11 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.
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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
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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- Zöllner S.
- Åsvold 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 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
Mapping the human genetic architecture of COVID-19
- Author
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- 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
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
- Author
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- Caceres-Agra JJ
- Cagova L
- Calbo E
- Calderón EJ
- Cale E
- Callaghan M
- Callam S
- Calvo CM
- Camacho S
- Campbell A
- Campbell B
- Campbell H
- Campbell R
- Campbell S
- Campos MC
- 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
- Chand M
- Chandler B
- Chandna H
- Chapman S
- Charles B
- Charlesworth R
- Charnock R
- Charris HM
- Chaux JG
- Chaves-Santiago WG
- Chechi K
- Cheema Y
- Chen J
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- Chetam L
- Cheyne C
- 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
- Cochrane P
- Cockerill H
- Cockrell M
- Coe R
- Coetzee S
- Coghlan P
- Cohrane C
- Coker D
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- Colley N
- Collier D
- Collier D
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- Collins A
- Collins C
- Collins E
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- Collins K
- Collins R
- Collins V
- Collis M
- Combes E
- Conde-Vicente R
- Conejo IP
- Connell J
- Connolly K
- Connor M
- Convery K
- Conyngham J-A
- Cooke GS
- Cookson R
- Cooper J
- Cooper L
- Cooper L
- 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
- Cottle J
- Coulding M
- Coutts A
- Coventry T
- Covernton P
- Cowley A
- Cowley N
- Cowton A
- Cox A
- Coyle J
- Craig H
- Craig J
- Crawley R
- Creagh-Brown B
- Crew A
- Crickmore V
- Cristiano D
- Croft M
- Crowe R
- Crowley M
- Cruz C
- Cruz MS
- Cruz R
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- Csabi P
- Cuerda VM
- Cuesta L
- Cullum L
- Cunha GCR
- Cunningham A
- Cunningham M
- Cupitt J
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- Cutting P
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- Da Gloria EF
- Da Rocha J
- da Silva Filipe A
- da Silva GV
- Daglish J
- Dagutao Z
- Dale K
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- Dalmau D
- Dalton C
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- Daly Z
- Dalziel J
- DAmato F
- Dance A
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- Daniel E
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- Dark P
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- Dawson D
- Day A
- Day N
- de Andrés R
- de Araújo JNG
- 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
- De Martino-Rodríguez A
- de Neef M
- De Queiroz JG
- de Quirós FGB
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- de Sousa Alves Neri JL
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- Debreceni G
- Deery J
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- Dela Rosa A
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- Dexter C
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- Dickson H
- Dietl B
- Digby B
- Digby S
- Ding L
- Diz-de Almeida S
- Djeugam B
- Doble P
- Dobson E
- Docherty AB
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- Domínguez-Garrido E
- Donaldson A
- Donaldson D
- Donegan C
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- Doonan R
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- dos Santos KA
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- España PP
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- Fernandez-Nestosa MJ
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- Fernández-Robelo U
- Fernández-Rodríguez A
- Fernández-Sampedro M
- Fernández-Sánchez R
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- Ferrero SF
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- García FR
- García I
- García L
- García M
- García MG
- 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
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)
A second update on mapping the human genetic architecture of COVID-19
- Author
- Abd Elghafar MS
- Abdel-Aziz M
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- Wyllie DH
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- Yamada Y
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- Yamasaki M
- Yang J
- Yaspan B
- Yassen AM
- Yasui Y
- Yates B
- Yatomi M
- Ye C
- Yermakovich D
- Yeung RSM
- Yi X
- Yonekawa A
- Yoo S
- Yoon K
- Yoshida K
- Yoshida S
- Yoshida S
- Yoshida T
- Yoshihara T
- Yoshiya K
- Yoshiyama T
- Young M
- Yue F
- Yun N
- Yáñez CE
- Yáñez Z
- Zainulabid UA
- Zainy T
- Zak A
- Zaki A
- Zamikula J
- Zamudio IPM
- Zanella A
- Zapata-Contreras D
- Zapatamartinez M
- Zarate R
- Zarei N
- Zavaleta DAF
- Zawadzki P
- Zawati MH
- Zborowski AC
- Zeberg H
- Zechner M
- Zhang Q
- Zhao X
- Zheng C
- Zheng T
- Zhlawi HJ
- Zhlawi MWJ
- Zholdybayeva E
- Zhou W
- Zhu W
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- Zongo O
- Zorloni C
- Zuñiga-Pacheco P
- Zárate RN
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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
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
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- Antoni MD
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- Cornely OA
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- Cortes B
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- Cosgrove D
- Cosier T
- Cossarizza A
- Costantino G
- Cother N
- Coton Z
- Coulding M
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- Da Gloria EF
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- de Brabander J
- de Bree G
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- de Gordoa LO-R
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- De Grandi A
- de Jong H
- de Jong MD
- De la Horra C
- De Neef M
- de Pablo R
- de Rojas I
- de Salazar A
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- De Vivo O
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- di Bartolomeo C
- Di Biagio A
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- Di Sarno L
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- Zanelli G
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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
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.
