ArticlemedRxiv : the preprint server for health sciences2021
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
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Article in medRxiv : the preprint server for health sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
69 authors at 20 institutions in 10 countries.
Lucija Klaric *MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.
Jack S Gisby *Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
Artemis Papadaki *Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
Marisa D MuckianCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, UK.
Erin Macdonald-DunlopCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, UK.
Jing Hua ZhaoBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Alex TokolyiDepartment of Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
Elodie PersynBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Erola Pairo-CastineiraRoslin Institute, University of Edinburgh, Easter Bush, Edinburgh, UK.
Andrew P MorrisCentre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
Anette KalnapenkisInstitute of Genomics, University of Tartu, 51010, Estonia.
Anne RichmondMRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.
Arianna LandiniCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, UK.
Åsa K HedmanDepartment of Medicine, Karolinska Institute, Stockholm, Sweden.
Bram PrinsBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Daniela ZanettiDepartment of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Eleanor WheelerMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Chen YaoPopulation Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
John R PetrieInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Jingyuan FuDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Lasse FolkersenDanish National Genome Center, Copenhagen, Denmark.
Mark WalkerFaculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Martin MagnussonDepartment of Clinical Sciences, Lund University, Malmö, Sweden.
Niclas ErikssonUppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden.
Niklas Mattsson-CarlgrenClinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
Paul R H J TimmersMRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.
Shih-Jen HwangPopulation Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Stefan EnrothDepartment of Immunology, Genetics and Pathology, Uppsala University, Sweden.
Stefan GustafssonDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden.
Urmo VosaInstitute of Genomics, University of Tartu, 51010, Estonia.
Yan ChenDepartment of Medicine, Karolinska Institute, Stockholm, Sweden.
Agneta SiegbahnDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden.
Alexander ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Åsa JohanssonDepartment of Immunology, Genetics and Pathology, Uppsala University, Sweden.
Barbara ThorandInstitute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany.
Bruna GiganteDivision of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Caroline HaywardMRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.
Christian HerderInstitute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Christian GiegerInstitute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany.
Claudia LangenbergMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Daniel LevyPopulation Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Daria V ZhernakovaDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
J Gustav SmithDepartment of Cardiology, Clinical Sciences, Lund University.
Harry CampbellCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, UK.
Johan SundstromDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden.
John DaneshBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Karl MichaëlssonDepartment of Surgical Sciences, Unit of Medical Epidemiology, Uppsala University, Uppsala, Sweden.
Karsten SuhreDepartment of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar.
Lars LindDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden.
Lars WallentinDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden.
Leonid PadyukovDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Sweden.
Mikael LandénDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Nicholas J WarehamMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Andreas GötesonInstitute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Oskar HanssonClinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
Per ErikssonDivision of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Rona J StrawbridgeInstitute of Health and Wellbeing, College of Medicine, Veterinary and Life Sciences, University of Glasgow, UK.
Themistocles L AssimesDepartment of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Tonu EskoInstitute of Genomics, University of Tartu, 51010, Estonia.
Ulf GyllenstenDepartment of Immunology, Genetics and Pathology, Uppsala University, Sweden.
J Kenneth BaillieIntensive Care Unit, Royal Infirmary of Edinburgh, 54 Little France Drive, Edinburgh, EH16 5SA, UK.
Dirk S PaulBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Peter K JoshiCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, UK.
Adam S ButterworthBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Anders MälarstigDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Nicola PirastuCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, UK.
James F Wilson *MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.
James E Peters *Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
University of Cambridge · GBUppsala University · SEUniversity of Edinburgh · GBKarolinska Institutet · SEWestern General Hospital · GBLund University · SENational Institutes of Health · USUniversity of Tartu · EEFred Hutch Cancer Center · USHelmholtz Zentrum München · DEImperial College London · GBKarolinska University Hospital · SERoslin Institute · GBUniversity Medical Center Groningen · NLDeutsches Diabetes-Zentrum e.V. · DENewcastle University · GBStanford University · USUniversity of Glasgow · GBUniversity of Gothenburg · SEUniversity of Manchester · GB
Funding
WOMEN'S HEALTH INITIATIVE - CLINICAL COORDINATING CENTER: TASK AREA B - LONG LIFE STUDY VISIT 2 LIMITED HOME VISIT75N92021D00001 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI ANDERSON, GARNET L. · 2021 to 2025
$52.0MWOMEN'S HEALTH INITIATIVE (WHI) REGIONAL CENTER (RC): TASK AREA A AND A275N92021D00002 · NHLBI · STATE UNIVERSITY OF NEW YORK AT BUFFALO · PI WACTAWSKI-WENDE, JEAN · 2021 to 2025
$6.9MWOMEN'S HEALTH INITIATIVE (WHI) REGIONAL CENTER (RC) - TO EXERCISE OPTION PERIOD ONE (1) AND REVISE CONTRACT ARTICLES.75N92021D00004 · NHLBI · STANFORD UNIVERSITY · PI STEFANICK, MARCIA · 2021 to 2025
$6.5MWOMEN'S HEALTH INITIATIVE (WHI) REGIONAL CENTER (RC) - TO EXERCISE OPTION PERIOD ONE (1) AND REVISE CONTRACT ARTICLES.75N92021D00003 · NHLBI · OHIO STATE UNIVERSITY · PI JACKSON, REBECCA · 2021 to 2025
$5.0MWOMEN'S HEALTH INITIATIVE (WHI) REGIONAL CENTER (RC) - TO EXERCISE OPTION PERIOD ONE (1) AND REVISE CONTRACT ARTICLES.75N92021D00005 · NHLBI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI VITOLINS, MARA · 2021 to 2025
$4.2MProteomic determinants of direct measures of insulin sensitivityR01DK114183 · NIDDK · STANFORD UNIVERSITY · PI ASSIMES, THEMISTOCLES LEONARD · 2018 to 2022
$3.5MWhole Genome Sequence Analysis of Ischemic Stroke in the Women's Health InitiativeR01HL136574 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI KOOPERBERG, CHARLES L, REINER, ALEXANDER P · 2017 to 2020
$3.1MMedical Research Council MC_UU_00006/1Medical Research Council MC_UU_00007/10Medical Research Council MC_UU_12015/1Medical Research Council MR/R026408/1Medical Research Council MR/S003061/1Medical Research Council MR/S004068/2Medical Research Council MR/V027638/1NHLBI NIH HHS 75N92021D00001NHLBI NIH HHS 75N92021D00002NHLBI NIH HHS R01 HL136574NIDDK NIH HHS R01 DK114183Wellcome TrustWHI NIH HHS 75N92021D00003WHI NIH HHS 75N92021D00004WHI NIH HHS 75N92021D00005
Abstract
Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the
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