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https://repository.monashhealth.org/monashhealthjspui/handle/1/35317| Title: | Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting. | Authors: | Aparicio H.J.;Del C. Valdes Hernandez M.;Luciano M.;Liewald D.;Deary I.J.;Starr J.M.;Bastin M.E.;Maniega S.M.;Slagboom P.E.;Beekman M.;Deelen J.;Uh H.-W.;Lemmens R.;Brodaty H.;Wright M.J.;Ames D.;Boncoraglio G.B.;Hopewell J.C.;Beecham A.H.;Blanton S.H.;Wright C.B.;Sacco R.L.;Wen W.;Thalamuthu A.;Armstrong N.J.;Chong E.;Schofield P.R.;Kwok J.B.;van der Grond J.;Stott D.J.;Ford I.;Jukema J.W.;Vernooij M.W.;Hofman A.;Uitterlinden A.G.;van der Lugt A.;Wittfeld K.;Grabe H.J.;Hosten N.;von Sarnowski B.;Volker U.;Levi C.;Jimenez-Conde J.;Sharma P.;Sudlow C.L.M.;Rosand J.;Woo D.;Cole J.W.;Meschia J.F.;Slowik A.;Thijs V.;Lindgren A.;Melander O.;Grewal R.P.;Rundek T.;Rexrode K.;Rothwell P.M.;Arnett D.K.;Jern C.;Johnson J.A.;Benavente O.R.;Wasssertheil-Smoller S.;Lee J.-M.;Wong Q.;Mitchell B.D.;Rich S.S.;McArdle P.F.;Geerlings M.I.;van der Graaf Y.;de Bakker P.I.W.;Asselbergs F.W.;Srikanth V.;Thomson R.;McWhirter R.;Moran C.;Callisaya M.;Phan T. ;Rutten-Jacobs L.C.A.;Bevan S.;Tzourio C.;Mather K.A.;Sachdev P.S.;van Duijn C.M.;Worrall B.B.;Dichgans M.;Kittner S.J.;Markus H.S.;Ikram M.A.;Fornage M.;Launer L.J.;Seshadri S.;Longstreth W.T.;Debette S.;Chauhan G.;Adams H.H.H.;Satizabal C.L.;Bis J.C.;Teumer A.;Sargurupremraj M.;Hofer E.;Trompet S.;Hilal S.;Smith A.V.;Jian X.;Malik R.;Traylor M.;Pulit S.L.;Amouyel P.;Mazoyer B.;Zhu Y.-C.;Kaffashian S.;Schilling S.;Beecham G.W.;Montine T.J.;Schellenberg G.D.;Kjartansson O.;Gudnason V.;Knopman D.S.;Griswold M.E.;Windham B.G.;Gottesman R.F.;Mosley T.H.;Schmidt R.;Saba Y.;Schmidt H.;Takeuchi F.;Yamaguchi S.;Nabika T.;Kato N.;Rajan K.B.;Aggarwal N.T.;De Jager P.L.;Evans D.A.;Psaty B.M.;Rotter J.I.;Rice K.;Lopez O.L.;Liao J.;Chen C. ;Cheng C.-Y.;Wong T.Y.;Ikram M.K.;van der Lee S.J.;Amin N.;Chouraki V.;Destefano A.L.;Romero J.R.;Maillard P.;Decarli C.;Wardlaw J.M. | Institution: | (Chauhan, Sargurupremraj, Kaffashian, Schilling, Tzourio, Debette) Bordeaux Population Health Research Center, Bordeaux, France (Mazoyer) INSERM U1219, Groupe d'Imagerie Neurofonctionnelle CNRS/CEAU5293, Bordeaux, France (Chauhan, Sargurupremraj, Mazoyer, Kaffashian, Schilling, Tzourio, Debette) University of Bordeaux, Bordeaux, France (Debette) Department of Neurology, Bordeaux University Hospital, Bordeaux, France (Adams, Vernooij, Hofman, Ikram) Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands (Adams, Vernooij, van der Lugt, Ikram) Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands (Uitterlinden) Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands (Ikram) Department of Neurology, Erasmus MC, Rotterdam, Netherlands (Satizabal, Chouraki, Aparicio, Romero, Maillard, Seshadri) Department of Neurology, Boston University School of Medicine, United States (Destefano, Seshadri) Department of Biostatistics, Boston University School of Public Health, United States (Satizabal, Chouraki, Destefano, Aparicio, Romero, Maillard, Seshadri) The National Heart, Lung, and Blood Institute's Framingham Heart Study, MA, United States (Bis, Psaty) Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, United States (Psaty, Longstreth) Department of Epidemiology, University of Washington, Seattle, United States (Psaty) Department of Health Services, University of Washington, Seattle, United States (Rice, Wong) Department of Biostatistics, University of Washington, Seattle, United States (Longstreth) Department of Neurology, University of Washington, Seattle, United States (Montine) Department of Pathology, University of Washington, Seattle, United States (Montine) Department of Pathology, Standford University, CA, United States (Teumer) Institute for Community Medicine, University Medicine Greifswald, Germany (Grabe) Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany (Hosten) Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Germany (von Sarnowski) Department of Neurology, University Medicine Greifswald, Germany (Hofer, Schmidt) Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (Hofer) Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (Saba, Schmidt) Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria (Trompet, Jukema) Department of Cardiology, Leiden University Medical Center, Netherlands (Trompet) Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Netherlands (Slagboom, Beekman, Deelen) Molecular Epidemiology, Leiden University Medical Center, Netherlands (Uh) Medical Statistics and Bioinformatics, Leiden University Medical Center, Netherlands (van der Grond) Department of Radiology, Leiden University Medical Center, Netherlands (Hilal, Chen, Ikram) Department of Pharmacology, National University of Singapore, Singapore (Cheng) Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Smith, Gunason) Icelandic Heart Association, Kopavogur, Iceland (Jian, Fornage) Institute of Molecular Medicine, University of Texas Health Science Center, Houston, United States (Fornage) Human Genetics Center, University of Texas Health Science Center, Houston, United States (Malik, Dichgans) Institute