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- Åsvold Bjørn Olav
- 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
Mapping the human genetic architecture of COVID-19
- Author
- A. A. Roger Thompson
- A. Cerny
- A. Conen
- A. Guillet
- A. Gulati
- A. H. Koos Zwinderman
- A. Meikle
- A. Munting
- A. Perret
- Aarno Palotie
- Aarno Palotie
- Aaron Blandino Ortiz
- Aaron Butler
- Aarti Shah
- Aayesha Kazi
- Abdelhakim Altabaibeh
- Abdul Ashish
- Abdul Kayani
- Abhinav Gupta
- Abigail Crew
- Abigail Knighton
- Abigail Short
- Abigail Taylor
- Abiola Harrison
- Achille Iolascon
- Adam Auton
- Adam Brayne
- Adam Brown
- Adam Finn
- Adam Loveridge
- Adam S. Butterworth
- Adam Wolverson
- Adama Fofano
- Adeline Busson
- Adolfo de Salazar
- Adolfo Garrido Chercoles
- Adriana Botello
- Adriana Garmendia
- Adriana Palom
- Adrie Kromhout
- Agilan Kaliappan
- Agilan Kaliappan
- Agnese Verzuri
- Agnieska Szemiel
- Agnieszka Kubisz-Pudelko
- Agostino Ognibene
- Agostino Riva
- Agustín Albillos
- Agustín Ruiz
- Ahilanadan Dushianthan
- Ahmed Zaki
- Ahna Girshick
- Ahsan Khan
- Ai Nakamura
- Ailbhe Brady
- Ailsa Golightly
- Ailstair Nichol
- Ainhi Mac
- Aislynn Taggart
- Ajay Raithatha
- Akifumi Endo
- Akihiko Kawana
- Akihiko Tanaka
- Akihiro Ito
- Akihiro Ono
- Akiko Fujiwara
- Akiko Yonekawa
- Akinori Kimura
- Akira Ando
- Akira Umeda
- Alain Vuylsteke
- Alan MacLean
- Alan Maclean
- Alan Morrison
- Alan Neal
- Alan Vuylsteke
- Alanna Wall
- Alasdair Bamford
- Alastair McGregor
- Alastair Rose
- Alastair Thomas
- Alba-Estela Garcia-Fernandez
- Albert Blanco-Grau
- Albert Tenesa
- Albert V. Smith
- Alberto Mantovani
- Alberto Zanella
- Alec Chiu
- Aled Morgan
- Alejandra Doce Carracedo
- Alejandro Martín-Quirós
- Alejandro Pascual-Iglesias
- Aleksander Rygh Holten
- Alena Mayer
- Alessandra Bandera
- Alessandra Guarnaccia
- Alessandra Renieri
- Alessandra Renieri
- Alessandra Stella
- Alessandra Vergori
- Alessandro Cherubini
- Alessandro De Grandi
- Alessandro Pancrazi
- Alessandro Protti
- Alessia Giorli
- Alessio Aghemo
- Alessio Gerussi
- Alex Cloherty
- Alex Howlett
- Alex Ioannidis
- Alex McCurdy
- Alex Puxty
- Alex Schuurman
- Alex Stuckey
- Alexander Chernitsov
- Alexander J. Mentzer
- Alexander Labkowsky
- Alexander P. J. Vlaar
- Alexander Rakitko
- Alexander Teumer
- Alexander W. Charney
- Alexandra Aksentijevich
- Alexandra Metcalfe
- Alexandra Williams
- Alexandre Belisle
- Alexandre Bolze
- Alexandre C. Pereira
- Alfredo Brusco
- Alfredo Ramirez
- Alfredo Serrano-Ruiz
- Ali G. Gharavi
- Alice Braun
- Alice Collignon
- Alice Donati
- Alice Harvey
- Alice Michael Mitchell
- Alice Nicholson
- Alice Poole
- Alice Thomas
- Alicia A. C. Waite
- Alicia Knight
- Alicia Price
- Alicia R. Martin
- Alicia Staderoli
- Alicia Utrilla
- Alison Brown
- Alison Durie
- Alison Harrison
- Alison Lewis
- Alison Lye
- Alison M. Meynert
- Alison Quinn
- Alison Turnbull
- Alison Williams
- Alison Wilson
- Alissa Kent
- Alistair Gales
- Alistair Hughes
- Alistair Nichol
- Alistair Rose
- Alistair Roy
- Allison Daniels
- Almut Nebel
- Alun Rees
- Alyssia Mesdagh
- Amanda Ayers
- Amanda Cowton
- Amanda Lyle
- Amanda McGregor
- Amanda Sanderson
- Amanda Tyler
- Amanda Whileman
- Amara Khan
- Amber Cox
- Amber Ford
- Ambreen Tariq
- Amelia Daniel
- Amelia Stacey
- Ami Wilkinson
- Amie Reddy
- Amit Patel
- Amitaa Maharajh
- Amritha Menon
- Amro Katary
- Amy Bowes
- Amy Clark
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- Andreas Lind
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- Andrew Drummond
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- Andrew Higham
- Andrew Higham
- Andrew Law
- Andrew P. Boughton
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- Andrew Ustianowski
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- Xueqing Wang
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- Yang Wu
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- Yaser Al-Sarraj
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- Yasmin Hussain
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- Yasuko Fuchimoto
- Yasunari Kaneyama
- Yasunari Miyazaki
- Yasushi Nakano
- Yat S. So
- Yen-Chen Anne Feng
- Yeon-Sook Kim
- Yi Ding
- Yohan Bossé
- Yohei Funatsu
- Yohei Mikami
- Yoji Nagasaki
- Yoko Shibata
- Yolanda Baird
- Yong Huang
- Yoosoo Chang
- Yoshiaki Inoue
- Yoshifumi Kimizuka
- Yoshifumi Uwamino
- Yoshihiko Nakamura
- Yoshihiro Eriguchi
- Yoshihiro Hirai
- Yoshikazu Mutoh
- Yoshimi Noda
- Yoshinori Hasegawa
- Yoshinori Tanino
- Yoshinori Yasui
- Yoshitaka Oyamada
- Yoshito Takeda
- Yoshiyuki Sekikawa
- Yosuke Omae
- Yosuke Tanigawa
- Yosuke Tanigawa
- Yotaro Takaku
- Young Rock Jang
- Younghun Han
- Younhe Lee
- Youssef Bouysran
- Yu Kusaka
- Yu Min Kang
- Yuichi Adachi
- Yuichi Maeda
- Yuichiro Kitagawa
- Yuichiro Yamada
- Yuji Uchimura
- Yuk-Lam Ho
- Yuki Bradford
- Yuki Sato
- Yuki Togashi
- Yukiko Nakajima
- Yukinori Okada
- Yukinori Okada
- Yuko Kitagawa
- Yuko Komase
- Yusuf Cheema
- Yusuke Chihara
- Yusuke Suzuki
- Yuta Kono
- Yuval Itan
- Yuya Shirai
- Yves Beguin
- Yvette Thirlwall
- Yvonne Jackson
- Zacharia Hamidi
- Zahira Maqsood
- Zakaula Belagodu
- Zaman Afrasiabi
- Zehra Karadeniz
- Zena Bradshaw
- Zhijian Yang
- Ziortza Fernandez
- Zoe Alldis
- Zoe Coton
- Zoe Daly
- Zoe Garland
- Zoe Lamond
- Zoe Prime
- Zoe Scott
- Zohra Omar
- Zohreh Farzad
- Zoltan Takats
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 08/07/2021
- Field of study
AbstractThe 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.</jats:p
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar Mohamed S.
- Abdel-Aziz Mahmoud
- Abdelrazik Marwa
- Abdollahi Hamed
- Abdullah Tala
- Abecasis Goncalo R.
