14 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.
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- Wakefield P.
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- Waldron J.
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- Woodford C.
- Woodruff M.
- Woods L.
- Woodyatt W.
- Woolley A. E.
- Worner R.
- Worsley L.
- Wray G.
- Wren L.
- Wright D.
- Wright J.
- Wright M.
- Wrobel N.
- Wu Y.
- Wulandari R.
- Wyllie D. H.
- Wynter I.
- Xavier K.
- Xue X.
- Yadav A.
- Yang J.
- Yassen A. M.
- Yates B.
- Ye C.
- Yun N.
- Zainy T.
- Zak A.
- Zaki A.
- Zamikula J.
- Zanella I.
- Zborowski A. C.
- Zeberg H.
- Zechner M.
- Zguro K.
- Zhang M.
- Zhao J. H.
- Zheng C.
- Zhou W.
- Zitter L.
- Zlatopolsky M.
- Zollner S.
- Zongo O.
- Zucchi P.
- Zyndorf M.
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
Get PDFCritical 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
Genetic mechanisms of critical illness in COVID-19.
- Author
- A A Roger Thompson
- A Abraheem
- A Agasou
- A Ahmed
- A Ali
- A Allan
- A Altabaibeh
- A Alvaro
- A Aspinwall
- A Ayers
- A Bamford
- A Barron
- A Bashyal
- A Bellini
- A Bociek
- A Botello
- A Bowes
- A Brady
- A Brayne
- A Brown
- A Brown
- A Butler
- A Campbell
- A Carter
- A Collins
- A Cowley
- A Cowton
- A Cowton
- A Cox
- A Crew
- A Dance
- A Daniel
- A Daniels
- A Dela Rosa
- A Drummond
- A Durie
- A E Heron
- A Easthope
- A Easthope
- A Evans
- A Fofano
- A Gales
- A Ganesan
- A Gardner
- A Garg
- A Gherman
- A Gordon
- A Gratrix
- A Gulati
- A Gupta
- A Haigh
- A Haldeos
- A Harrison
- A Harvey
- A Hayes
- A Higham
- A Higham
- A Hilldrith
- A Holden
- A Hormis
- A Hutcheon
- A Javaid
- A Joseph
- A Kaliappan
- A Katary
- A Kay
- A Kayani
- A Kent
- A Kirkby
- A Knight
- A Kubisz-Pudelko
- A Kuravi
- A Lewis
- A Loveridge
- A Lyle
- A Mayer
- A McAlpine
- A McCarthy
- A McGregor
- A McGregor
- A Meikle
- A Mitchell
- A Mitra
- A Morris
- A Morrison
- A Naranjo
- A Nicholson
- A Nicholson
- A Nilsson
- A Noakes
- A Patel
- A Pickard
- A Poole
- A Price
- A Puxty
- A Quinn
- A Quinn
- A Raithatha
- A Rattray
- A Reddy
- A Reed
- A Reyes
- A Rose
- A Rose
- A Rostron
- A Roy
- A Roynon-Reed
- A S Raj
- A Salberg
- A Sanderson
- A Serrano-Ruiz
- A Solesbury
- A Sukha
- A Swain
- A Tariq
- A Thomas
- A Thomas
- A Todd
- A Tomas
- A Tridente
- A Tucci
- A Turnbull
- A Uriel
- A Ustianowski
- A Vochin
- A Vuylsteke
- A Waite
- A Walden
- A Whileman
- A Wilkinson
- A Williams
- A Williams
- A Wilson
- A Zak
- A Zaki
- Achille Iolascon
- Adam Auton
- Adam Brown
- Agnese Verzuri
- Agostino Ognibene
- Agostino Riva
- Ailsa Golightly
- Alan Maclean
- Alessandra
- Alessandra Stella
- Alessandra Vergori
- Alessia Giorli
- Alexander J Mentzer
- Alice Donati
- Alison M Meynert
- Alistair Nichol
- Ana da Silva Filipe
- Andrea Antinori
- Andrea Cossarizza
- Andrea Ganna
- Andrea Tommasi
- Andrew Rambaut
- Andrew Stenhouse
- Andy Law
- Anjali J Shastri
- Anna Canaccini
- Anna Maria Pinto
- Annarita Giliberti
- Annemarie B Docherty
- Antonella D'Arminio Monforte
- Antonia Ying Wai Ho
- Antonio Di Biagio
- Antony Symons
- Arianna Emiliozzi
- Arianna Gabrieli
- Audrey Coutts
- B Anwar
- B Attwood
- B Baines
- B Blackledge
- B Borislavova
- B Chandler
- B Charles
- B Creagh-Brown
- B David
- B Deacon
- B Deacon
- B Digby
- B Faulkner
- B Fuller
- B Gumbrill
- B Gurung
- B Hadebe
- B Hairsine
- B Hopkins
- B Johnston
- B Lenagh
- B Masunda
- B Ogg
- B Patel
- B Player
- B Purewal
- B Scholefield
- B Shelley
- B Sloan
- B Thomas
- B Wadams
- B Welsh
- B Wilkinson
- B Winter-Goodwin
- B Yates
- Baillie J Kenneth
- Barbara Rossetti
- Beale Rupert
- Beatrice Alex
- Benjamin Bach
- Bretherick Andrew D
- Bruno Frediani
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- C Dennis
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- C Stuart
- C Summers
- C Swan
