8 research outputs found
The Influence Of Gender-Stereotyped Interests On Ratings Of A Perceived Homosexual
- Publication venue
- Publication date
- 01/01/1985
- Field of study
This study was conducted to examine the effects of the label "homosexual" and gender of subjects on personality ratings of a man possessing typically masculine, feminine, or neutral interests
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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- Afilalo M.
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- Afrasiabi Z.
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- Al-Awdah L.
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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
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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- Wyllie D.H.
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- Xue X.
- Yadav A.
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- Yassen A.M.
- Yates B.
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- Zainy T.
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- Zanella I.
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- Zhao J.H.
- Zheng C.
- Zhou W.
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- Zlatopolsky M.
- Zongo O.
- Zucchi P.
- Zyndorf M.
- Zöllner S.
- Åsvold B.O.
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
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
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial
- Author
- Aboagye J.
- Adams K.
- Aley P.K.
- Ali A.
- Allen E.R.
- Allen L.
- Allison J.L.
- Andritsou F.
- Angus B.
- Anslow R.
- Arbe-Barnes E.H.
- Babbage G.
- Baker M.
- Baker N.
- Baker P.
- Baleanu I.
- Barker D.
- Barnes E.
- Barrett J.R.
- Barrett K.
- Bates L.
- Batten A.
- Beadon K.
- Beckley R.
- Belij-Rammerstorfer S.
- Bellamy D.
- Berg A.
- Bermejo L.
- Berrie E.
- Berry L.
- Beveridge A.
- Bewley K.
- Bibi S.
- Bijker E.M.
- Birch G.
- Bittaye M.
- Blackwell L.
- Bletchly H.
- Blundell C.L.
- Blundell S.R.
- Bolam E.
- Boland E.
- Bormans D.
- Borthwick N.
- Boukas K.
- Bower T.
- Bowring F.
- Boyd A.
- Brenner T.
- Brown P.
- Brown-O'Sullivan C.
- Bruce S.
- Brunt E.
- Burbage J.
- Burgoyne J.
- Buttigieg K.R.
- Byard N.
- Cabera Puig I.
- Camara S.
- Cao M.
- Cappuccini F.
- Carr M.
- Carroll M.W.
- Cashen P.
- Cathie K.
- Cavey A.
- Chadwick J.
- Challis R.
- Chapman D.
- Chappell H.
- Charles D.
- Charlton S.
- Chelysheva I.
- Cho J.-S.
- Cicconi P.
- Cifuentes L.
- Clark E.
- Clutterbuck E.A.
- Colin-Jones R.
- Collins S.
- Conlon C.P.
- Coombes N.S.
- Cooper C.
- Cooper R.
- Crocker W.E.M.
- Crosbie S.
- Cullen D.
- Cunningham C.
- Cuthbertson F.
- Dando L.
- Datoo B.E.
- Datoo M.S.
- Datta C.
- Davies H.
- Davies S.
- Davis E.J.
- Davis J.
- Dearlove D.
- Demissie T.
- Di Marco S.
- Di Maso C.
- DiTirro D.
- Docksey C.
- Dold C.
- Dong T.
- Donnellan F.R.
- Douglas A.D.
- Douglas N.
- Downing C.
- Drake J.
- Drake-Brockman R.
- Drury R.E.
- Dunachie S.J.
- Edwards C.J.
- Edwards N.J.
- El Muhanna O.
- Elias S.C.
- Elliott R.S.
- Elmore M.J.
- Emary K.R.W.
- English M.R.
- Ewer K.J.
- Faust S.N.
- Fedosyuk S.
- Felle S.
- Feng S.
- Ferreira Da Silva C.
- Field S.
- Fisher R.
- Fixmer C.
- Flaxman A.L.
- Folegatti P.M.
- Ford K.J.
- Fowler J.
- Francis E.
- Frater J.
- Furze J.
- Fuskova M.