for Stroke and Dementia Research, Klinikum der Universitat Munchen, Ludwig-Maximilians-Universitat, Munich, Germany (Traylor, Rutten-Jacobs, Markus) Clinical Neurosciences, University of Cambridge, United Kingdom (Bevan) School of Life Sciences, University of Lincoln, United Kingdom (Rutten-Jacobs) German Center for Neurodegenerative Diseases (DZNE), Population Health Sciences, Bonn, Germany (Pulit) Department of Medical Genetics, University Medical Center Utrecht, Utrecht University, Netherlands (Ikram) Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Netherlands (Geerlings, van der Graaf) Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, and Utrecht University, Netherlands (de Bakker) Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, and Utrecht University, Netherlands (Asselbergs) Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, and Utrecht University, Netherlands (Amouyel, Chouraki) Institut Pasteur de Lille, Lille University, INSERM, Lille University Hospital, France (Zhu) Department of Neurology, Peking Union Medical College Hospital, Beijing, China (Beecham, Beecham, Blanton) John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, FL, United States (Sacco, Rundek) Department of Neurology, Miller School of Medicine, University of Miami, FL, United States (Sacco, Rundek) Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, FL, United States (Sacco, Rundek) Department of Epidemiology and Public Health Sciences, Miller School of Medicine, University of Miami, FL, United States (Beecham, Blanton, Sacco) Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, FL, United States (Schellenberg) Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, United States (Kjartansson) Departments of Neurology & Radiology, Landspitali National University Hospital, Iceland (Gunason) Faculty of Medicine, University of Iceland, Reykjavik, Iceland (Knopman) Department of Neurology, Mayo Clinic, Rochester, MN, United States (Griswold) Department of Data Science, University of Mississippi Medical Center, Jackson, United States (Windham, Mosley) Department of Medicine, University of Mississippi Medical Center, Jackson, United States (Gottesman) Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States (Takeuchi, Kato) Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (Yamaguchi) The Third Department of Internal Medicine, Shimane University School of Medicine, Japan (Nabika) Department of Functional Pathology, Shimane University School of Medicine, Japan (Rajan, Aggarwal, Evans) Rush University Medical Center, Chicago, IL, United States (Rexrode) Brigham and Women's Hospital, United States (De Jager) Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, United States (Psaty) Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States (Rotter) Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, United States (Rotter) Departments of Pediatrics, Medicine, and Human Genetics, UCLA, Los Angeles, CA, United States (Lopez) Department of Neurology, University of Pittsburgh, PA, United States (Liao) Singapore Eye Research Institute, Singapore (Cheng, Wong, Ikram) Duke-NUS Graduate Medical School, Singapore (Cheng, Wong, Ikram) Singapore Eye Research Institute, Singapore National Eye Centre, Singapore (Ikram) Memory Aging & Cognition Centre (MACC), National University Health System, Singapore (van der Lee, Amin, van Duijn) Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus MC University Medical Center, Rotterdam, Netherlands (Decarli) Department of Neurology, University of California, Davis, United States (Wardlaw, Del C. Valdes Hernandez, Bastin, Maniega) Brain Research Imaging Centre, University of Edinburgh, United Kingdom (Wardlaw, Del C. Valdes Hernandez, Bastin, Sudlow) Centre for Clinical Brain Sciences, University of Edinburgh, United Kingdom (Wardlaw, Del C. Valdes Hernandez) Edinburgh Dementia Research Centre, University of Edinburgh, United Kingdom (Wardlaw, Del C. Valdes Hernandez, Luciano, Liewald, Deary, Starr, Bastin, Maniega) Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (Starr) Alzheimer Scotland Dementia Research Centre, University of Edinburgh, United Kingdom (Sudlow) Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom (Lemmens) Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Belgium (Lemmens) Center for Brain & Disease Research, VIB, Laboratory of Neurobiology, Belgium (Lemmens) Department of Neurology, University Hospitals Leuven, Belgium (Thijs) Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia (Brodaty, Wen, Thalamuthu, Armstrong, Chong, Mather, Sachdev) Centre for Healthy Brain Ageing, Psychiatry, University of New South Wales, Sydney, Australia (Brodaty) Dementia Centre for Research Collaboration, University of New South Wales, Sydney, Australia (Schofield, Kwok) School of Medical Sciences, University of New South Wales, Sydney, Australia (Armstrong) Mathematics & Statistics, Murdoch University, Perth, Australia (Thalamuthu, Schofield, Mather) Neuroscience Research Australia, Randwick, Australia (Kwok) Brain and Mind Centre, The University of Sydney, Camperdown, Australia (Wright) Queensland Brain Institute, University of Queensland, Brisbane, Australia (Ames) National Ageing Research Institute, Melbourne, Australia (Ames) Academic Unit for Psychiatry of Old Age, University of Melbourne, Australia (Boncoraglio) Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy (Hopewell, van Duijn) CTSU, Nuffield Department of Population Health, University of Oxford, United Kingdom (Rothwell) Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom (Wright) National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, United States (Stott) Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, United Kingdom (Ford) Robertson Centre for Biostatistics, University of Glasgow, United Kingdom (Wittfeld, Grabe) German Center for Neurodegenerative Diseases (DZNE), Site Rostock, Greifswald, Germany (Volker) Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Germany (Levi) John Hunter Hospital, Hunter Medical Research Institute and University of Newcastle, Callaghan, Australia (Jimenez-Conde) Neurovascular Research Group (NEU-VAS), Neurology Department, IMIM-Hospital del Mar, Barcelona, Spain (Sharma) Institute of Cardiovascular Research, Royal Holloway University of London & St Peters and Ashford Hospital, United Kingdom (Rosand) Center for Human Genetic Research and Department of Neurology, Program in Medical and Population Genetics, Broad Institute, Massachusetts General Hospital, Harvard Medical School, Boston, United States (Woo) University of Cincinnati College of Medicine, OH, United States (Cole, Kittner) Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, United States (Meschia) Department of Neurology, Mayo Clinic Jacksonville, FL, United States (Slowik) Department of Neurology, Jagiellonian University, Krakow, Poland (Lindgren) Department of Clinical Sciences Lund, Neurology, Lund University, Sweden (Lindgren) Department of Neurology and Rehabilitation Medicine, Skane University Hospital, Sweden (Melander) Department of Clinical Sciences Malmo, Lund University, Sweden (Grewal) Neuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, South Orange, NJ, United States (Arnett) College of Public Health, University of Kentucky, Lexington, United States (Jern) Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden (Johnson) Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, United States (Johnson) Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, United States (Benavente) Department of Neurology, University of British Columbia, Vancouver, Canada (Wasssertheil-Smoller) Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States (Lee) Stroke Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States (Mitchell, McArdle) Department of Medicine, University of Maryland School of Medicine, Baltimore, United States (Rich) Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, United States (Asselbergs) Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands (Asselbergs) Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (Asselbergs) Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, United Kingdom (Srikanth, Moran, Callisaya) Peninsula Clinical School, Monash Health, Monash University, Melbourne, Australia (Phan) Frankston Hospital, Central Clinical School, and School of Clinical Sciences, Monash Health, Monash University, Melbourne, Australia (Srikanth, McWhirter, Callisaya) Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia (Thomson) Western Sydney University, NSW, Australia (Worrall) Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville, United States (Sachdev) Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, Australia (Dichgans) Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (Launer) Intramural Research Program, National Institute on Aging, NIH, Bethesda, MD, United States (Satizabal, Seshadri) University of Texas Health Sciences Center and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, United States | Issue Date: | 18-May-2019 | Copyright year: | 2019 | Publisher: | Lippincott Williams and Wilkins (E-mail: kathiest.clai@apta.org) | Place of publication: | United States | Publication information: | Neurology. 92 (5) (pp E486-E503), 2019. Date of Publication: 29 Jan 2019. | Journal: | Neurology | Abstract: | Objective To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10-8; and LINC00539/ZDHHC20, p = 5.82 x 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 x 10-25; p [SSBI] = 5.23 x 10-14 for hypertension), smoking (p[BI]= 4.4 x 10-10; p [SSBI] = 1.2 x 10 -4), diabetes (p[BI] = 1.7 x 10 -8; p [SSBI] = 2.8 x 10 -3), previous cardiovascular disease (p [BI] = 1.0 x 10-18; p [SSBI] = 2.3 x 10-7), stroke (p [BI] = 3.9 x 10-69; p [SSBI] = 3.2 x 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 x 10-157; p [SSBI] = 3.16 x 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p <= 0.0022), without indication of directional pleiotropy. Conclusion In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1212/WNL.0000000000006851 | PubMed URL: | 30651383 [http://www.ncbi.nlm.nih.gov/pubmed/?term=30651383] | ISSN: | 0028-3878 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/35317 | Type: | Article | Type of Clinical Study or Trial: | Systematic review and/or meta-analysis |
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