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- C Wrey Brown
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- Carmen Marciano
- Caroline Abernathy
- Carrol Gamble
- Caterina Lo Rizzo
- Catherine A Shaw
- Catherine H Weldon
- Caulfield Mark
- Ceilia Boz
- Cesira Nencioni
- Chelsea Ye
- Chiara Fallerini
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- Chiara Spertilli
- Chloe Donohue
- Chris Ponting
- Christoper A Green
- Cinthia E Jannes
- Clare Jackson
- Clohisey Sara
- Cristina Mussini
- D Antcliffe
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- D Martin
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- D Tetla
- D Thornton
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- D Vedage
- D Walker
- D Warren
- D Williams
- D Wood
- D Wright
- Daniela Francisci
- Daniella Coker
- Danilo Tacconi
- David A van Heel
- David Bennet
- David L Robertson
- David Stuart
- Dawn Law
- Debby Bogaert
- Derek Murphy
- Domenico A Coviello
- E Abaleke
- E Allan
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- E Andrews
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- E B Jude
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- E Beranova
- E Bevan
- E Black
- E Brinkworth
- E Collins
- E Combes
- E Davies
- E Dobson
- E Dooks
- E Fisher
- E Gendall
- E Goff
- E Goodwin
- E Gordon
- E Heeney
- E Horsley
- E Hughes
- E Johnson
- E Knights
- E Lee
- E London
- E Maccacari
- E Massey
- E McKenna
- E Meadows
- E Moncur
- E Morino
- E Mwaura
- E Peasgood
- E Perkins
- E Radford
- E Raith
- E Raith
- E Salciute
- E Smith
- E Smithson
- E Stoddard
- E Stones
- E Thomas
- E Tilney
- E Timlick
- E Treus Gude
- E Virgilio
- E Watson
- E Wilby
- Edoardo Conticini
- Egle Saviciute
- Elena Bargagli
- Elena Desanctis
- Elisa Benetti
- Elisa Frullanti
- Elisabetta Menatti
- Elisabetta Schiaroli
- Ellie Mcmaster
- Emma C Thomson
- Emmanuelle Marques
- Enrico Martinelli
- Esther Duncan
- Esther Merlini
- Ewen M Harrison
- F Anderson
- F Auld
- F Bibi
- F Davies
- F Farquhar
- F Fisher
- F Hurford
- F Kibutu
- F McNeela
- F Moore
- F Nasir
- F Trim
- F Wakinshaw
- F Williams
- Fabio Lena
- Fawkes Angie
- Federico Anedda
- Federico Franchi
- Ferdinando Giannattasio
- Filip Taneski
- Filippo Aucella
- Filippo Biscarini
- Floriana Valentino
- Fourman Max Head
- Francesca Andretta
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- Furniss James
- G Andrew
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- G Bell
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- G Sera Howe
- G Sloane
- G Subramanian
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- G Turner
- G Watson
- G Wray
- Gabriella Coiro
- Gabriella Doddato
- Gail Carson
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- Gary Leeming
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- Giancarlo Bosio
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- Graham S Cooke
- Griffiths Fiona
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- H Reschreiter
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- H Sainsbury
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- H Tench
- H Tiveran
- H Turner
- H Whittle
- H Willis
- H Wood
- Haley Chris
- Hanning Mal
- Harrison David
- Hayley Hardwick
- Hayward Caroline
- Helen Szoor-McElhinney
- Hinds Charles
- Ho Antonia
- Horby Peter
- I Ali Mohamed Ali
- I Balagosa
- I Birkinshaw
- I Burn
- I Chadbourn
- I D Clement
- I Edmond
- I Frost
- I Hass
- I Hussain
- I Lancoma-Malcolm
- I Leadbitter
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- I Otahal
- I Turner-Bone
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- I White
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- Ilaria Meloni
- Immacolata Andolfo
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- J Allan
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- J Biddle
- J Birch
- J Birch