- Galian-Rubio P.
- Galloway C.
- Garlant H.
- Gavrila M.
- Gbesemete D.
- Gibbons F.
- Gibbons K.
- Gilbert S.C.
- Gilbride C.
- Gill H.
- Godwin K.
- Gordon-Quayle K.
- Gorini G.
- Goulston L.
- Grabau C.
- Gracie L.
- Graham N.
- Green C.
- Greenwood N.
- Griffiths O.
- Gupta G.
- Hallis B.
- Hamilton E.
- Hanumunthadu B.
- Harris S.A.
- Harris T.
- Harrison D.
- Hart T.C.
- Hartnell B.
- Haskell L.
- Hawkins S.
- Henry J.A.
- Hermosin Herrera M.
- Hill A.V.S.
- Hill D.
- Hill J.
- Hodges G.
- Hodgson S.H.C.
- Horton K.L.
- Hou M.M.
- Howe E.
- Howell N.
- Howes J.
- Huang B.
- Humphreys J.
- Humphries H.E.
- Iveson P.
- Jackson F.
- Jackson S.
- Jauregui S.
- Jeffers H.
- Jenkin D.
- Joe C.C.D.
- Jones B.
- Jones C.E.
- Jones E.
- Jones K.
- Joshi A.
- Kailath R.
- Keen J.
- Kelly D.
- Kelly D.M.
- Kelly E.J.
- Kelly S.
- Kerr D.
- Kerridge S.
- Khan L.
- Khozoee B.
- Killen A.
- Kinch J.
- King L.D.W.
- King T.B.
- Kingham L.
- Klenerman P.
- Knight J.C.
- Knott D.
- Koleva S.
- Lambe T.
- Lang G.
- Larkworthy C.W.
- Larwood J.P.J.
- Law R.
- Lawrie A.M.
- Lee A.
- Lee K.Y.N.
- Lees E.A.
- Lelliott A.
- Leung S.
- Li Y.
- Lias A.M.
- Linder A.
- Lipworth S.
- Liu S.
- Liu X.
- Lloyd S.
- Loew L.
- Lopez Ramon R.
- Lwin M.N.
- Madhavan M.
- Mainwaring D.O.
- Makinson R.
- Mallett G.
- Mansatta K.
- Marchevsky N.G.
- Marinou S.
- Marius P.
- Marlow E.
- Marriott P.
- Marshall J.L.
- Martin J.
- Masters S.
- McEwan J.
- McGlashan J.L.
- McInroy L.
- McRobert N.
- Megson C.
- Mentzer A.J.
- Minassian A.M.
- Mirtorabi N.
- Mitton C.
- Moore M.
- Moran M.
- Morey E.
- Morgans R.
- Morris S.J.
- Morrison H.M.
- Morshead G.
- Morter R.
- Moya N.A.
- Mujadidi Y.
- Mukhopadhyay E.
- Muller J.
- Munro A.P.S.
- Munro C.
- Murphy S.
- Mweu P.
- Noé A.
- Nugent F.L.
- O'Brien K.
- O'Connor D.
- O'Reilly P.J.
- Oguti B.
- Olchawski V.
- Oliveira C.
- Osborne P.
- Owen L.
- Owens D.R.
- Owino N.
- Pacurar M.
- Papageorgiou P.
- Parracho H.
- Parsons K.
- Patel B.
- Patrick-Smith M.
- Peng Y.
- Penn E.J.
- Peralta-Alvarez M.P.
- Perring J.
- Petropoulos C.
- Phillips D.J.
- Pipini D.
- Plested E.
- Pollard A.J.
- Pollard S.
- Poulton I.
- Pratt D.
- Presland L.
- Proud P.C.
- Provstgaard-Morys S.
- Pueschel S.
- Pulido D.
- Rabara R.
- Radia K.
- Rajapaska D.
- Ramasamy M.N.
- Ramos Lopez F.
- Rand J.
