Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes · SciRah

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Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Rainer Malik^a, Ganesh Chauhan^b, Matthew Traylor^c, Muralidharan Sargurupremraj^{d e}, Yukinori Okada^{f g h}, Aniket Mishra^{d e}, Loes C.A. Rutten‐Jacobs^c, Anne‐Katrin Gieseⁱ, Sander W. van der Laan^j, Sólveig Grétarsdóttir^k, Christopher D. Anderson^{l m n}, Michael Chong

Nature Genetics Nature Portfolio2018-03-12 1,606 citations104 references

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Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy. Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

TL;DRA multiancestry genome-wide-association meta-analysis and discovered 22 new stroke risk loci, indicating mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. (Semantic Scholar)

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Discussion

^aInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
^bCentre for Brain Research, Indian Institute of Science, Bangalore, India
^cINSERM U1219 Bordeaux Population Health Research Center, University of Bordeaux, France
^dDepartment of Neurology, Institute for Neurodegenerative Disease, Bordeaux University Hospital, Bordeaux, France
^eStroke Research Group, Division of Clinical Neurosciences, University of Cambridge, Cambridge, UK
^fDepartment of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
^gLaboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
^hLaboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
ⁱDepartment of Neurology, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA
^jLaboratory of Experimental Cardiology, Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
^kdeCODE genetics/AMGEN Inc., Reykjavik, Iceland
^lCenter for Genomic Medicine, MGH, Boston, MA, USA
^mJ. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA, USA
ⁿProgram in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
^oPopulation Health Research Institute, McMaster University, Hamilton, Ontario, Canada
^pDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
^qDepartment of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
^rDepartment of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
^sDepartment of Clinical Sciences, Lund University, Malmö, Sweden
^tCentre Hospitalier Université Lille, Epidemiology and Public Health Department, Lille, France
^uINSERM, Institut Pasteur de Lille, LabEx DISTALZ-UMR1167, Risk Factors and Molecular Determinants of Aging-Related Diseases, Université Lille, Lille, France
^vAA Martinos Center for Biomedical Imaging, Department of Radiology, MGH, Harvard Medical School, Boston, MA, USA
^wCardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA
^xDivision of Neurology, Faculty of Medicine, Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada
^ySchool of Life Science, University of Lincoln, Lincoln, UK
^zDepartment of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy
^aaDepartment of Neurology, Mayo Clinic Rochester, Rochester, MN, USA
^abMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
^acNational Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK
^adNeurovascular Research Laboratory, Vall d'Hebron Institut of Research, Neurology and Medicine Departments-Universitat Autònoma de Barcelona, Vall d'Hebrón Hospital, Barcelona, Spain
^aeStroke Pharmacogenomics and Genetics, Fundacio Docència i Recerca MutuaTerrassa, Terrassa, Spain
^afCenter for Translational Science, George Washington University, Washington, DC, USA
^agChildren's Research Institute, Children's National Medical Center, Washington, DC, USA
^ahDivision of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA
^aiHarvard Medical School, Boston, MA, USA
^ajCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
^akDepartment of Neurology, University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA
^alDepartments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA
^amInstitute of Cardiovascular Research, Royal Holloway University of London, London, UK, and Ashford and St Peters Hospital, Surrey, UK