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8 research outputs found

Whole-genome sequencing reveals host factors underlying critical COVID-19

Author: Abd Elghafar M. S.
Abdel-Aziz M.
Abdelrazik M.
Abdollahi H.
Abdullah T.
Abecasis G. R.
Abedalthagafi M.
Abel L.
Abernathy C.
Abraheem A.
Abul-Husn N. S.
Acquilini D.
Adams C.
Adams E. L.
Adams K.
Adamsara A.
Adanini O.
Adeleye O.
Adra D.
Afilalo J.
Afilalo M.
Afolabi D.
Afrasiabi Z.
Agasou A.
Agrawal S.
Aguero D.
Ahmad N.
Ahmadi S.
Ahmed A.
Ahmed C.
Akeroyd L.
Akhtar M. N.
Akinkugbe O.
Aksentijevich A.
Al-Afghani H.
Al-Awdah L.
Alaamery M.
Alahmadey Z. Z.
Alaverdian D.
Alavere H.
Albader A.
Albaiceta G. M.
Albakri J. K.
AlBardis H.
Albeladi M.
Albesher N.
Albrich W.
AlDhawi N.
Aldridge J.
Aleagha A. E.
Alexander P.
Alfonso J.
Alghamdi B.
Alghamdi J.
Ali A.
Ali A.
Ali I. A. M.
Ali S.
Aliannejad R.
Aljawini N.
AlJohani S.
Alkwai S.
Allan A.
Allan E.
Allan J.
Alldis Z.
Allen L.
Allen M.
Allen S.
Allibone S.
Allison K. S.
Allos R.
Ally S. M.
AlMalik A.
Almalki F.
Almohammed I.
Almutairi M.
Alotaibi S.
Alowayn A. M.
Alqahtani S.
Alqubaishi F.
Alrashed M.
Alshareef A.
Alsolm E.
Alswailm M.
Altabaibeh A.
Alvaro A.
AlZahrani D.
Amin V.
Amirsavadkouhi A.
Amitrano S.
Anastasescu E.
Anderson F.
Anderson J.
Anderson M.
Anderson P.
Anderson S.
Anderson S.
Anderson T.
Andolfo I.
Andretta F.
Andreucci E.
Andrew A.
Andrew B.
Andrew G.
Andrews E.
Andrews S. J.
Anedda F.
Anemoli V.
Annis A.
Antcliffe D.
Antinori A.
Antoni M. D.
Anumakonda V.
Apetri E.
Aquino M.
Arabi Y. M.
Aravindan L.
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Publication venue: 'Springer Science and Business Media LLC'
Publication date: 01/01/2022
Field of study

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

PubliCatt

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

Whole-genome sequencing reveals host factors underlying critical COVID-19

Author: Abd Elghafar M.S.
Abdel-Aziz M.
Abdelrazik M.
Abdollahi H.
Abdullah T.
Abecasis G.R.
Abecasis G.R.
Abedalthagafi M.
Abel L.
Abernathy C.
Abraheem A.
Abul-Husn N.S.
Acquilini D.
Adams C.
Adams E.L.
Adams K.
Adamsara A.
Adanini O.
Adeleye O.
Adra D.
Afilalo J.
Afilalo M.
Afolabi D.
Afrasiabi Z.
Agasou A.
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Publication venue: Springer Science and Business Media LLC
Publication date: 07/07/2022
Field of study