- Abecasis Goncalo R.
- Abedalthagafi Malak
- Abel Lynn
- Abernathy Caroline
- Abraheem Azmerelda
- Abul-Husn Noura S.
- Acquilini Donatella
- Adams Colene
- Adams Emma L.
- Adams Katie
- Adamsara Alireza
- Adanini Oluronke
- Adeleye Olumide
- Adra Darin
- Afilalo Jonathan
- Afilalo Marc
- Afolabi Deborah
- Afrasiabi Zaman
- Agasou Anita
- Agrawal Shruti
- Agüero Daiana
- Ahmad Norfaizan
- Ahmadi Saeideh
- Ahmed Ashar
- Ahmed Cecilia
- Akeroyd Louise
- Akhtar Muhammad Nauman
- Akinkugbe Olugbenga
- Aksentijevich Alexandra
- Al Harthi Fawz
- Al Mutairi Amal
- Al-Afghani Hani
- Al-Awdah Laila
- Alaamery Manal
- Alahmadey Ziab Z.
- Alaverdian Diana
- Alavere Helene
- Albader Anoud
- Albaiceta Guillermo M.
- Albakri Jehad K.
- AlBardis Hadeel
- Albeladi Maha
- Albesher Nour
- Albrich Werner
- AlDhawi Nouf
- Aldridge Jonathan
- Aleagha Afshar Etemadi
- Alexander Peter
- Alfonso Jordan
- Alghamdi Bader
- Alghamdi Jahad
- Ali Altaf
- Ali Asifa
- Ali Inthakab Ali Mohamed
- Ali Syamlan
- Aliannejad Rasoul
- Aljawini Nora
- AlJohani Sameera
- Alkwai Sarah
- Allan Angela
- Allan Elizabeth
- Allan John
- Alldis Zoe
- Allen Louise
- Allen Meryem
- Allen Schvearn
- Allibone Suzanne
- Allison Kathryn Sian
- Allos Raili
- Almaden-Boyle Christine
- AlMalik Abdulaziz
- Almalki Faisal
- Almohammed Iman
- Almutairi Mansour
- Alotaibi Sara
- Alowayn Albandary M.
- Alqahtani Saleh
- Alqubaishi Fatimah
- Alrashed May
- Alshareef Abdulraheem
- Alsolm Ebtehal
- Alswailm Moneera
- Altabaibeh Abdelhakim
- Alvaro Ana
- AlZahrani Deema
- Amin Vishal
- Amirsavadkouhi Ali
- Amitrano Sara
- Anastasescu Elena
- Anderson Felicity
- Anderson Jennifer
- Anderson Madeleine
- Anderson Peter
- Anderson Samantha
- Anderson Susan
- Anderson Taya
- Andolfo Immacolata
- Andretta Francesca
- Andreucci Elena
- Andrew Angela
- Andrew Benedict
- Andrew Gillian
- Andrews Eleanor
- Andrews Shea J.
- Anedda Federico
- Anemoli Valentina
- Annis Aubrey
- Antcliffe David
- Antinori Andrea
- Antoni Melania Degli
- Anumakonda Vikram
- Apetri Elena
- Aquino Maia
- Arabi Yaseen M.
- Aravindan Latha
- Arbane Gill
- Archer Katie
- Arden Tracie
- Arias Sonia Sousa
- Arif Sarwat
- Armstrong Jacob
- Armstrong Lisa
- Armstrong Ruth
- Arning Nicolas
- Arnold Sophie
- Arranz Maria J.
- Arribas Elisa
- Artuso Rosangela
- Arumugam Prabhu
- Arumugam Prabhu
- Ascolillo Steven
- Ashraf Saima
- Ashton Lydia
- Aslibekyan Stella
- Astin-Chamberlain Raine
- Atkinson Elizabeth G.
- Attwood Ben
- Aucella Filippo
- Auld Daniel
- Auld Fiona
- Austin Karen
- Austin Pauline
- Auton Adam
- Ayers Amanda
- Azarzar Samira
- Åsvold Bjørn Olav
- Bachetti Tiziana
- Baikady Ravishankar Rao
- Baillie J. Kenneth
- Baillie J. Kenneth
- Baillie J. Kenneth
- Baines Balvinder
- Baines Deborah
- Baines Kizzy
- Baird Yolanda
- Bakthavatsalam Dhanalakshmi
- Balaconis Mary K.
- Baldassarri Margherita
- Ball Catherine A.
- Baltzell Asher Haug
- Bamford Alasdair
- Bamford Peter
- Banach Dorota
- Bancroft Hollie
- Band Gavin
- Bandini Maria
- Bandla Nageswar
- Bano Shereen
- Baptista David
- Barakeh Duna
- Baras Aris
- Baras Aris
- Baratti Stefano
- Barber Russell
- Barberis Luigi
- Barberis Luigi
- Barbieri Chiara
- Barclay Lucy
- Bargagli Elena
- Barhoush Eman
- Barker Joann
- Barnes Kathleen C.
- Baroni Silvia
- Barrett Fiona
- Barron Anthony
- Barry Peter
- Bartels Meike
- Bartley Shauna
- Baruah Rosie
- Bashyal Archana
- Basikolo Cathrine
- Bassetti Matteo
- Bastion Victoria
- Bates Hayley
- Bates Michelle
- Batini Chiara
- Battle Ceri
- Bauchmuller Kris
- Baxter Nicola
- Baya Nikolas
- Bayo Lee-Ann
- Beadle Jane
- Bean Sarah
- Beaumont Karen
- Beavis Sarah
- Beck Andrew
- Beckmann Noam D.
- Bedini Josep L.
- Bee Catherine E.
- Beech Emily
- Beech Valerie
- Beekes Mandy
- Beesley Kate
- Begg Colin
- Beguin Yves
- Behan Teresa
- Beith Claire Marie
- Belagodu Zakaula
- Belbin Gillian M.