- Ratcliffe H.
- Rawlinson T.
- Rayhan S.
- Rees B.
- Reyes Pabon E.
- Rhead S.
- Ritchie A.J.
- Roberts H.
- Robertson I.
- Robinson H.
- Roche S.
- Rollier C.S.
- Romani R.
- Rose Z.
- Ross-Russell A.L.
- Rudiansyah I.
- Sabheha S.
- Saich S.
- Salvador S.
- Sanders H.
- Sanders K.
- Satti I.
- Sayce C.
- Schmid A.B.
- Schofield E.
- Screaton G.
- Seddiqi S.
- Sedik C.
- Segireddy R.R.
- Selby B.
- Shaik I.
- Sharpe H.R.
- Shaw R.
- Shea A.
- Silk S.
- Silva-Reyes L.
- Singh N.
- Skelly D.T.
- Smith C.C.
- Smith D.C.
- Smith D.J.
- Smith N.
- Snape M.D.
- Song R.
- Spencer A.J.
- Spoors L.
- Stafford E.
- Stamford I.
- Stockdale L.
- Stockley D.
- Stockwell L.V.
- Stokes M.
- Strickland L.H.
- Stuart A.
- Sulaiman S.
- Summerton E.
- Swash Z.
- Szigeti A.
- Tahiri-Alaoui A.
- Tanner R.
- Tarrant R.
- Taylor I.
- Taylor K.
- Taylor U.
- te Water Naude R.
- Themistocleous A.
- Themistocleous Y.
- Thomas K.M.
- Thomas M.
- Thomas T.M.
- Thompson A.
- Thompson K.
- Thornton-Jones V.
- Tinh L.
- Tomic A.
- Tonks S.
- Towner J.
- Tran N.
- Tree J.A.
- Truby A.
- Turner C.
- Turner R.
- Ulaszewska M.
- Varughese R.
- Verbart D.
- Verheul M.K.
- Vichos I.
- Villafana T.L.
- Voysey M.
- Walker L.
- Wand M.E.
- Warren S.C.
- Watkins B.
- Watson M.E.E.
- Welch J.
- West A.J.
- White C.
- White R.
- Williams P.
- Woodyer M.
- Worth A.T.
- Wright D.
- Wrin T.
- Yao X.L.
- Zbarcea D.-A.
- Zizi D.
- Publication venue
- 'Elsevier BV'
- Publication date
- 19/12/2020
- Field of study
Background
Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older.
Methods
In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18–55 years, 56–69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18–55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56–69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5–6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18–55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.
Findings
Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18–55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56–69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18–55 years group, 22 (73%) of 30 in the 56–69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18–55 years group, 23 (77%) in the 56–69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18–55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898–33 550], n=39; 56–69 years, 16 170 AU/mL [10 233–40 353], n=26; and ≥70 years 17 561 AU/mL [9705–37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18–55 years, 193 [IQR 113–238], n=39; 56–69 years, 144 [119–347], n=20; and ≥70 years, 161 [73–323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18–55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841–2428], n=24; 56–69 years: 797 SFCs [383–1817], n=29; and ≥70 years: 977 SFCs [458–1914], n=48).
Interpretation
ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities.
Funding
UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca
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
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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
Recommended from our members
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
- Author
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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 ‘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
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- Tamayo-Velasco A
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- Timpson NJ
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- Tivenan H
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- Tusié-Luna T
- Tutt G
- Tutton R
- Twiss S
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- Yeung RSM
- Yi X
- Yonekawa A
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- Yoshida T
- Yoshihara T
- Yoshiya K
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- Young M
- Yue F
- Yun N
- Yáñez CE
- Yáñez Z
- Zainulabid UA
- Zainy T
- Zak A
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- Zamikula J
- Zamudio IPM
- Zanella A
- Zapata-Contreras D
- Zapatamartinez M
- Zarate R
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- Zavaleta DAF
- Zawadzki P
- Zawati MH
- Zborowski AC
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- Zhlawi MWJ
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- Özer O
- Überla K
- Þorsteinsdóttir U
- Publication venue
- Nature Research
- Publication date
- 21/06/2023
- Field of study
1997 Amerasia Journal
- Author
- Abueg Francis R
- Adachi Nobuhiro
- Alba Richard D
- Alexander
- Alexander Meena
- Ali Mehmed
- Aliani Ayesha
- Allen James P
- Allen James P
- Allibhai Gulshan
- Almeida Rhea
- Almendraia Laarni C
- Amerman Stephen Kent
- Ang Len
- Aquilar D.
