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Stroke genetics informs drug discovery and risk prediction across ancestries - Nature.com

Stroke genetics informs drug discovery and risk prediction across ancestries - Nature.com

Stroke genetics informs drug discovery and risk prediction across ancestries - Nature.com
Sep 30, 2022 26 mins, 27 secs

e, Kaplan–Meier event rates for ischaemic stroke in European participants in five clinical trials (Methods) by tertile of GRS at 3 years (the GRS uses effect estimates of the cross-ancestry AS GWAS as weights) showing higher GRS increases risk of ischaemic stroke (Ptrend = 1.4 × 10−4).

While this suggests that the transferability of iPGS models from Europeans to East Asians might be limited (Supplementary Table 45), it does indicate that an ancestry-specific stroke iPGS approach yields similar improvement in predictive ability relative to their base models.

Similar associations were observed when using effect estimates from stroke GWAS meta-analyses in Europeans or for AIS (Supplementary Table 52).

Our results highlight the importance of ancestry-specific and cross-ancestry genomic studies for the transferability of genomic risk prediction across populations, and the urgent need to substantially increase participant diversity in genomic studies, especially from the most under-represented regions such as Africa, to avoid exacerbation of health disparities in the era of precision medicine and precision public health48.

Finally, leveraging data from 5 clinical trials in 52,600 patients with cardiometabolic disease, we showed that a cross-ancestry GRS predicted ischaemic stroke, independently of clinical risk factors, and outperforming previous genetic risk evaluation35.

Our study includes a considerable contribution of non-European stroke genetics resources (n = 61,528/616,014 cases/controls for the GWASs and follow-up and an additional n = 1,718/3,055 for the PGS/GRS studies).

Despite the notable size of the follow-up study sample, with nearly 90,000 additional patients who had a stroke, this analysis remains underpowered, especially for low-frequency variants and ancestry- and subtype-specific associations, as most follow-up studies were derived from large biobanks with event ascertainment based on electronic health records and no suitable stroke subtype information.

In conclusion, our genomic findings derived from >200,000 patients who had a stroke worldwide provide critical insights to inform future biological research on stroke pathogenesis, highlight potential drug targets for intervention and provide tools for genetic risk prediction across ancestries.

Information on participating studies (discovery and follow-up), study design, and definitions of stroke and stroke subtypes is provided in the Supplementary Information.

Proteome-wide significant genes and the corresponding pQTLs were determined using Bonferroni correction, on the number of proteins tested across the reference panel and correcting for the 5 stroke phenotypes (P < 1.7 × 10−4 for ROS/MAP and P < 2.2 × 10−8 for the Banner Sun Health Institute study).

Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France.

Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.

Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Division of Molecular Pathology, Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan.

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.

Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan.

Department of Internal Medicine, University of Turku, Turku, Finland.

Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

Department of Neurology, Oslo University Hospital, Oslo, Norway.

Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.

Department of Neurology and Cerebrovascular Disease Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.

DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.

Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria.

Neuroscience and Ageing Research Unit Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, NigeriaA

Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, State College, PA, USAM

The Danish Twin Registry, Department of Public Health, University of Southern Denmark, Odense, DenmarkW

Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.

Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA.

MRC Population Health Research Unit, University of Oxford, Oxford, UK.

Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.

NeuroGenomics and Informatics Center, Washington University School of Medicine, Saint Louis, MO, USAL

Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.

Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.

Post-Graduation Program on Health and Environment, Department of Medicine and Joinville Stroke Biobank, University of the Region of Joinville, Santa Catarina, Brazil.

Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Clinical Trial Service and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Department of Neurology, Donders Center for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.

Institute of Biomedicine, Department of Laboratory Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.

Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Department of Biology, Brody School of Medicine Center for Health Disparities, East Carolina University, Greenville, NC, USA.

