeenthiravasan, Virginie Alauzy, Fanny Alby-Laurent, Lucie Allard, Marie Alexandra Alyanakian, Blanca Amador Borrero

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

36 Scopus citations

Abstract

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10⁻⁴) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10⁻⁴). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10⁻³), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10⁻⁸). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10⁻⁵). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Original language	English
Article number	22
Journal	Genome medicine
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s13073-023-01173-8
State	Published - Dec 2023

Keywords

COVID-19
Immunity
Rare variants
Type I interferon

Access to Document

10.1186/s13073-023-01173-8

Cite this

NIAID-USUHS COVID Study Group, COVID Human Genetic Effort, COVIDeF Study Group, French COVID Cohort Study Group, CoV-Contact Cohort, COVID Clinicians, COVID-STORM Clinicians, Amsterdam UMC Covid-19 Biobank, Orchestra Working Group, Matuozzo, D., Talouarn, E., Marchal, A., Zhang, P., Manry, J., Seeleuthner, Y., Zhang, Y., Bolze, A., Chaldebas, M., Milisavljevic, B., ... Borrero, B. A. (2023). Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19. Genome medicine, 15(1), Article 22. https://doi.org/10.1186/s13073-023-01173-8

@article{eedab4ec149e4ee29ed80ddd2dbd2f9c,

title = "Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19",

abstract = "Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.",

keywords = "COVID-19, Immunity, Rare variants, Type I interferon",

author = "{NIAID-USUHS COVID Study Group} and {COVID Human Genetic Effort} and {COVIDeF Study Group} and {French COVID Cohort Study Group} and {CoV-Contact Cohort} and {COVID Clinicians} and {COVID-STORM Clinicians} and {Amsterdam UMC Covid-19 Biobank} and {Orchestra Working Group} and Daniela Matuozzo and Estelle Talouarn and Astrid Marchal and Peng Zhang and Jeremy Manry and Yoann Seeleuthner and Yu Zhang and Alexandre Bolze and Matthieu Chaldebas and Baptiste Milisavljevic and Adrian Gervais and Paul Bastard and Takaki Asano and Lucy Bizien and Federica Barzaghi and Hassan Abolhassani and {Abou Tayoun}, Ahmad and Alessandro Aiuti and {Alavi Darazam}, Ilad and Allende, {Luis M.} and Rebeca Alonso-Arias and Arias, {Andr{\'e}s Augusto} and Gokhan Aytekin and Peter Bergman and Simone Bondesan and Bryceson, {Yenan T.} and Bustos, {Ingrid G.} and Oscar Cabrera-Marante and Sheila Carcel and Paola Carrera and Giorgio Casari and Khalil Cha{\"i}bi and Roger Colobran and Antonio Condino-Neto and Covill, {Laura E.} and Delmonte, {Ottavia M.} and {El Zein}, Loubna and Carlos Flores and Gregersen, {Peter K.} and Marta Gut and Filomeen Haerynck and Rabih Halwani and Selda Hancerli and Lennart Hammarstr{\"o}m and Nevin Hatipoğlu and Adem Karbuz and Sevgi Keles and Christ{\`e}le Kyheng and Rafael Leon-Lopez and Franco, {Jose Luis} and Davood Mansouri and Javier Martinez-Picado and {Metin Akcan}, Ozge and Isabelle Migeotte and Morange, {Pierre Emmanuel} and Guillaume Morelle and Andrea Martin-Nalda and Giuseppe Novelli and Antonio Novelli and Figen Palabiyik and Qiang Pan-Hammarstr{\"o}m and {de Diego}, {Rebeca P{\'e}rez} and Laura Planas-Serra and Pleguezuelo, {Daniel E.