- Archibold Randal C
- Archibold Randal C
- Asian Pacific American
- Astin Helen S
- Ayuyang Rachelle Q
- Babich Phillip
- Bacho Peter
- Bacon Jean Leslie
- Bahri
- Bahri Deepika
- Baird V.
- Bankston
- Bankston C. L.
- Bankston Carl L
- Bankston Carl L
- Bannerji Himanji
- Baron G. Deborah G.
- Barrett Giles A
- Barrett James R
- Batayola Maria
- Bates Timothy
- Beem K. J.
- Belden Elionne L. W.
- Bemak Fred
- Bemak Fred
- Bermejo
- Berson Misha
- Berthelsen Christian
- Bhachu Amarjet S
- Bhattachargng N.
- Biers D.
- Bindon J. R.
- Bird Joyce Adair
- Bizzini Silva Caporale
- Bjorck J. P.
- Black J.
- Boisse Joseph A
- Bonner Arthur
- Bonzon Teodulo Cruz
- Booth Alan
- Bracero William
- Brah A.
- Braun K. L.
- Braun K. L.
- Braun Kathryn
- Brock R. N.
- Brown K.
- Brown Maria Wilhelmina B
- Buchholdt Thelma
- Buriel Raymond
- Buriel Raymond
- Cabrera Yvette
- Cage Mary Crystal
- Cahill Peter
- Cameron M.
- Carbo Nick
- Carolyn
- Castro Rafaela Castro
- Catolico Olivia
- Cha Dia
- Chai Arlene J
- Chan Connie
- Chan Sharon
- Chan Sucheng
- Chang Hsiao-Hung
- Chang Juliana
- Chang Juliana
- Chang Leonard
- Chang Pang-Mei
- Chao Patricia
- Chao Ruth K
- Chemerinsky Erwin
- Chen Chiung Hwang
- Chen Eric
- Chen LanDuh
- Chen Shu-Fen
- Chen Shyh-Jer
- Chen V. T.
- Cheng Cliff
- Cheon Jun Ku
- Cheung King-Kok
- Chew Pat K
- Chew Pat K
- Chin Justin
- Chin Ku-Sup
- Ching Jennifer
- Cho P. J.
- Chow Esther
- Choy Wayson
- Chua Lawerence
- Chuh K.
- Chun A.
- Chung Rita
- Church A. Timothy
- Cimatu Y.
- Ciria-Cruz Rene P
- Claiborne William
- Cole
- Congressional Asian Pacific Caucus
- Connell
- Constable Pamela
- Corp
- Courtenay P.
- Cox David
- Craib Raymond B
- Crain Madeleine
- Creese Peterson
- Cummings S.
- Curry George E
- Dabydeen Cyril
- Dabydeen David
- Damico Chantel Renae
- Das Ajit K
- Dasgupta S. D.
- Dasgupta Shamita Das
- Davanzo C. E.
- David G.
- Davidov Judith Fryer
- Davison Mariquita Athena
- Daye Douglas D
- De Cristoforo Violet Kazue
- Degabriele M.
- Department of Education
- Detzner Daniel F
- Dhooper S. S.