- Belfield Holly
- Belhaj Yasmine
- Beligni Giada
- Belisle Alexandre
- Bell Dina
- Bell Gillian
- Bell Michael
- Bell Stephanie
- Bellamy Mary
- Belli Mary Ann
- Bellini Arianna
- Bellwood Ruth
- Below Jennifer
- Bemand Thomas
- Benetti Elisa
- Benham Leonie
- Bennett David
- Bennett Sara
- Bentley David
- Bentley Michael
- Benyon Sarah
- Beranova Eva
- Bercades Georgia
- Bergantini Laura
- Bergomi Paola
- Berkowitz Nathan
- Bernardo David
- Bevan Emily
- Bewley Jeremy
- Bhatia Nikhil
- Bhatterjee Ravi
- Bhuie Parminder
- Bi Rehana
- Bianchi Francesco
- Bibert Stéphanie
- Bibi Fatima
- Biddle Jack
- Biggs Heather
- Birch Janine
- Birch Jenny
- Birch Sophie
- Birchall Kathryn
- Birchall Katie
- Bird Sarah
- Birkinshaw Isobel
- Birt Mark
- Biscarini Filippo
- Black Ethel
- Black Karen
- Blackledge Bethan
- Blackledge Bethan
- Blackman Helen
- Blakemore Hayley
- Blay Natalia
- Blow Sarah
- Blunt Mark
- Board Sarah
- Bochud Pierre-Yves
- Bociek Aneta
- Boezen Marike
- Boillat Noémie
- Bokhari Maria
- Bolton Matthew
- Bolton Rachel
- Bonner Stephen
- Booker Lauren
- Borislavova Borislava
- Borra Catherine
- Botello Adriana
- Botfield Liam
- Bottà Giordano
- Bouab Meriem
- Bough Laura
- Boughton Andrew P.
- Bowes Amy
- Bowles Ruth
- Boyle Pauline
- Boyle Rosalind
- Boz Ceilia
- Bradford Yuki
- Bradley Clare
- Bradley Paul
- Bradley-Potts Joanne
- Bradshaw Zena
- Brady Ailbhe
- Brady Megan
- Brady Rebecca
- Brandwood Craig
- Branney Debbie
- Brantwood Craig
- Brassard Nathalie
- Brayne Adam
- Brealey David
- Brealey David
- Bremmer Pamela
- Brenner Bluma
- Bretherick Andrew D.
- Brett Michael
- Brett Stephen
- Brickell Kathy
- Bridgett Victoria
- Brimfield Lutece
- Brinkworth Elaine
- Briton Kate
- Britvan Bari
- Bromley Matt
- Brooke Hollie
- Brooks Suzanne
- Brown Adam
- Brown Alison
- Brown Alison
- Brown Ellen
- Brown Joanna
- Bruce Michelle
- Brumpton Ben M.
- Bruno Raffaele
- Brunton Mark
- Bruttini Mirella
- Bryant Jade
- Bryant Sam
- Buckley Clare
- Buckley Sarah
- Bunni Lara
- Burda Dorota
- Buring Julie E.
- Burn Iona
- Burnett Caroline
- Burns Karen
- Burt Karen
- Burtenshaw Andrew
- Burton Maudrian
- Busani Stefano
- Bussotti Maurizio
- Butcher Deborah
- Butler Aaron
- Butler Joanna
- Butler Susan
- Butler-Laporte Guillaume
- Butterworth Adam S.
- Butterworth-Cowin Nicola
- Button Heather
- Buxbaum Joseph D.
- Cabrelli Louise
- Cagova Lenka
- Caldarelli Gian Piero
- Callaghan Marie
- Callier Shawneequa
- Cameli Paolo
- Campbell Andy
- Campbell Archie
- Campbell Helen
- Campbell Rachael
- Campbell Rachael
- Campbell Suzanne
- Campos Sara
- Camsooksai Julie
- Canaccini Anna
- Cantarini Luca
- Cantor Michael N.
- Capasso Mario
- Capitani Katia
- Cappelli Silvia
- Capps Nigel
- Carbral-Ortega Llucia
- Carella Massimo
- Carey Dave J.
- Carmody Margaret
- Carmody Siobhain
- Carnahan Mandy
- Carreras Anna
- Carriero Miriam Lucia
- Carter Anne
- Carter David
- Carter Emma
- Carter Joseph
- Carter Sasha
- Carungcong Jaime
- Casey Matt
- Castaño-Vinyals Gemma
- Castelli Francesco
- Castle Karen
- Castori Marco
- Caswell Melanie
- Catena Emanuele
- Caterson Jess
- Cathcart Susanne
- Catlow Laura
- Caulfield Mark J.
- Caulfield Mark J.
- Cavazza Anna
- Cawley Kathryn
- Cawthron Kay
- Cárcel-Márquez Jara
- Ceri Stefano
- Chablani Manish
- Chadbourn Indra
- Chamnanphon Monpat
- Chan Georgia
- Chan Georgia
- Chan Rebekah
- Chandler Ben
- Chang Xiao
- Chapman Susan
- Chariyavilaskul Pajaree
- Charles Bethan
- Charlesworth Ruth
- Charney Alexander W.
- Charnock Rob
- Chasman Daniel I.
- Chassé Michaël
- Chaudhary Kumardeep
- Chavan Sameer
- Cheema Yusuf
- Chen Hung-Hsin
- Chen Jiantao
- Cheng Nathan
- Cherian Shiney
- Chetam Luke
- Chetruengchai Wanna
- Cheyne Claire
- Childs Danielle
- Chittoor Geetha
- Cho Judy H.
- Cho Kelly
- Choi Sam
- Choudhury Yasmin
- Chukkambotla Srikanth
- Churchhouse Claire
- Chwialkowska Karolina
- Claassen Sabine
- Clamp Sarah
- Clapham Melanie
- Claringbould Annique
- Clark Amy
- Clark Martyn
- Clark Michele
- Clark Richard
- Clark Richard
- Clark Sarah
- Clark Victoria
- Clarke Daphene
- Clarke Noreen
- Clarkson Michelle
- Clayton Sarah
- Clement Ian
- Clements Suzanne
- Clohisey Hendry Sara
- Coates Charlotte
- Cockrell Maeve
- Coetzee Samantha
- Coghlan Phoebe
- Coignet Marie
- Coiro Gabriella
- Coker Daniella
- Cole Jade
- Cole Joby
- Cole Stephen
- Coleman Dabheoc
- Coles Holly
- Colley Julie
- Collier David
- Collier Dawn
- Collins Amy
- Collins Brett L.
- Collins Ciara
- Collins Emma
- Collins Erin
- Collins Katy
- Collins Rebecca
- Collis Matthew
- Colobrán Roger
- Colombo Riccardo
- Combes Edward
- Connolly Karen
- Conticini Edoardo
- Convery Karen
- Conyngham Jo-Anna
- Cooper Joshua
- Cooper Lisa
- Corcoran Eleanor
- Cordioli Mattia
- Cornell Sarah
- Corral Maria Alvarez
- Corridi Marta
- Cortés Beatriz
- Cosgrove Denise
- Cosier Tracey
- Cossarizza Andrea
- Cother Naiara
- Coto Eliecer
- Coton Zoe
- Coulding Martina
- Coutts Audrey
- Coventry Tina
- Coviello Domenico A.