} and Carolina Prando and Aurora Pujol and Reyes, {Luis Felipe} and Rivi{\`e}re, {Jacques G.} and Carlos Rodriguez-Gallego and Julian Rojas and Patrizia Rovere-Querini and Agatha Schl{\"u}ter and Mohammad Shahrooei and Ali Sobh and Pere Soler-Palacin and Yacine Tandjaoui-Lambiotte and Imran Tipu and Cristina Tresoldi and Jesus Troya and {van de Beek}, Diederik and Mayana Zatz and Pawel Zawadzki and Al-Muhsen, {Saleh Zaid} and Alosaimi, {Mohammed Faraj} and Alsohime, {Fahad M.} and Hagit Baris-Feldman and Butte, {Manish J.} and Constantinescu, {Stefan N.} and Cooper, {Megan A.} and Dalgard, {Clifton L.} and Jacques Fellay and Heath, {James R.} and Lau, {Yu Lung} and Lifton, {Richard P.} and Tom Maniatis and Mogensen, {Trine H.} and {von Bernuth}, Horst and Alban Lermine and Michel Vidaud and Anne Boland and Deleuze, {Jean Fran{\c c}ois} and Robert Nussbaum and Amanda Kahn-Kirby and France Mentre and Sarah Tubiana and Guy Gorochov and Florence Tubach and Pierre Hausfater and Saleh Al-Muhsen and Fahd Al-Mulla and Anderson, {Mark S.} and Evangelos Andreakos and Arias, {Andr{\'e}s A.} and Feldman, {Hagit Baris} and Alexandre Belot and Biggs, {Catherine M.} and Dusan Bogunovic and Anastasiia Bondarenko and Bousfiha, {Ahmed A.} and Petter Brodin and Bustamante, {Carlos D.} and Samya Chakravorty and John Christodoulou and Murkesh Desai and Drolet, {Beth A.} and Baghdadi, {Jamila El} and Sara Espinosa-Padilla and Franco, {Jos{\'e} Luis} and Antoine Froidure and David Hagin and Henrickson, {Sarah E.} and Hsieh, {Elena W.Y.} and Eystein Husebye and Kohsuke Imai and Yuval Itan and Jarvis, {Erich D.} and Timokratis Karamitros and Kai Kisand and Ku, {Cheng Lung} and Yun Ling and Lucas, {Carrie L.} and L{\'a}szl{\'o} Mar{\'o}di and Milner, {Joshua D.} and Kristina Mironska and Tomohiro Morio and Ng, {Lisa F.P.} and Cliona O{\textquoteright}Farrelly and Satoshi Okada and Planas, {Anna M.} and Lluis Quintana-Murci and Laurent Renia and Igor Resnick and Carlos Rodr{\'i}guez-Gallego and Vanessa Sancho-Shimizu and Anna Sediva and Sepp{\"a}nen, {Mikko R.J.} and Anna Shcherbina and Ondrej Slaby and Snow, {Andrew L.} and Pere Soler-Palac{\'i}n and Spaan, {Andr{\'a}s N.} and Ivan Tancevski and Tangye, {Stuart G.} and Sathishkumar Ramaswamy and Turvey, {Stuart E.} and Furkan Uddin and Uddin, {Mohammed J.} and Vinh, {Donald C.} and Casanova, {Jean Laurent} and Casanova, {Jean Laurent} and Yannick Vacher and Anne Gysembergh-Houal and Lauren Demerville and Abla Chachoua and Sebastien Abad and Radhiya Abassi and Abdelrafie Abdellaoui and Abdelkrim Abdelmalek and Hendy Abdoul and Helene Abergel and Fariza Abeud and Sophie Abgrall and Noemie Abisror and Marylise Adechian and Nordine Aderdour and Admane, {Hakeem Farid} and Frederic Adnet and Sara Afritt and Helene Agostini and Claire Aguilar and Sophie Agut and Aiello, {Tommaso Francesco} and Kaci, {Marc Ait} and Oufella, {Hafid Ait} and Gokula Ajeenthiravasan and Virginie Alauzy and Fanny Alby-Laurent and Lucie Allard and Alyanakian, {Marie Alexandra} and Borrero, {Blanca Amador}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1186/s13073-023-01173-8",