- Diaz-Veizades Jeannette
- Dickerson Debra
- Dill
- Divakaruni
- Domyanan Faye
- Dong Harvey
- Doucet Dorothy
- Drachman Diane
- Eaton Winnifred
- Ebenkamp Becky
- Economic Census
- Edman Jeanne L
- Edmondson Brad
- Elliott Kathryn Sabrena
- Engardio Pete
- Erkut Sumru
- Espin Oliva M
- Espiritu Yen Le
- Ethnic Newswatch D.
- Evans Kathy M
- Everett S.
- Fabros Alex S. Jr.
- Fadiman Anne
- Fan Carol C
- Fan Stephen
- Fang Di.
- Farber David
- Farley Maggie
- Feng Hua
- Feng Kathay
- Feng P.
- Feng Peter
- Fenkl Heinz Insu
- Fenton John Y
- Fernandez Sandy M
- Ferrer Editha Tubao
- Fienberg Joyce S
- Fong L. Y. S.
- Fong Rowena
- Foster Sesshu
- Francia Luis H
- Fujikane Candace Lei
- Fujita Rony Dorothy Bintang
- Fukaya Michiyo
- Fumia Molly
- Galado L.
- Galang M. Evelina.
- Galli-Banducci Joanne
- Gao Yan
- Garment Industry Abuse
- Gee Michele J
- Gervais Karen G
- Gnaniah Natarajan Jawahar
- Goodman Peter S
- Goodwin A. Lin.
- Goodwin A. Lin.
- Gose Ben
- Gotanda Philip Kan
- Grabiel Susan Ann
- Graves A. B.
- Gray Maryann Jacobi
- Greenberger Ellen
- Greenwood Roberta S
- Groves Martha
- Guillermo Emil
- Gunnings Thomas S
- Gunnings Thomas S
- Gup Ted
- Gutierrez Guadalupe
- Ha Julie
- Ha Julie
- Hadar Leon
- Hagedorn Jessica-Tarahata
- Haleck Peggy Ann
- Hall R. E.
- Hall Sandra Kimberley
- Halualani Rona Tamiko
- Hamamoto Darrell Y
- Hamanaka Lionelle
- Hamilton Beatrice
- Hampton Robert L
- Hams-Hastick Eda
- Han Young-Taek
- Hanawa Yukiko
- Hanawa Yukiko
- Harada V. H.
- Hayashi Carl T
- Hayashi Dennis
- Henry Sarah
- Herbert Annalissa Arangcon
- Hesford W.
- Hickey M. Gail.
- Hicks Jonathan P
- Higa Karin
- Hing Bill Ong
- Ho Foo Nin
- Hodne Barbara D
- Hofstede Geert
- Holdaway Simon
- Holmes Steven A
- Holzman Clare G
- Holzman Clare G
- Hong Terry
- Hoobler Dorothy
- Hopkins MaryCarol
- Hornberger Nancy H
- Horton John
- Houston Velina Hasu
- Houston Velina Hasu
- Howard Nancy Jill
- Hsu L. K.
- Hsu Ruth
- Hu Wei-Yin
- Hua Thao
- Huang Fung-Yea
- Huang Jianyi
- Huebler Dana
- Hughes H. G. A.
- Hui K. K.
- Human
- Hune Shirley
- Hwang L.
- Hyun Helen H
- Ibrahim Farah
- Ichihashi Yamato
- Ichiyama Michael A
- Igasaki Paul M
- Ikeda Stewart David
- Iki Darcie Chiyoko
- Ina Satsuki
- Inada Lawson Fusao
- Investigation M.S.
- Iritani Evelyn
- Ishiikuntz M.
- Iwamasa Gayle Y
- Iwamasa Gayle Y
- Iyer Nalini
- Izumi Lance T
- Jacinto
- Jacobs Brian W
- Jacoby
- Jia John H
- Jin Ha.
- Jin Hee Keun
- Johnson Alex M. Jr.
- Jong Richard Kenneth
- Journal
- Junh C.