Department of Neurology and Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, MD, USA.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Department of Neurology, Korea University Guro Hospital, Seoul, Republic of Korea

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

Department of Neurology, University Hospital Würzburg, Würzburg, Germany

The MIND Center, University of Mississippi Medical Center, Jackson, MS, USA

Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

College of Medicine Nursing and Health Science, NUI Galway, Galway, Ireland

Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan

Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig Maximilian University Munich, Munich, Germany

Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA

McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA

Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

Division of Cardiology, Department of Medicine, Columbia University, New York, NY, USA

Stroke Unit, Department of Neurology, Oslo University Hospital, Oslo, Norway

Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA

Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

Department of Medicine, Division of Cardiovascular Disease, Emory University School of Medicine, Atlanta, GA, USA

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju, Republic of Korea

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark

Department of Neurology, University of Virginia, Charlottesville, VA, USA

Department of Public Health Science, University of Virginia, Charlottesville, VA, USA

Department of Neurology, College of Medicine, The Pennsylvania State University, State College, PA, USA

Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany

Clinical Trial Center, University Hospital Würzburg, Würzburg, Germany

Department of Neurology, University of Washington, Seattle, WA, USA

Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Republic of Korea

Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada

Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada

Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

Division of Medicine, Turku University Hospital, Turku, Finland

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA

Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA

Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan

Department of Neurology, Boston University School of Medicine, Boston, MA, USA

Department of Medicine, University of Ibadan, Ibadan, Nigeria

Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA

Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine, Baltimore, MD, USA

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Initiative for Research and Education to Advance Community Health, Washington State University, Seattle, WA, USA

Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

Johns Hopkins University School of Medicine, Baltimore, MD, USA

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Brown University Warren Alpert Medical School, Providence, RI, USA

College of Public Health, University of Kentucky, Lexington, KY, USA

HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

Department of Research, Innovation and Education, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA

Department of Pediatrics and Rady Children’s Hospital, University of California San Diego, La Jolla, CA, USA

Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT—The Arctic University of Norway, Tromsø, Norway

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA

Clinic of Thoracic and Occupational Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA

Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway

Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, USA

Department of Internal Medicine and the Center for Clinical and Translational Science, Ohio State University, Columbus, OH, USA

Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA

Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA

Center for Vascular Emergencies, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA

Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA

Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands

Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands

Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

Department of Neurology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

John Hunter Hospital, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia

Faculty of Health, University of Technology Sydney, Ultimo, New South Wales, Australia

Department of Neurology, IMIM-Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain

Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

Department of Neurology, Medical University of Graz, Graz, Austria

Department of Neurology, Jagiellonian University, Krakow, Poland

Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Melbourne, Victoria, Australia

Department of Neurology, Austin Health, Heidelberg, Victoria, Australia

Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden

Department of Neurology, Rehabilitation Medicine, Memory Disorders, Geriatrics, Skåne University Hospital, Lund, Sweden

Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, FL, USA

BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK

National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK

Department of Emergency Medicine, Washington University School of Medicine, Saint Louis, MO, USA

Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy

Department of Neurology, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA

Department of Neurology, VIB Center for Brain & Disease Research, University Hospitals Leuven, Leuven, Belgium

Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, USA

Region Västra Götaland, Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden

Chang Gung Memorial Hospital, Linkou Medical Center in Taiwan, Taoyuan City, Taiwan

Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Department of Neurology, University Medicine Greifswald, Greifswald, Germany

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA

Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville and Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain

BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, University of Glasgow, Glasgow, UK

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA, USA

Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

Boston University School of Public Health, Boston, MA, USA

Department of Neurology and Stroke Center, Basel University Hospital, Basel, Switzerland

Neurorehabilitation Unit, University of Basel and University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter Hospital, Basel, Switzerland

Department of Neurology, Yale University School of Medicine, New Haven, CT, USA

Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Public Health Stream, Hunter Medical Research Institute, New Lambton, New South Wales, Australia

College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, New South Wales, Australia

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA

MRC Epidemiology Unit, School of Clinical Medicine, Institute of Metabolic Science, University of Cambridge, Cambridge, UK

Computational Medicine, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany

Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Department of Neurology, Justus Liebig University, Giessen, Germany

Department of Public Health, Bordeaux University Hospital, Bordeaux, France

School of Medicine, Dentistry and Nursing at the University of Glasgow, Glasgow, UK

Department of Neurology, Memory Clinic, Bordeaux University Hospital, Bordeaux, France

Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany

Hero DMC Heart Institute, Dayanand Medical College & Hospital, Ludhiana, India

Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden

Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada

Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada

Departments of Neurology & Radiology, Landspitali National University Hospital, Reykjavik, Iceland

Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany

Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA

Department of Medical Sciences, Uppsala University, Uppsala, Sweden

BioBankJapan, Laboratory of Clinical Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan

Department of Epidemiology, University of Maryland School of Medicine, Baltimore, MD, USA

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Department of Neurology, Caen University Hospital, Caen, France

Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

Landspitali University Hospital, Reykjavik, Iceland

Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain

Department of Epidemiology and Medical Statistics, University of Ibadan, Ibadan, Nigeria

Department of Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Department of Medicine, University of Ghana Medical School, Accra, Ghana

Department of Medicine, Ahmadu Bello University, Zaria, Nigeria

Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria

Jos University Teaching Hospital, Jos, Nigeria

Department of Medicine, Aminu Kano Teaching Hospital, Kano, Nigeria

Department of Medicine, Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria

Department of Health Promotion and Education, University of Ibadan, Ibadan, Nigeria

Department of Radiology, College of Medicine, University of Ibadan, Ibadan, Nigeria

Fuwai Hospital, Chinese Academy of Medical Sciences, National Center for Cardiovascular Diseases, Beijing, China

Department of Public Policy, Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

Department of Neurology, Haga Hospital, The Hague, The Netherlands

Department of Neurology, Amphia Hospital, Breda, The Netherlands

Department of Neurology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands

Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands

Department of Neurology, Catharina Hospital, Eindhoven, The Netherlands

Department of Neurology, Catharina Wilhelmina Hospital, Nijmegen, The Netherlands

Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

Stroke Unit, Department of Internal Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

Department of Neurology, Akershus University Hospital, Lørenskog, Norway

Clinic of Laboratory Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Essen, Germany

Department of Medicine I, University Hospital Würzburg, Würzburg, Germany

Stroke Unit, Department of Neurology, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Department of Neurology, Biocruces-Bizkaia Health Research Institute, Bilbao, Spain

Stroke Unit, Department of Neurology, University Hospital of Valladolid, Valladolid, Spain

Department of Neurology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain

Stroke Unit, Department of Neurology, Hospital Universitari Vall d’Hebron, Barcelona, Spain

Department of Neurology, University Hospital Central de Asturias (HUCA), Oviedo, Spain

Department of Neurology, Son Espases University Hospital, Illes Balears Health Research Institute (IdISBa), Palma, Spain

Department of Neurology, University Hospital of Albacete, Albacete, Spain

Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

The Centre for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA

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The TIMI Study Group has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, The Medicines Company, Zora Biosciences, Janssen Research and Development, Siemens Healthcare Diagnostics and Softcell Medical; F.K.K

has consultancies with Anthos, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen and Pfizer, institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital from Anthos, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Janssen, National Institutes of Health and Novartis, and consultancies with Anthos, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen and Pfizer

is supported by a personal fellowship from the British Heart Foundation (FS/14/55/30806), and acknowledges additional support from the Nuffield Department of Population Health (NDPH), University of Oxford, the British Heart Foundation Centre for Research Excellence, Oxford, and the Oxford Biomedical Research Centre

reports grants from German Ministry of Research and Education, during the conduct of the study, research grants from the German Ministry of Research and Education, European Union, Charité–Universitätsmedizin Berlin, Berlin Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert Koch Institute, German Heart Foundation, Federal Joint Committee (G-BA) within the Innovationfond, German Research Foundation, Bavarian State (ministry for science and the arts), German Cancer Aid, Charité–Universitätsmedizin Berlin (within Mondafis; supported by an unrestricted research grant to the Charité from Bayer), University Göttingen (within FIND-AF randomized; supported by an unrestricted research grant to the University Göttingen from Boehringer- Ingelheim), University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim and Daiichi Sankyo), outside the submitted work; K.G.H

is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG) within the UNION-CVD Clinician-Scientist Programme (project number 413657723) and has been previously supported by a MD/PhD Fellowship of the Interdisciplinary Center for Clinical Research, University Hospital Würzburg


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