language = "English",

volume = "15",

journal = "Genome medicine",

issn = "1756-994X",

number = "1",

}

NIAID-USUHS COVID Study Group, COVID Human Genetic Effort, COVIDeF Study Group, French COVID Cohort Study Group, CoV-Contact Cohort, COVID Clinicians, COVID-STORM Clinicians, Amsterdam UMC Covid-19 Biobank, Orchestra Working Group, Matuozzo, D, Talouarn, E, Marchal, A, Zhang, P, Manry, J, Seeleuthner, Y, Zhang, Y, Bolze, A, Chaldebas, M, Milisavljevic, B, Gervais, A, Bastard, P, Asano, T, Bizien, L, Barzaghi, F, Abolhassani, H, Abou Tayoun, A, Aiuti, A, Alavi Darazam, I, Allende, LM, Alonso-Arias, R, Arias, AA, Aytekin, G, Bergman, P, Bondesan, S, Bryceson, YT, Bustos, IG, Cabrera-Marante, O, Carcel, S, Carrera, P, Casari, G, Chaïbi, K, Colobran, R, Condino-Neto, A, Covill, LE, Delmonte, OM, El Zein, L, Flores, C, Gregersen, PK, Gut, M, Haerynck, F, Halwani, R, Hancerli, S, Hammarström, L, Hatipoğlu, N, Karbuz, A, Keles, S, Kyheng, C, Leon-Lopez, R, Franco, JL, Mansouri, D, Martinez-Picado, J, Metin Akcan, O, Migeotte, I, Morange, PE, Morelle, G, Martin-Nalda, A, Novelli, G, Novelli, A, Palabiyik, F, Pan-Hammarström, Q, de Diego, RP, Planas-Serra, L, Pleguezuelo, DE, Prando, C, Pujol, A, Reyes, LF, Rivière, JG, Rodriguez-Gallego, C, Rojas, J, Rovere-Querini, P, Schlüter, A, Shahrooei, M, Sobh, A, Soler-Palacin, P, Tandjaoui-Lambiotte, Y, Tipu, I, Tresoldi, C, Troya, J, van de Beek, D, Zatz, M, Zawadzki, P, Al-Muhsen, SZ, Alosaimi, MF, Alsohime, FM, Baris-Feldman, H, Butte, MJ, Constantinescu, SN, Cooper, MA, Dalgard, CL, Fellay, J, Heath, JR, Lau, YL, Lifton, RP, Maniatis, T, Mogensen, TH, von Bernuth, H, Lermine, A, Vidaud, M, Boland, A, Deleuze, JF, Nussbaum, R, Kahn-Kirby, A, Mentre, F, Tubiana, S, Gorochov, G, Tubach, F, Hausfater, P, Al-Muhsen, S, Al-Mulla, F, Anderson, MS, Andreakos, E, Arias, AA, Feldman, HB, Belot, A, Biggs, CM, Bogunovic, D, Bondarenko, A, Bousfiha, AA, Brodin, P, Bustamante, CD, Chakravorty, S, Christodoulou, J, Desai, M, Drolet, BA, Baghdadi, JE, Espinosa-Padilla, S, Franco, JL, Froidure, A, Hagin, D, Henrickson, SE, Hsieh, EWY, Husebye, E, Imai, K, Itan, Y, Jarvis, ED, Karamitros, T, Kisand, K, Ku, CL, Ling, Y, Lucas, CL, Maródi, L, Milner, JD, Mironska, K, Morio, T, Ng, LFP, O’Farrelly, C, Okada, S, Planas, AM, Quintana-Murci, L, Renia, L, Resnick, I, Rodríguez-Gallego, C, Sancho-Shimizu, V, Sediva, A, Seppänen, MRJ, Shcherbina, A, Slaby, O, Snow, AL, Soler-Palacín, P, Spaan, AN, Tancevski, I, Tangye, SG, Ramaswamy, S, Turvey, SE, Uddin, F, Uddin, MJ, Vinh, DC, Casanova, JL, Casanova, JL, Vacher, Y, Gysembergh-Houal, A, Demerville, L, Chachoua, A, Abad, S, Abassi, R, Abdellaoui, A, Abdelmalek, A, Abdoul, H, Abergel, H, Abeud, F, Abgrall, S, Abisror, N, Adechian, M, Aderdour, N, Admane, HF, Adnet, F, Afritt, S, Agostini, H, Aguilar, C, Agut, S, Aiello, TF, Kaci, MA, Oufella, HA, Ajeenthiravasan, G, Alauzy, V, Alby-Laurent, F, Allard, L, Alyanakian, MA & Borrero, BA 2023, 'Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19', Genome medicine, vol. 15, no. 1, 22. https://doi.org/10.1186/s13073-023-01173-8

