9 research outputs found
Crossbow Volume 1
- Author
- Publication venue
- Monterey, California: Naval Postgraduate School
- Publication date
- 01/12/2001
- Field of study
Student Integrated ProjectIncludes supplementary materialDistributing naval combat power into many small ships and unmanned air vehicles that capitalize on emerging technology offers a transformational way to think about naval combat in the littorals in the 2020 time frame. Project CROSSBOW is an engineered systems of systems that proposes to use such distributed forces to provide forward presence to gain and maiantain access, to provide sea control, and to project combat power in the littoral regions of the world. Project CROSSBOW is the result of a yearlong, campus-wide, integrated research systems engineering effort involving 40 student researchers and 15 supervising faculty members. This report (Volume I) summarizes the CROSSBOW project. It catalogs the major features of each of the components, and includes by reference a separate volume for each of the major systems (ships, aircraft, and logistics). It also prresents the results of the mission and campaign analysis that informed the trade-offs between these components. It describes certain functions of CROSSBOW in detail through specialized supporting studies. The student work presented here is technologically feasible, integrated and imaginative. The student project cannot by itself provide definitive designs or analyses covering such a broad topic. It does strongly suggest that the underlying concepts have merit and deserve further serious study by the Navy as it transforms itself
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- Author
- Abbass Hakam
- Adhikari Neill
- Affleck Julia
- Agno Sathianathan Ronan
- Ahmad Norfaizan
- Ahmed Iram
- Ainscough Kate
- Al Qasim Eman
- Al Swaidan Lolowa
- Al-Bassam Wisam
- Al-Beidh Farah
- Al-Beidh Farah
- Albert Martin
- Alegria Ana
- Alexander Brian
- Alexander Peter
- Allan Angela
- Allan Elizabeth
- Allen Louise
- Allibone Suzanne
- Amaro dos Santos Catorze Teodoro
- Anderson Tom
- Andric Zdravko
- Angus Derek
- Angus Derek C
- Anjum Aisha
- Ankert Juliane
- Annane Djillali
- Annane Djillali
- Anstey Matthew
- Antcliffe David
- Aparicio Christelle
- Appelt Peter
- Arabi Yaseen
- Arabi Yaseen
- Arbane Gill
- Archer Simon
- Aref Noah
- Arias Ana-Marie
- Arishi Hatim
- Arnold Donald
- Asghar Adeeba
- Ashelford Angela
- Attwood Ben
- Austin Karen
- Aysel Florescu Simin
- Azaiz Amine
- Babel JakŔa
- Babio-Galan Maite
- Badie Julio
- Bagshaw Sean
- Baillie Kenneth
- Baker Evelyn
- Bakthavatsalam Dhanalakshmi
- Bamford Peter
- Banach Dorota
- Bannard-Smith Jonathan
- Barbazza Leanne
- Barber Russell
- Barge Deborah
- Barnes Nicky
- BarÅ”iÄ Bruno
- Bashyal Archana
- Basile Kim
- Bass Frances
- Bates Michelle
- Bauchmuller Kris
- Bean Sarah
- Beane Abigail
- Beane Abigail
- Beasley Richard
- Begin Phillipe
- Bellemare David
- Benettaib Fatna
- Benzekri Dalila
- Berdaguer Fernando Daniel
- Bergin Colin
- Berry Lindsay
- Berry Lindsay
- Berry Scott
- Berry Scott
- Bhimani Zahra
- Bhimani Zahra
- Bihari Shailesh
- Bihari Shilesh
- Binnie Alexandra
- Bion Julian
- Biradar Vishwanath
- Birch Janine
- Birch Jenny
- Birchall Katie
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- Black Ethel
- Bloos Frank
- Board Jasmin
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- Bonten Marc
- Bonten Marc
- Borgatta Barbara
- Borrill Zoe
- Bosch Ziekenhuis Jeroen
- Boschert Catherine
- Bossard Isabelle
- Boumahni Dounia
- Bourgoin Charlotte
- Bourne Michelle
- Bourne Richard
- Bouwman Wietske
- Bowler Helen
- Boyd Craig
- Bracke Stephanie
- Bradbury Charlotte
- Bradbury Charlotte
- Bradley-Potts Joanne
- Brailsford Jane
- Brain Matthew
- Brant Emily
- Breen Patrick
- Brett Stephen
- Brewer Chris
- Brickell Kathy
- Brightling Chris
- Brillinger Nicole
- Brimfield Lutece
- Brinkerhoff Gail
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- Brunkhorst Frank
- Brunkhorst Frank
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- Buehner Ulrike
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- Elin Hall Rebecca
- Ellis Christine
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- Estcourt Lise
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- Everitt Robert
- Evers Mirjam
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- Hadebe Bernard
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- Hamilton David Oliver
- Hamilton-Davies Colin
- Hamlyn Vincent
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- Harris Nichola
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- Higgins Lisa
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- Horvat Christopher
- Howcroft Clare
- Howle Ryan
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- Hugill Keith
- Hullegie Sebastiaan
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- Hutton Paula