- Cowley Anne
- Cowley Nicholas
- Cowton Amanda
- Cox Amber
- Coyle Judy
- Craig Jayne
- Crawley Rikki
- Creagh-Brown Ben
- Crew Abigail
- Crickmore Vikki
- Crisp Nikki
- Criste Kristine
- Cristiano Daniele
- Croci Leonardo
- Croci Susanna
- Croft Maria
- Crook Derrick W.
- Crooks Kristy
- Crotti Lia
- Crowe Rebecca
- Crowley Maria
- Cruz Carina
- Cullell Natalia
- Cullum Louise
- Cunningham Amy
- Cunningham Mishell
- Cupitt Jason
- Curgenven Hollie
- Cusack Rebecca
- Cusick Caroline
- Cutler Sean
- D'Alessandro Miriana
- D'Arminio Monforte Antonella
- D'Mellow Kenton
- D'Sylva Stuart
- Da Gloria Edna Fernandes
- Daga Sergio
- Daglish Jacqueline
- Dale Katie
- Dale Sam
- Dalmau David
- Daly Mark J.
- Daly Zoe
- Dalziel Jack
- Dance Annalisa
- Danesh John
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- Daniel Priya
- Daniels Allison
- Darcis Gilles
- Dark Paul
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- Das Mihaela
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- Davies Kim
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- Davison Chloe
- Dawson Deborah
- Dawson Joy
- Day Nicky
- Daya Michelle
- de Almeida Martins Laura Gomes
- de Cid Rafael
- de Felipe Mimbrera Alicia
- de Geus Eco
- de Gordoa Laura Ortiz-Ruiz
- de la Cal-Sabater Paloma
- De Neef Mark
- De Vivo Oreste
- Deacon Bethan
- Deacon Bethan
- Dearden Joy
- Death Yasmin
- Debreceni Gabor
- DeDiego Marta L.
- Deelen Patrick
- Deery Joanne
- Dei Simona
- Dela Rosa Arnold
- Delgado Carlos Castro
- Della Monica Matteo
- Demetriou Carrie
- Denmade Craig
- Dennis Catherine
- Dent Kathy
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- Di Angelantonio Emanuele
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- Durrant Georgia
- Duskova Michaela
- Dykes Joseph
- Eapen Beena
- Earle Sarah G.
- Eastgate-Jackson Christine
- Easthope Amy
- Easthope Amy
- Easthope Amy
- Easton Jack
- Ebano Patrizia
- Eckbad Charlotte
- Edmond Ian
- Edwards Michelle
- Efford Georgia
- Egan Jasmine
- Eid Mohammed A.
- El-Jawhari Jehan J.
- El-Lawaty Walaa M.
- El-shanshory Mohamed R.
- El-Sherbiny Yasser M.
- Elgar Greg
- Elhadidy Tamer A.
- Elhassan Munzir
- Elliott Katherine S.
- Elliott Kerry
- Elliott Paul
- Ellis Hannah
- Elnagdy Marwa H.
- Elsaadany Mohamed
- Elston Kay
- Eltayeb Ayaa
- Eltoukhy Madonna M.
- Emiliozzi Arianna
- English Katy
- Erard Véronique
- Esko Tõnu
- Esparza-Gordillo Jorge
- Evitts Jayne
- Ezeobu Obiageri
- Fabbiani Massimiliano
- Fagan Andrew
- Falcone Marco
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- Farquhar Fiona
- Farré Xavier
- Farzad Zohreh
- Faulkner Beverley
- Faulkner Maria
- Fava Francesca
- Fawkes Angie
- Fawkes Angie
- Fawns-Ritchie Chloe
- Fawzy Mohammad S.
- Fearby Maggie
- Felemban Walaa A.
- Felton Timothy
- Feng Yen-Chen Anne
- Ferguson Susie
- Feri Marco
- Fernandes Kay
- Fernandes Rita
- Fernandez Ziortza
- Fernandez-Cadenas Israel
- Fernandez-Roman Jaime
- Ferreira Manuel A. R.
- Ferreira Manuel A. R.
- Ferri Claudio
- Fidler Katy
- Filipe Helder
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- Fowler Tom
- Fowler Tom A.
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- Franchi Federico
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- Franke Lude
- Frankham Jordan
- Frater Alasdair
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- Free Robert C.
- Frippiat Frederic
- Frise Matthew
- Frithiof Robert
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- Gatti Francesca
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- Giannattasio Ferdinando
- Gibson Sian
- Gignoux Christopher R.
- Gilbert Kayleigh
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- Gill Jaspret
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- Glessner Joseph T.
- Goddard Peter
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- Golding Hannah
- Goldstein Jacqueline I.
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- Gratrix Andrew
- Grau Neus
- Grauslyte Lina
- Green Jackie
- Green Robert C.
- Greer Sandra
- Gregory Jane
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- Griffin Denise
- Griffiths Christopher J.
- Griffiths Fiona
- Griffiths Fiona
- Grimmer Lisa
- Grip Jonathan
- Guarnaccia Alessandra
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- Gulati A.
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- Gupta Rahul
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- Guzman Charlotte
- Hadebe Bernard
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- Hairsine Brigid
- Hakonarson Hakon
- Hakonarson Hakon
- Halawani Roaa T.
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- Hales Dawn
- Halkes Matthew
- Hall Kathryn
- Halls Rosslyn
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- Hamilton David O.
- Hamilton Debbie
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- Harris Nichola
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- Hegazy Mohamed A. F.
- Helgeland Øyvind
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- Hey Samuel
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- Hiester Liam L.
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- Higham Andrew
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- Hijazi Muhammad
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- Hinds Charles
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- Hollox Edward J.
- Home Marie
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- Hope Dave
- Hope Susan
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- Horby Peter
- Horby Peter
- Hormis Anil
- Horner Daniel
- Hornsby James
- Horowitz Julie E.
- Horowitz Julie E.
- Horsley Elizabeth
- Hosseini Abdolmajid
- Houlden Henry
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- Houston Gordon
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- Howe Gwenllian Sera
- Howie Lucy
- Howle Ryan
- Howlett Alex
- Hruska Martin
- Huang Qin Qin
- Huckins Laura M.