TY - JOUR

T1 - Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

AU - NIAID-USUHS COVID Study Group

AU - COVID Human Genetic Effort

AU - COVIDeF Study Group

AU - French COVID Cohort Study Group

AU - CoV-Contact Cohort

AU - COVID Clinicians

AU - COVID-STORM Clinicians

AU - Amsterdam UMC Covid-19 Biobank

AU - Orchestra Working Group

AU - Matuozzo, Daniela

AU - Talouarn, Estelle

AU - Marchal, Astrid

AU - Zhang, Peng

AU - Manry, Jeremy

AU - Seeleuthner, Yoann

AU - Zhang, Yu

AU - Bolze, Alexandre

AU - Chaldebas, Matthieu

AU - Milisavljevic, Baptiste

AU - Gervais, Adrian

AU - Bastard, Paul

AU - Asano, Takaki

AU - Bizien, Lucy

AU - Barzaghi, Federica

AU - Abolhassani, Hassan

AU - Abou Tayoun, Ahmad

AU - Aiuti, Alessandro

AU - Alavi Darazam, Ilad

AU - Allende, Luis M.

AU - Alonso-Arias, Rebeca

AU - Arias, Andrés Augusto

AU - Aytekin, Gokhan

AU - Bergman, Peter

AU - Bondesan, Simone

AU - Bryceson, Yenan T.

AU - Bustos, Ingrid G.

AU - Cabrera-Marante, Oscar

AU - Carcel, Sheila

AU - Carrera, Paola

AU - Casari, Giorgio

AU - Chaïbi, Khalil

AU - Colobran, Roger

AU - Condino-Neto, Antonio

AU - Covill, Laura E.

AU - Delmonte, Ottavia M.

AU - El Zein, Loubna

AU - Flores, Carlos

AU - Gregersen, Peter K.

AU - Gut, Marta

AU - Haerynck, Filomeen

AU - Halwani, Rabih

AU - Hancerli, Selda

AU - Hammarström, Lennart

AU - Hatipoğlu, Nevin

AU - Karbuz, Adem

AU - Keles, Sevgi

AU - Kyheng, Christèle

AU - Leon-Lopez, Rafael

AU - Franco, Jose Luis

AU - Mansouri, Davood

AU - Martinez-Picado, Javier

AU - Metin Akcan, Ozge

AU - Migeotte, Isabelle

AU - Morange, Pierre Emmanuel

AU - Morelle, Guillaume

AU - Martin-Nalda, Andrea

AU - Novelli, Giuseppe

AU - Novelli, Antonio

AU - Palabiyik, Figen

AU - Pan-Hammarström, Qiang

AU - de Diego, Rebeca Pérez

AU - Planas-Serra, Laura

AU - Pleguezuelo, Daniel E.

AU - Prando, Carolina

AU - Pujol, Aurora

AU - Reyes, Luis Felipe

AU - Rivière, Jacques G.

AU - Rodriguez-Gallego, Carlos

AU - Rojas, Julian

AU - Rovere-Querini, Patrizia

AU - Schlüter, Agatha

AU - Shahrooei, Mohammad

AU - Sobh, Ali

AU - Soler-Palacin, Pere

AU - Tandjaoui-Lambiotte, Yacine

AU - Tipu, Imran

AU - Tresoldi, Cristina

AU - Troya, Jesus

AU - van de Beek, Diederik

AU - Zatz, Mayana

AU - Zawadzki, Pawel

AU - Al-Muhsen, Saleh Zaid

AU - Alosaimi, Mohammed Faraj

AU - Alsohime, Fahad M.

AU - Baris-Feldman, Hagit

AU - Butte, Manish J.

AU - Constantinescu, Stefan N.

AU - Cooper, Megan A.

AU - Dalgard, Clifton L.

AU - Fellay, Jacques

AU - Heath, James R.

AU - Lau, Yu Lung

AU - Lifton, Richard P.

AU - Maniatis, Tom

AU - Mogensen, Trine H.