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- J Brown
- J Bryant
- J Butler
- J Camsooksai
- J Carter
- J Caterson
- J Cebrian Suarez
- J Cockerill-Taylor
- J Cole
- J Colley
- J Cooper
- J Cupitt
- J Cuttler
- J Daglish
- J Dasgin
- J Dawson
- J Dearden
- J Deery
- J Donnachie
- J Dykes
- J Easton
- J Egan
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- J Finn
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- J Gregory
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- J Jones
- J Jones
- J K Baillie
- J Kassam
- J Kenneth Baillie
- J Kenneth Baillie
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- McAuley Danny
- Meera Chand
- Meynert Alison
- Michelle Girvan
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- Victoria Shaw
- Vitart Veronique
- W Harrison
- W Khaliq
- W Khaliq
- W McCormick
- W Woodyatt
- Walker Susan
- Walsh Timothy
- Wang Bo
- Wei Shen Lim
- Wendy S Barclay
- William A Paxton
- William Greenhalf
- Wilson James F
- Wrobel Nicola
- Wu Yang
- X Qiu
- Y Baird
- Y Choudhury
- Y Hussain
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- Y Thirlwall
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- Yang Zhijian
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- Z Fernandez
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- Z Maqsood
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- Z Scott
- Zechner Marie
- Zhai Ranran
- Zheng Chenqing
- Publication venue
- Nature
- Publication date
- 01/01/2020
- Field of study
Get PDFHost-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
- Author
- A. Abraheem
- A. Agasou
- A. Ahmed
- A. Ali
- A. Allan
- A. Altabaibeh
- A. Alvaro
- A. Aspinwall
- A. Ayers
- A. Bamford
- A. Barron
- A. Bashyal
- A. Bellini
- A. Bociek
- A. Botello
- A. Bowes
- A. Brady
- A. Brayne
- A. Brown
- A. Brown
- A. Butler
- A. Carter
- A. Collins
- A. Cowley
- A. Cowton
- A. Cowton
- A. Cox
- A. Crew
- A. Dance
- A. Daniel
- A. Daniels
- A. Dela Rosa
- A. Drummond
- A. Durie
- A. E. Heron
- A. Easthope
- A. Easthorpe
- A. Evans.
- A. Fofano
- A. Gales
- A. Ganesan
- A. Gardner
- A. Garg
- A. Gherman
- A. Gordon
- A. Gratrix
- A. Gulati
- A. Gupta
- A. Haigh
- A. Haldeos
- A. Harrison
- A. Harvey
- A. Hayes
- A. Higham
- A. Higham
- A. Hilldrith
- A. Holden
- A. Hormis
- A. Hutcheon
- A. Javaid
- A. Joseph
- A. Kaliappan
- A. Katary
- A. Kay
- A. Kayani
- A. Kent
- A. Kirkby
- A. Knight
- A. Kubisz-Pudelko
- A. Kuravi
- A. Lewis
- A. Loveridge
- A. Lyle
- A. Mayer
- A. McAlpine
- A. McCarthy
- A. McGregor
- A. McGregor
- A. Meikle
- A. Mitchell
- A. Mitra
- A. Morris
- A. Morrison
- A. Naranjo
- A. Nicholson
- A. Nicholson
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- A. Patel
- A. Pickard
- A. Price
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- A. Quinn
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- A. Salberg
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- A. Swain
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- A. Thomas
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- V. Amin
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- Valentina Anemoli
- Valentina Borgo
- Valentina Perticaroli
- Verena Keitel
- Veronique Vitart
- W. Harrison
- W. Khaliq
- W. Khaliq
- W. McCormick
- W. Woodyatt
- Wadha Al-Muftah
- WES/WGS Working Group Within the HGI
- Wiktoria Izdebska
- Wilna Oosthuyzen
- X. Qiu
- Xia Shen
- Y. Baird
- Y. Choudhury
- Y. Hussain
- Y. Jackson
- Y. Thirlwall
- Yanara Marincevic-Zuniga
- Yang Wu
- Yaser Al-Sarraj
- Z. Alldis
- Z. Belagodu
- Z. Bradshaw
- Z. Coton
- Z. Daly
- Z. Farzad
- Z. Fernandez
- Z. Garland
- Z. Maqsood
- Z. Omar
- Z. Prime
- Z. Scott
- Zhijian Yang
- Publication venue
- Publication date
- 01/01/2022
- Field of study
Get PDFThe combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)
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.
