Contributors: Erasmus University Medical Center Rotterdam (Erasmus MC); Epidémiologie et Biostatistique Bordeaux; Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM); University of Washington Seattle; University of Michigan Ann Arbor; University of Michigan System; Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands; Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique; Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS); John P. Hussman Institute for Human Genomics; University of Miami Leonard M. Miller School of Medicine (UMMSM); Rush University Medical Center Chicago; University of Edinburgh (Edin.); Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Depts of Radiology; Leiden University Medical Center (LUMC); Universiteit Leiden = Leiden University -Universiteit Leiden = Leiden University; Department of Materials Science and Metallurgy Cambridge University (DMSM); University of Cambridge UK (CAM); JRC Institute for Transuranium Elements Karlsruhe (ITU ); European Commission - Joint Research Centre Karlsruhe (JRC); Greifswald University Hospital; Division of Biomedical Statistics and Informatics; Mayo Clinic; Division of Biomedical Statistics and Informatics, Mayo Clinic; Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)); Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS); Boston University School of Medicine (BUSM); Boston University Boston (BU); Genetics; The University of Texas Health Science Center at Houston (UTHealth); Taub Institute for Research on Alzheimer's Disease and the Aging Brain; Columbia University New York; Perelman School of Medicine; University of Pennsylvania; INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France; Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE); École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP); Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers CNAM (CNAM)-Centre National de la Recherche Scientifique (CNRS); Université Lille Nord de France (COMUE); Department of neurology; Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296); Service NEUROSPIN (NEUROSPIN); Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS); Dept of Psychology; Molecular Epidemiology; Harvard Medical School Boston (HMS); Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA; Broad Institute of MIT and Harvard (BROAD INSTITUTE); Harvard Medical School Boston (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital Boston -Harvard Medical School Boston (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital Boston; Program in Translational NeuroPsychiatric Genomics; Brigham and Women's Hospital Boston; Columbia Mailman School of Public Health; Laboratoire pharmaceutique Lilly France Neuilly-sur-Seine; Institute of Molecular Biology & Biochemistry; Johns Hopkins University School of Medicine Baltimore; Faculty of Medicine; University of Iceland Reykjavik; The Icelandic Heart Association, Kopavogur, Iceland; Institutes for Community Medicine; Department of Epidemiology, University of Washington; Group Health Research Institute, Group Health Cooperative; University of North Carolina Chapel Hill (UNC); University of North Carolina System (UNC); National University of Singapore (NUS); Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS); Université Grenoble Alpes 2016-2019 (UGA 2016-2019 ); Université Grenoble Alpes - UFR Langage, lettres et arts du spectacle, information et communication - Dpt Sciences de l'information et de la communication (UGA UFR LLASIC SIC); Mayo Clinic Rochester; Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology; University of Sheffield Medical School; East China University of Science and Technology; Medstar Research Institute; Institut de pharmacologie et de biologie structurale (IPBS); Université Toulouse III - Paul Sabatier (UT3); Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS); Bioinformatics; GlaxoSmithKline; National Institutes of Health Bethesda, MD, USA (NIH); Institute of Clinical Chemistry and Laboratory Medicine; Universität Greifswald - University of Greifswald; Delft University of Technology (TU Delft); Cardiovascular Health Research Unit, University of Washington; Department of Medicine, University of Washington; Department of Health Services, University of Washington; Department of Biostatistics, University of Washington; Cedars-Sinai Medical Center; Dept of Neurology, Univ Medicine of Greifswald, Germany; Department of Physics Stockholm; Stockholm University
نبذة مختصرة : International audience ; The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
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