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

White Rose Research Online

Mapping the human genetic architecture of COVID-19

Author: Abdelrazik M.
Abdullah T.
Abe R.
Abe S.
Abecasis G. R.
Abel L.
Abernathy C.
Abraheem A.
Abul-Husn N. S.
Acosta-Herrera M.
Acquilini D.
Adachi T.
Adachi Y.
Adams C.
Adams K.
Adanini O.
Adeleye O.
Adeniji K.
Adra D.
Afifi N.
Afilalo J.
Afilalo M.
Afolabi D.
Afrasiabi Z.
Afset J. E.
Agasou A.
Aghemo A.
Agranoff D.
Agrawal S.
Aguirre L. A.
Agwuh K.
Ahmad H. F.
Ahmad N.
Ahmed A.
Ahmed C.
Ahmed K. A.
Ai M.
Ail D.
Akeroyd L.
Akhtar M. N.
Akhtar S.
Akinkugbe O.
Aksentijevich A.
Al Thani A.
Al-Muftah W.
Al-Sarraj Y.
Alarcon C.
Alarcon-Riquelme M. E.
Alasdair F.
Alaverdian D.
Alavere H.
Albertos R.
Albillos A.
Albrecht W.
Albrich W.
Albrich W. C.
Aldera E. L.
Aldridge J.
Alegria A.
Alex B.
Alexander P.
Alfonso J.
Algera A. G.
Ali A.
Ali I. A. M.
Ali S.
Aliberti S.
Allan A.
Allan E.
Allan J.
Alldis Z.
Allen L.
Allen S.
Allibone S.
Allison K. S.
Allos R.
Ally S. M.
Almaden-Boyle C.
Altabaibeh A.
Altmuller J.
Alvaro A.
Amar D.
Amin V.
Amitrano S.
Amiya S.
Ampuero J.
Anan R.
Anania S.
Anastasescu E.
Anderson F.
Anderson J.
Anderson M.
Anderson P.
Anderson S.
Anderson S.
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Ando A.
Andolfo I.
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Andretta F.
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Zoller H.
Zollner S.
Zongo O.
Zucchi P.
Zyndorf M.
Publication venue: 'Springer Science and Business Media LLC'
Publication date: 01/01/2021
Field of study

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Archivio istituzionale della ricerca - Politecnico di Milano

Archivio della ricerca - Università degli studi di Napoli Federico II

Archivio della Ricerca - Università degli Studi di Siena

Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

Archivio istituzionale della ricerca - Università di Genova

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Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

Archivio istituzionale della ricerca - Università di Padova

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Abedalthagafi M
Abel L
Abel L
Abellan J
Abernathy C
Abraheem A
Acklery A
Acosta-Isaac R
Adam R
Adams C
Adams K
Adams N
Adanini O
Afolabi D
Agasou A
Agravante K
Agravante K
Agrawal S
Aguado JM
Aguilar C
Aguilar PM
Aguilera-Albesa S
Ahmad N
Ahmadhaider N
Ahmed A
Ahmed C
Aitkin E
Akeroyd L
Akhtar MN
Akinkugbe O
Al-Moasseb H
Alasdair F
Alba J
Albu S
Alcalá-Gallardo KAM
Alcoba-Florez J
Aldridge J
Alex B
Alexander P
Alfonso J
Algarin-Lara HR
Ali A
Ali HH
Ali IAM
Ali S
Allan A
Allan E
Allan J
Alldis Z
Allen L
Allen M
Allen S
Allibone S
Allison KS
Ally SM
Almadana V
Almaden-Boyle C
Almeida J
Almoguera B
Alonso MR
Altabaibeh A
Alvarez N
Alvaro A
Alves MDM
Amamio M
Amamio M
Amin V
Anastasescu E
Anderson J
Anderson M
Anderson P
Anderson S
Anderson S
Anderson T
Andreou P
Andreu-Bernabeu Á
Andrew A
Andrew B
Andrew G
Andrews J
Andrikopoulos P
Antcliffe D
Antoine P
Antonijoan MR
Antony S
Anumakonda V
Anwer M
Apetri E
Aquino M
Arana-Arri E
Aranda C
Arango C
Araque C
Araujo IMT
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Aravindan L
Arbane G
Arcanjo AC
Archer K
Arden T
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Armistead J
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Arranz MJ
Artiga M-J
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Ashok SR
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Álvarez-Navia F
Íñiguez M
Publication venue: Springer Nature
Publication date: 17/05/2023
Field of study