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- Williams M.
- Williams P.
- Williams S.
- Williams T.
- Willis C.
- Willis H.
- Wills M.
- Willson J.
- Wilson A.
- Wilson D.J.
- Wilson J.
- Wilson J.F.
- Wilson J.F.
- Winnard S.
- Winter-Goodwin B.
- Wolf-Roberts R.
- Wolford B.
- Wong J.
- Wood D.
- Wood H.-L.
- Wood S.
- Wood T.
- Woodford C.
- Woodruff M.
- Woods L.
- Woodyatt W.
- Woolley A.E.
- Worner R.
- Worsley L.
- Wray G.
- Wren L.
- Wrey Brown C.
- Wright D.
- Wright J.
- Wright M.
- Wrobel N.
- Wu Y.
- Wulandari R.
- Wyllie D.H.
- Wynter I.
- Xavier K.
- Xue X.
- Yadav A.
- Yang J.
- Yassen A.M.
- Yates B.
- Ye C.
- Yun N.
- Zainy T.
- Zak A.
- Zaki A.
- Zamikula J.
- Zanella I.
- Zborowski A.C.
- Zeberg H.
- Zechner M.
- Zechner M.
- Zguro K.
- Zhang M.
- Zhao J.H.
- Zheng C.
- Zhou W.
- Zitter L.
- Zlatopolsky M.
- Zongo O.
- Zucchi P.
- Zyndorf M.
- Zöllner S.
- Åsvold B.O.
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
Get PDFCritical 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
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
- Author
- ?ivko Iris
- Abbass Hakam
- Abdeladim Lilia
- Abdelhady Hesham
- Abdelkharim Hussam
- Abdelrazik Marwa
- Abdi Zakee
- Abdukahil Sheryl Ann
- Abel Lynn
- Abraham Jacinta
- Abrahamson Gail
- Abusamra Yousuf
- Aceto Romina
- Adams Nick
- Adams Peter
- Adebambo Olumide
- Adhikari Neill
- Adhikari Sheetal
- Affleck Julia
- Agha Gloria
- Aghemo Alessio
- Agno Ronan
- Ahmad Norfaizan
- Ain Quratul
- Ainscough Kate
- Ainsworth James
- Aitken Lindianne
- Akamp Ceren
- Al Enezi Farhan
- Al-Bassam Wisam
- Al-Beidh Farah
- Albert Martin
- Albrett Jonathan
- Alderman Meera
- Aldo Bonizzoni Matteo
- Alegria Ana
- Alessandro Carà Gianmarco
- Alexander Brian
- Alexander Peter
- Alfonso Jordan
- Ali Maryam
- Ali Murtaza
- Allam Hayat
- Allen Barbara
- Allen Louise
- Allibone Suzanne
- Almeshhedani Hasham
- AlQahtani Samah
- Alswaidan Lolowa
- Altomy Mohammed
- Al Amri Ali
- Al Qasim Eman
- Amatya Sameena
- Ambrosino Richard
- Anderson Thomas
- Andreae Mark
- Aneman Anders
- Angus Derek C.
- Anjum Aisha
- Ankert Juliane
- Annane Djillali
- Anne-Laure Fedou
- Anstey Matthew
- Antcliffe David
- Anthony Alpha
- Antoine Marchalot
- Antoine Pierre
- Antoine Studer
- Anumakonda Vikram
- Aparicio Christelle
- Aquino Maia
- Arabi Yaseen M.