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- Johnson David
- Johnson Rebekah
- Johnston Paul
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- McAuley Daniel
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- Montgomery Stephanie
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- Newman Tabitha
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- Nicholson Sarah
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- Pletz Mathias
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- Pogson David
- Polderman F
- Polgarova Petra
- Pomeroy Fiona
- Porteous Rebecca
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- Potter Alison
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- Powell Matthew
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- Reynolds John
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- Rowan Kathryn
- Rowan Kathy
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- Saunders Christina
- Saunders Christina
- Schischka Livia
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- Schutgens Roger
- Schweikert Sacha
- SchĆ¼tze Bianka
- Scully Michael
- Sellers Katharine
- Selvamoni Selvin
- Senya Ho Jan
- Seppelt Ian
- Serri Karim
- Sever Helena
- Seymour Christopher
- Seymour Christopher
- Shah Asim
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- Shaw David
- Shaw Joanne
- Shearer Audrey
- Sheffield Jonathan
- Shehabi Yahya
- Shovelton Charmaine
- Shrestha Tapaswi
- Shyamsundar Murali
- Siami Shidasp
- Silversides Jon
- Sim Malcolm
- Simmonds Catherine
- Simons Koen
- Simpson Joanne
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- Singleton Jo
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- Small Charlotte
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- Smith John
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- Strzelecka Anna
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- Sutterlin Laetitia
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- Sweet Katie
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- Tallott Mandy
- Tatham Kate Colette
- Templeton Maie
- Thomas Amy
- Thomas Helen
- Thomas Matt
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- Thrush Jessica
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- Turki Salah
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- Turner-Bone Ian
- Turns Margaret
- Uddin Ruzena
- Udy Andrew
- Uyeki Tim
- Vaara Suvi
- Vahtera Annukka
- Vamplew Luke
- van Bentum Puijk Wilma
- van Bentum-Puijk Wilma
- van Bentum-Puijk Wilma
- van Beurden Marloes
- van de Veerdonk Frank
- van de Veerdonk Frank
- Van Der Heyden Kym
- van der Poll Tom
- vanāt Hoff Willian
- Vates Jennifer
- Vautier Sarah
- Vazquez-Grande Gloria
- Venkatesh Bala
- Venkatesh Balasubramanian
- Venz Ellen
- Verlander Mark
- Verrier Nathalie
- Victor Saji
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- Voicu Sebastian
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- Vujaklija BrajkoviÄ Ana
- Vuylsteke Alain
- Wagh Atul
- Walden Andrew
- Walker Rachel
- Walsh Joanne
- Walsh Tim
- Walsham James
- Ward Kathryn
- Warnock Majella
- Waterson Sharon
- Watkins Claire
- Watpool Irene
- Watters Malcolm
- Waugh Victoria
- Webb Steve
- Webb Steven A
- Wedd Steve
- Weismann Dirk
- Weissman Alexandra
- Wells Colin
- Welters Ingeborg
- Wetherill Bill
- Whelan Ruth
- Whileman Amanda
- Whitbread Jennifer
- White Hayden
- White Ian
- White Katie
- Whitehead Christina
- Wibrow Bradley
- Wigbers J
- Wilby Elizabeth
- Wild Laura
- Wild Laura
- Wilding Laura
- Wiley Daisy
- Wilhelmsen Elva
- Wilkinson Dean
- Willams Felicity
- Williams Alexandra
- Williams Erin
- Williams Hannah
- Williams Karen
- Williams Patricia
- Williams Patricia
- Williams Penny
- Williams Tony
- Williams Virginie
- Williamson Dawn
- Williamson James
- Wilson Karen
- Wilson Maggie
- Wiseman Sophie
- Wong Helen
- Wood Erica
- Wood Hannah
- Wood Tracy
- Woods Jane
- Woods Lindsey
- Worner Ruth
- Wren Jess
- Wren Lynn
- Wrey Brown Caroline
- Writing Committee for the REMAP-CAP Investigators
- Xavier Kugan
- Xia Le Tai Charlotte
- Yarad Elizabeth
- Yates David
- Young Chelsea
- Young Ian
- Young Meredith
- Young Paul
- Yusuff Hakeem
- Zaharia Miahela Florentina
- Zaidi Abbas
- Zaki Ahmed
- Zaman Mohsin
- Zammit Claire
- Zapalac Marija
- Zarychanski Ryan
- Zarychanski Ryan
- Zhao Xiao Bei
- Zinzoni Vanessa
- Zitter Letizia
- Äimoti Renata
- Publication venue
- JAMA: Journal of the American Medical Association
- Publication date
- 06/10/2020
- Field of study
Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (nā=ā143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (nā=ā152), or no hydrocortisone (nā=ā108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (nā=ā137), shock-dependent (nā=ā146), and no (nā=ā101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707
Genetic mechanisms of critical illness in COVID-19.