- Hudig Lisa
- Hudson Anne
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- Hughes Alistair
- Hughes Gareth
- Hughes Rachel Anne
- Hugill Keith
- Hull Robert
- Hulme Jonathan
- Hultström Michael
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- Humphreys Sally
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- Hunt Karen A.
- Hurford Fran
- Hurt William James
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- Hutton Paula
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- Jha Rajeev
- Jhanji Shaman
- Jim Ruddy
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- Joe West
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- Johnson Emily
- Johnson Laura
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- Johnston Brian
- Jones Cathy
- Jones Dawn
- Jones Gareth A. L.
- Jones James
- Jones Jessica
- Jones Megan
- Jones Oliver
- Jones Rhianna
- Jones Sian
- Jones Tim Owen
- Jordan Daniel M.
- Jose Sanal
- Joseph Anna
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- Josyula Navya Shilpa
- Joy Rosie
- Jude Edward
- Jung Junghyun
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- Justice Anne E.
- Kadiri Salma
- Kaliappan Agilan
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- Kallon Delordson
- Kamdar Dhryata
- Kamundi Charlotte
- Kanai Masahiro
- Kannan Thogulava
- Kanu Rebecca
- Kapoor Ritoo
- Karczewski Konrad J.
- Karjalainen Juha
- Karlson Elizabeth W.
- Karp Avrohom
- Karthik Komala
- Kasipandian Vidya
- Kassam Jamila
- Katary Amro
- Kaufmann Daniel E.
- Kaul Sundeep
- Kaunisto Mari
- Kausar Rizwana
- Kay Andrea
- Kayani Abdul
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- Kaye Duncan
- Kazi Aayesha
- Keating Liza
- Keating Sean
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- Keenan Samantha
- Keith Sarah
- Keller Katherine
- Kelly Diane
- Kelly Fiona
- Kelly Sinead
- Kelsall Olivia
- Kennard-Holden Gareth
- Kennedy-Hay Sophie
- Kenny Eimear E.
- Kent Alissa
- Kent Harriet
- Kent Melanie
- Kerr Shona M.
- Keshet-Price Jocelyn
- Khade Reena
- Khafaga Walid T.
- Khaliq Waqas
- Khaliq Waqas
- Khan Meherunnisa
- Khattab Amin K.
- Khera Jacyntha
- Kibutu Faith
- Kimchi Nofar
- Kinch Ashley
- King Bernadette
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- Kirkby Amy
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- Kitson Ross
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- Klaric Lucija
- Knight Alicia
- Knight Julian
- Knight Julian
- Knight Spencer
- Knighton Abigail
- Knights Ellen
- Knowles Karen
- Koelling Nils
- Kogevinas Manolis
- Kolakaluri Laurel
- Kong Thomas
- Koskelainen Sami
- Kosmicki Jack A.
- Kosmicki Jack A.
- Kousathanas Athanasios
- Kousathanas Athanasios
- Krishnamurthy Vinodh
- Kristiansson Kati
- Kubisz-Pudelko Agnieszka
- Kumar Rita
- Kumar Rohit
- Kumar Sumit
- Kuravi Aditya
- La Rovere Maria Teresa
- Laane Edward
- Labkowsky Alexander
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- Langley Margaret
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- Lankester Liana
- Lanting Pauline
- Latham Scott
- Lathrop G. Mark
- Latif Monica
- Laurent Laetitia
- Law Andy
- Law Andy
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- Law Sarah
- Lawton Tom
- Lazo Maria
- Läll Kristi
- Leader Joseph B.
- Lean Richard
- Leaver Susannah
- Ledgard Camilla
- Lee Emma
- Lee Paul H.
- Lee Stephanie
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- Leigh Michael
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- Lepamets Maarja
- Levy Tess
- Lewis Alison
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- Lewis Tracy
- Léonard Philippe
- Li Binglan
- Li Kevin W.
- Li Rui
- Liao Rachel G.
- Liderth Sarah
- Lidstone-Scott Rebecca
- Liew Jade
- Liggett Steven
- Lim Lai
- Lim Li
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- Loosley Ronda
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- Maharajh Amitaa
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- Mahmoud Ebrahim S.
- Mal Hanning
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- Martin Daniel
- Martin Hilary C.
- Martin Jane
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- McAuley Danny
- McCafferty Sarah
- McCormack Louise
- McCormick Jacqueline
- McCormick Joseph B.
- McCormick Wendy
- McCreath Gordan
- McCulloch Corrienne
- McCurdy Alex
- McCurdy Shannon
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- McGowan Janet
- McGregor Alastair
- McGregor Amanda
- McGuigan Peter J.
- McGuinness Heather
- McHugh Tara
- McIvor Shane
- McKechnie Stuart
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- Meghari Hamza
- Meigs James B.
- Meikle Alistair
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- Michael Angiy
- Michael Helen T.
- Michalak-Glinska Natalia
- Middleton Hayley
- Milani Lili
- Millar Johnny
- Millar Jonathan
- Millen Gemma
- Milligan Barry
- Mills Gary H.
- Millward Helen
- Milner Leanne
- Miraglia Federica Gaia
- Mirshahi Tooraj
- Mirshahi Tooraj
- Misset Benoit
- Mitchard Sarah
- Mitchell Alice Michael
- Mitchelmore Oliver
- Mitra Atideb
- Moahmed Hanteera S.
- Moghaddam Seyed Behrooz Mohseni
- Mohamed Ally Sameena
- Mohamed Attia A. S.
- Moncur Eleanor
- Mondelli Mario Umberto
- Monnery Sonja
- Montagnani Francesca
- Montaser Rugia
- Montgomery Hugh
- Montgomery Hugh
- Moore Faye
- Moore Luke Stephen Prockter
- Moore Shona C.
- Mooser Vincent
- Moreno Victor
- Moreno-Cuesta Jeronimo
- Morgan Aled
- Morgan James
- Morino Eriko
- Morrice Kirstie
- Morrice Kirstie
- Morris Anna
- Morris Lucy
- Morris Marcela
- Morris Sheila
- Morrison Alan
- Morrison David R.