- Arachchige Malka
- Aravindan Latha
- Arbane Gill
- Archambault Patrick
- Archer Simon
- Aref Noah
- Arias Ana-Marie
- Arias Sonia
- Arishi Hatim
- Arnold Donald
- Arnold John
- Arnott Andrew
- Arora Anand
- Aryal Diptesh
- Asghar Adeeba
- Asif Namra
- Aspinwall Angelique
- Attokaran Antony
- Attwood Ben
- Au Carly
- Audry Mathilde
- Austin Karen
- Austin Pauline
- Auvet Adrien
- Avard Bronwyn
- Awan Sidra
- Ayee Robert
- Azaiz Amine
- Azzaui Harun
- Babu Suresh
- Bacon Gina
- Badalamenti Salvatore
- Badie Julio
- Bagavathy Kavitha
- Bagot Catherine
- Bagshaw Sean
- Baig Nadia
- Baikady Ravishankar
- Bailey Lucy
- Baillie Kenneth
- Bain William
- Baker Alice
- Baker Evelyn
- Baker Stuart
- Bakthavatsalam Dhanalakshmi
- Balaie Morteza
- Balls-Burgess Sam
- Bamford Amy
- Bamford Peter
- Banach Dorota
- Bannard-Smith Jonathan
- Barbash Ian
- Barber Russell
- Barbier François
- Barge Deborah
- Bariola Ryan
- Barker Gareth
- Barker Stephanie
- Barnes Nicky
- Baron Rebecca M.
- Barreau Amelie
- Barreau Amélie
- Bart Robert
- Bartholomew Jazz
- Bartley Shauna
- Barton David
- Barton Frances
- Bashyal Archana
- Basile Kim
- Bass Frances
- Bassford Christopher
- Bastos Joana Margarida Pereira Sousa
- Bates Michelle
- Bates Samantha
- Batista Teresa Margarida Oliveira
- Bauchmuller Kris
- Bayne Madeleine
- Bean Sarah
- Beane Abi
- Beane Abigail
- Beard Gregory
- Beasley Richard
- Beaudoin Rosalie
- Beavis Sarah
- Beddows Seonaid
- Bedford Caroline
- Beer Deborah
- Beer Sally
- Begin Phillipe
- Begum Salma
- Bell Gillian
- Bellemare David
- Belletti Allesandro
- Bendjemar Lynda
- Benettaib Fatna
- Bensen Nicole
- Bentley Andrew
- Benyon Sarah
- Benzekri Dalila
- Beqai Besa
- Berdaguer Fernando
- Beresford Stephanie
- Bergin Colin
- Berry Lindsay R.
- Berry Scott
- Berryman Emily
- Bertel Melanie
- Best-Lane Janis
- Besten Henny
- Bevan Emily
- Bewley Jeremy
- Beyerl Ashley
- Bhagani Sanjay
- Bhandal Khushpreet
- Bharaj Kiranjit
- Bhattarai Bina
- Bhattarai Binita
- Bhonagiri Deepak
- Biddie Simon
- Bigas Judit
- Bihari Shailesh
- Bin Hasan Mohd Shahnaz
- Bindels Manon
- Binnie Alexandra
- Biradar Vishwanath
- Birch Catherine
- Birch Janine
- Birch Sophie
- Birchall Kathrine
- Birkinshaw Isobel
- Black Ethel
- Blackledge Bethany
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- Blanck Wendy
- Bland Yvonne
- Blank Elisabeth
- Bleasdale John
- Bloomfield Jack
- Bloos Frank
- Board Jasmin
- Boardman Melanie
- Boari Gianluca
- Bocher Simon
- Bociek Aneta
- Boivin Anne-Helene
- Boivin Anne-Hélène
- Bojunga Jörg
- Bomken Charlotte
- Bonaccorso Allesandra
- Bongaerts Katherine
- Bonner Stephen
- Bonten Marc J. M.
- Borgatta Barbara
- Borislavova Borislava
- Borrill Zoe
- Boschert Catherine
- Bossard Isabelle
- Bothma Pieter
- Boudineau Michel
- Boulanger Marie-Claude
- Boumahni Dounia
- Bouman Angela
- Bounab Rania
- Bourgoin Charlotte
- Bourne Michelle
- Bourne Richard
- Boutin Mireille
- Bouvier Elodie
- Bouw-Ruiter Marianne
- Boué Yvonnick
- Bowen James
- Bowler Helen
- Boyd Craig
- Boyles Rebecca
- Bracke Stephanie
- Bradbury Charlotte A.