- Kafka Phillipa
- Kafka Phillipa
- Kagawa-Singer Marjorie
- Kain Geoffrey
- Kang Joshua Minsoo
- Kang K. Connie
- Kang K. Connie.
- Kang K. Connie.
- Kang K. Connie.
- Kang K. Connie.
- Kang K. Connie.
- Kawahara Lewis Sho
- Kawanabe Kenzo
- Kawarasaki Yasuko
- Kele Kaono Sargent Jerry
- Kendall Diana Elizabeth
- Khare Brij B
- Kiang P. N.
- Kibria N.
- Kibria Nazli
- Kim Ai Ra
- Kim Bok-Lim C
- Kim Bryan S
- Kim David
- Kim E. J.
- Kim Elaine H
- Kim Elaine H
- Kim Elaine H
- Kim Eugene J
- Kim Eunmi
- Kim Heather
- Kim Helen
- Kim Hyun Sook
- Kim Hyung-Chan
- Kim Jung Ha
- Kim K. A.
- Kim Man-Hyung
- Kim Patti
- Kim SeungHee
- Kim Yeunhee Joyce
- King Rebecca Chiyoko
- King Rebecca Chiyoko
- Klein Chris
- Klein Karen E
- Kneubuhl John
- Knox Jo.
- Kondo
- Kono S.
- Koshy Susan
- Kotkin Joel
- Kurashige Scott Tadao
- Kurian Manju S
- Kwan Kwong-Liem
- Kwok Daphne
- Kwon Victoria Hyonchu
- Laboy Julio
- Laboy Julio
- Lai James
- Lam Kit-Chun
- Lam Robert E
- Landres Jonathan Shawn
- Lau Ana Lidia
- Lawerence L.
- Lawrence Charles
- Lawsin Emily Porcincula
- Leach Kristine
- Lee Anthony W
- Lee Carmen Michelle
- Lee Chull
- Lee Evelyn
- Lee Joann
- Lee Josephine Ding
- Lee June J. H.
- Lee Marion
- Lee Mee Sook
- Lee Okhee
- Lee Stacey
- Lee Susan K
- Leonard Jonathan S
- Leonard Karen Isaksen
- Leong Frederick T. L.
- Lessinger Johanna
- Lester D.
- Lester Paul Martin
- Leung Paul K
- Lewis Gregory B
- Lian Ming-Gong
- Libby Donald L
- Liem R.
- Lim In-Sook
- Lin Chin
- Lin Keh-Ming
- Lin Sam Chu
- Lin Sam Chu
- Lind Beth Beutler
- Linden S.
- Ling Huping
- Lisa Skirloff
- Litz John R
- Liu Bao Hong
- Liu John
- Liu Peter
- Liu William
- Lobo Arun Peter
- Loh Sandra Tsing
- Loh Sandra Tsing
- Loue Sana
- Lowe John
- Lowe Lisa
- Lowell Waverly B
- Lu Jennifer
- Ludwig Sami
- Luis Anastacio
- Lynch Annette
- Lynch W.
- Ma Sheng-Mei
- Ma Sheng-Mei
- MacDonald Heather
- Mageli Eldrid
- Mah Kim Sue
- Maitino John R
- Makabe Tomoko
- Makinodan Takashi
- Malley Robert
- Manalansan Martin F. IV.
- Mancini Kimberly Sue
- Marr M. D.
- Martin Quentin E
- Mast Robert H
- Mathur Sobhag
- Matsuda Man J
- Matsuda Mari J
- Matsunaga D. S.
- Matsuoka Jon K
- Matsuoka Jon K
- Matteson D. R.
- Mau W. C.
- Maybury-Lewis David
- McCarthy Kevin F
- McCoy Merwin Andreas
- McGlinn L.
- McIntyre Bryce Telfer
- McKay Sandra Lee
- McKelvey Robert S
- McKenzie-Pollock Lorna
- Mcphee S. J.