- Author
- A A Roger Thompson
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- S Whiteley
- S Williams
- S Wood
- S Yussuf
- Sabino Scolletta
- Samreen Ijaz
- Sandro Mancarella
- Sandro Panese
- Sara Amitrano
- Sara McDonald
- Sarah Law
- Sarah McCafferty
- Saverio Giuseppe Parisi
- Saye Khoo
- Scott Richard
- Semple Malcolm G
- Serafina Valente
- Serena Ludovisi
- Sergio Daga
- SeƔn Keating
- Shankar-Hari Manu
- Shen Xia
- Shih Barbara
- Shiranee Sriskandan
- Shona C Moore
- Silvia Cappelli
- Simona Marcantonio
- Simone Furini
- Sophie Halpin
- Sophie Venturelli
- Stefania Mantovani
- Stefano Baratti
- Stefano Ceri
- Stefano Rusconi
- Stella Aslibekyan
- Stephanie Roberts
- Stephen R Knight
- Summers Charlotte
- Susanna Croci
- Susanna Guerrini
- T Anderson
- T Arden
- T Baird
- T Behan
- T Bemand
- T Cosier
- T Coventry
- T Duncan
- T Felton
- T Geary
- T Hazleton
- T Joefield
- T Kannan
- T Lawton
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- T O Jones
- T Pogreban
- T Rees
- T Samakomva
- T Smith
- T Smith
- T Szakmany
- T Varghes
- T Williams
- T Wood
- Tammy Gilchrist
- Tenesa Albert
- Teresa Filshtein-Sonmez
- Thomas M Drake
- Thushan de Silva
- Tim Walsh
- Tom Fletcher
- Tom Solomon
- Tony Wackett
- Trevor Paterson
- Tullio Trotta
- Turtle Lance
- U Poultney
- V Amin
- V Anumakonda
- V Bastion
- V Cannons
- V Crickmore
- V Gopal
- V Irvine
- V Kasipandian
- V Krishnamurthy
- V Lake
- V Linnett
- V Martinson
- V Nagarajan
- V Page
- V Parris
- V Parris
- V Pristopan
- V Ratnam
- V Rivers
- V Sarathy
- V Thomas
- V Thwaites
- V Tuckey
- V Turner
- V Wagstaff
- V Waugh
- Valentina Anemoli
- Vanessa Sancho-Shimizu
- 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
- Y Jackson
- Y Thirlwall
- Yang Jian
- Yang Zhijian
- Z Alldis
- Z Belagodu
- Z Bradshaw
- Z Coton
- Z Daly
- Z Farzad
- Z Fernandez
- Z Garland
- Z Maqsood
- Z Omar
- Z Prime
- Z Scott
- Zechner Marie
- Zhai Ranran
- Zheng Chenqing
- Publication venue
- Nature
- Publication date
- 01/01/2020
- Field of study
Host-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, PĀ =Ā 1.65Ā ĆĀ 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, PĀ =Ā 2.3Ā ĆĀ 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, PĀ =Ā 3.98Ā ĆĀ Ā 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, PĀ =Ā 4.99Ā ĆĀ 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
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.
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- Adanini O.
- Adeleye O.
- Adra D.
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- Aksentijevich A.
- Al-Afghani H.
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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 hospitalization2ā4 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 genesāincluding reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)āin 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
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar M.S.
- Abdel-Aziz M.
- Abdelrazik M.
- Abdollahi H.
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- Zƶllner S.
- Ć svold B.O.
- 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 genesāincluding reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)āin 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
Mapping the human genetic architecture of COVID-19
- Author
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- Zhai R.
- Zhang M.
- Zhao J. H.
- Zhen J.
- Zheng C.
- Zheng T.
- Zhou W.
- Zhu W.
- Zitter L.
- Zlatopolsky M.
- 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 diseases3ā7. 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.
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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
The 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
Recommended from our members
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
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- 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 āMonocyte gene expression dataā 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 GenomeāPhenome 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 BaldiĆ³n-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana MarĆa Baldion) and has now been amended in the HTML and PDF versions of the article.Copyright Ā© 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), monocyteāmacrophage 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 Scientistās 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) āA way of making Europeā, FundaciĆ³n Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 āApuestas cientĆficas del ITER para colaborar en la lucha contra la COVID-19ā to C.F.) and FundaciĆ³n Canaria Instituto de InvestigaciĆ³n Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de SupercomputaciĆ³n 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)
Mapping the human genetic architecture of COVID-19
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- Zanelli G
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- Zhen J
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- 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