- Bradley Paul
- Brady Kara
- Brailsford Jane
- Brain Matthew
- Brakké Karen
- Brant Emily
- Brasselet Aurélie
- Breen Patrick
- Bremmer Pamela
- Brend Morwenna
- Brennan Aoife
- Bretagnol Anne
- Brett Stephen
- Brewer Chris
- Brickell Kathy
- Bridges Sarah
- Brieger Klaus-Gerd
- Brightling Chris
- Brimfield Lutece
- Brittain Michael
- Britton Kate
- Brochard Laurent
- Brodbeck Andreas
- Brohi Farooq
- Brooks Nicole
- Brown Cynthia
- Brown Julia
- Brown Louise
- Brown Nerissa
- Brown Zarah
- Brugman Curt
- Brunetta Enrico
- Brunkhorst Frank M.
- Brunskill Nigel
- Bryan-Morris Kayla
- Bryden Emma
- Budd Joanna
- Buehner Ulrike
- Buhay Megan
- Buhr Heidi
- Burbee Dylan
- Burda Dorota
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- Burke David
- Burke Tara
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- Burnish Rachel
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- Butler Amelia
- Butler Magdalena
- Butler Susan
- Buxton Meredith
- Buzgau Adrian
- Byrne Kathleen
- Byrne Rahim
- Cabrelli Louise
- Cabreros Leilani
- Cairns Tom
- Calfee Carolyn
- Callahan Jean-Christophe
- Cambalova Lenka
- Campbell Andrew
- Campbell Bridget
- Campbell Debbie
- Campbell Hilary
- Campbell Lewis
- Campbell Marion
- Campbell Ryan
- Campion Alexandra
- Campisi Josie
- Camsooksai Julie
- Caplin Cecile
- Carbonneau Elaine
- Carmichael Samantha
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- Carn Vanessa
- Carpio Lillian
- Carr Zoe
- Carr-Wilkinson Joanne
- Carrier François
- Carrier Marc
- Carter Angus
- Carter Brittney
- Carter David
- Carter Jay
- Carter Michael
- Casali Sherry
- Casey Ruth
- Casey Siobhan
- Castelain Vincent
- Castle James
- Cathcart Susanne
- Catorze Nuno José Teodoro Amaro dos Santos
- Cattelan Jessy
- Cavayas Alexandros
- Cawley Kathryn
- Cecconi Maurizio
- Centofanti John
- Chambers Emma
- Champanerkar Shreekant
- Chan Carmen
- Chan Charles
- Chan Peter
- Chapman Rachel
- Chapman Susan
- Charles Bethan
- Charles Walton
- Charlewood Richard
- Charlton Sam
- Charron Cyril
- Chartier Delphine
- Chasse Michael
- Chassé Michaël
- Chen Jonathan
- Chen Lixian
- Chen Yan
- Cheng Allen C.
- Cherian Shiney
- Chhablani Manish
- Chin Teri
- Chudeau Nicolas
- Chukkambotla Sri
- Ciccarelli Michele
- Cirstea Emanuel
- Clair Bernard
- Clark Amy
- Clark Michele
- Clark Richard
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- Clarke Frances
- Clarke Jennifer
- Claxton Andrew
- Cleary Joanne
- Clement Ian
- Clere-Jehl Raphael
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- Clermont Gilles
- Clinton Alison
- Cloutier Ève
- Cockrell Maeve
- Codreanu Daniel
- Coetzee Samantha
- Coghlan Phoebe
- Cole Jade
- Coles Jennifer
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- Collier Dawn
- Collins Amy
- Collins Daniel
- Collins Emma
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- Combaux Daniele
- Commons Robert
- Comp Susan
- Concha Pablo
- Connolly Karen
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- Constantino-Occhipinti Claudia
- Contou Damien
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- Conway Robert
- Conzelmann Nadine
- Cook Deborah
- Cook Tim
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- Cooke Justin
- Cooper Jamie
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- Corcoran Kathleen
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- Cornell Thomas
- Cort Jon
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- Currie Andrew
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- Côté Émilie
- D?Amato Fabiola
- D?Aragon Frédérick
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- Daher Rana
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- Daley Jessica
- Dalton James
- Daly James
- Daly Zoe
- Daneman Nick
- Dark Paul
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- Darreau Cedric
- Daugherty Jason
- Davey Miriam
- Davidson Neil
- Davies Ellie
- Davies Gwyneth
- Davies Jennifer
- Davies Louisa
- Davies Michelle
- Davies Rhys
- Dawson Laura Ann
- Dawvda Ashlish
- Day Christopher
- Da Rocha Joana
- De Bus Liesbet
- de Courcy-Golder Kim
- de Groot Klaas
- de Jong Menno
- de Jonge Evert
- De Keulenaer Bart
- de la Torre Cisneros Julian
- de Man Angelique
- De Neef Mark
- De Smeytere Anouska
- Deacon Bethan
- Dean Steven
- Dean Tessa
- Dearden Joy
- Dechert William
- Declercq Pierre-Louis
- Degracia Anna
- del Sorbo Lorenzo
- Dela Rosa Arnold
- Delaney Kirsha
- Dell Abbie
- del Prado Michael
- Demetriou Carrie
- Dempster Debra
- Denham Lynn
- Denmade Craig
- Dent Martin
- Depante Maria
- Depuydt Pieter
- Dequin Pierre-François
- Derde Lennie P. G.