- Moss Stuart
- Mostoles Loreta
- Motherwell Nichola
- Moultrie Sam
- Moutschen Michel
- Moutsianas Loukas
- Moutsianas Loukas
- Msiska Maines
- Mtuwa Sheila
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- Mulcahy Michelle
- Mulla Suleman
- Mullan Dee
- Munt Sheila
- Mupudzi Mcdonald
- Murdoch Euan
- Murdoch Sophie
- Murphy Anthony
- Murphy Carl
- Murphy Lee
- Murphy Lee
- Murphy Lorna
- Murphy Shawn N.
- Murphy Sheena
- Mussini Cristina
- Mutch Rachel
- Mwaura Esther
- Mwaura Lucy
- Naaber Paul
- Naderpour Zeinab
- Nadkarni Girish N.
- Nagra Imrun
- Naisbitt Jay
- Nakanishi Tomoko
- Naranjo Andres
- Nasir Farah
- Nayak Monalisa
- Nazari Roonak
- Neal Alan
- Neale Benjamin M.
- Nencioni Cesira
- Neofytos Dionysios
- Netherton Kimberley
- Newell Helen
- Newey Luke
- Newman Julie
- Newman Tabitha
- Newton Maria
- Ng Anthony
- Nguyen Huy
- Niavarani Ahmadreza
- Niblo Kristi
- Nichol Ailstair
- Nichol Alistair
- Nichol Alistair
- Nicholson Alice
- Nicholson Anne
- Nicol Liz
- Niemi Mari E. K.
- Nikitas Nikitas
- Nilaratanakul Voraphoj
- Nilsson Annette
- Nivard Michel
- Nixon Rachel
- Nkambul Lindo
- Nkambul Lindokuhle
- Nkambule Lindokuhle
- Noble Harriet
- Nolan Claire
- Norman Kathryn
- Norris John
- Nortcliffe Tonicha
- North Julie
- North Kari
- Noto Keith
- Novis Catherine
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- Nune Arvind
- Nussle Semira Gonseth
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- Odhams Christopher A.
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- Openshaw Peter J. M.
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- Rudkin Justine K.
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- Semple Malcolm G.
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- Shankar-Hari Manu
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- Sharififard Bahareh
- Shastri Anjali J.
- Shaw David
- Shaw Douglas M.
- Shaw Lisa
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- Shelton Janie F.
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- Shen Xia
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- Tracy Baird
- Trankiem Amy
- Tranter Helen
- Trembath Richard C.
- Tridente Ascanio
- Trim Fiona
- Trivedi Bhavi
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- Uitterlinden Andre G.
- Underwood Slayton J.
- Vaghi Massimo
- Vaida Marius
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- Valentine Jennifer
- Valentino Floriana
- van Blokland Irene
- van Heel David A.
- van Koutrik Lynne
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- Venkatesh Harish
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- Venturelli Sophie
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- Verlander Mark
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- Verma Anurag
- Verma Shefali S.
- Vertue Mark
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- Vitart Veronique
- Vizcaychipi Marcela Paola
- Vochin Ana
- Voide Cathy
- von Frenckell Christian
- von Hohenstaufen Kathrin Aprile
- Vonk Judith M.
- Vulesevic Branka
- Vuylsteke Alain
- Wackett Tony
- Wadams Beverley
- Waddington Natalia
- Wagstaff Veronica
- Wain Louise V.
- Waite Alicia A. C.
- Wakefield Phillipa
- Wakinshaw Fiona
- Waldron Joanne
- Walker Danielle
- Walker Rachel
- Walker Sara
- Walker Susan
- Walker Susan
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- Walsh Timothy
- Walsh Timothy
- Walters Raymond K.
- Walton Olivia
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- Watson Geoff
- Watson James
- Watters Malcolm
- Waugh Victoria
- Weaver Jane
- Webster Andrea
- Webster Denise
- Webster K.
- Wei Shuying
- Weiss Scott T.
- Weldon Catherine H.
- Wells Colin
- Welters Ingeborg D.
- Weston Heather
- Whileman Amanda
- Whitbread Jennifer
- White Deborah
- White Ian
- White Katie
- White Matthew
- White Nigel
- White Nikki
- Whiteley Simon
- Whiteside Jonathan
- Whittle Helen
- Whitton Christopher
- Whyte Clare
- Wicks Stephen J.
- Wilby Elizabeth
- Wilcox Louise
- Wilcox Rebecca
- Wild Helen
- Wild Laura
- Wild Laura
- Wilding Laura
- Wiles Matthew
- Wilkins Joy
- Wilkinson Ami
- Wilkinson Brian
- Willer Cristen
- Williams Alexander T.
- Williams Alexandra
- Williams Alison
- Williams Angharad
- Williams Dewi
- Williams Emma
- Williams Felicity
- Williams Gemma
- Williams Hannah
- Williams Karen
- Williams Marie
- Williams Patricia
- Williams Sarah
- Williams Toran
- Willis Charlotte
- Willis Heather
- Wills Maryanne
- Willson Jayne
- Wilson Alison
- Wilson Daniel J.
- Wilson James F.
- Wilson James F.
- Wilson Jean
- Winnard Sarah
- Winter-Goodwin Barbara
- Wolf-Roberts Rebecca
- Wolford Brooke
- Wong Joanna
- Wood Di
- Wood Hannah-Louise
- Wood Suzanne
- Wood Tracy
- Woodford Christopher
- Woodruff Meriel
- Woods Lindsey
- Woodyatt Wiesia
- Woolley Ann E.
- Worner Ruth
- Worsley Lucy
- Wray Gemma
- Wren Lynn
- Wrey Brown Caroline
- Wright David
- Wright John
- Wright Mary
- Wrobel Nicola
- Wu Yang
- Wulandari Retno
- Wyllie David H.
- Wynter Inez
- Xavier Kugan
- Xue Xiaoqing
- Yadav Ashish
- Yang Jian
- Yassen Amr M.
- Yates Bryan
- Ye Chelsea
- Yun Nikki
- Zainy Tala
- Zak Anne
- Zaki Ahmed
- Zamikula Julie
- Zanella Isabella
- Zborowski Anelise C.