Data availability: Downloadable summary data are available through the GenOMICC data site (https://genomicc.org/data). Summary statistics are available, but without the 23andMe summary statistics, except for the 10,000 most significant hits, for which full summary statistics are available. The full GWAS summary statistics for the 23andMe discovery dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For further information and to apply for access to the data, see the 23andMe website (https://research.23andMe.com/dataset-access/). All individual-level genotype and whole-genome sequencing data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform (https://odap.ac.uk). A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data service. Monocyte RNA-seq data are available under the title ‘Monocyte gene expression data’ within the Oxford University Research Archives (https://doi.org/10.5287/ora-ko7q2nq66). Sequencing data will be made freely available to organizations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research through a data access agreement. Sequencing data have been deposited at the European Genome–Phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007111.Extended data figures and tables are available online at https://www.nature.com/articles/s41586-023-06034-3#Sec21 .Supplementary information is available online at https://www.nature.com/articles/s41586-023-06034-3#Sec22 .Code availability: Code to calculate the imputation of P values on the basis of SNPs in linkage disequilibrium is available at GitHub (https://github.com/baillielab/GenOMICC_GWAS).Acknowledgements: We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements).Change history: 11 July 2023: A Correction to this paper has been published at: https://doi.org/10.1038/s41586-023-06383-z. -- In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.Copyright © The Author(s) 2023, Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0)