- McRoy Ruth G
- Meston C. M.
- Miah M. R.
- Michalowski Margaret
- Michigan
- Mieder Wolfgang
- Miike Lawrence
- Milbank Dana
- Miles M.
- Miller P. J.
- Min Pyong Gap
- Minemura Emi
- Mineta Norman Y
- Mishra S. I.
- Mitsui James Masao
- Miyares Ines M
- Mooko Daren Rikio
- Moon Ailee
- Mori Lisa
- Morimoto Toyotomi
- Morris Anne
- Mortimer Lisa Michelle
- Moua James Lue
- Mozingo Joe
- Mui A. C.
- Mukherjee Bharati
- Mura David
- Murray A.
- Myers Dowell
- Myers Samuel L
- Nagourney Adam
- Nakafuji Hirohiko
- Nakagawa Martha
- Nakagawa Martha
- Nakagawa Martha
- Nakajima Gene A
- Nakanishi Don T
- Nakashima Ellen
- Nakayama Takeshi
- Nakayama Takeshi
- Nakayama Takeshi
- Nash Phil Tajitsu
- Nash Phil Tajitsu
- Nash Phil Tajitsu
- Natsume Kelly Eli
- Nelson Brian
- Nelson Karen R
- Ness Sally A
- Nguyen
- Nifong Christina
- Nifong Christina
- Nordquist Joan
- Nunez
- Nunez
- Obligacion Freddie R
- Okazaki Sumie
- Ong A.
- Ong Aihwa
- Ono Kent A
- Ordinario J.
- Oser Alan S
- Ownbey Shiretta F
- Pang Valerie Ooka
- Parameswaran Uma
- Park Andrew Sung
- Park Clara C
- Park Edward J. W.
- Park Kyeyoung
- Park Kyeyoung
- Parson Russ
- Pasquil Corky
- Patel Nisha
- Patel Saniiv A
- Patsiorkovsky Valeri
- Penn Christie D
- Pham Kristine
- Phan Tuong
- Picard Michel
- Piercy Fred
- Pierre Robert E
- Pilapil Virgilio R
- Pinhey Thomas K
- Pinyuchon M.
- Portes Alejandro
- Portes Alejandro
- Pradhan Sachindra N
- Pratt Institute
- Price Darby Li Po
- Prosser D.
- Qian Zhenchao
- Qr Bebout L.
- Quintiliani Karen I
- Ralston Helen
- Ramirez Charito
- Raphael K. G.
- Ratliff Sharon K
- Ray Brian K
- Reavill Lisa Kay
- Reed Ishmael
- Regalado S.
- Reinecke John E
- Research Publications' American Journey
- Rhee S.
- Richards Phillip M
- Richey C. A.
- Riedmann Agnes
- Rinaldo Peter M
- Rita Emilio Santa
- Ritenbaugh Cheryl
- Ritts Charlie
- Robinson Kathryn
- Rodgers W. H.
- Rodriguez Felix I
- Rohe R.
- Roland Alan
- Rong X. L.
- Rony Fatimah Tobing
- Root Maria P. P.
- Root Maria P. P.
- Ropp Steven Masami
- Rosenbaum Emily
- Ross G. W.
- Rushie Salman
- Sack William H
- Sahay Sarita
- Sakamaki Sachiko
- Sakamoto Arthur
- San Francisco
- San Juan E.
- Sandercock Leonie
- Sanders Jimy M
- Sandhu Daya Singh
- Sarangi Srikant
- Sawada Mitziko
- Scharnhorst Gary
- Schiele Jerome H
- Schneider Alison
- Sechzer Jeri A
- Sengupta Somini
- Sethi Rita Chaudhry
- Shah Nasra M
- Shah Robina
- Shah S.
- Shah Sonia
- Sharma Sanjay
- Shea Pegi Deitz
- Shen Yichin
- Shih F.J.