- Deshpande Kush
- Detry Michelle A.
- Deye Nicolas
- de la Fuente Carmen
- De Waele Jan
- Dheke Krishan
- Di Lucca Giuseppe
- Dias Priya
- Dice Julie
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- Diridis Kristina
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- Ebenezer R
- Edmunds Natasha
- Edwards Alexandra
- Efford Georgia
- Egreteau Pierre
- Ehrmann Stephan
- Eichenauer Dennis
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- Higgins Alisa M.
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- Huijbens Danique
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- Kaye Callum
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- Keatley Claire
- Keeler Sheryl
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- Keen Sherbrina
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- Khare Divya
- Khoso Nasir
- Khoud Ahmed
- Khwaja Kosar
- Kidwai Aneela
- Kiiski Heikki
- Kilner Mari
- Kim Edy Y.
- Kimpton Sarah
- King Andrew
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- Wong Jenny
- Wong Onyee
- Wood Erica
- Wood Hannah
- Wood Tracy
- Woods Jane
- Woods Lindsey
- Woodward Robert
- Woolett Melissa
- Worner Ruth
- Wren Jess
- Wren Lynn
- Wrey Brown Caroline
- Wright Chris
- Wright Kim
- Wunderley Renee
- Wyatt Rachel
- Wylie Katharine
- Xavier Kugan
- Yamagishi Yoshiaki
- Yamashita Chizuru
- Yang Yang
- Yarad Elizabeth
- Yates Bryan
- Yates David
- Yealy Donald
- Young Ian
- Young Meredith
- Young Paul
- Youngstein Taryn
- Yu Haili
- Yusuff Hakeem
- Zaharia Mihaela
- Zaidi Abbas
- Zaki Ahmed
- Zaman Mohsin
- Zarychanski Ryan
- Zdanavidiene Ausra
- Zhao Xiao
- Zinzoni Vanessa
- Zitter Letizia
- Zouita Louisa
- Publication venue
- 'American Medical Association (AMA)'
- Publication date
- 11/04/2023
- Field of study
Get PDFIMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
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- Publication venue
- country:DEU
- Publication date
- 01/01/2021
- Field of study
Get PDFMapping 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.
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- Afilalo J.
- Afilalo M.
- Afolabi D.
- Afrasiabi Z.
- Afset J. E.
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- 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.
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- Alfonso J.
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- Ali S.
- Aliberti S.
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- Allan E.
- Allan J.
- Alldis Z.
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- Allen S.
- Allibone S.
- Allison K. S.
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- Almaden-Boyle C.
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- Altmuller J.
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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2021
- Field of study
Get PDFThe 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
Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
- Author
- Abaleke E.
- Abdelrazik M.
- Abedalthagafi M.
- Abel L.
- Abernathy C.
- Abraheem A.
- Adamek A.
- Adams C.
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- Al-Moasseb M.
- Al-Muftah W.
- Al-Sarraj Y.
- Alaamery M.
- Alaverdian D.
- AlBardis H.
- Alexander P.
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- Ali Mohamed Ali I.