Brunel University Research Archive

Mapping the human genetic architecture of COVID-19

Author: Abdelrazik M
Abdullah T
Abe R
Abe S
Abecasis GR
Abel L
Abernathy C
Abraheem A
Abul-Husn NS
Acosta-Herrera M
Acquilini D
Acquilini D
Adachi T
Adachi Y
Adams C
Adams K
Adanini O
Adeleye O
Adeniji K
Adra D
Afifi N
Afilalo J
Afilalo M
Afolabi D
Afrasiabi Z
Afset JE
Agasou A
Aghemo A
Agranoff D
Agrawal S
Aguirre LA
Agwuh K
Ahmad HF
Ahmad N
Ahmed A
Ahmed C
Ahmed KA
Ai M
Ail D
Akeroyd L
Akhtar MN
Akhtar S
Akinkugbe O
Aksentijevich A
Al Thani A
Al-Muftah W
Al-Sarraj Y
Alarcon C
Alarcon-Riquelme ME
Alasdair F
Alaverdian D
Alavere H
Albertos R
Albillos A
Albrecht W
Albrich W
Albrich WC
Aldera EL
Aldridge J
Alegria A
Alex B
Alexander P
Alfonso J
Algera AG
Ali A
Ali IMA
Ali S
Aliberti S
Allan A
Allan E
Allan J
Alldis Z
Allen L
Allen S
Allibone S
Allison KS
Allos R
Ally SM
Almaden-Boyle C
Altabaibeh A
Altmueller J
Alvaro A
Amar D
Amin V
Amitrano S
Amiya S
Ampuero J
Anan R
Anania S
Anastasescu E
Anderson F
Anderson J
Anderson M
Anderson P
Anderson S
Anderson S
Anderson T
Ando A
Andolfo I
Andrade V
Andretta F
Andreucci E
Andreucci E
Andrew A
Andrew B
Andrew G
Andrews E
Andrews SJ
Andrews SJ
Andrews SJ
Andrews SJ
Andrikopoulos P
Anedda F
Aneli S
Anemoli V
Angelini C
Angus B
Annis A
Antcliffe D
Antinori A
Antoni MD
Anumakonda V
Anwar M
Anzai T
Apetri E
Arai D
Arana E
Arbane G
Archer K
Arciero E
Arden T
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Arif S
Arimura K
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Armstrong JA
Armstrong L
Armstrong R
Arning N
Arnold S
Arora J
Artuso R
Arumugam P
Asakura T
Asano K
Aschard H
Ascolillo S
Ashish A
Ashley E
Ashraf S
Ashraf S
Ashton L
Ashworth M
Asiimwe IG
Aslibekyan S
Asselta R
Atanasovska B
Atkinson D
Atkinson EG
Attwood B
Aucella F
Augustin M
Auld D
Auld F
Austin K
Austin P
Auton A
Auton A
Avendano-Ortiz J
Awano N
Ayers A
Azarzar S
Aziz F
Azuma M
Azuure C
Azzolini E
Baba R
Baba T
Bach B
Bacher P
Bachetti T
Badalamenti S
Badia JR
Badji RM
Bahmer T
Baikady RR
Baillie JK
Baillie JK
Baillie JK
Baillie JK
Baines B
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Bakthavatsalam D
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Band G
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Basude S
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Bergomi P
Berkowitz N
Bernardo D
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Bertrand A
Best N
Bettini LR
Beudel M
Bevan E
Bewley J
Bhardwaj N
Bhatia N
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Biggs H
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Blakemore H
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Board S
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Bocciolone M
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Bochud PY
Bochud PY
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Boezen M
Bogaard HJ
Bogaert D
Boillat N
Boillat-Blanco N
Bokhari M
Bolton M
Bolton R
Bolze A
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Bomers M
Bonfanti P
Bonner S
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Borislavova B
Borra C
Bos L
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Bosio G
Bosse Y
Botello A
Bothma P
Botta G
Botta M
Boua PR
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Boughton AP
Boujemla B
Bouras K
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Britvan B
Bromley M
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Brooks S
Brouwer MC
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Brown CW
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Bruce M
Brunak S
Bruno R
Brunton M
Brusco A
Bruttini M
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Buckley C
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Bulik CM
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Burda D
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Burn I
Burnett C
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Burtenshaw A
Burtenshaw A
Burton M
Busani S
Busson A
Bussotti M
Bustamante C
Butcher D
Buti M
Butler A
Butler S
Butler-Laporte G
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Butler-Laporte G
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Butte MJ
Butterworth AS
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Buxbaum JD
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Cabrelli L
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Cadilla CL
Cagova L
Caldarelli GP
Calderon EJ
Callaghan M
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Cameli P
Campbell A
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Canaccini A
Canakoglu A
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Cantor MN
Capasso M
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Cappadona C
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Cardamone G
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Carli D
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Carmody M
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Carnahan M
Carnero-Montoro E
Carrabba M
Carracedo AD
Carreras Nolla A
Carreras A
Carriero ML
Carson G
Carter A
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Catterall BWA
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Chadbourn I
Chadwick D
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Chambler D
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Charney AW
Charnock R
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Chaudhary K
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Chen H-H
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Chernitsov A
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Claassen S
Claire W
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Clapham M
Claringbould A
Clarinval M
Clark A
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Clark M
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Clarke EA
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Clarkson M
Clayton S
Clement I
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Clerc O
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Clohisey S
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Coates C
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Coghlan P
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Conyngham J-A
Cooke GS
Cooper J
Cooper L
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Corcoran E
Cordero AIH
Cordioli M
Cordioli M
Cordioli M
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Cordioli M
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Cornell S
Cornely OA
Corral MA
Correia GDS
Corridi M
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Costantino G
Cother N
Coton Z
Coulding M
Coutts A
Coventry T
Coviello DA
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Cowley A
Cowley N
Cowton A
Cox A
Cox H
Cox NJ
Coyle J
Craig J
Crawley R
Creagh-Brown B
Crew A
Crickmore V
CRiPSI
Crisp N
Criste K
Cristiano D
Croci L
Croci S
Croft M
Crook DW
Crooks K
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Crowe R
Crowley M
Cruz C
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Cunningham A
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Curgenven H
Curtis CJ
Cusack R
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Cutino-Moguel M-T
Cutler S
D'Acremont V
D'Alessandro M
D'Amato M
D'Angio M
D'Sylva S
Da Gloria EF
Dabe S
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Daly MJ
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Damas JK
Dance A
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Daniel A
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Darcis G
Dark P
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Davey M
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de Gordoa LO-R
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de Jong MD
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de Pablo R
de Rojas I
de Salazar A
de Silva T
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Death Y
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Dunmore C
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Dutta AK
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Earle SG
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Edmond I
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Eggermann T
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Ellinghaus D
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Niemi MEK
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Packham S
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Pagani JL
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Page VJ
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Pairo-Castineira E
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Pancrazi A
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Pantet O
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Park D
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Park WB
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Parkinson N
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Parmar C
Parravicini P
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Parsons P
Partha R
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Parzibut G
Pasaniuc B
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Pascual-Iglesias A
Pasko D
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Passmore H
Patel A
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Schulte EC
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Yoshiya K
Yoshiyama T
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Younes SE
Young P
Yun N
Zak A
Zaki A
Zambon M
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Zanella A
Zanella I
Zanelli G
Zara F
Zara F
Zarate R
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Zborowski AC
Zeberg H
Zechner M
Zechner M
Zguro K
Zhai R
Zhang JE
Zhang M
Zhao JH
Zhen J
Zheng C
Zheng T
Zhou W
Zhou W
Zhu W
Zitter L
Zlatopolsky M
Zoller H
Zollner S
Zongo O
zu Bentrup FM
Zucchi P
Zwinderman AHK
Zyndorf M
Publication venue
Publication date: 01/01/2021
Field of study