- Zeberg Hugo
- Zechner Marie
- Zechner Marie
- Zguro Kristina
- Zhang Miao
- Zhao Jing Hua
- Zheng Chenqing
- Zhou Wei
- Zitter Letizia
- Zlatopolsky Menachem
- Zongo Olivier
- Zöllner Sebastian
- Zucchi Patrizia
- Zyndorf Marissa
- Publication venue
- 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
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- A. Gulati
- Aarno Palotie
- Aaron Butler
- Aayesha Kazi
- Abdelhakim Altabaibeh
- Abdolmajid Hosseini
- Abdul Kayani
- Abdulaziz AlMalik
- Abdulraheem Alshareef
- Abhinav Gupta
- Abigail Crew
- Abigail Knighton
- Abigail Short
- Abigail Taylor
- Abiola Harrison
- Achille Iolascon
- Adam Auton
- Adam Brayne
- Adam Brown
- Adam Loveridge
- Adam S. Butterworth
- Adama Fofano
- Aditya Kuravi
- Adriana Botello
- Afshan Siddiq
- Afshar Etemadi Aleagha
- Agilan Kaliappan
- Agnese Verzuri
- Agnieszka Kubisz-Pudelko
- Agostino Ognibene
- Agostino Riva
- Ahmadreza Niavarani
- Ahmed Zaki
- Ahna Girshick
- Aida Fiz-López
- Ailbhe Brady
- Ailsa Golightly
- Ailstair Nichol
- Ainhi Mac
- Ajay Raithatha
- Alain Vuylsteke
- Alan Maclean
- Alan Morrison
- Alan Neal
- Alanna Wall
- Alasdair Bamford
- Alasdair Frater
- Alasdair Hay
- Alastair McGregor
- Alastair Rose
- Alastair Thomas
- Alba Parra Martínez
- Albandary M. Alowayn
- Albert Tenesa
- Albert Tenesa
- Albert V. Smith
- Aled Morgan
- Alessandra Guarnaccia
- Alessandra Renieri
- Alessandra Stella
- Alessandra Vergori
- Alessandro Pancrazzi
- Alessia Giorli
- Alex Howlett
- Alex Lyon
- Alex McCurdy
- Alex Puxty
- Alex Serra-Llovich
- Alex Soriano
- Alex Stuckey
- Alex Stuckey
- Alexander Labkowsky
- Alexander T. Williams
- Alexander W. Charney
- Alexandra Aksentijevich
- Alexandra Metcalfe
- Alexandra Williams
- Alexandre Belisle
- Alexandre C. Pereira
- Alfredo Serrano-Ruiz
- Ali Amirsavadkouhi
- Ali Sobh
- Alice Donati
- Alice Harvey
- Alice Michael Mitchell
- Alice Nicholson
- Alice Poole
- Alice Thomas
- Alicia A. C. Waite
- Alicia de Felipe Mimbrera
- Alicia Knight
- Alicia Price
- Alicia R. Martin
- Alireza Adamsara
- Alison Brown
- Alison Brown
- Alison Durie
- Alison Ghosh
- Alison Harrison
- Alison Lewis
- Alison Lye
- Alison Quinn
- Alison Turnbull
- Alison Williams
- Alison Wilson
- Alissa Kent
- Alistair Gales
- Alistair Hughes
- Alistair Meikle
- Alistair Nichol
- Alistair Nichol
- Alistair Roy
- Allison Daniels
- Altaf Ali
- Alun Rees
- Amal Al Mutairi
- Amanda Ayers
- Amanda Cowton
- Amanda Lyle
- Amanda McGregor
- Amanda Sanderson
- Amanda Tyler
- Amanda Whileman
- Amber Cox
- Amber Ford
- Ambreen Tariq
- Amelia Daniel
- Amelia Stacey
- Ami Wilkinson
- Amie Reddy
- Amin K. Khattab
- Amit Patel
- Amitaa Maharajh
- Amr M. Yassen
- Amr Samir
- Amro Katary
- Amy Bowes
- Amy Clark
- Amy Collins
- Amy Cunningham
- Amy Easthope
- Amy Easthope
- Amy Easthope
- Amy Gardner
- Amy Kirkby
- Amy Pickard
- Amy Shepherd
- Amy Trankiem
- Ana Alvaro
- Ana Lisboa
- Ana Luisa Tomas
- Ana Vochin
- Anastasia Lucas
- Anca Gherman
- Andre G. Uitterlinden
- Andrea Antinori
- Andrea Cossarizza
- Andrea Ganna
- Andrea Kay
- Andrea Martín-Nalda
- Andrea Tommasi
- Andrea Webster
- Andres Metspalu
- Andres Naranjo
- Andrew Beck
- Andrew Burtenshaw
- Andrew D. Bretherick
- Andrew Fagan
- Andrew Gratrix
- Andrew Higham
- Andrew Higham
- Andrew P. Boughton
- Andrew Stenhouse
- Andrew Swain
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- Victoria Waugh
- Vidya Kasipandian
- Vikki Crickmore
- Vikram Anumakonda
- Vincent Mooser
- Vincenzo Forgetta
- Vinodh Krishnamurthy
- Vishal Amin
- Voraphoj Nilaratanakul
- Vorasuk Shotelersuk
- Véronique Erard
- Walaa A. Felemban
- Walaa M. El-Lawaty
- Walid T. Khafaga
- Wanna Chetruengchai
- Waqas Khaliq
- Waqas Khaliq
- Watsamon Jantarabenjakul
- Wei Zhou
- Wendy Goddard
- Wendy Harrison
- Wendy McCormick
- Wenhan Lu
- Werner Albrich
- West Joe
- Wiesia Woodyatt
- William James Hurt
- Wilna Oosthuyzen
- Wilna Oosthuyzen
- Xavier Farré
- Xia Shen
- Xiao Chang
- Xiaoqing Xue
- Xinyi Qiu
- Xueyang Wang
- Yan V. Sun
- Yang Wu
- Yaseen M. Arabi
- Yasmin Choudhury
- Yasmin Death
- Yasmin Hussain
- Yasmine Belhaj
- Yasser M. El-Sherbiny
- Yen-Chen Anne Feng
- Yolanda Baird
- Yuk-Lam Ho
- Yuki Bradford
- Yunsung Lee
- Yusuf Cheema
- Yuval Itan
- Yves Beguin
- Yvette Thirlwall
- Yvonne Jackson
- Zahira Maqsood
- Zakaula Belagodu
- Zaman Afrasiabi
- Zeinab Naderpour
- Zena Bradshaw
- Zhu Wanying
- Ziab Z. Alahmadey
- Ziortza Fernandez
- Zoe Alldis
- Zoe Coton
- Zoe Daly
- Zoe Garland
- Zoe Lamond
- Zoe Prime
- Zoe Scott
- Zohra Omar
- Zohreh Farzad
- Øyvind Helgeland
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/03/2022
- Field of study
AbstractCritical 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.</jats:p