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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
No full textThe combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management
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
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- Publication venue
- 'American Medical Association (AMA)'
- Publication date
- 30/11/2022
- Field of study
No full textImportance 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
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
- Author
- Abdelrazik M
- Abedalthagafi M
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- Aguado JM
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- Bird S
- Birkinshaw I
- Birt M
- Birt M
- Bishop L
- Biss J
- Black C
- Black E
- Black K
- Blackledge B
- Blackledge B
- Blackman H
- Blakemore H
- Blanca-López N
- Blancas R
- Bland Y
- Blow S
- Blowing H
- Blunt M
- Board S
- Bociek A
- Bogaert D
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- Bokhari M
- Bolger A
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- Borja AL
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- Bradshaw Z
- Brady A
- Brady L
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- Brandwood C
- Branney D
- Bravo E
- Brayne A
- Brealey D
- Brealey D
- Brearey S
- Bremmer P
- Bretherick AD
- Brett M
- Brett S
- Brickell K
- Bridgett V
- Brimfield L
- Brinkworth E
- Brion M
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- Brochado-Kith Ó
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- Brown E
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- Burn I
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- Bustos M
- Butcher D
- Butler A
- Butler J
- Butler S
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- Butterworth-Cowin N
- Button H
- Buttriss C
- Cabello A
- Cabral-Ortega L
- Cabrelli L
- Caceres-Agra JJ
- Cagova L
- Calbo E
- Calderón EJ
- Cale E
- Callaghan M
- Callam S
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- Campbell A
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- Campos S
- Camsooksai J
- Candalija AC
- Candon AM
- Capitán CF
- Capozzi L
- Capps N
- Carbonell C
- Cardona-Huerta S
- Cardwell A
- Carioca AAF
- Carmody M
- Carmody S
- Carnahan M
- Carpintero MS
- Carracedo A
- Carracedo A
- Carratto TMT
- Carrera LG
- Carrillo-Avila JA
- Carson G
- Cart C
- Carter A
- Carter D
- Carter E
- Carter J
- Carter M
- Carter S
- Cartlidge D
- Carungcong J
- Carvalho MCC
- Casasnovas C
- Casey M
- Castano L
- Castaño CF
- Castaño JAT
- Castelao JE
- Castillo MA
- Caswell M
- Caterson J
- Cathcart S
- Catlow L
- Cavazza A
- Cave A
- Cawley K
- Cawley K
- Cawthron K
- Cañadas Y
- Ceballos FC
- Cha M
- Chablani M
- Chadwick R
- Chan R
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- Chaves-Santiago WG
- Chechi K
- Cheema Y
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- Chikowore P
- Childs D
- Chiquillo-Gómez S
- Chisholm C
- Choudhr O
- Choudhury Y
- Chukkambotla S
- Chávez MEQ
- Cid-Lopez MA
- Cienfuegos-Jimenez O
- Cinquina Z
- Clamp S
- Clapham M
- Clarey E
- Claridge H
- Clark A
- Clark A
- Clark M
- Clark M
- Clark R
- Clark R
- Clark S
- Clark S
- Clark V
- Clarke N
- Clarkson M
- Clayton S
- Clement I
- Clements S
- Clohisey S
- Coates C
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- Conejo IP
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- Cooke GS
- Cookson R
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- Cooper L
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- Corcoran E
- Corcoran K
- Cordero-Lorenzana ML
- Corella D
- Corin C
- Cornell S
- Cornell T
- Corner A
- Corral MA
- Corrales A
- Cortes-Sanchez JL
- Corton M
- Cosgrove D
- Cosier T
- Costa TX
- Cother N
- Coton Z
- Cottam L-J
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- Coventry T
- Covernton P
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- Cristiano D
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- Cuerda VM
- Cuesta L
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- De Beger S
- de Bustamante AD
- de Gordoa LO-R
- de Heredia ML
- de Juan C
- De la Cruz Troca J
- de la Horra C
- de la Hoz AB
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- de Neef M
- De Queiroz JG
- de Quirós FGB
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- de Sousa Alves Neri JL
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- Djeugam B
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- García FR
- García I
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- García M
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- García PM
- García-de-Vicuña A
- García-García I
- García-Ibarbia C
- García-Montero AC
- García-Soidán A
- García-Vázquez E
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- Íñiguez M
- Publication venue
- Springer Nature
- Publication date
- 17/05/2023
- Field of study
Get PDFData 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)