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Long-term (180-Day) outcomes in critically Ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

Author: Abbass H
Abdeladim L
Abdelhady H
Abdelkharim H
Abdelrazik M
Abdi Z
Abdukahil SA
Abel L
Abraham J
Abrahamson G
Abusamra Y
Aceto R
Adams P
Adebambo O
Adhikari N
Affleck J
Agha G
Aghemo A
Agno R
Aguilar-Dano A
Ahmad N
Ain Q
Ainscough K
Ainsworth J
Aitken L
Akamp C
Al Enezi F
Al-Bassam W
Al-Beidh F
Albert M
Albrett J
Alderink B
Alderman M
Alegria A
Alexander B
Alexander P
Alfonso J
Ali F
Ali M
Ali M
Allam H
Allen B
Allen L
Allibone S
AlQahtani S
Alswaidan L
Altaf W
Altomy M
Al Amri A
Al Qasim E
Amatya S
Ambrosino R
Anders J
Anderson T
Andreae M
Andric Z
Aneman A
Angus DC
Anjum A
Ankert J
Annane D
Anne-Laure F
Anstey M
Antcliffe D
Anthony A
Antoine M
Antoine P
Anumakonda V
Aparicio C
Arabi YM
Arachchige M
Aravindan L
Arbane G
Archer S
Aref N
Arias A-M
Arias S
Arishi H
Arnold D
Arnold J
Aryal D
Asghar A
Asif N
Aspinwall A
Attanayaka U
Attokaran A
Attwood B
Au C
Austin K
Austin P
Avard B
Awan S
Azaiz A
Azergui N
Azzaui H
Babel J
Babu S
Bacon G
Badalamenti S
Badie J
Bagavathy K
Bagot C
Bagshaw S
Baig N
Baikady R
Baillie K
Bain W
Baker E
Baker S
Bakthavatsalam D
Balaie M
Bamford A
Bamford P
Banach D
Bannard-Smith J
Barbash I
Barbazza L
Barber R
Barbier F
Barge D
Bari S
Bariola R
Barker G
Barnes N
Baron R
Barreau A
Bart R
Bartholomew J
Bartley S
Barton D
Barton F
Bashyal A
Basile K
Bass F
Bassford C
Bastola S
Bastos JMPS
Bates M
Bates S
Batista TMO
Bauchmuller K
Bayne M
Bean S
Beane A
Beard G
Beasley R
Beavis S
Beddows S
Bedford C
Beer D
Begin P
Begum S
Bell G
Bellemare D
Beltran M
Bendjemar L
Benettaib F
Bensen N
Benyon S
Benzekri D
Berdaguer F
Bergin C
Berry LR
Berry S
Berryman E
Bertel M
Best-Lane J
Besten H
Bevan E
Bewley J
Beyerl A
Bhagani S
Bhandal K
Bhattarai B
Bhimani Z
Bhonagiri D
Biddie S
Bihari S
Binnie A
Biradar V
Birch C
Birch J
Birch J
Birchall K
Birkinshaw I
Black E
Blackledge B
Blakemore H
Bland Y
Blank E
Bloos F
Board J
Boardman M
Bocher S
Bociek A
Boivin A-H
Bojunga J
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Bonten MJM
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Zapalac M
Zarychanski R
Zhao X
Zinzoni V
Zitter L
Zouita L
Publication venue: 'American Medical Association (AMA)'
Publication date: 30/11/2022
Field of study

Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months

Spiral - Imperial College Digital Repository

A second update on mapping the human genetic architecture of COVID-19

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Abdel-Aziz M
Abdelrazik M
Abdullah MS
Abe R
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Abel L
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Abernathy C
Abraham R
Abraheem A
Abu Alragheb BO
Abulail JA
Acklery A
Acosta-Herrera M
Adachi T
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Adams C
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Adanini O
Afifi N
Afilalo J
Afilalo M
Afolabi D
Afrasiabi Z
Afset JE
Agasou A
Aghemo A
Agravante K
Agrawal A
Agrawal S
Aguado JM
Aguilar C
Aguilar SEV
Aguilar-Salinas CA
Aguilera-Albesa S
Agüero D
Ahmad HF
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Ahmadhaider N
Ahmed A
Ahmed C
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Ai M
Ain Q
Aitkin E
Akeroyd L
Akhtar MN
Akinkugbe O
Al-Ani A
Al-Ja’afreh MM
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Al-Kasasbeh MM
Al-Moasseb H
Al-Muftah W
Al-Sarraj Y
Alamer LM
Alasdair F
Alawneh FM
Alawneh LM
Albaiceta GM
Albano G
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Aldridge J
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Alfonso J
Alhousani TN
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Yoshihara T
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Yue F
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Zainulabid UA
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Zamudio IPM
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Zborowski AC
Zeberg H
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Zhang Q
Zhao X
Zheng C
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Zhlawi HJ
Zhlawi MWJ
Zholdybayeva E
Zhou W
Zhu W
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Zoller H
Zongo O
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Álvarez BG
Ávila-Arcos MA
Ávila-Arcos MC
Özer O
Überla K
Þorsteinsdóttir U
Publication venue: Nature Research
Publication date: 21/06/2023
Field of study

Spiral - Imperial College Digital Repository

Whole-genome sequencing reveals host factors underlying critical COVID-19

Author: Abd Elghafar Mohamed S.
Abdel-Aziz Mahmoud
Abdelrazik Marwa
Abdollahi Hamed
Abdullah T.
Abecasis Goncalo
Abedalthagafi M.
Abel Lynn
Abernathy C.
Abraheem Azmeralde
Abul-Husn Noura S.
Acquilini D.
Adams C.
Adams Emma L.
Adams K.
Adamsara Alireza
Adanini Olurenke
Adeleye O.
Adra D.
Afilalo J.
Afilalo M.
Afolabi D.
Afrasiabi Z.
Agasou A.
Agrawal Shruti
Agüero D.
Ahmad N.
Ahmadi Saeideh
Ahmed A.
Ahmed Cecilia
Akeroyd L.
Akhtar M.N.
Akinkugbe O.
Aksentijevich Alexandra
Al-Afghani H.
Al-Awdah L.
Alaamery M.
Alahmadey Z.Z.
Alaverdian D.
Alavere H.
Albader A.
Albaiceta G.M.
Albakri J.K.
AlBardis H.
Albeladi M.
Albesher N.
Albrich W.
AlDhawi N.
Aldridge J.
Aleagha Afshar Etemadi
Alexander Peter.
Alfonso J.
Alghamdi B.
Alghamdi J.
Ali A.
Ali Altaf
Ali I.A.M.
Ali Syamlan
Aliannejad Rasoul
Aljawini N.
AlJohani S.
Alkwai S.
Allan A.
Allan E.
Allan J.
Alldis Zoe
Allen L.
Allen Meryem
Allen Schvearn
Allibone S.
Allison K.S.
Allos R.
Ally S.M.
AlMalik A.
Almalki F.
Almohammed I.
Almutairi M.
Alotaibi S.
Alowayn A.M.
Alqahtani S.
Alqubaishi F.
Alrashed M.
Alshareef A.
Alsolm E.
Alswailm M.
Altabaibeh A.
Alvaro A.
AlZahrani D.
Amin V.
Amirsavadkouhi Ali
Amitrano Sara
Anastasescu E.
Anderson F.
Anderson J.
Anderson Madeleine
Anderson Peter
Anderson S.
Anderson S.
Anderson T.
Andolfo I.
Andretta F.
Andreucci E.
Andrew Angela
Andrew B.
Andrew Gratrix
Andrews E.
Andrews Shea J.
Anedda F.
Anemoli V.
Annis A.
Antcliffe David
Antinori Andrea
Antoni M.D.
Anumakonda V.
Apetri E.
Aquino Maia
Arabi Y.M.
Aravindan Latha
Arbane Gill
Archer Katie
Arden T.
Arias Sonia Sousa
Arif S.
Armstrong Jacob
Armstrong Lisa
Armstrong Ruth
Arning N.
Arnold Sophie
Arranz María Jesús
Arribas E.
Artuso R.
Arumugam Prabhu
Ascolillo Steven
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Publication venue
Publication date: 01/01/2022
Field of study

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

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