AU - von Bernuth, Horst

AU - Lermine, Alban

AU - Vidaud, Michel

AU - Boland, Anne

AU - Deleuze, Jean François

AU - Nussbaum, Robert

AU - Kahn-Kirby, Amanda

AU - Mentre, France

AU - Tubiana, Sarah

AU - Gorochov, Guy

AU - Tubach, Florence

AU - Hausfater, Pierre

AU - Al-Muhsen, Saleh

AU - Al-Mulla, Fahd

AU - Anderson, Mark S.

AU - Andreakos, Evangelos

AU - Arias, Andrés A.

AU - Feldman, Hagit Baris

AU - Belot, Alexandre

AU - Biggs, Catherine M.

AU - Bogunovic, Dusan

AU - Bondarenko, Anastasiia

AU - Bousfiha, Ahmed A.

AU - Brodin, Petter

AU - Bustamante, Carlos D.

AU - Chakravorty, Samya

AU - Christodoulou, John

AU - Desai, Murkesh

AU - Drolet, Beth A.

AU - Baghdadi, Jamila El

AU - Espinosa-Padilla, Sara

AU - Franco, José Luis

AU - Froidure, Antoine

AU - Hagin, David

AU - Henrickson, Sarah E.

AU - Hsieh, Elena W.Y.

AU - Husebye, Eystein

AU - Imai, Kohsuke

AU - Itan, Yuval

AU - Jarvis, Erich D.

AU - Karamitros, Timokratis

AU - Kisand, Kai

AU - Ku, Cheng Lung

AU - Ling, Yun

AU - Lucas, Carrie L.

AU - Maródi, László

AU - Milner, Joshua D.

AU - Mironska, Kristina

AU - Morio, Tomohiro

AU - Ng, Lisa F.P.

AU - O’Farrelly, Cliona

AU - Okada, Satoshi

AU - Planas, Anna M.

AU - Quintana-Murci, Lluis

AU - Renia, Laurent

AU - Resnick, Igor

AU - Rodríguez-Gallego, Carlos

AU - Sancho-Shimizu, Vanessa

AU - Sediva, Anna

AU - Seppänen, Mikko R.J.

AU - Shcherbina, Anna

AU - Slaby, Ondrej

AU - Snow, Andrew L.

AU - Soler-Palacín, Pere

AU - Spaan, András N.

AU - Tancevski, Ivan

AU - Tangye, Stuart G.

AU - Ramaswamy, Sathishkumar

AU - Turvey, Stuart E.

AU - Uddin, Furkan

AU - Uddin, Mohammed J.

AU - Vinh, Donald C.

AU - Casanova, Jean Laurent

AU - Vacher, Yannick

AU - Gysembergh-Houal, Anne

AU - Demerville, Lauren

AU - Chachoua, Abla

AU - Abad, Sebastien

AU - Abassi, Radhiya

AU - Abdellaoui, Abdelrafie

AU - Abdelmalek, Abdelkrim

AU - Abdoul, Hendy

AU - Abergel, Helene

AU - Abeud, Fariza

AU - Abgrall, Sophie

AU - Abisror, Noemie

AU - Adechian, Marylise

AU - Aderdour, Nordine

AU - Admane, Hakeem Farid

AU - Adnet, Frederic

AU - Afritt, Sara

AU - Agostini, Helene

AU - Aguilar, Claire

AU - Agut, Sophie

AU - Aiello, Tommaso Francesco

AU - Kaci, Marc Ait

AU - Oufella, Hafid Ait

AU - Ajeenthiravasan, Gokula

AU - Alauzy, Virginie

AU - Alby-Laurent, Fanny

AU - Allard, Lucie

AU - Alyanakian, Marie Alexandra

AU - Borrero, Blanca Amador

PY - 2023/12

Y1 - 2023/12

N2 - Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

AB - Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

KW - COVID-19

KW - Immunity

KW - Rare variants

KW - Type I interferon

UR - http://www.scopus.com/inward/record.url?scp=85160044322&partnerID=8YFLogxK

U2 - 10.1186/s13073-023-01173-8

DO - 10.1186/s13073-023-01173-8

M3 - Article

C2 - 37020259

AN - SCOPUS:85160044322

SN - 1756-994X

VL - 15

JO - Genome medicine

JF - Genome medicine

IS - 1

M1 - 22

ER -

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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