- Shinagawa Larry Hajime
- Shinagawa Larry Hajime
- Shioya Tara
- Shou S. I.
- Shum L. M.
- Sidanius Jim
- Sidanius Jim
- Singh Gurharpal
- Siu Sau-Fong W
- Skandera-Trombley L.
- Smith
- Smith C. J.
- So Christine
- Sodowsky Gargi Roysircar
- Sohng Sue
- Sonenshein Raphael J
- Song Young I
- Sorenson Susan B
- Spencer Jon Michael
- Spickard
- Spickard
- Spring Marline
- Ssasz F. M.
- Standen
- Stanley T. J.
- Steele Matthew S
- Stokes Larry D
- Stolzenberg R. M.
- Stone Sherry
- Stuhr-Rommereim Rebecca
- Sturma Michael
- Su Z. X.
- Sue David
- Suguro Ed.
- Sun Lena H
- Sun Teresa
- Sun W. Y.
- Tafarrodi Zahra Niccu
- Taira D. A.
- Takagi Dana
- Takagi Tani
- Takahashi Jere
- Takanashi Kelly Kiku
- Tam C. F.
- Tam Reuben
- Tamaki Julie
- Tan Amy
- Tan Benghoe
- Tan Michael L
- Tawa Renee
- Taylor Charles R
- Tempest Rone
- Tempo Phyllis M
- Thiesmeyer Lynn
- Thompson Bryan
- Thongthiraj Rapeepanchanok Malinee
- Thornton Michael C
- Ting Joshua
- Tiongson Amy E
- Tokaji Daniel P
- Torok John Hayakawa
- Trask H.
- Trask Haunani-Kay
- Travisrobyns S. R
- True Reiko Homma
- Tsang Daniel C
- Tseuneyoshi Sandy
- Tsui Kitty
- Tuttle C. R.
- Tyau Kathleen
- Tyner J.
- Ubalde Anatalio
- Um Shin Ja
- Unrau Harlan D
- Valverde
- Van Zevern Claire
- Varma S. C.
- Velasco J. D.
- Vengco-Dalan Janette
- Verduyn Christl
- Vigd James Diego
- Vogt Gayle H
- Vorachack Karla
- Waldinger Roger David
- Walker Adrian
- Wallace Steven P
- Wang Karin
- Wang L.
- Wang Ping
- Watada Terry
- Watanabe S.
- Watkins
- Wechsler Jeffrey
- Wei Virginia W
- Weinberg Meyer
- Weiss Kenneth R
- Weiss Rachel
- West J.
- Westermeyer Joseph
- Whang Patricia A
- Williams Dave
- Williams Raymond Brady
- Wink P. B.
- Wong Janet S
- Wong K. Scott.
- Wong Nellie
- Wong Steve
- Woo Deborah
- Woodland Hills California
- Woods L. Shelton.
- Woods Ruth Dial
- Wright Richard A
- Wrobleski David Eugene
- Wrynn Alison M
- Wu
- Wu Cheryl
- Xiaojing Zhou
- Xin K. R.
- Xinyang Wang
- Xu G.
- Xu Wu
- Yamamoto Eric K
- Yang Belle
- Yang Haiou
- Yang Hyunah
- Yang Jeff
- Yatabe Suzie
- Yau John
- Yeh C. J.
- Yen Alfred C
- Yen Judy
- Yew Chay
- Ying Yu-Wen
- Yip Alethea
- Yip Alethea
- Yip Alethea
- Yogi Stan
- Yokota Kariann Akemi
- Yoo David
- Yoo David
- Yoon In-Jin
- Yoon In-Jin
- Yoshimi Jeff
- Yoshino Ronald W
- Yu Henry
- Yu Ning
- Yu Ping
- Yuen N.
- Yukawa Joyce
- Zack Naomi
- Zhou Min
- Znah Lin
- Publication venue
- 'UCLA American Indian Studies Center'
- Publication date
- Field of study